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Sample records for peptide-derivatized dendrimers inhibit

  1. Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers.

    PubMed

    Wan, Jingjing; Brust, Andreas; Bhola, Rebecca F; Jha, Prerna; Mobli, Mehdi; Lewis, Richard J; Christie, Macdonald J; Alewood, Paul F

    2016-05-01

    Peptide dendrimers are a novel class of macromolecules of emerging interest with the potential of delayed renal clearance due to their molecular size and enhanced activity due to the multivalency effect. In this work, an active analogue of the disulfide-rich χ-conotoxin χ-MrIA (χ-MrIA), a norepinephrine reuptake (norepinephrine transporter) inhibitor, was grafted onto a polylysine dendron. Dendron decoration was achieved by employing copper-catalyzed alkyne-azide cycloaddition with azido-PEG chain-modified χ-MrIA analogues, leading to homogenous 4-mer and 8-mer χ-MrIA dendrimers with molecular weights ranging from 8 to 22 kDa. These dendrimers were investigated for their impact on peptide secondary structure, in vitro functional activity, and potential anti-allodynia in vivo. NMR studies showed that the χ-MrIA tertiary structure was maintained in the χ-MrIA dendrimers. In a functional norepinephrine transporter reuptake assay, χ-MrIA dendrimers showed slightly increased potency relative to the azido-PEGylated χ-MrIA analogues with similar potency to the parent peptide. In contrast to χ-MrIA, no anti-allodynic action was observed when the χ-MrIA dendrimers were administered intrathecally in a rat model of neuropathic pain, suggesting that the larger dendrimer structures are unable to diffuse through the spinal column tissue and reach the norepinephrine transporter. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:26910400

  2. Dendrimer-Based Selective Proteostasis-Inhibition Strategy to Control NSCLC Growth and Progression

    PubMed Central

    Walworth, Kyla; Bodas, Manish; Campbell, Ryan John; Swanson, Doug; Sharma, Ajit; Vij, Neeraj

    2016-01-01

    Elevated valosin containing protein (VCP/p97) levels promote the progression of non-small cell lung carcinoma (NSCLC). Although many VCP inhibitors are available, most of these therapeutic compounds have low specificity for targeted tumor cell delivery. Hence, the primary aim of this study was to evaluate the in vitro efficacy of dendrimer-encapsulated potent VCP-inhibitor drug in controlling non-small cell lung carcinoma (NSCLC) progression. The VCP inhibitor(s) (either in their pure form or encapsulated in generation-4 PAMAM-dendrimer with hydroxyl surface) were tested for their in vitro efficacy in modulating H1299 (NSCLC cells) proliferation, migration, invasion, apoptosis and cell cycle progression. Our results show that VCP inhibition by DBeQ was significantly more potent than NMS-873 as evident by decreased cell proliferation (p<0.0001, MTT-assay) and migration (p<0.05; scratch-assay), and increased apoptosis (p<0.05; caspase-3/7-assay) as compared to untreated control cells. Next, we found that dendrimer-encapsulated DBeQ (DDNDBeQ) treatment increased ubiquitinated-protein accumulation in soluble protein-fraction (immunoblotting) of H1299 cells as compared to DDN-control, implying the effectiveness of DBeQ in proteostasis-inhibition. We verified by immunostaining that DDNDBeQ treatment increases accumulation of ubiquitinated-proteins that co-localizes with an ER-marker, KDEL. We observed that proteostasis-inhibition with DDNDBeQ, significantly decreased cell migration rate (scratch-assay and transwell-invasion) as compared to the control-DDN treatment (p<0.05). Moreover, DDNDBeQ treatment showed a significant decrease in cell proliferation (p<0.01, MTT-assay) and increased caspase-3/7 mediated apoptotic cell death (p<0.05) as compared to DDN-control. This was further verified by cell cycle analysis (propidium-iodide-staining) that demonstrated significant cell cycle arrest in the G2/M-phase (p<0.001) by DDNDBeQ treatment as compared to control-DDN. Moreover

  3. Dendrimer-Based Selective Proteostasis-Inhibition Strategy to Control NSCLC Growth and Progression.

    PubMed

    Walworth, Kyla; Bodas, Manish; Campbell, Ryan John; Swanson, Doug; Sharma, Ajit; Vij, Neeraj

    2016-01-01

    Elevated valosin containing protein (VCP/p97) levels promote the progression of non-small cell lung carcinoma (NSCLC). Although many VCP inhibitors are available, most of these therapeutic compounds have low specificity for targeted tumor cell delivery. Hence, the primary aim of this study was to evaluate the in vitro efficacy of dendrimer-encapsulated potent VCP-inhibitor drug in controlling non-small cell lung carcinoma (NSCLC) progression. The VCP inhibitor(s) (either in their pure form or encapsulated in generation-4 PAMAM-dendrimer with hydroxyl surface) were tested for their in vitro efficacy in modulating H1299 (NSCLC cells) proliferation, migration, invasion, apoptosis and cell cycle progression. Our results show that VCP inhibition by DBeQ was significantly more potent than NMS-873 as evident by decreased cell proliferation (p<0.0001, MTT-assay) and migration (p<0.05; scratch-assay), and increased apoptosis (p<0.05; caspase-3/7-assay) as compared to untreated control cells. Next, we found that dendrimer-encapsulated DBeQ (DDNDBeQ) treatment increased ubiquitinated-protein accumulation in soluble protein-fraction (immunoblotting) of H1299 cells as compared to DDN-control, implying the effectiveness of DBeQ in proteostasis-inhibition. We verified by immunostaining that DDNDBeQ treatment increases accumulation of ubiquitinated-proteins that co-localizes with an ER-marker, KDEL. We observed that proteostasis-inhibition with DDNDBeQ, significantly decreased cell migration rate (scratch-assay and transwell-invasion) as compared to the control-DDN treatment (p<0.05). Moreover, DDNDBeQ treatment showed a significant decrease in cell proliferation (p<0.01, MTT-assay) and increased caspase-3/7 mediated apoptotic cell death (p<0.05) as compared to DDN-control. This was further verified by cell cycle analysis (propidium-iodide-staining) that demonstrated significant cell cycle arrest in the G2/M-phase (p<0.001) by DDNDBeQ treatment as compared to control-DDN. Moreover

  4. Inhibition and dispersion of Pseudomonas aeruginosa biofilms by glycopeptide dendrimers targeting the fucose-specific lectin LecB.

    PubMed

    Johansson, Emma M V; Crusz, Shanika A; Kolomiets, Elena; Buts, Lieven; Kadam, Rameshwar U; Cacciarini, Martina; Bartels, Kai-Malte; Diggle, Stephen P; Cámara, Miguel; Williams, Paul; Loris, Remy; Nativi, Cristina; Rosenau, Frank; Jaeger, Karl-Erich; Darbre, Tamis; Reymond, Jean-Louis

    2008-12-22

    The human pathogenic bacterium Pseudomonas aeruginosa produces a fucose-specific lectin, LecB, implicated in tissue attachment and the formation of biofilms. To investigate if LecB inhibition disrupts these processes, high-affinity ligands were obtained by screening two 15,536-member combinatorial libraries of multivalent fucosyl-peptide dendrimers. The most potent LecB-ligands identified were dendrimers FD2 (C-Fuc-LysProLeu)(4)(LysPheLysIle)(2)LysHisIleNH(2) (IC(50) = 0.14 microM by ELLA) and PA8 (OFuc-LysAlaAsp)(4)(LysSerGlyAla)(2)LysHisIleNH(2) (IC(50) = 0.11 microM by ELLA). Dendrimer FD2 led to complete inhibition of P. aeruginosa biofilm formation (IC(50) approximately 10 microM) and induced complete dispersion of established biofilms in the wild-type strain and in several clinical P. aeruginosa isolates. These experiments suggest that LecB inhibition by high-affinity multivalent ligands could represent a therapeutic approach against P. aeruginosa infections by inhibition of biofilm formation and dispersion of established biofilms. PMID:19101469

  5. Peptides derivatized with bicyclic quaternary ammonium ionization tags. Sequencing via tandem mass spectrometry.

    PubMed

    Setner, Bartosz; Rudowska, Magdalena; Klem, Ewelina; Cebrat, Marek; Szewczuk, Zbigniew

    2014-10-01

    Improving the sensitivity of detection and fragmentation of peptides to provide reliable sequencing of peptides is an important goal of mass spectrometric analysis. Peptides derivatized by bicyclic quaternary ammonium ionization tags: 1-azabicyclo[2.2.2]octane (ABCO) or 1,4-diazabicyclo[2.2.2]octane (DABCO), are characterized by an increased detection sensitivity in electrospray ionization mass spectrometry (ESI-MS) and longer retention times on the reverse-phase (RP) chromatography columns. The improvement of the detection limit was observed even for peptides dissolved in 10 mM NaCl. Collision-induced dissociation tandem mass spectrometry of quaternary ammonium salts derivatives of peptides showed dominant a- and b-type ions, allowing facile sequencing of peptides. The bicyclic ionization tags are stable in collision-induced dissociation experiments, and the resulted fragmentation pattern is not significantly influenced by either acidic or basic amino acid residues in the peptide sequence. Obtained results indicate the general usefulness of the bicyclic quaternary ammonium ionization tags for ESI-MS/MS sequencing of peptides. PMID:25303389

  6. Naked Polyamidoamine Polymers Intrinsically Inhibit Angiotensin II-Mediated EGFR and ErbB2 Transactivation in a Dendrimer Generation- and Surface Chemistry-Dependent Manner.

    PubMed

    Akhtar, Saghir; El-Hashim, Ahmed Z; Chandrasekhar, Bindu; Attur, Sreeja; Benter, Ibrahim F

    2016-05-01

    The effects of naked polyamidoamine (PAMAM) dendrimers on renin-angiotensin system (RAS) signaling via Angiotensin (Ang) II-mediated transactivation of the epidermal growth factor receptor (EGFR) and the closely related family member ErbB2 (HER2) were investigated. In primary aortic vascular smooth muscle cells, a cationic fifth-generation (G5) PAMAM dendrimer dose- and time-dependently inhibited Ang II/AT1 receptor-mediated transactivation of EGFR and ErbB2 as well as their downstream signaling via extracellular-regulated kinase 1/2 (ERK1/2). Inhibition even occurred at noncytotoxic concentrations at short (1 h) exposure times and was dependent on dendrimer generation (G7 > G6 > G5 > G4) and surface group chemistry (amino > carboxyl > hydroxyl). Mechanistically, the cationic G5 PAMAM dendrimer inhibited Ang II-mediated transactivation of EGFR and ErbB2 via inhibition of the nonreceptor tyrosine kinase Src. This novel, early onset, intrinsic biological action of PAMAM dendrimers as inhibitors of the Ang II/AT1/Src/EGFR-ErbB2/ERK1/2 signaling pathway could have important toxicological and pharmacological implications. PMID:26985693

  7. Optimization of a Class of Tryptophan Dendrimers That Inhibit HIV Replication Leads to a Selective, Specific, and Low-Nanomolar Inhibitor of Clinical Isolates of Enterovirus A71.

    PubMed

    Rivero-Buceta, Eva; Sun, Liang; Martínez-Gualda, Belén; Doyagüez, Elisa G; Donckers, Kim; Quesada, Ernesto; Camarasa, María-José; Delang, Leen; San-Félix, Ana; Neyts, Johan; Leyssen, Pieter

    2016-08-01

    Tryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomolar/high-picomolar range. PMID:27246775

  8. Efficacy of dendrimer-mediated angiostatin and TIMP-2 gene delivery on inhibition of tumor growth and angiogenesis: in vitro and in vivo studies.

    PubMed

    Vincent, Loïc; Varet, Julia; Pille, Jean-Yves; Bompais, Heidi; Opolon, Paule; Maksimenko, Andrei; Malvy, Claude; Mirshahi, Manouchehr; Lu, He; Vannier, Jean-Pierre; Soria, Claudine; Li, Hong

    2003-06-20

    Gene transfer is an attractive approach to fight cancer by targeting cancer cells or their vasculature. Our study reports the inhibition of tumor growth and angiogenesis by a nonviral method using dendrimers associated with 36-mer anionic oligomers (ON36) for delivering angiostatin (Kringle 1-3) and tissue inhibitor of metalloproteinase (TIMP)-2 genes. The optimal concentrations of dendrimers and ON36 for an efficient green fluorescent protein (GFP) plasmid delivery in endothelial cells (HMEC-1) and cancer cells (MDA-MB-435) were first chosen. Then the efficacy of transfection was determined by testing angiostatin and TIMP-2 secretion by Western blot and the biologic effects were evaluated. Angiostatin gene transfer markedly reduced in vitro (i) HMEC-1 but not MDA-MB-435 proliferation; (ii) HMEC-1 and MDA-MB-435 wound healing reparation; and (iii) capillary tube formation. TIMP-2 gene transfer did not affect cell proliferation but strongly inhibited (i) wound healing of HMEC-1 and MDA-MB-435 cells; and (ii) capillary tube formation. Supernatants of transfected-MDA-MB-435 cells also inhibited the formation of angiogenic networks on Matrigel, indicating a paracrine effect. In vivo, intratumoral angiostatin or TIMP-2 gene delivery using dendrimers associated with ON36 effectively inhibited tumor growth by 71% and 84%, respectively. Combined gene transfer resulted in 96% inhibition of tumor growth. Tumor-associated vascularization was also greatly reduced. These findings provide a basis for the further development of nonviral delivery of genes to fight cancer. PMID:12704680

  9. Investigations on dendrimer space reveal solid and liquid tumor growth-inhibition by original phosphorus-based dendrimers and the corresponding monomers and dendrons with ethacrynic acid motifs

    NASA Astrophysics Data System (ADS)

    El Brahmi, Nabil; Mignani, Serge M.; Caron, Joachim; El Kazzouli, Saïd; Bousmina, Mosto M.; Caminade, Anne-Marie; Cresteil, Thierry; Majoral, Jean-Pierre

    2015-02-01

    The well-known reactive diuretic ethacrynic acid (EA, Edecrin), with low antiproliferative activities, was chemically modified and grafted onto phosphorus dendrimers and the corresponding simple branched phosphorus dendron-like derivatives affording novel nanodevices showing moderate to strong antiproliferative activities against liquid and solid tumor cell lines, respectively.The well-known reactive diuretic ethacrynic acid (EA, Edecrin), with low antiproliferative activities, was chemically modified and grafted onto phosphorus dendrimers and the corresponding simple branched phosphorus dendron-like derivatives affording novel nanodevices showing moderate to strong antiproliferative activities against liquid and solid tumor cell lines, respectively. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr05983b

  10. Dendrimer Prodrugs.

    PubMed

    da Silva Santos, Soraya; Igne Ferreira, Elizabeth; Giarolla, Jeanine

    2016-01-01

    The main objective of this review is to describe the importance of dendrimer prodrugs in the design of new drugs, presenting numerous applications of these nanocomposites in the pharmaceutical field. Therefore, the use of dendrimer prodrugs as carrier for drug delivery, to improve pharmacokinetic properties of prototype, to promote drug sustained-release, to increase selectivity and, consequently, to decrease toxicity, are just some examples of topics that have been extensively reported in the literature, especially in the last decade. The examples discussed here give a panel of the growing interest dendrimer prodrugs have been evoking in the scientific community. PMID:27258239

  11. Involvement of functional groups on the surface of carboxyl group-terminated polyamidoamine dendrimers bearing arbutin in inhibition of Na⁺/glucose cotransporter 1 (SGLT1)-mediated D-glucose uptake.

    PubMed

    Sakuma, Shinji; Kanamitsu, Shun; Teraoka, Yumi; Masaoka, Yoshie; Kataoka, Makoto; Yamashita, Shinji; Shirasaka, Yoshiyuki; Tamai, Ikumi; Muraoka, Masahiro; Nakatsuji, Yohji; Kida, Toshiyuki; Akashi, Mitsuru

    2012-04-01

    A carboxyl group-terminated polyamidoamine dendrimer (generation: 3.0) bearing arbutin, which is a substrate of Na⁺/glucose cotransporter 1 (SGLT1), via a nonbiodegradable ω-amino triethylene glycol linker (PAMAM-ARB), inhibits SGLT1-mediated D-glucose uptake, as does phloridzin, which is a typical SGLT1 inhibitor. Here, since our previous research revealed that the activity of arbutin was dramatically improved through conjugation with the dendrimer, we examined the involvement of functional groups on the dendrimer surface in inhibition of SGLT1-mediated D-glucose uptake. PAMAM-ARB, with a 6.25% arbutin content, inhibited in vitro D-glucose uptake most strongly; the inhibitory effect decreased as the arbutin content increased. In vitro experiments using arbutin-free original dendrimers indicated that dendrimer-derived carboxyl groups actively participated in SGLT1 inhibition. However, the inhibitory effect was much less than that of PAMAM-ARB and was equal to that of glucose moiety-free PAMAM-ARB. Data supported that the glucose moiety of arbutin was essential for the high activity of PAMAM-ARB in SGLT1 inhibition. Analysis of the balance of each domain further suggested that carboxyl groups anchored PAMAM-ARB to SGLT1, and the subsequent binding of arbutin-derived glucose moieties to the target sites on SGLT1 resulted in strong inhibition of SGLT1-mediated D-glucose uptake. PMID:22352425

  12. Inhibition of bacterial growth and intramniotic infection in a guinea pig model of chorioamnionitis using PAMAM dendrimers.

    PubMed

    Wang, Bing; Navath, Raghavendra S; Menjoge, Anupa R; Balakrishnan, Bindu; Bellair, Robert; Dai, Hui; Romero, Roberto; Kannan, Sujatha; Kannan, Rangaramanujam M

    2010-08-16

    Dendrimers have emerged as topical microbicides to treat vaginal infections. This study explores the in vitro, in vivo antimicrobial activity of PAMAM dendrimers, and the associated mechanism. Interestingly, topical cervical application of 500 microg of generation-4 neutral dendrimer (G(4)-PAMAM-OH) showed potential to treat the Escherichia coli induced ascending uterine infection in guinea pig model of chorioamnionitis. Amniotic fluid collected from different gestational sacs of infected guinea pigs posttreatment showed absence of E. coli growth in the cultures plated with it. The cytokine level [tumor necrosis factor (TNFalpha) and interleukin (IL-6 and IL-1beta)] in placenta of the G(4)-PAMAM-OH treated animals were comparable to those in healthy animals while these were notably high in infected animals. Since, antibacterial activity of amine-terminated PAMAM dendrimers is known, the activity of hydroxyl and carboxylic acid terminated PAMAM dendrimers was compared with it. Though the G(4)-PAMAM-NH(2) shows superior antibacterial activity, it was found to be cytotoxic to human cervical epithelial cell line above 10 microg/mL, while the G(4)-PAMAM-OH was non-cytotoxic up to 1mg/mL concentration. Cell integrity, outer (OM) and inner (IM) membrane permeabilization assays showed that G(4)-PAMAM-OH dendrimer efficiently changed the OM permeability, while G(4)-PAMAM-NH(2) and G(3.5)-PAMAM-COOH damaged both OM and IM causing the bacterial lysis. The possible antibacterial mechanism are G(4)-PAMAM-NH(2) acts as polycation binding to the polyanionic lipopolysaccharide in E. coli, the G(4)-PAMAM-OH forms hydrogen bonds with the hydrophilic O-antigens in E. coli membrane and the G(3.5)-PAMAM-COOH acts as a polyanion, chelating the divalent ions in outer cell membrane of E. coli. This is the first study which shows that G(4)-PAMAM-OH dendrimer acts as an antibacterial agent. PMID:20580797

  13. Inhibition of hIAPP Amyloid Aggregation and Pancreatic β-Cell Toxicity by OH-Terminated PAMAM Dendrimer.

    PubMed

    Gurzov, Esteban N; Wang, Bo; Pilkington, Emily H; Chen, Pengyu; Kakinen, Aleksandr; Stanley, William J; Litwak, Sara A; Hanssen, Eric G; Davis, Thomas P; Ding, Feng; Ke, Pu Chun

    2016-03-01

    Human islet amyloid polypeptide (hIAPP, or amylin) forms amyloid deposits in the islets of Langerhans, a phenomenon that is associated with type-2 diabetes impacting millions of people worldwide. Accordingly, strategies against hIAPP aggregation are essential for the prevention and eventual treatment of the disease. Here, it is shown that generation-3 OH-terminated poly(amidoamine) dendrimer, a polymeric nanoparticle, can effectively halt the aggregation of hIAPP and shut down hIAPP toxicity in pancreatic MIN6 and NIT-1 cells as well as in mouse islets. This finding is supported by high-throughput dynamic light scattering experiment and thioflavin T assay, where the rapid evolution of hIAPP nucleation and elongation processes is halted by the addition of the dendrimer up to 8 h. Discrete molecular dynamics simulations further reveal that hIAPP residues bound strongly with the dendrimer near the c-terminal portion of the peptide, where the amyloidogenic sequence (residues 22-29) locates. Furthermore, simulations of hIAPP dimerization reveal that binding with the dendrimer significantly reduces formation of interpeptide contacts and hydrogen bonds, thereby prohibiting peptide self-association and amyloidosis. This study points to a promising nanomedicinal strategy for combating type-2 diabetes and may have broader implications for targeting neurological disorders whose distinct hallmark is also amyloid fibrillation. PMID:26808649

  14. Dendrimer 101.

    PubMed

    Balogh, Lajos P

    2007-01-01

    In this chapter dendrimer basics are reviewed. It is impossible to describe, refer to or even list the related literature (our "dendrimer" database consists of over 7,000 papers and patents), thus selection of references has been made based on personal preference, often choosing clarity over details and overarching principles instead of detailed chemical structures. A large number of excellent reviews are available to those who are interested in more detail in particular areas. References will take the reader to original scientific papers that provide more detail about a particular topic, describe experiments, and draw conclusions reflecting each author's personal views. Even listing of books and reviews must be partial, as they number in the hundreds. PMID:18217341

  15. Influence of PAMAM dendrimers on the human insulin

    NASA Astrophysics Data System (ADS)

    Nowacka, Olga; Miłowska, Katarzyna; Ionov, Maksim; Bryszewska, Maria

    2015-12-01

    Dendrimers are specific class of polymeric macromolecules with wide spectrum of properties. One of the promising activities of dendrimers involves inhibition of protein fibril formation. Aggregation and fibrillation of insulin occurs in insulin-dependent diabetic patients after repeated administration, due to these processes being very easily triggered by the conditions of drug administration. The aim of this work was to study the influence of various generations PAMAM dendrimers on human insulin zeta potential, secondary structure and dithiotreitol (DTT)-induced aggregation. We observed the dependence between the number of positive charges on the surface of the PAMAM dendrimer and the values of zeta potential. Addition of dendrimers to insulin caused insignificant changes in the secondary structure. There was a small decrease in ellipticity, but it did not result in alterations in the circular dichroism (CD) spectrum shape. Dendrimers neither induced protein aggregation nor inhibited the aggregation process induced by DTT, except for 0.01 µmol/l concentration.

  16. Special Issue: "Functional Dendrimers".

    PubMed

    Tomalia, Donald A

    2016-01-01

    This special issue entitled "Functional Dendrimers" focuses on the manipulation of at least six "critical nanoscale design parameters" (CNDPs) of dendrimers including: size, shape, surface chemistry, flexibility/rigidity, architecture and elemental composition. These CNDPs collectively define properties of all "functional dendrimers". This special issue contains many interesting examples describing the manipulation of certain dendrimer CNDPs to create new emerging properties and, in some cases, predictive nanoperiodic property patterns (i.e., dendritic effects). The systematic engineering of CNDPs provides a valuable strategy for optimizing functional dendrimer properties for use in specific applications. PMID:27517890

  17. Light-harvesting dendrimers.

    PubMed

    Balzani, Vincenzo; Ceroni, Paola; Maestri, Mauro; Vicinelli, Veronica

    2003-12-01

    Dendrimers are well-defined, tree-like macromolecules, with a high degree of order and the possibility to contain selected chemical units in predetermined sites of their structure. Dendrimers are currently attracting the interest of many scientists because of their unusual chemical and physical properties and the wide range of potential applications. It is possible to design and synthesize dendrimers containing a variety of chromophoric groups organized in the dimensions of time, energy and space so as to obtain efficient light-harvesting devices that can be useful for solar energy conversion and other purposes. PMID:14644173

  18. Influence of dendrimer's structure on its activity against amyloid fibril formation

    SciTech Connect

    Klajnert, B. . E-mail: aklajn@biol.uni.lodz.pl; Cortijo-Arellano, M.; Cladera, J.; Bryszewska, M.

    2006-06-23

    Inhibition of fibril assembly is a potential therapeutic strategy in neurodegenerative disorders such as prion and Alzheimer's diseases. Highly branched, globular polymers-dendrimers-are novel promising inhibitors of fibril formation. In this study, the effect of polyamidoamine (PAMAM) dendrimers (generations 3rd, 4th, and 5th) on amyloid aggregation of the prion peptide PrP 185-208 and the Alzheimer's peptide A{beta} 1-28 was examined. Amyloid fibrils were produced in vitro and their formation was monitored using the dye thioflavin T (ThT). Fluorescence studies were complemented with electron microscopy. The results show that the higher the dendrimer generation, the larger the degree of inhibition of the amyloid aggregation process and the more effective are dendrimers in disrupting the already existing fibrils. A hypothesis on dendrimer-peptide interaction mechanism is presented based on the dendrimers' molecular structure.

  19. Electrostatic Swelling and Conformational Variation Observed in High-Generation Polyelectrolyte Dendrimers

    SciTech Connect

    Butler, Paul D; Chen, Wei-Ren; Herwig, Kenneth W; Hong, Kunlun; Liu, Yun; Porcar, L.; Shew, Chwen-Yang; Smith, Gregory Scott; Chen, Hsin-Lung; Chen, Chun-Yu; Li, Xin; Liu, Emily

    2010-01-01

    A coordinated study combining small angle neutron scattering (SANS) and small angle x-ray scattering (SAXS) measurements was conducted to investigate the structural characteristics of aqueous (D2O) generation 7 and 8 (G7 & G8) PAMAM dendrimer solutions as a function of molecular protonation at room temperature. The change in intra-molecular conformation was clearly exhibited in the data analysis by separating the variation in the inter-molecular correlation. Our results unambiguously demonstrate an increased molecular size and evolved intra-molecular density profile upon increasing the molecular protonation. This is contrary to the existing understanding that in higher generation polyelectrolyte dendrimers, steric crowding stiffens the local motion of dendrimer segments exploring additional available intra-dendrimer volume and therefore inhibits the electrostatic swelling. Our observation is relevant to elucidation of the general microscopic picture of polyelectrolyte dendrimer structure, as well as the development of dendrimer-based packages with based on the stimuli-responsive principle.

  20. Mathematical Description of Dendrimer Structure

    NASA Technical Reports Server (NTRS)

    Majoros, Istvan J.; Mehta, Chandan B.; Baker, James R., Jr.

    2004-01-01

    Characteristics of starburst dendrimers can be easily attributed to the multiplicity of the monomers used to synthesize them. The molecular weight, degree of polymerization, number of terminal groups and branch points for each generation of a dendrimer can be calculated using mathematical formulas incorporating these variables. Mathematical models for the calculation of degree of polymerization, molecular weight, and number of terminal groups and branching groups previously published were revised and elaborated on for poly(amidoamine) (PAMAM) dendrimers, and introduced for poly(propyleneimine) (POPAM) dendrimers and the novel POPAM-PAMAM hybrid, which we call the POMAM dendrimer. Experimental verification of the relationship between theoretical and actual structure for the PAMAM dendrimer was also established.

  1. Antiviral mechanism of polyanionic carbosilane dendrimers against HIV-1.

    PubMed

    Vacas-Córdoba, Enrique; Maly, Marek; De la Mata, Francisco J; Gómez, Rafael; Pion, Marjorie; Muñoz-Fernández, M Ángeles

    2016-01-01

    Nanotechnology-derived platforms, such as dendrimers, are very attractive in several biological applications. In the case of human immunodeficiency virus (HIV) infection, polyanionic carbosilane dendrimers have shown great potential as antiviral agents in the development of novel microbicides to prevent the sexual transmission of HIV-1. In this work, we studied the mechanism of two sulfated and naphthylsulfonated functionalized carbosilane dendrimers, G3-S16 and G2-NF16. They are able to inhibit viral infection at fusion and thus at the entry step. Both compounds impede the binding of viral particles to target cell surface and membrane fusion through the blockage of gp120-CD4 interaction. In addition, and for the first time, we demonstrate that dendrimers can inhibit cell-to-cell HIV transmission and difficult infectious synapse formation. Thus, carbosilane dendrimers' mode of action is a multifactorial process targeting several proteins from viral envelope and from host cells that could block HIV infection at different stages during the first step of infection. PMID:27103798

  2. Hollow spherical supramolecular dendrimers.

    PubMed

    Percec, Virgil; Peterca, Mihai; Dulcey, Andrés E; Imam, Mohammad R; Hudson, Steven D; Nummelin, Sami; Adelman, Peter; Heiney, Paul A

    2008-10-01

    The synthesis of a library containing 12 conical dendrons that self-assemble into hollow spherical supramolecular dendrimers is reported. The design principles for this library were accessed by development of a method that allows the identification of hollow spheres, followed by structural and retrostructural analysis of their Pm3n cubic lattice. The first hollow spherical supramolecular dendrimer was made by replacing the tapered dendron, from the previously reported tapered dendritic dipeptide that self-assembled into helical pores, with its constitutional isomeric conical dendron. This strategy generated a conical dendritic dipeptide that self-assembled into a hollow spherical supramolecular dendrimer that self-organizes in a Pm3n cubic lattice. Other examples of hollow spheres were assembled from conical dendrons without a dipeptide at their apex. These are conical dendrons originated from tapered dendrons containing additional benzyl ether groups at their apex. The inner part of the hollow sphere assembled from the dipeptide resembles the path of a spherical helix or loxodrome and, therefore, is chiral. The spheres assembled from other conical dendrons are nonhelical, even when they contain stereocenters on the alkyl groups from their periphery. Functionalization of the apex of the conical dendrons with diethylene glycol allowed the encapsulation of LiOTf and RbOTf in the center of the hollow sphere. These experiments showed that hollow spheres function as supramolecular dendritic capsules and therefore are expected to display functions complementary to those of other related molecular and supramolecular structures. PMID:18771261

  3. Effect of Terminal Groups of Dendrimers in the Complexation with Antisense Oligonucleotides and Cell Uptake.

    PubMed

    Márquez-Miranda, Valeria; Peñaloza, Juan Pablo; Araya-Durán, Ingrid; Reyes, Rodrigo; Vidaurre, Soledad; Romero, Valentina; Fuentes, Juan; Céric, Francisco; Velásquez, Luis; González-Nilo, Fernando D; Otero, Carolina

    2016-12-01

    Poly(amidoamine) dendrimers are the most recognized class of dendrimer. Amino-terminated (PAMAM-NH2) and hydroxyl-terminated (PAMAM-OH) dendrimers of generation 4 are widely used, since they are commercially available. Both have different properties, mainly based on their different overall charges at physiological pH. Currently, an important function of dendrimers as carriers of short single-stranded DNA has been applied. These molecules, known as antisense oligonucleotides (asODNs), are able to inhibit the expression of a target mRNA. Whereas PAMAM-NH2 dendrimers have shown to be able to transfect plasmid DNA, PAMAM-OH dendrimers have not shown the same successful results. However, little is known about their interaction with shorter and more flexible molecules such as asODNs. Due to several initiatives, the use of these neutral dendrimers as a scaffold to introduce other functional groups has been proposed. Because of its low cytotoxicity, it is relevant to understand the molecular phenomena involving these types of dendrimers. In this work, we studied the behavior of an antisense oligonucleotide in presence of both types of dendrimers using molecular dynamics simulations, in order to elucidate if they are able to form stable complexes. In this manner, we demonstrated at atomic level that PAMAM-NH2, unlike PAMAM-OH, could form a well-compacted complex with asODN, albeit PAMAM-OH can also establish stable interactions with the oligonucleotide. The biological activity of asODN in complex with PAMAM-NH2 dendrimer was also shown. Finally, we revealed that in contact with PAMAM-OH, asODN remains outside the cells as TIRF microscopy results showed, due to its poor interaction with this dendrimer and cell membranes. PMID:26847692

  4. Effect of Terminal Groups of Dendrimers in the Complexation with Antisense Oligonucleotides and Cell Uptake

    NASA Astrophysics Data System (ADS)

    Márquez-Miranda, Valeria; Peñaloza, Juan Pablo; Araya-Durán, Ingrid; Reyes, Rodrigo; Vidaurre, Soledad; Romero, Valentina; Fuentes, Juan; Céric, Francisco; Velásquez, Luis; González-Nilo, Fernando D.; Otero, Carolina

    2016-02-01

    Poly(amidoamine) dendrimers are the most recognized class of dendrimer. Amino-terminated (PAMAM-NH2) and hydroxyl-terminated (PAMAM-OH) dendrimers of generation 4 are widely used, since they are commercially available. Both have different properties, mainly based on their different overall charges at physiological pH. Currently, an important function of dendrimers as carriers of short single-stranded DNA has been applied. These molecules, known as antisense oligonucleotides (asODNs), are able to inhibit the expression of a target mRNA. Whereas PAMAM-NH2 dendrimers have shown to be able to transfect plasmid DNA, PAMAM-OH dendrimers have not shown the same successful results. However, little is known about their interaction with shorter and more flexible molecules such as asODNs. Due to several initiatives, the use of these neutral dendrimers as a scaffold to introduce other functional groups has been proposed. Because of its low cytotoxicity, it is relevant to understand the molecular phenomena involving these types of dendrimers. In this work, we studied the behavior of an antisense oligonucleotide in presence of both types of dendrimers using molecular dynamics simulations, in order to elucidate if they are able to form stable complexes. In this manner, we demonstrated at atomic level that PAMAM-NH2, unlike PAMAM-OH, could form a well-compacted complex with asODN, albeit PAMAM-OH can also establish stable interactions with the oligonucleotide. The biological activity of asODN in complex with PAMAM-NH2 dendrimer was also shown. Finally, we revealed that in contact with PAMAM-OH, asODN remains outside the cells as TIRF microscopy results showed, due to its poor interaction with this dendrimer and cell membranes.

  5. Dendrimers Application Related to Bioimaging

    PubMed Central

    Barrett, Tristan; Ravizzini, Gregory; Choyke, Peter L.; Kobayashi, Hisataka

    2009-01-01

    Dendrimers are a class of synthetically produced highly branched, spherical nanostructures that can be used as carrier molecules for imaging agents. A variety of dendrimers exist and each has biological properties that will alter its biodistribution. Dendrimers are composed of combinations of core types such as ethylene diamine (EDA), diaminobutyl (DAB), polyamidoamine (PAMAM) and polypropylimine (PPI) and different surface residues such as amine, carboxyl, and alcoholic groups. Increasing the number of primary amine groups attached to the core will increase the size of the dendrimer, which is known by the term ‘generation’ of the dendrimer. Because dendrimers are highly structured in size and shape and have a low poly-dispersity index, each dendrimer generation has distinct pharmacokinetic and pharmacodynamic properties which may prove advantageous for particular medical applications. Research has centered on developing these macromolecules as imaging agents for numerous modalities including magnetic resonance imaging, X-ray computed tomography, optical imaging and nuclear medicine. Another prospective function of dendrimers is as drug delivery vectors, whereby therapeutic payloads are encapsulated within the shell, or incorporated onto their multivalent surface, and targeted to tumor cells using ligands that specifically bind to cancer cells or in normal cells altered by nearby cancer cells. Furthermore, the larger size of high generation dendrimers offers potential to develop dual purpose agents that can act both as imaging agents and as delivery vectors, or can be imaged with more than one modality. Herein, we discuss the current and future applications of dendrimers in medicine and the central role they play in the emerging field of nanotechnology. PMID:19150767

  6. Cationic PAMAM Dendrimers as Pore-Blocking Binary Toxin Inhibitors

    PubMed Central

    2015-01-01

    Dendrimers are unique highly branched macromolecules with numerous groundbreaking biomedical applications under development. Here we identified poly(amido amine) (PAMAM) dendrimers as novel blockers for the pore-forming B components of the binary anthrax toxin (PA63) and Clostridium botulinum C2 toxin (C2IIa). These pores are essential for delivery of the enzymatic A components of the internalized toxins from endosomes into the cytosol of target cells. We demonstrate that at low μM concentrations cationic PAMAM dendrimers block PA63 and C2IIa to inhibit channel-mediated transport of the A components, thereby protecting HeLa and Vero cells from intoxication. By channel reconstitution and high-resolution current recording, we show that the PAMAM dendrimers obstruct transmembrane PA63 and C2IIa pores in planar lipid bilayers at nM concentrations. These findings suggest a new potential role for the PAMAM dendrimers as effective polyvalent channel-blocking inhibitors, which can protect human target cells from intoxication with binary toxins from pathogenic bacteria. PMID:24954629

  7. Dynamics of internally functionalized dendrimers.

    PubMed

    Grimm, Jonas; Dolgushev, Maxim

    2016-07-28

    The internally functionalized dendrimers are novel polymers that differ from conventional dendrimers by having additional functional units which do not branch out further. We investigate the dynamics of these structures with the inclusion of local semiflexibility and analyze their eigenmodes. The functionalized units clearly manifest themselves leading to a group of eigenvalues which are not present for homogeneous dendrimers. This part of the spectrum reveals itself in the local relaxation, leading to a corresponding process in the imaginary part of the complex dielectric susceptibility. PMID:27357106

  8. Dendrimers: synthesis, applications, and properties

    PubMed Central

    2014-01-01

    Dendrimers are nano-sized, radially symmetric molecules with well-defined, homogeneous, and monodisperse structure that has a typically symmetric core, an inner shell, and an outer shell. Their three traditional macromolecular architectural classes are broadly recognized to generate rather polydisperse products of different molecular weights. A variety of dendrimers exist, and each has biological properties such as polyvalency, self-assembling, electrostatic interactions, chemical stability, low cytotoxicity, and solubility. These varied characteristics make dendrimers a good choice in the medical field, and this review covers their diverse applications. PMID:24994950

  9. Antiviral mechanism of polyanionic carbosilane dendrimers against HIV-1

    PubMed Central

    Vacas-Córdoba, Enrique; Maly, Marek; De la Mata, Francisco J; Gómez, Rafael; Pion, Marjorie; Muñoz-Fernández, Mª Ángeles

    2016-01-01

    Nanotechnology-derived platforms, such as dendrimers, are very attractive in several biological applications. In the case of human immunodeficiency virus (HIV) infection, polyanionic carbosilane dendrimers have shown great potential as antiviral agents in the development of novel microbicides to prevent the sexual transmission of HIV-1. In this work, we studied the mechanism of two sulfated and naphthylsulfonated functionalized carbosilane dendrimers, G3-S16 and G2-NF16. They are able to inhibit viral infection at fusion and thus at the entry step. Both compounds impede the binding of viral particles to target cell surface and membrane fusion through the blockage of gp120–CD4 interaction. In addition, and for the first time, we demonstrate that dendrimers can inhibit cell-to-cell HIV transmission and difficult infectious synapse formation. Thus, carbosilane dendrimers’ mode of action is a multifactorial process targeting several proteins from viral envelope and from host cells that could block HIV infection at different stages during the first step of infection. PMID:27103798

  10. Toward multivalent signaling across G protein-coupled receptors from poly(amidoamine) dendrimers.

    PubMed

    Kim, Yoonkyung; Hechler, Béatrice; Klutz, Athena M; Gachet, Christian; Jacobson, Kenneth A

    2008-02-01

    Activation of the A2A receptor, a G protein-coupled receptor (GPCR), by extracellular adenosine, is antiaggregatory in platelets and anti-inflammatory. Multiple copies of an A2A agonist, the nucleoside CGS21680, were coupled covalently to PAMAM dendrimers and characterized spectroscopically. A fluorescent PAMAM-CGS21680 conjugate 5 inhibited aggregation of washed human platelets and was internalized. We envision that our multivalent dendrimer conjugates may improve overall pharmacological profiles compared to the monovalent GPCR ligands. PMID:18176997

  11. Phosphorus dendrimers and photodynamic therapy. Spectroscopic studies on two dendrimer-photosensitizer complexes: Cationic phosphorus dendrimer with rose bengal and anionic phosphorus dendrimer with methylene blue.

    PubMed

    Dabrzalska, Monika; Zablocka, Maria; Mignani, Serge; Majoral, Jean Pierre; Klajnert-Maculewicz, Barbara

    2015-08-15

    Dendrimers due to their unique architecture may play an important role in drug delivery systems including chemotherapy, gene therapy and recently, photodynamic therapy as well. We investigated two dendrimer-photosensitizer systems in context of potential use of these systems in photodynamic therapy. The mixtures of an anionic phosphorus dendrimer of the second generation and methylene blue were studied by UV-vis spectroscopy while that of a cationic phosphorus dendrimer (third generation) and rose bengal were investigated by spectrofluorimetric methods. Spectroscopic analysis of these two systems revealed the formation of dendrimer-photosensitizer complexes via electrostatic interactions as well as π stacking. The stoichiometry of the rose bengal-cationic dendrimer complex was estimated to be 7:1 and 9:1 for the methylene blue-anionic dendrimer complex. The results suggest that these polyanionic or polycationic phosphorus dendrimers can be promising candidates as carriers in photodynamic therapy. PMID:26117192

  12. Carboxymethyl chitosan-poly(amidoamine) dendrimer core-shell nanoparticles for intracellular lysozyme delivery.

    PubMed

    Zhang, Xiaoyang; Zhao, Jun; Wen, Yan; Zhu, Chuanshun; Yang, Jun; Yao, Fanglian

    2013-11-01

    Intracellular delivery of native, active proteins is challenging due to the fragility of most proteins. Herein, a novel polymer/protein polyion complex (PIC) nanoparticle with core-shell structure was prepared. Carboxymethyl chitosan-grafted-terminal carboxyl group-poly(amidoamine) (CM-chitosan-PAMAM) dendrimers were synthesized by amidation and saponification reactions. (1)H NMR was used to characterize CM-chitosan-PAMAM dendrimers. The TEM images and results of lysozyme loading efficiency indicated that CM-chitosan-PAMAM dendrimers could self-assemble into core-shell nanoparticles, and lysozyme was efficiently encapsulated inside the core of CM-chitosan-PAMAM dendrimer nanoparticles. Activity of lysozyme was completely inhibited by CM-chitosan-PAMAM Dendrimers at physiological pH, whereas it was released into the medium and exhibited a significant enzymatic activity in an acidic intracellular environment. Moreover, the CM-chitosan-PAMAM dendrimer nanoparticles did not exhibit significant cytotoxicity in the range of concentrations below 3.16 mg/ml. The results indicated that these CM-chitosan-PAMAM dendrimers have excellent properties as highly potent and non-toxic intracellular protein carriers, which would create opportunities for novel applications in protein delivery. PMID:24053810

  13. Aminolevulinic acid dendrimers in photodynamic treatment of cancer and atheromatous disease.

    PubMed

    Rodriguez, L; Vallecorsa, P; Battah, S; Di Venosa, G; Calvo, G; Mamone, L; Sáenz, D; Gonzalez, M C; Batlle, A; MacRobert, A J; Casas, A

    2015-09-26

    The use of endogenous protoporphyrin IX after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). We have previously reported that the conjugation of ALA dendrimers enhances porphyrin synthesis. The first aim of this work was to evaluate the ability of ALA dendrimers carrying 6 and 9 ALA residues (6m-ALA and 9m-ALA) to photosensitise cancer cells. For this aim, we employed LM3 mammary carcinoma cells. In these tumour cells, at low concentrations porphyrin synthesis from dendrimers was higher compared to ALA, whereas at high concentrations, porphyrin synthesis was similar from both compounds. Topical application of ALA dendrimers on the skin overlying a subcutaneous LM3 implanted tumour showed no diffusion of the molecules either to distant skin sites or to the adjacent tumour, suggesting a promising use of the ALA macromolecules in superficial cancer models. As a second objective, we proposed the use of ALA-dendrimers in vascular PDT for the treatment of atherosclerosis. Thus, we focused our studies on ALA-dendrimer's selectivity towards macrophages in comparison with endothelial cells. For this aim we employed Raw 264.7 macrophages and HMEC-1 microvasculature cells. Porphyrin synthesis induced in macrophages by 6m-ALA and 9m-ALA (3 h, 0.025 mM) was 6 and 4.6 times higher respectively compared to the endothelial cell line, demonstrating the high affinity of ALA dendrimers for macrophages. On the other hand, ALA employed at low concentrations was slightly selective (1.7-fold) for macrophages. Inhibition studies suggested that ALA dendrimer uptake in macrophages is mainly mediated by caveloae-mediated endocytosis. Our main conclusion is that in addition to being promising molecules in PDT of superficial cancer, ALA dendrimers may also find applications in vascular PDT, since in vitro they showed selectivity to the macrophage component of the atheromatous plaque, as compared to the vascular endothelium. PMID

  14. Are structural properties of dendrimers sensitive to the symmetry of branching? Computer simulation of lysine dendrimers

    NASA Astrophysics Data System (ADS)

    Falkovich, S.; Markelov, D.; Neelov, I.; Darinskii, A.

    2013-08-01

    Poly-L-lysine (PLL) dendrimers are promising systems for biomedical applications due to their biocompatibility. These dendrimers have a specific topology: two spacers of different lengths come out of each branching point and thus the branching is asymmetric. Because of this asymmetry terminal groups are located at branches of different lengths, unlike dendrimers with a symmetric branching. This paper presents the results of the first systematic molecular dynamics simulation of such asymmetric PLL dendrimers. It is shown that PLL dendrimers are porous molecules with all terminal groups equally accessible to water. We have found that in spite of an asymmetry of branching the general structural characteristics of PLL dendrimers are rather similar to those of dendrimers with symmetric branching. We have also found that the structural characteristics of PLL dendrimers obey the general laws for dendrimers and that their electrostatic properties agree with the predictions of a general analytic theory.

  15. Cationic poly(amidoamine) dendrimers induced cyto-protective autophagy in hepatocellular carcinoma cells

    NASA Astrophysics Data System (ADS)

    Li, Yubin; Wang, Shaofei; Wang, Ziyu; Qian, Xiaolu; Fan, Jiajun; Zeng, Xian; Sun, Yun; Song, Ping; Feng, Meiqing; Ju, Dianwen

    2014-09-01

    Poly(amidoamine) (PAMAM) dendrimers are proposed as one of the most promising nanomaterials for biomedical applications because of their unique tree-like structure, monodispersity and tunable properties. In this study, we found that PAMAM dendrimers could induce the formation of autophagosomes and the conversion of microtubule-associated protein 1 light chain 3 (LC3) in hepatocellular carcinoma HepG2 cells, while the inhibition of the Akt/mTOR and activation of the Erk 1/2 signaling pathways were involved in autophagy-induced by PAMAM dendrimers. We also investigated the suppression of autophagy with the obviously enhanced cytotoxicity of PAMAM dendrimers. Moreover, the blockage of a reactive oxygen species (ROS) could enhance the growth inhibition and apoptosis of hepatocellular carcinoma cells, induced by PAMAM dendrimers through reducing autophagic effects. Taken together, these findings explored the role and mechanism of autophagy induced by PAMAM dendrimers in HepG2 cells, provided new insight into the effect of autophagy on drug delivery nanomaterials and tumor cells and contributed to the use of a drug delivery vehicle for hepatocellular carcinoma treatment.

  16. Effects of Polyamidoamine Dendrimers on a 3-D Neurosphere System Using Human Neural Progenitor Cells.

    PubMed

    Zeng, Yang; Kurokawa, Yoshika; Zeng, Qin; Win-Shwe, Tin-Tin; Nansai, Hiroko; Zhang, Zhenya; Sone, Hideko

    2016-07-01

    The practical application of engineered nanomaterials or nanoparticles like polyamidoamine (PAMAM) dendrimers has been promoted in medical devices or industrial uses. The safety of PAMAM dendrimers needs to be assessed when used as a drug carrier to treat brain disease. However, the effects of PAMAM on the human nervous system remain unknown. In this study, human neural progenitor cells cultured as a 3D neurosphere model were used to study the effects of PAMAM dendrimers on the nervous system. Neurospheres were exposed to different G4-PAMAM dendrimers for 72 h at concentrations of 0.3, 1, 3, and 10 μg/ml. The biodistribution was investigated using fluorescence-labeled PAMAM dendrimers, and gene expression was evaluated using microarray analysis followed by pathway and network analysis. Results showed that PAMAM dendrimer nanoparticles can penetrate into neurospheres via superficial cells on them. PAMAM-NH2 but not PAMAM-SC can inhibit neurosphere growth. A reduced number of MAP2-positive cells in flare regions were inhibited after 10 days of differentiation, indicating an inhibitory effect of PAMAM-NH2 on cell proliferation and neuronal migration. A microarray assay showed 32 dendrimer toxicity-related genes, with network analysis showing 3 independent networks of the selected gene targets. Inducible immediate early gene early growth response gene 1 (Egr1), insulin-like growth factor-binding protein 3 (IGFBP3), tissue factor pathway inhibitor (TFPI2), and adrenomedullin (ADM) were the key genes in each network, and the expression of these genes was significantly down regulated. These findings suggest that exposure of neurospheres to PAMAM-NH2 dendrimers affects cell proliferation and migration through pathways regulated by Egr1, IGFBP3, TFPI2, and ADM. PMID:27125967

  17. Dendrimer technologies for brain tumor.

    PubMed

    Mishra, Vijay; Kesharwani, Prashant

    2016-05-01

    Despite low prevalence, brain tumors are one of the most lethal forms of cancer. Unfortunately the blood-brain barrier (BBB), a highly regulated, well coordinated and efficient barrier, checks the permeation of most of the drugs across it. Hence, crossing this barrier is one of the most significant challenges in the development of efficient central nervous system therapeutics. Surface-engineered dendrimers improve biocompatibility, drug-release kinetics and aptitude to target the BBB and/or tumors and facilitate transportation of anticancer bioactives across the BBB. This review sheds light on different aspects of brain tumors and dendrimers based on different approaches for treatment including recent research, opportunities and challenges encountered in development of novel and efficient dendrimer-based therapeutics for the treatment of brain tumors. PMID:26891979

  18. Ordered Layered Dendrimers Constructed from Two Known Dendrimer Families: Inheritance and Emergence of Properties.

    PubMed

    Dib, Hanna; Rebout, Cyrille; Laurent, Régis; Mallet-Ladeira, Sonia; Sournia-Saquet, Alix; Sárosi, Menyhárt B; Hey-Hawkins, Evamarie; Majoral, Jean-Pierre; Delavaux-Nicot, Béatrice; Caminade, Anne-Marie

    2016-07-25

    A new concept is presented, namely the synthesis of dendrimers intrinsically composed in alternation of building blocks pertaining to two known families of dendrimers: phosphorhydrazone dendrimers and triazine-piperazine dendrimers. These mixed dendrimers with layered controlled architecture inherit their easy (31) P NMR characterization and their thermal stability from the phosphorhydrazone family, and their decreased solubility from the triazine-piperazine family. However, they have also their own and original characteristics. Both parent families are white powders, whereas the mixed dendrimers are yellow, orange, or red powders, depending on the generation. DFT calculations were carried out on model dendrons to understand these special color features. Remarkably, these dendrimers incorporating redox-active organic entities allow for the first time the monitoring of the growth of an organic dendrimer by electrochemistry while highlighting an even-odd generation behavior. PMID:27140418

  19. Perspective: Dendrimer drugs for infection and inflammation.

    PubMed

    Shaunak, Sunil

    2015-12-18

    Biologists are dissecting complex biological pathways at breath taking speed. It is opening up new opportunities for the therapeutic evaluation of novel dendrimer drugs. This review focuses on studies of small dendrimers decorated with sulfate, phosphonate, N-acetyl-cysteine, glucosamine and mannose in animal model studies of infection and inflammation. It highlights those animal model studies which have demonstrated the most promising dendrimer drug constructs as potential new medicines. The issues relating to their analytical chemistry that are slowing the progress of dendrimer drugs into the clinic are highlighted. It should be possible to solve these with additional analytical expertise because it is small dendrimers with only 16-32 peripheral groups that make for the best infection and inflammation related medicines. Public-private partnerships are now needed to progress these dendrimer drugs into proof-of-concept clinical trials. PMID:26168733

  20. Stimuli-responsive dendrimers in drug delivery.

    PubMed

    Wang, Hui; Huang, Quan; Chang, Hong; Xiao, Jianru; Cheng, Yiyun

    2016-03-01

    Dendrimers have shown great promise as carriers in drug delivery due to their unique structures and superior properties. However, the precise control of payload release from a dendrimer matrix still presents a great challenge. Stimuli-responsive dendrimers that release payloads in response to a specific trigger could offer distinct clinical advantages over those dendrimers that release payloads passively. These smart polymers are designed to specifically release their payloads at targeted regions or at constant release profiles for specific therapies. They represent an attractive alternative to targeted dendrimers and enable dendrimer-based therapeutics to be more effective, more convenient, and much safer. The wide range of stimuli, either endogenous (acid, enzyme, and redox potentials) or exogenous (light, ultrasound, and temperature change), allows great flexibility in the design of stimuli-responsive dendrimers. In this review article, we will highlight recent advances and opportunities in the development of stimuli-responsive dendrimers for the treatment of various diseases, with emphasis on cancer. Specifically, the applications of stimuli-responsive dendrimers in drug delivery as well as their mechanisms are intensively reviewed. PMID:26806314

  1. The unperturbed state of dendrimers

    NASA Astrophysics Data System (ADS)

    Ganazzoli, Fabio; La Ferla, Roberto

    2000-11-01

    We report a theoretical study of the unperturbed state of dendrimers, which is realized when the second virial coefficient becomes equal to zero. This condition is achieved through a vanishing of the intermolecular free energy, which is obtained by mutual compensation of the two- and three-body interactions between two molecules. This procedure, which permits us to determine the Θ temperature of dendrimers as a function of their generation, is coupled to the problem of the intramolecular conformation, determined by minimization of the intramolecular free energy. The latter accounts for the two- and three-body interactions within the molecule, and for the configurational entropy. We find that the Θ temperature is a decreasing function of the dendrimer generation g, the decrease becoming relatively fast at large g, but is almost independent of the number of segments (one or two in our case) between adjacent branch points. At the Θ temperature, the residual three-body interactions within the molecule not compensated by the two-body attractions induce a significant swelling over the random-walk conformation for g>2.

  2. Dendrimers for siRNA Delivery

    PubMed Central

    Biswas, Swati; Torchilin, Vladimir P.

    2013-01-01

    Since the discovery of the “starburst polymer”, later renamed as dendrimer, this class of polymers has gained considerable attention for numerous biomedical applications, due mainly to the unique characteristics of this macromolecule, including its monodispersity, uniformity, and the presence of numerous functionalizable terminal groups. In recent years, dendrimers have been studied extensively for their potential application as carriers for nucleic acid therapeutics, which utilize the cationic charge of the dendrimers for effective dendrimer-nucleic acid condensation. siRNA is considered a promising, versatile tool among various RNAi-based therapeutics, which can effectively regulate gene expression if delivered successfully inside the cells. This review reports on the advancements in the development of dendrimers as siRNA carriers. PMID:24275946

  3. Uses of Dendrimers for DNA Microarrays

    PubMed Central

    Caminade, Anne-Marie; Padié, Clément; Laurent, Régis; Maraval, Alexandrine; Majoral, Jean-Pierre

    2006-01-01

    Biosensors such as DNA microarrays and microchips are gaining an increasing importance in medicinal, forensic, and environmental analyses. Such devices are based on the detection of supramolecular interactions called hybridizations that occur between complementary oligonucleotides, one linked to a solid surface (the probe), and the other one to be analyzed (the target). This paper focuses on the improvements that hyperbranched and perfectly defined nanomolecules called dendrimers can provide to this methodology. Two main uses of dendrimers for such purpose have been described up to now; either the dendrimer is used as linker between the solid surface and the probe oligonucleotide, or the dendrimer is used as a multilabeled entity linked to the target oligonucleotide. In the first case the dendrimer generally induces a higher loading of probes and an easier hybridization, due to moving away the solid phase. In the second case the high number of localized labels (generally fluorescent) induces an increased sensitivity, allowing the detection of small quantities of biological entities.

  4. Cationic Polyamidoamine Dendrimers as Modulators of EGFR Signaling In Vitro and In Vivo

    PubMed Central

    Akhtar, Saghir; Al-Zaid, Bashayer; El-Hashim, Ahmed Z.; Chandrasekhar, Bindu; Attur, Sreeja; Yousif, Mariam H. M.; Benter, Ibrahim F.

    2015-01-01

    Cationic polyamidoamine (PAMAM) dendrimers are branch-like spherical polymers being investigated for a variety of applications in nanomedicine including nucleic acid drug delivery. Emerging evidence suggests they exhibit intrinsic biological and toxicological effects but little is known of their interactions with signal transduction pathways. We previously showed that the activated (fragmented) generation (G) 6 PAMAM dendrimer, Superfect (SF), stimulated epidermal growth factor receptor (EGFR) tyrosine kinase signaling—an important signaling cascade that regulates cell growth, survival and apoptosis- in cultured human embryonic kidney (HEK 293) cells. Here, we firstly studied the in vitro effects of Polyfect (PF), a non-activated (intact) G6 PAMAM dendrimer, on EGFR tyrosine kinase signaling via extracellular-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) in cultured HEK 293 cells and then compared the in vivo effects of a single administration (10mg/kg i.p) of PF or SF on EGFR signaling in the kidneys of normal and diabetic male Wistar rats. Polyfect exhibited a dose- and time-dependent inhibition of EGFR, ERK1/2 and p38 MAPK phosphorylation in HEK-293 cells similar to AG1478, a selective EGFR inhibitor. Administration of dendrimers to non-diabetic or diabetic animals for 24h showed that PF inhibited whereas SF stimulated EGFR phosphorylation in the kidneys of both sets of animals. PF-mediated inhibition of EGFR phosphorylation as well as SF or PF-mediated apoptosis in HEK 293 cells could be significantly reversed by co-treatment with antioxidants such as tempol implying that both these effects involved an oxidative stress-dependent mechanism. These results show for the first time that SF and PF PAMAM dendrimers can differentially modulate the important EGFR signal transduction pathway in vivo and may represent a novel class of EGFR modulators. These findings could have important clinical implications for the use of PAMAM

  5. Cationic Polyamidoamine Dendrimers as Modulators of EGFR Signaling In Vitro and In Vivo.

    PubMed

    Akhtar, Saghir; Al-Zaid, Bashayer; El-Hashim, Ahmed Z; Chandrasekhar, Bindu; Attur, Sreeja; Yousif, Mariam H M; Benter, Ibrahim F

    2015-01-01

    Cationic polyamidoamine (PAMAM) dendrimers are branch-like spherical polymers being investigated for a variety of applications in nanomedicine including nucleic acid drug delivery. Emerging evidence suggests they exhibit intrinsic biological and toxicological effects but little is known of their interactions with signal transduction pathways. We previously showed that the activated (fragmented) generation (G) 6 PAMAM dendrimer, Superfect (SF), stimulated epidermal growth factor receptor (EGFR) tyrosine kinase signaling-an important signaling cascade that regulates cell growth, survival and apoptosis- in cultured human embryonic kidney (HEK 293) cells. Here, we firstly studied the in vitro effects of Polyfect (PF), a non-activated (intact) G6 PAMAM dendrimer, on EGFR tyrosine kinase signaling via extracellular-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) in cultured HEK 293 cells and then compared the in vivo effects of a single administration (10mg/kg i.p) of PF or SF on EGFR signaling in the kidneys of normal and diabetic male Wistar rats. Polyfect exhibited a dose- and time-dependent inhibition of EGFR, ERK1/2 and p38 MAPK phosphorylation in HEK-293 cells similar to AG1478, a selective EGFR inhibitor. Administration of dendrimers to non-diabetic or diabetic animals for 24h showed that PF inhibited whereas SF stimulated EGFR phosphorylation in the kidneys of both sets of animals. PF-mediated inhibition of EGFR phosphorylation as well as SF or PF-mediated apoptosis in HEK 293 cells could be significantly reversed by co-treatment with antioxidants such as tempol implying that both these effects involved an oxidative stress-dependent mechanism. These results show for the first time that SF and PF PAMAM dendrimers can differentially modulate the important EGFR signal transduction pathway in vivo and may represent a novel class of EGFR modulators. These findings could have important clinical implications for the use of PAMAM dendrimers

  6. Development of PEGylated Cysteine-Modified Lysine Dendrimers with Multiple Reduced Thiols To Prevent Hepatic Ischemia/Reperfusion Injury.

    PubMed

    Katsumi, Hidemasa; Nishikawa, Makiya; Hirosaki, Rikiya; Okuda, Tatsuya; Kawakami, Shigeru; Yamashita, Fumiyoshi; Hashida, Mitsuru; Sakane, Toshiyasu; Yamamoto, Akira

    2016-08-01

    To inhibit hepatic ischemia/reperfusion injury, we developed polyethylene glycol (PEG) conjugated (PEGylated) cysteine-modified lysine dendrimers with multiple reduced thiols, which function as scavengers of reactive oxygen species (ROS). Second, third, and fourth generation (K2, K3, and K4) highly branched amino acid spherical lysine dendrimers were synthesized, and cysteine (C) was conjugated to the outer layer of these lysine dendrimers to obtain K2C, K3C, and K4C dendrimers. Subsequently, PEG was reacted with the C residues of the dendrimers to obtain PEGylated dendrimers with multiple reduced thiols (K2C-PEG, K3C-PEG, and K4C-PEG). Radiolabeled K4C-PEG ((111)In-K4C-PEG) exhibited prolonged retention in the plasma, whereas (111)In-K2C-PEG and (111)In-K3C-PEG rapidly disappeared from the plasma. K4C-PEG significantly prevented the elevation of plasma alanine aminotransferase (ALT) activity, an index of hepatocyte injury, in a mouse model of hepatic ischemia/reperfusion injury. In contrast, K2C-PEG, K3C-PEG, l-cysteine, and glutathione, the latter two of which are classical reduced thiols, hardly affected the plasma ALT activity. These findings indicate that K4C-PEG with prolonged circulation time is a promising compound to inhibit hepatic ischemia/reperfusion injury. PMID:27336683

  7. Fate and transformation products of amine-terminated PAMAM dendrimers under ozonation and irradiation.

    PubMed

    Santiago-Morales, Javier; Rosal, Roberto; Hernando, María D; Ulaszewska, Maria M; García-Calvo, Eloy; Fernández-Alba, Amadeo R

    2014-02-15

    This article deals with the degradation of a third-generation (G3) poly(amidoamine) (PAMAM) dendrimer under ozonation and irradiation. The identification and quantification of G3 PAMAM dendrimer and its transformation products has been performed by liquid chromatography-electrospray ionization-hybrid quadrupole time-of-flight-mass spectrometry. The dendrimer was completely depleted by ozone in less than 1 min. The effect of ultraviolet irradiation was attributed to hydroxyl-mediated oxidation. The transformation products were attributed to the oxidation of amines, which resulted in highly oxidized structures with abundance of carboxylic acids, which started from the formation of amine oxide and the scission of the CN bond of the amide group. We studied the toxicity of treated mixtures for six different organisms: the acute toxicity for the bacterium Vibrio fischeri and the microcrustacean Daphnia magna, the multigenerational growth inhibition of the alga Pseudokirchneriella subcapitata, and the seed germination phytotoxicity of Licopersicon esculentum, Lactuca sativa and Lolium perenne. Ozonation and irradiation originated transformation products are more toxic than the parent dendrimer. The toxicity of the dendrimer for the green alga was linked to a strong increase of intracellular reactive oxygen species with intense lipid peroxidation. PMID:24384376

  8. Dendrimer-TPGS mixed micelles for enhanced solubility and cellular toxicity of taxanes.

    PubMed

    Pooja, Deep; Kulhari, Hitesh; Singh, Mayank K; Mukherjee, Sudip; Rachamalla, Shyam Sunder; Sistla, Ramakrishna

    2014-09-01

    Taxanes are the most effective, efficient and broad spectrum anticancer drugs for the treatment of various cancers. However, poor aqueous solubility is the major problem in their delivery at higher concentrations in cancer cells. In this research work, poor solubility of taxanes is addressed by preparing dendrimer and d-α-tocopherol polyethylene glycol succinate (TPGS) mixed micelles by taking into consideration the advantages of TPGS such as solubility enhancement and P-glycoprotein inhibition. Dendrimer-TPGS mixed micelles were prepared by solvent casting method. Docetaxel (DTX) and paclitaxel (PTX) were chosen as model drugs representing the group of taxanes. Nanomicelles were characterized by DLS, FTIR, PXRD, in vitro drug release and hemolytic studies. Effects of pH and dendrimer to TPGS ratio on the solubility of taxanes were also studied. Solubility of DTX and PTX were increased by 20.36 and 34.95 folds, respectively, when formulated in dendrimer-TPGS mixed micelles. Drug release studies exhibited better release profile of encapsulated drug at acidic pH which is advantageous in enhanced intracellular drug release in cancer cells. Formulations were found to be biocompatible in hemolytic toxicity assay. Cytotoxicity studies revealed that anticancer activities of both drugs were enhanced after encapsulation in micelles against cancer cells while caused very low toxicity to normal cells. Thus, dendrimer-TPGS mixed micelles are promising alternate for delivery of poorly water-soluble drugs taxanes. PMID:25063311

  9. Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model.

    PubMed

    Zhou, Kejin; Nguyen, Liem H; Miller, Jason B; Yan, Yunfeng; Kos, Petra; Xiong, Hu; Li, Lin; Hao, Jing; Minnig, Jonathan T; Zhu, Hao; Siegwart, Daniel J

    2016-01-19

    RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, 5A2-SC8, provided a broad therapeutic window: identified as potent [EC50 < 0.02 mg/kg siRNA against FVII (siFVII)] in dose-response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7 g microRNA (miRNA) mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer's own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs. PMID:26729861

  10. HER2 specific delivery of methotrexate by dendrimer conjugated anti-HER2 mAb

    NASA Astrophysics Data System (ADS)

    Shukla, Rameshwer; Thomas, Thommey P.; Desai, Ankur M.; Kotlyar, Alina; Park, Steve J.; Baker, James R., Jr.

    2008-07-01

    Herceptin, a humanized monoclonal antibody that binds to human growth factor receptor-2 (HER2), was covalently attached to a fifth-generation (G5) polyamidoamine dendrimer containing the cytotoxic drug methotrexate. The specific binding and internalization of this conjugate labeled with FITC was clearly demonstrated in cell lines overexpressing HER2 by flow cytometry as well as confocal microscopic analysis. In addition, binding and uptake of antibody conjugated dendrimers was completely blocked by excess non-conjugated herceptin. The dendrimer conjugate was also shown to inhibit the dihydrofolate reductase with similar activity to methotrexate. Co-localization experiments with lysotracker red indicate that antibody conjugate, although internalized efficiently into cells, has an unusually long residence time in the lysosome. Somewhat lower cytotoxicity of the conjugate in comparison to free methotrexate was attributed to the slow release of methotrexate from the conjugate and its long retention in the lysosomal pocket.

  11. Poly Ethoxy Ethyl Glycinamide (PEE-G) Dendrimers: Dendrimers Specifically Designed for Pharmaceutical Applications.

    PubMed

    Toms, Steven; Carnachan, Susan M; Hermans, Ian F; Johnson, Keryn D; Khan, Ashna A; O'Hagan, Suzanne E; Tang, Ching-Wen; Rendle, Phillip M

    2016-08-01

    Poly ethoxy ethyl glycinamide (PEE-G) dendrimers have been specifically designed and synthesized with the aim of providing a readily available dendrimer scaffold that can be used to make products that can meet the stringent requirements of pharmaceutical applications. The synthesis has been refined to produce dendrimers that are of high HPLC purity. The suitability of PEE-G dendrimers for their designed use has been verified by subsequent measurements to demonstrate that they are of high stability, high aqueous solubility, low cytotoxicity, low immunogenicity and with low in vivo toxicity in an escalating-dose rat study. PEE-G dendrimers therefore provide a useful scaffold for researchers wanting to develop dendrimer-based drug candidates. PMID:27390296

  12. Ferrocene-containing carbohydrate dendrimers.

    PubMed

    Ashton, Peter R; Balzani, Vincenzo; Clemente-León, Miguel; Colonna, Barbara; Credi, Alberto; Jayaraman, Narayanaswamy; Raymo, Francisco M; Stoddart, J Fraser; Venturi, Margherita

    2002-02-01

    Aliphatic amines, incorporating one or three (branched) acylated beta-D-glucopyranosyl residues, were coupled with the acid chloride of ferrocenecarboxylic acid and with the diacid chloride of 1,1'-ferrocenedicarboxylic acid to afford four dendrimer-type, carbohydrate-coated ferrocene derivatives in good yields (54-92%). Deprotection of the peracylated beta-D-glucopyranosyl residues was achieved quantitatively by using Zemplén conditions, affording four water-soluble ferrocene derivatives. When only one of the two cyclopentadienyl rings of the ferrocene unit is substituted, strong complexes are formed with beta-cyclodextrin in H2O, as demonstrated by liquid secondary ion mass spectrometry (LSIMS), 1H NMR spectroscopy, electrochemical measurements, and circular dichroism spectroscopy. Molecular dynamics calculations showed that the unsubstituted cyclopentadienyl ring is inserted through the cavity of the toroidal host in these complexes. The electrochemical behavior of the protected and deprotected ferrocene-containing dendrimers was investigated in acetonitrile and water, respectively. The diffusion coefficient decreases with increasing molecular weight of the compound. The potential for oxidation of the ferrocene core, the rate constant of heterogeneous electron transfer, and the rate constant for the energy-transfer reaction with the luminescent excited state of the [Ru(bpy)3]2+ complex (bpy = 2,2'-bipyridine) are strongly affected by the number (one or two) of substituents and by the number (one or three) of carbohydrate branches present in the substituents. These effects are assigned to shielding of the ferrocene core by the dendritic branches. Electrochemical evidence for the existence of different conformers for one of the dendrimers in aqueous solution was obtained. PMID:11855715

  13. Investigation of Dendrimer-Membrane Interactions

    NASA Astrophysics Data System (ADS)

    Mecke, Almut; Hessler, Jessica; Lee, Inhan; Banaszak Holl, Mark; Orr, Bradford; Patri, Anil K.; Baker, J. R.

    2003-03-01

    Modified Polyamidoamine (PAMAM) dendrimers show great promise as targeted drug transport agents. Current research efforts point to the possibility of dramatic improvements to conventional chemotherapy by selectively delivering a therapeutic to antigen bearing tumor cells. In order to better understand the uptake mechanism of such devices into cells we are investigating dendrimer-surface adsorption and dendrimer-membrane interactions using atomic force microscopy, light scattering and computer simulations. Model systems consisting of supported DMPC lipid bilayers have shown interesting results suggesting the shape and architecture of nano-devices play an important role for their biologic activity. We are also investigating the effect of targeted drug vehicles on cells in vitro.

  14. First evidences of PAMAM dendrimer internalization in microorganisms of environmental relevance: A linkage with toxicity and oxidative stress.

    PubMed

    Gonzalo, Soledad; Rodea-Palomares, Ismael; Leganés, Francisco; García-Calvo, Eloy; Rosal, Roberto; Fernández-Piñas, Francisca

    2015-01-01

    This article reports novel results on the toxic mechanisms of action of amine- and hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers toward microorganisms of environmental relevance, namely a cyanobacterium of the genus Anabaena and the green alga Chlamydomonas reinhardtii. We used PAMAM ethylenediamine core dendrimers from generations G2 to G4, which displayed a positive charge, measured as ζ-potential, in culture media. All amine-terminated and most remarkably the G4 hydroxyl-terminated dendrimer inhibited the growth of both microorganisms. The effect on the growth of the green alga was significantly higher than that on the cyanobacterium. With concentrations expressed in terms of molarity, there was a clear relationship between dendrimer generation and toxicity, with higher toxicity for higher generation. Hormesis was observed for hydroxyl-terminated dendrimers at low concentrations. The cationic dendrimers and G4-OH significantly increased the formation of reactive oxygen species (ROS) in both organisms. ROS formation was not related with the chloroplast or photosynthetic membranes and photosystem II photochemistry was unaffected. Cell damage resulted in cytoplasm disorganization and cell deformities and was associated to an increase in ROS formation and lipid peroxidation in mitochondria in the green alga; cell wall and membrane disruption with apparent loss of cytoplasmic contents was found in the cyanobacterium. It was determined for the first time that cationic PAMAM dendrimers were quickly and largely internalized by both organisms. These results warn against the generalization of the use of dendrimers, which may pose significant risk for the environment and particularly for primary producers which are determinant for the health of natural ecosystems. PMID:25325159

  15. Photopolymeric multifunctional dendrimer toward holographic applications.

    PubMed

    Jeong, Yong-Cheol; Jung, Bokyung; Park, Jung-Ki

    2012-09-26

    We present a photopolymeric multifunctional dendrimer for holographic applications. In this study, we described a synthesis of multiphotoreactive dendrimer and phase compatible polymer matrix as well as a numerical simulation of the dendrimer. This holographic photopolymer containing a nanosized photoreactive organic dendrimer could address the aggregation issue of conventional inorganic nanoparticle additives and allowed writing-induced shrinkage to be successfully reduced to the extent of acceptable values for 130 μm thick film. In this report, holographic performance including diffraction efficiency (DE), transmission, photosensitivity, modulation of refractive index, polarization sensitivity, and volume shrinkage has been discussed. The page-wise recording by using an amplitude spatial light modulator (SLM) was also demonstrated. PMID:22950741

  16. Dendrimer-Linked Antifreeze Proteins Have Superior Activity and Thermal Recovery.

    PubMed

    Stevens, Corey A; Drori, Ran; Zalis, Shiran; Braslavsky, Ido; Davies, Peter L

    2015-09-16

    By binding to ice, antifreeze proteins (AFPs) depress the freezing point of a solution and inhibit ice recrystallization if freezing does occur. Previous work showed that the activity of an AFP was incrementally increased by fusing it to another protein. Even larger increases in activity were achieved by doubling the number of ice-binding sites by dimerization. Here, we have combined the two strategies by linking multiple outward-facing AFPs to a dendrimer to significantly increase both the size of the molecule and the number of ice-binding sites. Using a heterobifunctional cross-linker, we attached between 6 and 11 type III AFPs to a second-generation polyamidoamine (G2-PAMAM) dendrimer with 16 reactive termini. This heterogeneous sample of dendrimer-linked type III constructs showed a greater than 4-fold increase in freezing point depression over that of monomeric type III AFP. This multimerized AFP was particularly effective at ice recrystallization inhibition activity, likely because it can simultaneously bind multiple ice surfaces. Additionally, attachment to the dendrimer has afforded the AFP superior recovery from heat denaturation. Linking AFPs together via polymers can generate novel reagents for controlling ice growth and recrystallization. PMID:26267368

  17. Structure Activity Relationship of Dendrimer Microbicides with Dual Action Antiviral Activity

    PubMed Central

    Tyssen, David; Henderson, Scott A.; Johnson, Adam; Sterjovski, Jasminka; Moore, Katie; La, Jennifer; Zanin, Mark; Sonza, Secondo; Karellas, Peter; Giannis, Michael P.; Krippner, Guy; Wesselingh, Steve; McCarthy, Tom; Gorry, Paul R.; Ramsland, Paul A.; Cone, Richard; Paull, Jeremy R. A.; Lewis, Gareth R.; Tachedjian, Gilda

    2010-01-01

    Background Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published. Methods and Findings Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Time-of-addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina. Conclusions Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as Viva

  18. Dendrimers bind antioxidant polyphenols and cisplatin drug.

    PubMed

    Abderrezak, Amine; Bourassa, Philippe; Mandeville, Jean-Sebastian; Sedaghat-Herati, Reza; Tajmir-Riahi, Heidar-Ali

    2012-01-01

    Synthetic polymers of a specific shape and size play major role in drug delivery systems. Dendrimers are unique synthetic macromolecules of nanometer dimensions with a highly branched structure and globular shape with potential applications in gene and drug delivery. We examine the interaction of several dendrimers of different compositions mPEG-PAMAM (G3), mPEG-PAMAM (G4) and PAMAM (G4) with hydrophilic and hydrophobic drugs cisplatin, resveratrol, genistein and curcumin at physiological conditions. FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyse drug binding mode, the binding constant and the effects of drug complexation on dendrimer stability and conformation. Structural analysis showed that cisplatin binds dendrimers in hydrophilic mode via Pt cation and polymer terminal NH(2) groups, while curcumin, genistein and resveratrol are located mainly in the cavities binding through both hydrophobic and hydrophilic contacts. The overall binding constants of durg-dendrimers are ranging from 10(2) M(-1) to 10(3) M(-1). The affinity of dendrimer binding was PAMAM-G4>mPEG-PAMAM-G4>mPEG-PAMAM-G3, while the order of drug-polymer stability was curcumin>cisplatin>genistein>resveratrol. Molecular modeling showed larger stability for genisten-PAMAM-G4 (ΔG = -4.75 kcal/mol) than curcumin-PAMAM-G4 ((ΔG = -4.53 kcal/mol) and resveratrol-PAMAM-G4 ((ΔG = -4.39 kcal/mol). Dendrimers might act as carriers to transport hydrophobic and hydrophilic drugs. PMID:22427960

  19. Imaging Dendrimer-Grafted Graphene Oxide Mediated Anti-miR-21 Delivery With an Activatable Luciferase Reporter.

    PubMed

    Wang, Fu; Zhang, Beilei; Zhou, Lin; Shi, Yaru; Li, Zhiqiang; Xia, Yuqiong; Tian, Jie

    2016-04-13

    MicroRNAs (miRNAs) are a class of post-transcriptional gene regulators involved in various physiological processes including carcinogenesis, and they have emerged as potential targets for tumor theranostics. However, the employment of antisense oligonucleotides, termed anti-miRs, for antagonizing miRNA functions in vivo has largely been impeded by a lack of effective delivery carriers. Here, we describe the development of polyamidoamine (PAMAM) dendrimer and polyethylene glycol (PEG)-functionalized nanographene oxide (NGO) conjugate (NGO-PEG-dendrimer) for the efficient delivery of anti-miR-21 into non-small-cell lung cancer cells. To monitor the delivery of anti-miR-21 into cells and tumors, we also constructed an activatable luciferase reporter (Fluc-3xPS) containing three perfectly complementary sequences against miR-21 in the 3' untranslated region (UTR) of the reporter. Compared with bare dendrimer and Lipofectamine 2000 (Lipo2000), NGO-PEG-dendrimer showed considerably lower cytotoxicity and higher transfection efficiency. As demonstrated by in vitro bioluminescence imaging and Western blotting assays, NGO-PEG-dendrimer effectively delivered anti-miR-21 into the cytoplasm and resulted in the upregulation of luciferase intensity and PTEN target protein expression in a dose-dependent manner. Moreover, transfection with anti-miR-21 by NGO-PEG-dendrimer led to stronger inhibition of cell migration and invasion than did bare dendrimer or Lipo2000 transfection. The intravenous delivery of anti-miR-21 via NGO-PEG-dendrimer induced a significant increase in the bioluminescence signal within the Fluc-3xPS reporter-transplanted tumor areas. These results suggest that NGO-PEG-dendrimer could be an efficient and a potential nanocarrier for delivering RNA oligonucleotides. In addition, the strategy of combining NGO-PEG-dendrimer with an activatable luciferase reporter allows the image-guided monitoring of the delivery process, which can provide insights into the RNA

  20. Bifunctional Phosphorus Dendrimers and Their Properties.

    PubMed

    Caminade, Anne-Marie; Majoral, Jean-Pierre

    2016-01-01

    Dendrimers are hyperbranched and monodisperse macromolecules, generally considered as a special class of polymers, but synthesized step-by-step. Most dendrimers have a uniform structure, with a single type of terminal function. However, it is often desirable to have at least two different functional groups. This review will discuss the case of bifunctional phosphorus-containing dendrimers, and the consequences for their properties. Besides the terminal functions, dendritic structures may have also a function at the core, or linked off-center to the core, or at the core of dendrons (dendritic wedges). Association of two dendrons having different terminal functions leads to Janus dendrimers (two faces). The internal structure can also possess functional groups on one layer, or linked to one layer, or on several layers. Finally, there are several ways to have two types of terminal functions, besides the case of Janus dendrimers: either each terminal function bears two functions sequentially, or two different functions are linked to each terminal branching point. Examples of each type of structure will be given in this review, as well as practical uses of such sophisticated structures in the fields of fluorescence, catalysis, nanomaterials and biology. PMID:27120586

  1. Instability Patterns of Evaporative Dendrimer Deposits

    NASA Astrophysics Data System (ADS)

    Jung, Narina

    The purpose of this project is to understand the instability mechanism behind dendrimer pattern formation in evaporating micro-meter size droplets. Evaporation of droplets of alcohol-dendrimer solution leaves a unique solute pattern on a substrate, where the detailed structure depends on the system variables. We are interested in developing a theory of the morphology of the dendrimer deposits that encompasses evaporation effects, solvent hydrodynamics, and solute particle chemistry. Our approach is to consider a two-dimensional coarse-grained model of dendrimer particle deposition that involves two mechanisms: transfer of solute particles by a convective flow and an inter-particle attraction competing with the convective flow. The configuration of a drying droplet is determined by the distribution of particles on a substrate and the volume fraction of them in a droplet. The Hamiltonian of each configuration is defined to account for both a convective flow and an inter-particle attraction. The evolution of the Hamiltonian is computed by Monte Carlo method to simulate the dendrimer pattern formation and associate patterns with system parameters. We found four basic regimes of morphologies that range from ringlike, wavelike, and fingerlike to islandlike patterns depending on the number of particles and the relative strength of a convective flow and an interaction.

  2. Complexes of dendrimers with bovine serum albumin.

    PubMed

    Mandeville, J S; Tajmir-Riahi, H A

    2010-02-01

    We report the complexation of bovine serum albumin (BSA) with several dendrimers of different compositions mPEG-PAMAM (G3), mPEG-PAMAM (G4), and PAMAM (G4) at physiological conditions using constant protein concentration and various dendrimer contents. FTIR, CD, and fluorescence spectroscopic methods were used to analyze polymer binding mode, the binding constant, and the effects of dendrimer complexation on BSA stability and conformation. Structural analysis showed that dendrimers bind BSA via hydrophilic and hydrophobic interactions with a number of bound polymers (n): 1.30 for mPEG-PAMAM-G3, 1.30 for mPEG-PAMAM-G4, and 1.0 for PAMAM-G4. The polymer-BSA binding constants were K(mPEG-G3) = 5.0 (+/-0.8) x 10(3) M(-1), K(mPEG-G4) = 1.0 (+/-0.3) x 10(4) M(-1), and K(PAMAM-G4) = 1.1 (+/-0.4) x 10(4) M(-1). Dendrimer binding altered BSA conformation with a major reduction of alpha-helix and an increase in random coil and turn structures, indicating a partial protein unfolding. PMID:20085247

  3. Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model

    PubMed Central

    Zhou, Kejin; Nguyen, Liem H.; Miller, Jason B.; Yan, Yunfeng; Kos, Petra; Xiong, Hu; Li, Lin; Hao, Jing; Minnig, Jonathan T.; Siegwart, Daniel J.

    2016-01-01

    RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, 5A2-SC8, provided a broad therapeutic window: identified as potent [EC50 < 0.02 mg/kg siRNA against FVII (siFVII)] in dose–response experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7g microRNA (miRNA) mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer’s own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs. PMID:26729861

  4. Effects of solute-solute interactions on protein stability studied using various counterions and dendrimers.

    PubMed

    Schneider, Curtiss P; Shukla, Diwakar; Trout, Bernhardt L

    2011-01-01

    Much work has been performed on understanding the effects of additives on protein thermodynamics and degradation kinetics, in particular addressing the Hofmeister series and other broad empirical phenomena. Little attention, however, has been paid to the effect of additive-additive interactions on proteins. Our group and others have recently shown that such interactions can actually govern protein events, such as aggregation. Here we use dendrimers, which have the advantage that both size and surface chemical groups can be changed and therein studied independently. Dendrimers are a relatively new and broad class of materials which have been demonstrated useful in biological and therapeutic applications, such as drug delivery, perturbing amyloid formation, etc. Guanidinium modified dendrimers pose an interesting case given that guanidinium can form multiple attractive hydrogen bonds with either a protein surface or other components in solution, such as hydrogen bond accepting counterions. Here we present a study which shows that the behavior of such macromolecule species (modified PAMAM dendrimers) is governed by intra-solvent interactions. Attractive guanidinium-anion interactions seem to cause clustering in solution, which inhibits cooperative binding to the protein surface but at the same time, significantly suppresses nonnative aggregation. PMID:22125620

  5. Poly(amido amine) dendrimers in oral delivery.

    PubMed

    Yellepeddi, Venkata K; Ghandehari, Hamidreza

    2016-01-01

    Poly(amidoamine) (PAMAM) dendrimers have been extensively investigated for oral delivery applications due to their ability to translocate across the gastrointestinal epithelium. In this Review, we highlight recent advances in the evaluation of PAMAM dendrimers as oral drug delivery carriers. Specifically, toxicity, mechanisms of transepithelial transport, models of the intestinal epithelial barrier including isolated human intestinal tissue model, detection of dendrimers, and surface modification are discussed. We also highlight evaluation of various PAMAM dendrimer-drug conjugates for their ability to transport across gastrointestinal epithelium for improved oral bioavailability. In addition, current challenges and future trends for clinical translation of PAMAM dendrimers as carriers for oral delivery are discussed. PMID:27358755

  6. Increased Potency of the PHSCN Dendrimer as an Inhibitor of Human Prostate Cancer Cell Invasion, Extravasation, and Lung Colony Formation

    PubMed Central

    Yao, Hongren; Zeng, Zhao-Zhu; Fay, Kevin S.; Staszewski, Evan D.; Veine, Donna M.; Livant, Donna L.

    2011-01-01

    Background Activated α5β1 integrin occurs specifically on tumor cells and on endothelial cells of tumor–associated vasculature, and plays a key role in invasion and metastasis. The PHSCN peptide (Ac-PHSCN-NH2) preferentially binds activated α5β1, to block invasion in vitro, and inhibit growth, metastasis and tumor recurrence in preclinical models of prostate cancer. In Phase I clinical trial, systemic Ac-PHSCN-NH2 monotherapy was well tolerated, and metastatic disease progression was prevented for 4–14 months in one third of treated patients. Results We have developed a significantly more potent derivative, the PHSCN-polylysine dendrimer (Ac-PHSCNGGK-MAP). Using in vitro invasion assays with naturally serum-free basement membranes, we observed that the PHSCN dendrimer was 130– to 1900–fold more potent than the PHSCN peptide at blocking α5β1–mediated invasion by DU 145 and PC-3 human prostate cancer cells, whether invasion was induced by serum, or by the Ac-PHSRN-NH2 peptide, under serum-free conditions. The PHSCN dendrimer was also approximately 800 times more effective than PHSCN peptide at preventing DU 145 and PC-3 extravasation in the lungs of athymic mice. Chou-Talalay analysis suggested that inhibition of both invasion in vitro and extravasation in vivo by the PHSCN dendrimer are highly synergistic. We found that many extravasated DU 145 and PC-3 cells go on to develop into metastatic colonies, and that a single pretreatment with the PHSCN dendrimer was 100–fold more affective than the PHSCN peptide at reducing lung colony formation. Conclusions Since many patients newly diagnosed with prostate cancer already have locally advanced or metastatic disease, the availability of a well-tolerated, nontoxic systemic therapy, like the PHSCN dendrimer, which prevents metastatic progression by inhibiting invasion, could be very beneficial. PMID:20339907

  7. Convergent synthesis of dendrimers via the Passerini three-component reaction.

    PubMed

    Jee, Jo-Ann; Spagnuolo, Lauren A; Rudick, Jonathan G

    2012-07-01

    Tuning properties by programming the surface functional group composition of surface-block dendrimers has been limited to dendrimers with only two types of surface functionality (i.e., surface-diblock dendrimers). The Passerini reaction provides dendrimer products from precursor dendrons in reasonable yields. This proof-of-principle experiment opens the door to making surface-triblock dendrimers. PMID:22702475

  8. Molecular Dynamics Study of the Structure, Flexibility, and Hydrophilicity of PETIM Dendrimers: A Comparison with PAMAM Dendrimers.

    PubMed

    Kanchi, Subbarao; Suresh, Gorle; Priyakumar, U Deva; Ayappa, K G; Maiti, Prabal K

    2015-10-15

    A new class of dendrimers, the poly(propyl ether imine) (PETIM) dendrimer, has been shown to be a novel hyperbranched polymer having potential applications as a drug delivery vehicle. Structure and dynamics of the amine terminated PETIM dendrimer and their changes with respect to the dendrimer generation are poorly understood. Since most drugs are hydrophobic in nature, the extent of hydrophobicity of the dendrimer core is related to its drug encapsulation and retention efficacy. In this study, we carry out fully atomistic molecular dynamics (MD) simulations to characterize the structure of PETIM (G2-G6) dendrimers in salt solution as a function of dendrimer generation at different protonation levels. Structural properties such as radius of gyration (Rg), radial density distribution, aspect ratio, and asphericity are calculated. In order to assess the hydrophilicity of the dendrimer, we compute the number of bound water molecules in the interior of dendrimer as well as the number of dendrimer-water hydrogen bonds. We conclude that PETIM dendrimers have relatively greater hydrophobicity and flexibility when compared with their extensively investigated PAMAM counterparts. Hence PETIM dendrimers are expected to have stronger interactions with lipid membranes as well as improved drug encapsulation and retention properties when compared with PAMAM dendrimers. We compute the root-mean-square fluctuation of dendrimers as well as their entropy to quantify the flexibility of the dendrimer. Finally we note that structural and solvation properties computed using force field parameters derived based on the CHARMM general purpose force field were in good quantitative agreement with those obtained using the generalized Amber force field (GAFF). PMID:26378813

  9. Nitric Oxide-Releasing Dendrimers as Antibacterial Agents

    PubMed Central

    Sun, Bin; Slomberg, Danielle L.; Chudasama, Shalini L.; Lu, Yuan

    2012-01-01

    The antibacterial activity of a series of nitric oxide (NO)-releasing poly(propylene imine) (PPI) dendrimers was evaluated against both Gram-positive and Gram-negative pathogenic bacteria, including methicillin-resistant Staphylococcus aureus. A direct comparison of the bactericidal efficacy between NO-releasing and control PPI dendrimers (i.e., non-NO-releasing) revealed both enhanced biocidal action of NO-releasing dendrimers and reduced toxicity against mammalian fibroblast cells. Antibacterial activity for the NO donor-functionalized PPI dendrimers was shown to be a function of both dendrimer size (molecular weight) and exterior functionality. In addition to minimal toxicity against fibroblasts, NO-releasing PPI dendrimers modified with styrene oxide exhibited the greatest biocidal activity (≥9.999% killing) against all bacterial strains tested. The N-diazeniumdiolate NO donor-functionalized PPI dendrimers presented in this study hold promise as effective NO-based therapeutics for combating bacterial infections. PMID:23013537

  10. Solubilization of a dendrimer into a microemulsion.

    PubMed

    Nir, Ido; Aserin, Abraham; Libster, Dima; Garti, Nissim

    2010-12-23

    The present work investigates, for the first time, a system comprising a dendrimer incorporated into the water core of water-in-oil (W/O) microemulsion (ME). A second generation (G-2) poly(propyleneimine) dendrimer (PPI) was solubilized into W/O ME composed of AOT (sodium bis(2-ethylhexyl)sulfosuccinate), heptane, and water. Such a model system possessing the benefits of both dendrimers and ME, can potentially offer superior control of drug administration. The localization of PPI within the system, its specific interactions with the components of the carrier, and its effect on the ME structure was explored by SAXS, DSC, ATR-FTIR, and electrical conductivity measurements. Considerable water binding by PPI, accompanied by partial dehydration of AOT polar heads, was detected by ATR-FTIR and DSC analysis, suggesting that PPI acted as a "water pump". In addition, SAXS measurements showed periodicity increase and disordering of the droplets. Hence, localization of PPI within the core and interfacial regions of the droplets was assumed. Direct electrostatic interactions between PPI and the sulfonate group were not noticed, since the dendrimer molecules were mostly not protonated in the current basic environment at pH 12. However, slight hydrogen bonding between PPI and the S=O groups allowed the dendrimer to behave as a "spacer" between sodium and sulfonate ions. This affected the electrical conductivity behavior of the system, revealing that PPI favored the percolation process. Most likely, PPI decreased the rigidity of the interfacial layer, facilitating the diffusion of sodium ions through the channels. The characterized model system can be advantageously utilized to design specific delivery vehicles, allowing administration of dendrimers as a therapeutic agent from host MEs. PMID:21126032

  11. Dendrimer based nanotherapeutics for ocular drug delivery

    NASA Astrophysics Data System (ADS)

    Kambhampati, Siva Pramodh

    PAMAM dendrimers are a class of well-defined, hyperbranched polymeric nanocarriers that are being investigated for ocular drug and gene delivery. Their favorable properties such as small size, multivalency and water solubility can provide significant opportunities for many biologically unstable drugs and allows potentially favorable ocular biodistribution. This work exploits hydroxyl terminated dendrimers (G4-OH) as drug/gene delivery vehicles that can target retinal microglia and pigment epithelium via systemic delivery with improved efficacy at much lower concentrations without any side effects. Two different drugs Triamcinolone acetonide (TA) and N-Acetyl Cysteine (NAC) conjugated to G4-OH dendrimers showed tailorable sustained release in physiological relevant solutions and were evaluated in-vitro and in-vivo. Dendrimer-TA conjugates enhanced the solubility of TA and were 100 fold more effective at lower concentrations than free TA in its anti-inflammatory activity in activated microglia and in suppressing VEGF production in hypoxic RPE cells. Dendrimers targeted activated microglia/macrophages and RPE and retained for a period of 21 days in I/R mice model. The relative retention of intravitreal and intravenous dendrimers was comparable, if a 30-fold intravenous dose is used; suggesting intravenous route targeting retinal diseases are possible with dendrimers. D-NAC when injected intravenously attenuated retinal and choroidal inflammation, significantly reduced (˜73%) CNV growth at early stage of AMD in rat model of CNV. A combination therapy of D-NAC + D-TA significantly suppressed microglial activation and promoted CNV regression in late stages of AMD without causing side-effects. G4-OH was modified with linker having minimal amine groups and incorporation of TA as a nuclear localization enhancer resulted in compact gene vectors with favorable safety profile and achieved high levels of transgene expression in hard to transfect human retinal pigment

  12. New Dendrimers: Synthesis and Characterization of Popam – Pamam Hybrid Dendrimers

    PubMed Central

    Majoros, István J.; Williams, Christopher R.; Tomalia, Donald A.; Baker, James R.

    2010-01-01

    Recently developed multifunctional cancer therapeutic nano-device production is based on poly(amidoamine) PAMAM generation 5 (G5) dendrimer as a carrier 1-5. Scale up synthesis of this nano-device is limited because of long reaction sequence (12 reaction steps) and long and not easy work up of the products after each reaction step. Combination of poly(propyle-imine) and poly(amidoamine) synthesis can improve the production of the drug carrier. In this paper we give a general overview of the synthesis and characterization of a series of novel hybrid dendrimers which we coined as novel POMAM hybrid dendrimers, constructed from poly(propylene-imine) (PPI or POPAM) core and poly(amidoamine) PAMAM shells. The synthesis was accomplished by a divergent reiterating method involving repeating subsequent Michael addition and amidation reactions. Each generation of the newly synthesized dendrimer was characterized by using HPLC, GPC, NMR and AFM. PMID:21258604

  13. Nature of the effective interaction between dendrimers

    SciTech Connect

    Mandal, Taraknath Dasgupta, Chandan Maiti, Prabal K.

    2014-10-14

    We have performed fully atomistic classical molecular dynamics simulations to calculate the effective interaction between two polyamidoamine dendrimers. Using the umbrella sampling technique, we have obtained the potential of mean force (PMF) between the dendrimers and investigated the effects of protonation level and dendrimer size on the PMF. Our results show that the interaction between the dendrimers can be tuned from purely repulsive to partly attractive by changing the protonation level. The PMF profiles are well-fitted by the sum of an exponential and a Gaussian function with the weight of the exponential function dominating over that of the Gaussian function. This observation is in disagreement with the results obtained in previous analytic [C. Likos, M. Schmidt, H. Löwen, M. Ballauff, D. Pötschke, and P. Lindner, Macromolecules 34, 2914 (2001)] and coarse-grained simulation [I. Götze, H. Harreis, and C. Likos, J. Chem. Phys. 120, 7761 (2004)] studies which predicted the effective interaction to be Gaussian.

  14. Dendrimer-enabled transformation of Anaplasma phagocytophilum.

    PubMed

    Oki, Aminat T; Seidman, David; Lancina, Michael G; Mishra, Manoj K; Kannan, Rangaramanujam M; Yang, Hu; Carlyon, Jason A

    2015-01-01

    Anaplasma phagocytophilum is an obligate intracellular bacterium that causes the emerging infection, granulocytic anaplasmosis. While electroporation can transform A. phagocytophilum isolated from host cells, no method has been developed to transform it while growing inside the ApV (A. phagocytophilum-occupied vacuole). Polyamidoamine (PAMAM) dendrimers, well-defined tree-branched macromolecules used for gene therapy and nucleic acid delivery into mammalian cells, were recently shown to be effective in transforming Chlamydia spp. actively growing in host cells. We determined if we could adapt a similar system to transform A. phagocytophilum. Incubating fluorescently labeled PAMAM dendrimers with infected host cells resulted in fluorescein-positive ApVs. Incubating infected host cells or host cell-free A. phagocytophilum organisms with dendrimers complexed with pCis GFPuv-SS Himar A7 plasmid, which carries a Himar1 transposon cassette encoding GFPuv and spectinomycin/streptomycin resistance plus the Himar1 transposase itself, resulted in GFP-positive, antibiotic resistant bacteria. Yet, transformation efficiencies were low. The transformed bacterial populations could only be maintained for a few passages, likely due to random Himar1 cassette-mediated disruption of A. phagocytophilum genes required for fitness. Nonetheless, these results provide proof of principle that dendrimers can deliver exogenous DNA into A. phagocytophilum, both inside and outside of host cells. PMID:26369714

  15. Carbosilane dendrimers affect the fibrillation of α-synuclein

    NASA Astrophysics Data System (ADS)

    Milowska, Katarzyna; Gomez-Ramirez, Rafael; de la Mata, Francisco Javier; Gabryelak, Teresa; Bryszewska, Maria

    2015-12-01

    Participation of α-synuclein (ASN) in the pathogenesis of Parkinson's disease is undeniable. This protein is important for functioning of neurons. Conformational changes in ASN and its aggregation result in neurodegeneration. Therefore, the factors preventing aggregation need to be identified. The search for the potential agents preventing fibrillation of proteins in neurodegenerative diseases has also involved polymers such as dendrimers. The aim of this study was to examine the role of carbosilane dendrimers (CBS) in α-synuclein fibrillation process and to assess the structural changes in α-synuclein under the influence of dendrimers. ASN interactions with carbosilane dendrimers were examined by measuring the zeta potential. The fibrillation and structural changes were examined using CD spectroscopy. The results obtained in this study suggest that carbosilane dendrimers can be potential inhibitors of ASN fibril formation. The fact that dendrimers can prevent ASN fibrillation in suspension is important for further research because it may lead to the design of effective pharmacological strategies.

  16. Electrostatic theory of the assembly of PAMAM dendrimers and DNA.

    PubMed

    Perico, Angelo

    2016-05-01

    The electrostatic interactions mediated by counterions between a cationic PAMAM dendrimer, modelized as a sphere of radius and cationic surface charge highly increasing with generation, and a DNA, modelized as an anionic elastic line, are analytically calculated in the framework of condensation theory. Under these interactions the DNA is wrapped around the sphere. For excess phosphates relative to dendrimer primary amines, the free energy of the DNA-dendrimer complex displays an absolute minimum when the complex is weakly negatively overcharged. This overcharging opposes gene delivery. For a highly positive dendrimer and a DNA fixed by experimental conditions to a number of phosphates less than the number of dendrimer primary amines, excess amine charges, the dendrimer may at the same time bind stably DNA and interact with negative cell membranes to activate cell transfection in fair agreement with molecular simulations and experiments. PMID:26756793

  17. Azide Tripodal Dendrons from Behera's Amine and Their Clicked Dendrimers.

    PubMed

    Barmare, Farhana; Abadjian, Marie-Caline Z; Wiener, Erik C; Grotjahn, Douglas B

    2016-08-01

    Diazo transfer reactions on Behera's amine and its next-generation analogue formed G0 and G1 azide dendrons bearing three and nine tert-butyl-protected esters, respectively. The utility of the new dendrons was demonstrated by copper-catalyzed azide-alkyne cycloaddition, with 1,3,5-triethynylbenzene, forming two novel dendrimers in a convergent manner. Acid-mediated dendrimer deprotection was successful, and the resulting carboxy-terminated dendrimers were analyzed by NMR and DOSY experiments. PMID:27454340

  18. Synthesis and characterization of polyamidoamine dendrimer-coated multi-walled carbon nanotubes and their application in gene delivery systems

    NASA Astrophysics Data System (ADS)

    Pan, Bifeng; Cui, Daxiang; Xu, Ping; Ozkan, Cengiz; Feng, Gao; Ozkan, Mihri; Huang, Tuo; Chu, Bingfeng; Li, Qing; He, Rong; Hu, Guohan

    2009-03-01

    With the aim of improving the amount and delivery efficiency of genes taken by carbon nanotubes into human cancer cells, different generations of polyamidoamine dendrimer modified multi-walled carbon nanotubes (dMNTs) were fabricated, and characterized by high-resolution transmission electron microscopy, atomic force microscopy, x-ray photoelectron spectroscopy, Raman spectroscopy, Fourier transform infrared spectroscopy and thermogravimetric analysis, revealing the presence of dendrimer capped on the surface of carbon nanotubes. The dMNTs fully conjugated with FITC-labeled antisense c-myc oligonucleotides (asODN), those resultant asODN-dMNTs composites were incubated with human breast cancer cell line MCF-7 cells and MDA-MB-435 cells, and liver cancer cell line HepG2 cells, and confirmed to enter into tumor cells within 15 min by laser confocal microscopy. These composites inhibited the cell growth in time- and dose-dependent means, and down-regulated the expression of the c-myc gene and C-Myc protein. Compared with the composites of CNT-NH2-asODN and dendrimer-asODN, no. 5 generation of dendrimer-modified MNT-asODN composites exhibit maximal transfection efficiencies and inhibition effects on tumor cells. The intracellular gene transport and uptake via dMNTs should be generic for the mammalian cell lines. The dMNTs have potentials in applications such as gene or drug delivery for cancer therapy and molecular imaging.

  19. Biogenic and synthetic polyamines bind cationic dendrimers.

    PubMed

    Mandeville, Jean-Sebastian; Bourassa, Phillipe; Thomas, Thekkumkattil John; Tajmir-Riahi, Heidar-Ali

    2012-01-01

    Biogenic polyamines are essential for cell growth and differentiation, while polyamine analogues exert antitumor activity in multiple experimental model systems, including breast and lung cancer. Dendrimers are widely used for drug delivery in vitro and in vivo. We report the bindings of biogenic polyamines, spermine (spm), and spermidine (spmd), and their synthetic analogues, 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) to dendrimers of different compositions, mPEG-PAMAM (G3), mPEG-PAMAM (G4) and PAMAM (G4). FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyze polyamine binding mode, the binding constant and the effects of polyamine complexation on dendrimer stability and conformation. Structural analysis showed that polyamines bound dendrimers through both hydrophobic and hydrophilic contacts with overall binding constants of K(spm-mPEG-G3) = 7.6 × 10(4) M(-1), K(spm-mPEG-PAMAM-G4) = 4.6 × 10(4) M(-1), K(spm-PAMAM-G4) = 6.6 × 10(4) M(-1), K(spmd-mPEG-G3) = 1.0 × 10(5) M(-1), K(spmd-mPEG-PAMAM-G4) = 5.5 × 10(4) M(-1), K(spmd-PAMAM-G4) = 9.2 × 10(4) M(-1), K(BE-333-mPEG-G3) = 4.2 × 10(4) M(-1), K(Be-333-mPEG-PAMAM-G4) = 3.2 × 10(4) M(-1), K(BE-333-PAMAM-G4) = 3.6 × 10(4) M(-1), K(BE-3333-mPEG-G3) = 2.2 × 10(4) M(-1), K(Be-3333-mPEG-PAMAM-G4) = 2.4 × 10(4) M(-1), K(BE-3333-PAMAM-G4) = 2.3 × 10(4) M(-1). Biogenic polyamines showed stronger affinity toward dendrimers than those of synthetic polyamines, while weaker interaction was observed as polyamine cationic charges increased. The free binding energies calculated from docking studies were: -3.2 (spermine), -3.5 (spermidine) and -3.03 (BE-3333) kcal/mol, with the following order of binding affinity: spermidine-PAMAM-G-4>spermine-PAMMAM-G4>BE-3333-PAMAM-G4 consistent with spectroscopic data. Our results suggest that dendrimers can act as carrier vehicles for delivering antitumor polyamine analogues to target tissues

  20. On the Possibility of Facilitated Diffusion of Dendrimers Along DNA.

    PubMed

    Ficici, Emel; Andricioaei, Ioan

    2015-06-11

    We investigate the electrostatics, energetics, and dynamics of dendrimer-DNA interactions that mimic protein-DNA complexes as a means to design facilitated mechanisms by which dendrimers can slide and search DNA for targets. By using all-atom molecular dynamics simulations, we calculated the free energy profiles of dendrimer-binding around the DNA via umbrella sampling. We also calculated electrostatic interaction maps in comparison to proteins, as well as the dynamical changes induced by DNA-dendrimer interactions via NMR-measurable order parameters. Our results show that for dendrimers to go around DNA, there is a free-energy barrier of 8.5 kcal/mol from the DNA major groove to DNA minor groove, with a minimum in the major groove. This barrier height makes it unlikely for an all-amine dendrimer to slide along DNA longitudinally, but following a helical path may be possible along the major groove. Comparison of the nonbonded interaction energy and the interaction free-energy profiles reveal a considerable entropic cost as the dendrimer binds to DNA. This is also supported by the mobility patterns obtained from NMR-measurable order parameter values, which show a decreased mobility of the dendrimer N-H bond vectors in the DNA-binding mode. PMID:25989627

  1. Interactions of PAMAM dendrimers with negatively charged model biomembranes.

    PubMed

    Yanez Arteta, Marianna; Ainalem, Marie-Louise; Porcar, Lionel; Martel, Anne; Coker, Helena; Lundberg, Dan; Chang, Debby P; Soltwedel, Olaf; Barker, Robert; Nylander, Tommy

    2014-11-13

    We have investigated the interactions between cationic poly(amidoamine) (PAMAM) dendrimers of generation 4 (G4), a potential gene transfection vector, with net-anionic model biomembranes composed of different ratios of zwitterionic phosphocholine (PC) and anionic phospho-L-serine (PS) phospholipids. Two types of model membranes were used: solid-supported bilayers, prepared with lipids carrying palmitoyl-oleoyl (PO) and diphytanoyl (DPh) acyl chains, and free-standing bilayers, formed at the interface between two aqueous droplets in oil (droplet interface bilayers, DIBs) using the DPh-based lipids. G4 dendrimers were found to translocate through POPC:POPS bilayers deposited on silica surfaces. The charge density of the bilayer affects translocation, which is reduced when the ionic strength increases. This shows that the dendrimer-bilayer interactions are largely controlled by their electrostatic attraction. The structure of the solid-supported bilayers remains intact upon translocation of the dendrimer. However, the amount of lipids in the bilayer decreases and dendrimer/lipid aggregates are formed in bulk solution, which can be deposited on the interfacial layers upon dilution of the system with dendrimer-free solvent. Electrophysiology measurements on DIBs confirm that G4 dendrimers cross the lipid membranes containing PS, which then become more permeable to ions. The obtained results have implications for PAMAM dendrimers as delivery vehicles to cells. PMID:25310456

  2. Novel Water-Soluble Mucoadhesive Carbosilane Dendrimers for Ocular Administration.

    PubMed

    Bravo-Osuna, I; Vicario-de-la-Torre, M; Andrés-Guerrero, V; Sánchez-Nieves, J; Guzmán-Navarro, M; de la Mata, F J; Gómez, R; de Las Heras, B; Argüeso, P; Ponchel, G; Herrero-Vanrell, R; Molina-Martínez, I T

    2016-09-01

    The purpose of this research was to determine the potential use of water-soluble anionic and cationic carbosilane dendrimers (generations 1-3) as mucoadhesive polymers in eyedrop formulations. Cationic carbosilane dendrimers decorated with ammonium -NH3(+) groups were prepared by hydrosylilation of Boc-protected allylamine and followed by deprotection with HCl. Anionic carbosilane dendrimers with terminal carboxylate groups were also employed in this study. In vitro and in vivo tolerance studies were performed in human ocular epithelial cell lines and rabbit eyes respectively. The interaction of dendrimers with transmembrane ocular mucins was evaluated with a surface biosensor. As proof of concept, the hypotensive effect of a carbosilane dendrimer eyedrop formulation containing acetazolamide (ACZ), a poorly water-soluble drug with limited ocular penetration, was tested after instillation in normotensive rabbits. The methodology used to synthesize cationic dendrimers avoids the difficulty of obtaining neutral -NH2 dendrimers that require harsher reaction conditions and also present high aggregation tendency. Tolerance studies demonstrated that both prototypes of water-soluble anionic and cationic carbosilane dendrimers were well tolerated in a range of concentrations between 5 and 10 μM. Permanent interactions between cationic carbosilane dendrimers and ocular mucins were observed using biosensor assays, predominantly for the generation-three (G3) dendrimer. An eyedrop formulation containing G3 cationic carbosilane dendrimers (5 μM) and ACZ (0.07%) (289.4 mOsm; 5.6 pH; 41.7 mN/m) induced a rapid (onset time 1 h) and extended (up to 7 h) hypotensive effect, and led to a significant increment in the efficacy determined by AUC0(8h) and maximal intraocular pressure reduction. This work takes advantage of the high-affinity interaction between cationic carbosilane dendrimers and ocular transmembrane mucins, as well as the tensioactive behavior observed for these

  3. Dendrimers and Polyamino-Phenolic Ligands: Activity of New Molecules Against Legionella pneumophila Biofilms

    PubMed Central

    Andreozzi, Elisa; Barbieri, Federica; Ottaviani, Maria F.; Giorgi, Luca; Bruscolini, Francesca; Manti, Anita; Battistelli, Michela; Sabatini, Luigia; Pianetti, Anna

    2016-01-01

    Legionnaires’ disease is a potentially fatal pneumonia caused by Legionella pneumophila, an aquatic bacterium often found within the biofilm niche. In man-made water systems microbial biofilms increase the resistance of legionella to disinfection, posing a significant threat to public health. Disinfection methods currently used in water systems have been shown to be ineffective against legionella over the long-term, allowing recolonization by the biofilm-protected microorganisms. In this study, the anti-biofilm activity of previously fabricated polyamino-phenolic ligands and polyamidoamine dendrimers was investigated against legionella mono-species and multi-species biofilms formed by L. pneumophila in association with other bacteria that can be found in tap water (Aeromonas hydrophila, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae). Bacterial ability to form biofilms was verified using a crystal violet colorimetric assay and testing cell viability by real-time quantitative PCR and Plate Count assay. The concentration of the chemicals tested as anti-biofilm agents was chosen based on cytotoxicity assays: the highest non-cytotoxic chemical concentration was used for biofilm inhibition assays, with dendrimer concentration 10-fold higher than polyamino-phenolic ligands. While Macrophen and Double Macrophen were the most active substances among polyamino-phenolic ligands, dendrimers were overall twofold more effective than all other compounds with a reduction up to 85 and 73% of legionella and multi-species biofilms, respectively. Chemical interaction with matrix molecules is hypothesized, based on SEM images and considering the low or absent anti-microbial activity on planktonic bacteria showed by flow cytometry. These data suggest that the studied compounds, especially dendrimers, could be considered as novel molecules in the design of research projects aimed at the development of efficacious anti-biofilm disinfection treatments of water systems

  4. Dendrimers and Polyamino-Phenolic Ligands: Activity of New Molecules Against Legionella pneumophila Biofilms.

    PubMed

    Andreozzi, Elisa; Barbieri, Federica; Ottaviani, Maria F; Giorgi, Luca; Bruscolini, Francesca; Manti, Anita; Battistelli, Michela; Sabatini, Luigia; Pianetti, Anna

    2016-01-01

    Legionnaires' disease is a potentially fatal pneumonia caused by Legionella pneumophila, an aquatic bacterium often found within the biofilm niche. In man-made water systems microbial biofilms increase the resistance of legionella to disinfection, posing a significant threat to public health. Disinfection methods currently used in water systems have been shown to be ineffective against legionella over the long-term, allowing recolonization by the biofilm-protected microorganisms. In this study, the anti-biofilm activity of previously fabricated polyamino-phenolic ligands and polyamidoamine dendrimers was investigated against legionella mono-species and multi-species biofilms formed by L. pneumophila in association with other bacteria that can be found in tap water (Aeromonas hydrophila, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae). Bacterial ability to form biofilms was verified using a crystal violet colorimetric assay and testing cell viability by real-time quantitative PCR and Plate Count assay. The concentration of the chemicals tested as anti-biofilm agents was chosen based on cytotoxicity assays: the highest non-cytotoxic chemical concentration was used for biofilm inhibition assays, with dendrimer concentration 10-fold higher than polyamino-phenolic ligands. While Macrophen and Double Macrophen were the most active substances among polyamino-phenolic ligands, dendrimers were overall twofold more effective than all other compounds with a reduction up to 85 and 73% of legionella and multi-species biofilms, respectively. Chemical interaction with matrix molecules is hypothesized, based on SEM images and considering the low or absent anti-microbial activity on planktonic bacteria showed by flow cytometry. These data suggest that the studied compounds, especially dendrimers, could be considered as novel molecules in the design of research projects aimed at the development of efficacious anti-biofilm disinfection treatments of water systems in

  5. Multifunctional lactobionic acid-modified dendrimers for targeted drug delivery to liver cancer cells: investigating the role played by PEG spacer.

    PubMed

    Fu, Fanfan; Wu, Yilun; Zhu, Jingyi; Wen, Shihui; Shen, Mingwu; Shi, Xiangyang

    2014-09-24

    We report the development of a lactobionic acid (LA)-modified multifunctional dendrimer-based carrier system for targeted therapy of liver cancer cells overexpressing asialoglycoprotein receptors. In this study, generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers were sequentially modified with fluorescein isothiocyanate (FI) and LA (or polyethylene glycol (PEG)-linked LA, PEG-LA), followed by acetylation of the remaining dendrimer terminal amines. The synthesized G5.NHAc-FI-LA or G5.NHAc-FI-PEG-LA conjugates (NHAc denotes acetamide groups) were used to encapsulate a model anticancer drug doxorubicin (DOX). We show that both conjugates are able to encapsulate approximately 5.0 DOX molecules within each dendrimer and the formed dendrimer/DOX complexes are stable under different pH conditions and different aqueous media. The G5.NHAc-FI-PEG-LA conjugate appears to have a better cytocompatibility, enables a slightly faster DOX release rate, and displays better liver cancer cell targeting ability than the G5.NHAc-FI-LA conjugate without PEG under similar experimental conditions. Importantly, the developed G5.NHAc-FI-PEG-LA/DOX complexes are able to specifically inhibit the growth of the target cells with a better efficiency than the G5.NHAc-FI-LA/DOX complexes at a relatively high DOX concentration. Our results suggest a key role played by the PEG spacer that affords the dendrimer platform with enhanced targeting and therapeutic efficacy of cancer cells. The developed LA-modified multifunctional dendrimer conjugate with a PEG spacer may be used as a delivery system for targeted liver cancer therapy and offers new opportunities in the design of multifunctional drug carriers for targeted cancer therapy applications. PMID:25185074

  6. Characterization of crystalline dendrimer-stabilized gold nanoparticles

    NASA Astrophysics Data System (ADS)

    Shi, Xiangyang; Ganser, T. Rose; Sun, Kai; Balogh, Lajos P.; Baker, James R., Jr.

    2006-02-01

    Monodispersed, highly crystalline dendrimer-stabilized gold nanoparticles (Au DSNPs) were synthesized via hydrazine reduction chemistry and stabilized using primary amine-terminated poly(amidoamine) (PAMAM) dendrimers of different generations (generations 2-6) with the same molar ratios of dendrimer terminal nitrogen ligands/gold atoms. The sizes of the synthesized Au DSNPs decrease with the increase of the number of dendrimer generations. These Au DSNPs are fluorescent and display strong blue emission intensity at 458 nm. Polyacrylamide gel electrophoresis (PAGE) analysis indicates that all Au DSNPs are stable and both metal NPs and dendrimer stabilizers do not separate from each other during the electrophoresis process. The synthesized inorganic/organic hybrid Au DSNPs provide new nanoplatforms that will be further modified with various biological ligands for the application of biosensing and targeted cancer therapeutics.

  7. Developmental toxicity of low generation PAMAM dendrimers in zebrafish

    SciTech Connect

    King Heiden, Tisha C.; Dengler, Emelyne; Kao, Weiyuan John; Heideman, Warren; Peterson, Richard E.

    2007-11-15

    Biological molecules and intracellular structures operate at the nanoscale; therefore, development of nanomedicines shows great promise for the treatment of disease by using targeted drug delivery and gene therapies. PAMAM dendrimers, which are highly branched polymers with low polydispersity and high functionality, provide an ideal architecture for construction of effective drug carriers, gene transfer devices and imaging of biological systems. For example, dendrimers bioconjugated with selective ligands such as Arg-Gly-Asp (RGD) would theoretically target cells that contain integrin receptors and show potential for use as drug delivery devices. While RGD-conjugated dendrimers are generally considered not to be cytotoxic, there currently exists little information on the risks that such materials pose to human health. In an effort to compliment and extend the knowledge gleaned from cell culture assays, we have used the zebrafish embryo as a rapid, medium throughput, cost-effective whole-animal model to provide a more comprehensive and predictive developmental toxicity screen for nanomaterials such as PAMAM dendrimers. Using the zebrafish embryo, we have assessed the developmental toxicity of low generation (G3.5 and G4) PAMAM dendrimers, as well as RGD-conjugated forms for comparison. Our results demonstrate that G4 dendrimers, which have amino functional groups, are toxic and attenuate growth and development of zebrafish embryos at sublethal concentrations; however, G3.5 dendrimers, with carboxylic acid terminal functional groups, are not toxic to zebrafish embryos. Furthermore, RGD-conjugated G4 dendrimers are less potent in causing embryo toxicity than G4 dendrimers. RGD-conjugated G3.5 dendrimers do not elicit toxicity at the highest concentrations tested and warrant further study for use as a drug delivery device.

  8. PAMAM Dendrimers as Quantized Building Blocks for Novel Nanostructures.

    PubMed

    van Dongen, Mallory A; Vaidyanathan, S; Banaszak Holl, Mark M

    2013-12-21

    The desire to synthesize soft supramolecular structures with size scales similar to biological systems has led to work in assembly of polymeric nanomaterials. Recent advances in the isolation of generationally homogenous poly(amidoamine) (PAMAM) dendrimer enables their use as quantized building blocks. Here, we report their assembly into precise nanoclusters. In this work, click-functional ligands are stochastically conjugated to monomeric generation 5 PAMAM dendrimer and separated via reverse-phase HPLC to isolate dendrimers with precise numbers of click ligands per dendrimer particle. The click-ligand/dendrimer conjugates are then employed as modular building blocks for the synthesis of defined nanostructures. Complimentary click chemistry employing dendrimers with 1, 2, 3, or 4 ring-strained cyclooctyne ligands and dendrimers with 1 azide ligand were utilized to prepare megamer structures containing 2 to 5 ~30,000 kDa monomer units as characterized by mass spectrometry, size exclusion chromatography, and reverse-phase liquid chromatography. The resulting structures are flexible with masses ranging from 60,000 to 150,000 kDa, and are soluble in water, methanol, and dimethylsulfoxide. PMID:24319491

  9. PAMAM Dendrimers as Quantized Building Blocks for Novel Nanostructures

    PubMed Central

    van Dongen, Mallory A.; Vaidyanathan, S.; Banaszak Holl, Mark M.

    2013-01-01

    The desire to synthesize soft supramolecular structures with size scales similar to biological systems has led to work in assembly of polymeric nanomaterials. Recent advances in the isolation of generationally homogenous poly(amidoamine) (PAMAM) dendrimer enables their use as quantized building blocks. Here, we report their assembly into precise nanoclusters. In this work, click-functional ligands are stochastically conjugated to monomeric generation 5 PAMAM dendrimer and separated via reverse-phase HPLC to isolate dendrimers with precise numbers of click ligands per dendrimer particle. The click-ligand/dendrimer conjugates are then employed as modular building blocks for the synthesis of defined nanostructures. Complimentary click chemistry employing dendrimers with 1, 2, 3, or 4 ring-strained cyclooctyne ligands and dendrimers with 1 azide ligand were utilized to prepare megamer structures containing 2 to 5 ~30,000 kDa monomer units as characterized by mass spectrometry, size exclusion chromatography, and reverse-phase liquid chromatography. The resulting structures are flexible with masses ranging from 60,000 to 150,000 kDa, and are soluble in water, methanol, and dimethylsulfoxide. PMID:24319491

  10. Nanoscale effects in dendrimer-mediated targeting of neuroinflammation.

    PubMed

    Nance, Elizabeth; Zhang, Fan; Mishra, Manoj K; Zhang, Zhi; Kambhampati, Siva P; Kannan, Rangaramanujam M; Kannan, Sujatha

    2016-09-01

    Neuroinflammation, mediated by activated microglia and astrocytes, plays a key role in the pathogenesis of many neurological disorders. Systemically-administered dendrimers target neuroinflammation and deliver drugs with significant efficacy, without the need for ligands. Elucidating the nanoscale aspects of targeting neuroinflammation will enable superior nanodevices for eventual translation. Using a rabbit model of cerebral palsy, we studied the in vivo contributions of dendrimer physicochemical properties and disease pathophysiology on dendrimer brain uptake, diffusion, and cell specific localization. Neutral dendrimers move efficiently within the brain parenchyma and rapidly localize in glial cells in regions of injury. Dendrimer uptake is also dependent on the extent of blood-brain-barrier breakdown, glial activation, and disease severity (mild, moderate, or severe), which can lend the dendrimer to be used as an imaging biomarker for disease phenotype. This new understanding of the in vivo mechanism of dendrimer-mediated delivery in a clinically-relevant rabbit model provides greater opportunity for clinical translation of targeted brain injury therapies. PMID:27267631

  11. Efficient Synthesis of Fluorescent Squaraine Rotaxane Dendrimers

    PubMed Central

    Xiao, Shuzhang; Fu, Na; Peckham, Kaitlin; Smith, Bradley D.

    2009-01-01

    A squaraine rotaxane scaffold with four alkynes groups is readily converted into a range of dendritic architectures using high yielding copper catalyzed alkyne azide cycloaddition (CuAAC) chemistry. A convergent synthesis approach is more efficient than a divergent pathway. Dendritic squaraine rotaxanes with peripheral amine groups can be further functionalized to produce multivalent deep-red fluorescent derivatives that exhibit high brightness and outstanding chemical stability in biological solution. The surface groups on these functionalized fluorescent dendrimers include guanidinium, mannose, and phosphatidylcholine. PMID:19957971

  12. Cationic PAMAM Dendrimers Aggressively Initiate Blood Clot Formation

    PubMed Central

    Jones, Clinton F.; Campbell, Robert A.; Brooks, Amanda E.; Assemi, Shoeleh; Tadjiki, Soheyl; Thiagarajan, Giridhar; Mulcock, Cheyanne; Weyrich, Andrew S.; Brooks, Benjamin D.; Ghandehari, Hamidreza; Grainger, David W.

    2012-01-01

    Poly(amidoamine) (PAMAM) dendrimers are increasingly studied as model nanoparticles for a variety of biomedical applications, notably in systemic administrations. However, with respect to blood contacting applications, amine-terminated dendrimers have recently been shown to activate platelets and cause a fatal, disseminated intravascular coagulation (DIC)-like condition in mice and rats. We here demonstrate that, upon addition to blood, cationic G7 PAMAM dendrimers induce fibrinogen aggregation, which may contribute to the in vivo DIC-like phenomenon. We demonstrate that amine-terminated dendrimers act directly on fibrinogen in a thrombin-independent manner to generate dense, high-molecular-weight fibrinogen aggregates with minimal fibrin fibril formation. In addition, we hypothesize this clot-like behavior is likely mediated through electrostatic interactions between the densely charged cationic dendrimer surface and negatively charged fibrinogen domains. Interestingly, cationic dendrimers also induced aggregation of albumin, suggesting that many negatively charged blood proteins may be affected by cationic dendrimers. To investigate this further, zebrafish embryos (ZFE) were employed to more specifically determine the speed of this phenomenon and the pathway- and dose-dependency of the resulting vascular occlusion phenotype. These novel findings show that G7 PAMAM dendrimers significantly and adversely impact many blood components to produce rapid coagulation and strongly suggest that these effects are independent of classic coagulation mechanisms. These results also strongly suggest the need to fully characterize amine-terminated PAMAM dendrimers in regards to their adverse effects on both coagulation and platelets, which may contribute to blood toxicity. PMID:23062017

  13. Double targeting and aptamer-assisted controlled release delivery of epirubicin to cancer cells by aptamers-based dendrimer in vitro and in vivo.

    PubMed

    Taghdisi, Seyed Mohammad; Danesh, Noor Mohammad; Ramezani, Mohammad; Lavaee, Parirokh; Jalalian, Seyed Hamid; Robati, Rezvan Yazdian; Abnous, Khalil

    2016-05-01

    Clinical use of epirubicin (Epi) in the treatment of cancer has been limited, due to its cardiotoxicity. Targeted delivery of chemotherapeutic agents could increase their efficacy and reduce their off-target effects. High drug loading and excellent stability of DNA dendrimers make these DNA nanostructures unique candidates for biological applications. In this study a modified and promoted dendrimer using three kinds of aptamers (MUC1, AS1411 and ATP aptamers) was designed for targeted delivery of Epi and its efficacy was evaluated in target cells including MCF-7 cells (breast cancer cell) and C26 cells (murine colon carcinoma cell). Aptamers (Apts)-Dendrimer-Epi complex formation was analyzed by fluorometric analysis and gel retardation assay. Release profiles of Epi from the designed complex were assessed at pHs 5.4 and 7.4. For MTT assay (cytotoxic study) MCF-7 and C26 cells (target cells) and CHO cells (Chinese hamster ovary cell, nontarget) were treated with Epi, Apts-Dendrimer-Epi complex and Apts-Dendrimer conjugate. Internalization was evaluated using flow cytometry analysis. Finally, the developed complex was used for inhibition of tumor growth in vivo. 25μM Epi was efficiently intercalated to 1μM dendrimer. Epi was released from the Apts-Dendrimer-Epi complex in a pH-sensitive manner (more release at pH 5.5). The results of flow cytometry analysis indicated that the designed complex was efficiently internalized into target cells, but not into control cells. The internalization data were confirmed by the results of MTT assay. Apts-Dendrimer-Epi complex had less cytotoxicity in CHO cells compared to Epi alone. The complex had more cytotoxicity in C26 and MCF-7 cells compared to Epi alone. Moreover, the Apts-Dendrimer-Epi complex could efficiently prohibit tumor growth in vivo. In conclusion, the designed targeted drug delivery system inherited characteristics of pH-dependent drug release, high drug loading and tumor targeting in vitro and in vivo. PMID

  14. Evolution of dendrimer conformational structure with generation number

    NASA Astrophysics Data System (ADS)

    Betancourt, Beatriz A. Pazmiño; Douglas, Jack F.

    2016-05-01

    We simulate the conformational structure of a coarse-grained model of dendrimer molecules in a good solvent as a function of generation number G and find that they evolve through substantially more complex structures than regular star polymers with increasing arms because of their hierarchical topological structure. As G increases, they evolve from 3-arm stars to branched polymers that geometrically resemble lattice animals, and then percolation clusters for G = 4 - 6 range. For larger G, the dendrimers become similar to porous particles, but the molecule segregates segregates into subdomains at G = 9, reflecting the branching complexity of the first dendrimer generation.

  15. pH Responsiveness of Polyelectrolyte Dendrimers: A Dynamical Perspective

    SciTech Connect

    Chen, Wei-Ren; Herwig, Kenneth W; Hong, Kunlun; Li, Xin; Liu, Emily; Liu, Yun; Shew, Chwen-Yang; Smith, Gregory Scott; Zamponi, Michaela M; Jenkins, Timothy

    2011-01-01

    Quasielastic neutron scattering (QENS) experiments were carried out to investigate the internal dynamics of aqueous (D2O) G5 PAMAM dendrimer solutions as a function of molecular protonation at room temperature. The localized motion was clearly exhibited in data analysis by being separated from the global translational diffusion. Our results unambiguously point out that with the molecular charge increased continuously the local motion is stably enhanced. The charge-induced local dynamics of dendrimer segments may correspond to their interaction with the surrounding counterions and water molecules. The outcome may provide significant information for the application of dendrimer-based packages as drug delivery vehicles.

  16. Predicting cytotoxicity of PAMAM dendrimers using molecular descriptors

    PubMed Central

    Jones, David E; Ghandehari, Hamidreza

    2015-01-01

    Summary The use of data mining techniques in the field of nanomedicine has been very limited. In this paper we demonstrate that data mining techniques can be used for the development of predictive models of the cytotoxicity of poly(amido amine) (PAMAM) dendrimers using their chemical and structural properties. We present predictive models developed using 103 PAMAM dendrimer cytotoxicity values that were extracted from twelve cancer nanomedicine journal articles. The results indicate that data mining and machine learning can be effectively used to predict the cytotoxicity of PAMAM dendrimers on Caco-2 cells. PMID:26665059

  17. Simulation of complexes between linear polyelectrolyte and charged dendrimer

    NASA Astrophysics Data System (ADS)

    Pandav, Gunja; Ganesan, Venkat

    2014-03-01

    Complexes formed by electrostatic interactions between dendrimer having cationic terminal groups and anionic linear polyelectrolyte are studied using hybrid Monte Carlo simulations. The excluded volume interactions are modeled using a self-consistent field and the electrostatic interactions are computed by solving Poisson equation. Such framework facilitates simulating large scale three-dimensional systems. We primarily focus on the effect of dendrimer generation number, stiffness of polyelectrolyte chain and systematically study its effect on change in shape and size of complexes. Our results suggest that the dendrimer structure and charge distribution has a significant impact on the complex formation.

  18. Antibody h-R3-dendrimer mediated siRNA has excellent endosomal escape and tumor targeted delivery ability, and represents efficient siPLK1 silencing and inhibition of cell proliferation, migration and invasion

    PubMed Central

    Li, Jun; Liu, Jing; Li, Shengnan; Hao, Yanli; Chen, Lei; Zhang, Xiaoning

    2016-01-01

    The major obstacle to developing siRNA delivery is their extracellular and intracellular barriers. Herein, a humanized anti-EGFR monoclonal antibody h-R3 was developed to modify the self-assembled binary complexes (dendriplexes) of PAMAM and siRNA via electrostatic interactions, and two common ligands HSA and EGF were used as a control. Compared to dendriplexes, h-R3/EGF/HSA-dendriplexes showed increased particle size, decreased zeta potentials and lower cytotoxicity. Moreover, h-R3-dendriplexes presented greater cellular uptake and excellent endosomal escape ability in HepG2 cells. Ex vivo fluorescence imaging revealed that h-R3-dendriplexes showed higher targeted delivery and gene expression in the tumors than dendriplexes, HSA-dendriplexes and EGF-dendriplexes, which was in agreement with confocal results of cryosections. Furthermore, h-R3-dendriplexes for siPLK1 delivery indicated efficient gene silencing, potentiated cell growth inhibition and cell apoptosis, and suppressed cellular migration/invasion. These results indicate that h-R3-dendriplexes represent a great potential to be used as efficient targeted siRNA delivery carriers. PMID:26883109

  19. Specific vapor sorption properties of phosphorus-containing dendrimers.

    PubMed

    Gerasimov, Alexander V; Ziganshin, Marat A; Vandyukov, Alexander E; Kovalenko, Valeri I; Gorbatchuk, Valery V; Caminade, Anne-Marie; Majoral, Jean-Pierre

    2011-08-01

    Specific combination of guest sorption properties was observed for phosphorus-containing dendrimers, which distinguish them from ordinary polymers and clathrate-forming hosts. The sorption capacity for 30 volatile guests, binding reversibility, guest desorption kinetics and guest exchange, glass transition behavior and ability to be plasticized with guest were studied for phosphorus dendrimers of different generations (G(1)-G(4) and G(9)) using quartz crystal microbalance sensor, FTIR microspectroscopy, atomic force microscopy, simultaneous thermogravimetry and differential scanning calorimetry combined with mass-spectrometry of evolved vapors. The dendrimers were found to have a different selectivity for different homological series of guests, high glass transition points without plasticization with guest even at high temperatures and saturation levels, moderate guest-binding irreversibility and ability both for effective guest exchange and independent guest sorption. These properties constitute an advantage of the studied dendrimers as receptor materials in various applications. PMID:21546037

  20. Dendrimers in drug delivery and targeting: Drug-dendrimer interactions and toxicity issues

    PubMed Central

    Madaan, Kanika; Kumar, Sandeep; Poonia, Neelam; Lather, Viney; Pandita, Deepti

    2014-01-01

    Dendrimers are the emerging polymeric architectures that are known for their defined structures, versatility in drug delivery and high functionality whose properties resemble with biomolecules. These nanostructured macromolecules have shown their potential abilities in entrapping and/or conjugating the high molecular weight hydrophilic/hydrophobic entities by host-guest interactions and covalent bonding (prodrug approach) respectively. Moreover, high ratio of surface groups to molecular volume has made them a promising synthetic vector for gene delivery. Owing to these properties dendrimers have fascinated the researchers in the development of new drug carriers and they have been implicated in many therapeutic and biomedical applications. Despite of their extensive applications, their use in biological systems is limited due to toxicity issues associated with them. Considering this, the present review has focused on the different strategies of their synthesis, drug delivery and targeting, gene delivery and other biomedical applications, interactions involved in formation of drug-dendrimer complex along with characterization techniques employed for their evaluation, toxicity problems and associated approaches to alleviate their inherent toxicity. PMID:25035633

  1. Analytical model study of dendrimer/DNA complexes.

    PubMed

    Qamhieh, Khawla; Nylander, Tommy; Ainalem, Marie-Louise

    2009-07-13

    The interaction between positively charged poly(amido amine) (PAMAM) dendrimers of generation 4 and DNA has been investigated for two DNA lengths; 2000 basepairs (bp; L = 680 nm) and 4331 bp (L = 1472.5 nm) using a theoretical model by Schiessel for a semiflexible polyelectrolyte and hard spheres. The model was modified to take into account that the dendrimers are to be regarded as soft spheres, that is, the radius is not constant when the DNA interact with the dendrimer. For the shorter and longer DNA, the estimated optimal wrapping length, l(opt) is ≈15.69 and ≈12.25 nm, respectively, for dendrimers that retain their original size (R(o) = 2.25 nm) upon DNA interaction. However, the values of l(opt) for the dendrimers that were considered to have a radius of (R = 0.4R(o)) 0.9 nm were 9.3 and 9.4 nm for the short and long DNA, respectively, and the effect due to the DNA length is no longer observed. For l(opt) = 10.88 nm, which is the length needed to neutralize the 64 positive charges of the G4 dendrimer, the maximum number of dendrimers per DNA (N(max)) was ≈76 for the shorter DNA, which is larger than the corresponding experimental value of 35 for 2000 bp DNA. For the longer DNA, N(max) ≈ 160, which is close to the experimental value of 140 for the 4331 bp DNA. Charge inversion of the dendrimer is only observed when they retain their size or only slightly contract upon DNA interaction. PMID:19438230

  2. Cationic carbosilane dendrimers and oligonucleotide binding: an energetic affair

    NASA Astrophysics Data System (ADS)

    Marson, D.; Laurini, E.; Posocco, P.; Fermeglia, M.; Pricl, S.

    2015-02-01

    Generation 2 cationic carbosilane dendrimers hold great promise as internalizing agents for gene therapy as they present low toxicity and retain and internalize the genetic material as an oligonucleotide or siRNA. In this work we carried out complete in silico structural and energetical characterization of the interactions of a set of G2 carbosilane dendrimers, showing different affinity towards two single strand oligonucleotide (ODN) sequences in vitro. Our simulations predict that these four dendrimers and the relevant ODN complexes are characterized by similar size and shape, and that the molecule-specific ODN binding ability can be rationalized only by considering a critical molecular design parameter: the normalized effective binding energy ΔGbind,eff/Neff, i.e. the performance of each active individual dendrimer branch directly involved in a binding interaction.Generation 2 cationic carbosilane dendrimers hold great promise as internalizing agents for gene therapy as they present low toxicity and retain and internalize the genetic material as an oligonucleotide or siRNA. In this work we carried out complete in silico structural and energetical characterization of the interactions of a set of G2 carbosilane dendrimers, showing different affinity towards two single strand oligonucleotide (ODN) sequences in vitro. Our simulations predict that these four dendrimers and the relevant ODN complexes are characterized by similar size and shape, and that the molecule-specific ODN binding ability can be rationalized only by considering a critical molecular design parameter: the normalized effective binding energy ΔGbind,eff/Neff, i.e. the performance of each active individual dendrimer branch directly involved in a binding interaction. Electronic supplementary information (ESI) available: Additional figures and tables. See DOI: 10.1039/c4nr04510f

  3. Oligothiophene dendrimers as new building blocks for optical applications.

    PubMed

    Ramakrishna, Guda; Bhaskar, Ajit; Bauerle, Peter; Goodson, Theodore

    2008-03-13

    Thiophene branched structures have been proposed as candidates for photon harvesting and electron-hole transporting materials in novel organic light emitting diodes and solar energy conversion devices. To understand the photoinduced processes in a novel thiophene dendrimer system, the excited state dynamics and nonlinear optical properties of 3D oligothiophene dendrimers have been investigated. The key point of this contribution is that we have found that with these thiophene dendrimer systems, the excitation is delocalized over a large number of thiophene units in the dendrimer and there is an ultrafast energy transfer (200-300 fs) to the longest branch of dendrimer, which can be utilized for future optical devices. In terms of nonlinear optics, it was found that a super-linear increase of two-photon absorption cross-section is observed with an increase in thiophene dendrimer generation that can be explained by the increased excitation delocalization. Generation dependent torsional energy redistribution has also been observed, which planarizes the final emissive state on a picosecond time scale. PMID:18044856

  4. Organometallic rotaxane dendrimers with fourth-generation mechanically interlocked branches.

    PubMed

    Wang, Wei; Chen, Li-Jun; Wang, Xu-Qing; Sun, Bin; Li, Xiaopeng; Zhang, Yanyan; Shi, Jiameng; Yu, Yihua; Zhang, Li; Liu, Minghua; Yang, Hai-Bo

    2015-05-01

    Mechanically interlocked molecules, such as catenanes, rotaxanes, and knots, have applications in information storage, switching devices, and chemical catalysis. Rotaxanes are dumbbell-shaped molecules that are threaded through a large ring, and the relative motion of the two components along each other can respond to external stimuli. Multiple rotaxane units can amplify responsiveness, and repetitively branched molecules--dendrimers--can serve as vehicles for assembly of many rotaxanes on single, monodisperse compounds. Here, we report the synthesis of higher-generation rotaxane dendrimers by a divergent approach. Linkages were introduced as spacer elements to reduce crowding and to facilitate rotaxane motion, even at the congested periphery of the compounds up to the fourth generation. The structures were characterized by 1D multinuclear ((1)H, (13)C, and (31)P) and 2D NMR spectroscopy, MALDI-TOF-MS, gel permeation chromatography (GPC), and microscopy-based methods including atomic force microscopy (AFM) and transmission electron microscopy (TEM). AFM and TEM studies of rotaxane dendrimers vs. model dendrimers show that the rotaxane units enhance the rigidity and reduce the tendency of these assemblies to collapse by self-folding. Surface functionalization of the dendrimers with ferrocenes as termini produced electrochemically active assemblies. The preparation of dendrimers with a well-defined topological structure, enhanced rigidity, and diverse functional groups opens previously unidentified avenues for the application of these materials in molecular electronics and materials science. PMID:25902491

  5. Density Functional Study for Homodendrimers and Amphiphilic Dendrimers.

    PubMed

    Chen, Cangyi; Tang, Ping; Qiu, Feng; Shi, An-Chang

    2016-06-23

    The conformation of homodendrimers and amphiphilic dendrimers in various solvents is studied using classical density functional theory (DFT), in which the excluded-volume effects are treated explicitly. For homodendrimers in an athermal solvent, DFT results predict a remarkable fold-back behavior for the outer generation of segments, supporting the dense-core model. A coil-to-globule transition is observed for homodendrimers in a poor solvent. The size of the dendrimers, characterized by the radius of gyration, ⟨Rg⟩, is found to follow the scaling relationship, ⟨Rg⟩ ∼ N(ν), where N is the total number of segments of the dendrimers. For amphiphilic dendrimers, DFT results show that chemical modification in the outermost generation is an effective method to drive the ends toward the periphery of the dendrimers. In particular, a conformation with a hollow interior structure could be formed for amphiphilic dendrimers with longer end spacers in a selective solvent. The resulting unimolecular micelles with a hollow core and dense shell could serve as a unique candidate for encapsulation applications, such as sustained-drug-release nanocontainers. PMID:27243274

  6. Phenylene bridged boron-nitrogen containing dendrimers.

    PubMed

    Proń, Agnieszka; Baumgarten, Martin; Müllen, Klaus

    2010-10-01

    The synthesis and characterization of novel phenylene bridged boron-nitrogen containing π-conjugated dendrimers N3B6 and N3B3, with peripheral boron atoms and 1,3,5-triaminobenzene moiety as a core, are presented. UV-vis absorption and emission measurements reveal that the optical properties of the resulting compounds can be controlled by changing the donor/acceptor ratio: a 1:1 ratio results in a more efficient charge transfer than the 1:2 ratio. This was proven by the red shift of the emission maxima and the stronger solvatochromic effect in N3B3 compared to N3B6. PMID:20822169

  7. Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery

    PubMed Central

    Lee, Sang Joon; Jeong, Young-Il; Park, Hyung-Kyu; Kang, Dae Hwan; Oh, Jong-Suk; Lee, Sam-Gyu; Lee, Hyun Chul

    2015-01-01

    Background Since cancer cells are normally over-expressed cathepsin B, we synthesized dendrimer-methoxy poly(ethylene glycol) (MPEG)-doxorubicin (DOX) conjugates using a cathepsin B-cleavable peptide for anticancer drug targeting. Methods Gly-Phe-Leu-Gly peptide was conjugated with the carboxylic acid end groups of a dendrimer, which was then conjugated with MPEG amine and doxorubicin by aid of carbodiimide chemistry (abbreviated as DendGDP). Dendrimer-MPEG-DOX conjugates without Gly-Phe-Leu-Gly peptide linkage was also synthesized for comparison (DendDP). Nanoparticles were then prepared using a dialysis procedure. Results The synthesized DendGDP was confirmed with 1H nuclear magnetic resonance spectroscopy. The DendDP and DendGDP nanoparticles had a small particle size of less than 200 nm and had a spherical morphology. DendGDP had cathepsin B-sensitive drug release properties while DendDP did not show cathepsin B sensitivity. Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles. The DendGDP nanoparticles were found to be relatively concentrated in the tumor tissue and revealed stronger fluorescence intensity than at other body sites while doxorubicin and DendDP nanoparticles showed strong fluorescence intensity in the various organs, indicating that DendGDP has cathepsin B sensitivity. Conclusion DendGDP is sensitive to cathepsin B in tumor cells and can be used as a cathepsin B-responsive drug targeting strategy. We suggest that DendGDP is a promising vehicle for cancer cell targeting. PMID:26357473

  8. Synthesis and structural dependence of the functional properties of new green fluorescent poly(propyleneamine) dendrimers

    NASA Astrophysics Data System (ADS)

    Grabchev, Ivo; Mokreva, Pavlina; Gancheva, Valeria; Terlemezyan, Levon

    2013-04-01

    Two new green fluorescence poly(propyleneamine) dendrimers from second generation, comprising eight 1,8-naphthalimide signaling units in their periphery have been synthesized and investigated. Тheir photophysical characteristics have been determined in organic solvents of different polarity. Particular attention has been paid to the spectral characteristics of the solid dendrimer films. The photostability of the dendrimers has also been studied.

  9. Synthesis and Catalytic Evaluation of Dendrimer-Encapsulated Cu Nanoparticles: An Undergraduate Experiment Exploring Catalytic Nanomaterials

    ERIC Educational Resources Information Center

    Feng, Z. Vivian; Lyon, Jennifer L.; Croley, J. Sawyer; Crooks, Richard M.; Vanden Bout, David A.; Stevenson, Keith J.

    2009-01-01

    Copper nanoparticles were synthesized using generation 4 hydroxyl-terminated (G4-OH) poly(amidoamine) (PAMAM) dendrimers as templates. The synthesis is conducted by coordinating copper ions with the interior amines of the dendrimer, followed by chemical reduction to form dendrimer-encapsulated copper nanoparticles (Cu-DEN). The catalytic…

  10. Hexameric Mn(II) Dendrimer as MRI Contrast Agent

    PubMed Central

    Zhu, Jiang; Gale, Eric M.; Atanasova, Iliyana; Rietz, Tyson A.

    2014-01-01

    A Mn(II) chelating dendrimer was prepared as a contrast agent for MRI applications. The dendrimer comprises six tyrosine-derived [Mn(EDTA)(H2O)]2− moieties coupled to a cyclotriphosphazene core. Variable temperature 17O NMR revealed a single water co-ligand per Mn(II) that undergoes fast water exchange (kex = (3.0±0.1) × 108 s−1 at 37 °C). The 37 °C per Mn(II) relaxivity ranged from 8.2 to 3.8 mM−1s−1 from 0.47 to 11.7T, and is 6-fold higher on a per molecule basis. From this field dependence a rotational correlation time was estimated as 0.45±0.02 ns. The imaging and pharmacokinetic properties of the dendrimer were compared to clinically used [Gd(DTPA)(H2O)]2− in mice at 4.7T. On first pass, the higher per ion relaxivity of the dendrimer resulted in 2-fold greater blood signal than for [Gd(DTPA)(H2O)]2−. Blood clearance was fast and elimination occurred through both the renal and hepatobiliary routes. This Mn(II) containing dendrimer represents potential alternative to Gd-based contrast agents, especially in patients with chronic kidney disease where the use of current Gd-based agents may be contraindicated. PMID:25224391

  11. Synthesis, aggregation, and chiroptical properties of chiral, amphiphilic dendrimers.

    PubMed

    Laufersweiler, M J; Rohde, J M; Chaumette, J L; Sarazin, D; Parquette, J R

    2001-09-21

    The syntheses of amphiphilic dendrimers based on 3,5-dihydroxybenzyl alcohol containing tri- or tetrafunctional chiral central cores and allyl ester termini are described. Water solubility is imparted to the dendrimers via a palladium-catalyzed deprotection of the peripheral allyl esters. This method affords complete deprotection of the carboxylate surface because, in contrast to the basic hydrolysis of methyl ester termini, the solubility of partially hydrolyzed intermediates is maintained throughout the course of the deprotection, thereby avoiding precipitation during the reaction. Chiroptical analysis indicates that the structure of the dendrimers collapses in water, resulting in an increased steric effect upon the central core that is manifested by lower optical rotatory power. However, contributions to the chiroptical properties from the dendron branch segments were not evident in water or organic media, suggesting that chiral substructures were not developing in the branch segments of the dendrimers. Multiangle light scattering studies revealed that the dendrimers experienced significant aggregation in aqueous media that decreased at higher generations. This behavior could be rationalized by a change in conformational preference from a disklike conformation at low generations to a more globular conformation at higher generations. PMID:11559197

  12. Transepithelial transport of PAMAM dendrimers across isolated intestinal tissue

    NASA Astrophysics Data System (ADS)

    Hubbard, Dallin A.

    Poly(amido amine) (PAMAM) dendrimers have shown potential to carry poorly absorbed drugs across the intestinal barrier and into systemic circulation, reducing the need for intravenous injections. Much of the in vitro transepithelial transport of PAMAM dendrimers to date has been investigated using Caco-2 monolayers which lack the microvilli morphology and enzymes present in isolated intestinal tissues. In addition, a challenge in predicting oral absorption is establishing a correlation between transport across rodent and human intestinal tissues. This dissertation focused on investigating the transepithelial transport of PAMAM dendrimers across rat and human isolated intestinal tissues. Permeability values in isolated tissues were compared with those across Caco-2 cell monolayers. Results indicate a difference in transport of PAMAM dendrimers, morphological changes and transepithelial electrical resistance between Caco-2 cell monolayers, rat and human intestinal tissue models. A relatively high transport rate across the tissues, given the macromolecular nature of PAMAM dendrimers, shows promise for use of these constructs for oral delivery in human.

  13. Organometallic rotaxane dendrimers with fourth-generation mechanically interlocked branches

    PubMed Central

    Wang, Wei; Chen, Li-Jun; Wang, Xu-Qing; Sun, Bin; Li, Xiaopeng; Zhang, Yanyan; Shi, Jiameng; Yu, Yihua; Zhang, Li; Liu, Minghua; Yang, Hai-Bo

    2015-01-01

    Mechanically interlocked molecules, such as catenanes, rotaxanes, and knots, have applications in information storage, switching devices, and chemical catalysis. Rotaxanes are dumbbell-shaped molecules that are threaded through a large ring, and the relative motion of the two components along each other can respond to external stimuli. Multiple rotaxane units can amplify responsiveness, and repetitively branched molecules—dendrimers—can serve as vehicles for assembly of many rotaxanes on single, monodisperse compounds. Here, we report the synthesis of higher-generation rotaxane dendrimers by a divergent approach. Linkages were introduced as spacer elements to reduce crowding and to facilitate rotaxane motion, even at the congested periphery of the compounds up to the fourth generation. The structures were characterized by 1D multinuclear (1H, 13C, and 31P) and 2D NMR spectroscopy, MALDI-TOF-MS, gel permeation chromatography (GPC), and microscopy-based methods including atomic force microscopy (AFM) and transmission electron microscopy (TEM). AFM and TEM studies of rotaxane dendrimers vs. model dendrimers show that the rotaxane units enhance the rigidity and reduce the tendency of these assemblies to collapse by self-folding. Surface functionalization of the dendrimers with ferrocenes as termini produced electrochemically active assemblies. The preparation of dendrimers with a well-defined topological structure, enhanced rigidity, and diverse functional groups opens previously unidentified avenues for the application of these materials in molecular electronics and materials science. PMID:25902491

  14. Click synthesis of a polyamidoamine dendrimer-based camptothecin prodrug

    PubMed Central

    Zolotarskaya, Olga Yu.; Xu, Leyuan; Valerie, Kristoffer; Yang, Hu

    2015-01-01

    In the present work we report on the click synthesis of a new camptothecin (CPT) prodrug based on anionic polyamidoamine (PAMAM) dendrimer intended for cancer therapy. We applied ‘click’ chemistry to improve polymer-drug coupling reaction efficiency. Specifically, CPT was functionalized with a spacer, 1-azido-3,6,9,12,15-pentaoxaoctadecan-18-oic acid (APO), via EDC/DMAP coupling reaction. In parallel, propargylamine (PPA) and methoxypoly(ethylene glycol) amine were conjugated to PAMAM dendrimer G4.5 in sequence using an effective coupling agent 4-(4,6-dimethoxy-(1,3,5)triazin-2-yl)-4-methyl-morpholinium chloride (DMTMM). CPT-APO was then coupled to PEGylated PAMAM dendrimer G4.5-PPA via a click reaction using copper bromide/2,2’-bipyridine/ dimethyl sulfoxide (catalyst/ligand/solvent). Human glioma cells were exposed to the CPT-conjugate to determine toxicity and cell cycle effects using WST-1 assay and flow cytometry. The CPT-conjugate displayed a dose-dependent toxicity with an IC50 of 5 μM, a 185-fold increase relative to free CPT, presumably as a result of slow release. As expected, conjugated CPT resulted in G2/M arrest and cell death while the dendrimer itself had little to no toxicity. Altogether, highly efficient click chemistry allows for the synthesis of multifunctional dendrimers for sustained drug delivery. PMID:26640689

  15. Transepithelial Transport of PAMAM Dendrimers Across Isolated Human Intestinal Tissue.

    PubMed

    Hubbard, Dallin; Enda, Michael; Bond, Tanner; Moghaddam, Seyyed Pouya Hadipour; Conarton, Josh; Scaife, Courtney; Volckmann, Eric; Ghandehari, Hamidreza

    2015-11-01

    Poly(amido amine) (PAMAM) dendrimers have shown transepithelial transport across intestinal epithelial barrier in rats and across Caco-2 cell monolayers. Caco-2 models innately lack mucous barriers, and rat isolated intestinal tissue has been shown to overestimate human permeability. This study is the first report of transport of PAMAM dendrimers across isolated human intestinal epithelium. It was observed that FITC labeled G4-NH2 and G3.5-COOH PAMAM dendrimers at 1 mM concentration do not have a statistically higher permeability compared to free FITC controls in isolated human jejunum and colonic tissues. Mannitol permeability was increased at 10 mM concentrations of G3.5-COOH and G4-NH2 dendrimers. Significant histological changes in human colonic and jejunal tissues were observed at G3.5-COOH and G4-NH2 concentrations of 10 mM implying that dose limiting toxicity may occur at similar concentrations in vivo. The permeability through human isolated intestinal tissue in this study was compared to previous rat and Caco-2 permeability data. This study implicates that PAMAM dendrimer oral drug delivery may be feasible, but it may be limited to highly potent drugs. PMID:26414679

  16. W/O microemulsions as dendrimer nanocarriers: an EPR study.

    PubMed

    Rokach, Shifra; Ottaviani, Maria Francesca; Shames, Alexander I; Nir, Ido; Aserin, Abraham; Garti, Nissim

    2012-10-18

    A complex system, based on a dendrimer solubilized in the aqueous core of water-in-oil microemulsion, may combine the advantages of both dendrimers and microemulsions to provide better control of drug release. We report for the first time the use of EPR technique to determine the effect of solubilized dendrimer on the structure of the microemulsion. The solubilized poly(propyleneimine) (PPI-G2) interacts with sodium bis(2-ethylhexyl) sulfosuccinate (AOT). EPR analysis provided information on polarity, microviscosity, and molecular order of the systems. Polarity and microviscosity increased from unloaded water-in-oil microemulsion to the system loaded with 0.2 wt % PPI-G2, but remained unchanged with higher PPI-G2 loads. The degree of order also increased with 0.2 wt % PPI-G2 with only minor additional increase with larger quantities (25 wt %) of PPI-G2. Variations in pH only slightly affected the structure of microemulsion in the absence and presence of the loaded dendrimers. Aliphatic oils with longer lipophilic chains enhanced the structural order of the microemulsion. On increasing water content, polarity and degree of order increased. PPI-G2 dendrimer in small loads is attracted by the negatively charged AOT and thus intercalates in the interface of the droplets. Yet, at higher PPI-G2 loads, the excess molecules are solubilized in the water core. PMID:22989387

  17. Promising low-toxicity of viologen-phosphorus dendrimers against embryonic mouse hippocampal cells.

    PubMed

    Lazniewska, Joanna; Janaszewska, Anna; Miłowska, Katarzyna; Caminade, Anne-Marie; Mignani, Serge; Katir, Nadia; El Kadib, Abdelkrim; Bryszewska, Maria; Majoral, Jean-Pierre; Gabryelak, Teresa; Klajnert-Maculewicz, Barbara

    2013-01-01

    A new class of viologen-phosphorus dendrimers (VPDs) has been recently shown to possess the ability to inhibit neurodegenerative processes in vitro. Nevertheless, in the Central Nervous Systems domain, there is little information on their impact on cell functions, especially on neuronal cells. In this work, we examined the influence of two VPD (VPD1 and VPD3) of zero generation (G0) on murine hippocampal cell line (named mHippoE-18). Extended analyses of cell responses to these nanomolecules comprised cytotoxicity test, reactive oxygen species (ROS) generation studies, mitochondrial membrane potential (ΔΨm) assay, cell death detection, cell morphology assessment, cell cycle studies, as well as measurements of catalase (CAT) activity and glutathione (GSH) level. The results indicate that VPD1 is more toxic than VPD3. However, these two tested dendrimers did not cause a strong cellular response, and induced a low level of apoptosis. Interestingly, VPD1 and VPD3 treatment led to a small decline in ROS level compared to untreated cells, which correlated with slightly increased catalase activity. This result indicates that the VPDs can indirectly lower the level of ROS in cells. Summarising, low-cytotoxicity on mHippoE-18 cells together with their ability to quench ROS, make the VPDs very promising nanodevices for future applications in the biomedical field as nanocarriers and/or drugs per se. PMID:24084024

  18. Preferential accumulation within tumors and in vivo imaging by functionalized luminescent dendrimer lanthanide complexes

    PubMed Central

    Alcala, Marco A.; Shade, Chad M.; Uh, Hyounsoo; Kwan, Shu Ying; Bischof, Matthias; Thompson, Zachary P.; Gogick, Kristy A.; Meier, Adam R.; Strein, Timothy G.; Bartlett, David L.; Modzelewski, Ruth A.; Lee, Yong J.; Petoud, Stéphane; Brown, Charles Komen

    2011-01-01

    We have created a dendrimer complex suitable for preferential accumulation within liver tumors and luminescence imaging by substituting thirty-two naphthalimide fluorophores on the surface of the dendrimer and incorporating eight europium cations within the branches. We demonstrate the utility and performance of this luminescent dendrimer complex to detect hepatic tumors generated via direct subcapsular implantation or via splenic injections of colorectal cancer cells (CC531) into WAG/RijHsd rats. Luminescence imaging of the tumors after injection of the dendrimer complex via hepatic arterial infusion revealed that the dendrimer complex can preferentially accumulate within liver tumors. Further investigation indicated that dendrimer luminescence in hepatic tumors persisted in vivo. Due to the incorporation of lanthanide cations, this luminescence agent presents a strong resistance against photobleaching. These studies show the dendrimer complex has great potential to serve as an innovative accumulation and imaging agent for the detection of metastatic tumors in our rat hepatic model. PMID:21925728

  19. Generation-dependent effect of PAMAM dendrimers on human insulin fibrillation and thermal stability.

    PubMed

    Nowacka, Olga; Milowska, Katarzyna; Belica-Pacha, Sylwia; Palecz, Bartlomiej; Šipošová, Katarina; Gazova, Zuzana; Bryszewska, Maria

    2016-01-01

    We have studied the effect of polyamidoamine (PAMAM) dendrimers of various generations on the thermal stability and fibrillation of human insulin. Thermostability of human insulin used differential scanning calorimetry (DSC), which showed two phase-transitions for insulin at 60 and 82°C. After adding dendrimers at 0.6 μmol/l, the first peaks disappeared and the second peaks were higher. We posited that, in the presence of dendrimers, the dimers in the solution were transformed into hexamers. The effect of dendrimers on insulin fibrillation was monitored by measuring ThT fluorescence, and visualization of insulin fibrils by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The effect of PAMAM dendrimers on insulin fibrillation was strongly dependent on the dendrimers generation and dendrimer:protein ratio. PMID:26598047

  20. Reduction of percutaneous absorption of toxic chemicals by dendrimers.

    PubMed

    Moghimi, Hamid R; Varshochian, Reyhaneh; Kobarfard, Farzad; Erfan, Mohammad

    2010-03-01

    Polyamidoamine (PAMAM) dendrimer, a reactive nanoparticle, was investigated as a potential protectant against percutaneous absorption of chemicals. Permeation of furfural (model toxicant) through rat skin from a 1-mg/mL solution was studied in the absence and presence of PAMAM dendrimer, which was applied either as 1, 4, and 6 mg/mL in furfural solution (cotreatment) or 2.2 mg/cm(2) deposited on skin surface before furfural application (pretreatment). Furfural flux, about 70 microg/cm(2)/h in untreated samples, was decreased by PAMAM dendrimer in a concentration-dependent manner up to 12 times with the cotreatment methods and 2.3 times with the pretreatment method, indicating PAMAM's protective ability against cutaneous toxicants. PMID:19995245

  1. Enhanced bioactivity of internally functionalized cationic dendrimers with PEG cores

    PubMed Central

    Albertazzi, Lorenzo; Mickler, Frauke M.; Pavan, Giovanni M.; Salomone, Fabrizio; Bardi, Giuseppe; Panniello, Mariangela; Amir, Elizabeth; Kang, Taegon; Killops, Kato L.; Bräuchle, Christoph; Amir, Roey J.; Hawker, Craig J.

    2012-01-01

    Hybrid dendritic-linear block copolymers based on a 4-arm polyethylene glycol (PEG) core were synthesized using an accelerated AB2/CD2 dendritic growth approach through orthogonal amine/epoxy and thiol-yne chemistries. The biological activity of these 4-arm and the corresponding 2-arm hybrid dendrimers revealed an enhanced, dendritic effect with an exponential increase in cell internalization concomitant with increasing amine end-groups and low cytotoxicity. Furthermore, the ability of these hybrid dendrimers to induce endosomal escape combined with their facile and efficient synthesis makes them attractive platforms for gene transfection. The 4-arm-based dendrimer showed significantly improved DNA binding and gene transfection capabilities in comparison with the 2-arm derivative. These results combined with the MD simulation indicate a significant effect of both the topology of the PEG core and the multivalency of these hybrid macromolecules, on their DNA binding and delivery capablities. PMID:23140570

  2. On Topological Indices of Certain Families of Nanostar Dendrimers.

    PubMed

    Husin, Mohamad Nazri; Hasni, Roslan; Arif, Nabeel Ezzulddin; Imran, Muhammad

    2016-01-01

    A topological index of graph G is a numerical parameter related to G which characterizes its molecular topology and is usually graph invariant. In the field of quantitative structure-activity (QSAR)/quantitative structure-activity structure-property (QSPR) research, theoretical properties of the chemical compounds and their molecular topological indices such as the Randić connectivity index, atom-bond connectivity (ABC) index and geometric-arithmetic (GA) index are used to predict the bioactivity of different chemical compounds. A dendrimer is an artificially manufactured or synthesized molecule built up from the branched units called monomers. In this paper, the fourth version of ABC index and the fifth version of GA index of certain families of nanostar dendrimers are investigated. We derive the analytical closed formulas for these families of nanostar dendrimers. The obtained results can be of use in molecular data mining, particularly in researching the uniqueness of tested (hyper-branched) molecular graphs. PMID:27347913

  3. Recent advances in click chemistry applied to dendrimer synthesis.

    PubMed

    Arseneault, Mathieu; Wafer, Caroline; Morin, Jean-François

    2015-01-01

    Dendrimers are monodisperse polymers grown in a fractal manner from a central point. They are poised to become the cornerstone of nanoscale devices in several fields, ranging from biomedicine to light-harvesting. Technical difficulties in obtaining these molecules has slowed their transfer from academia to industry. In 2001, the arrival of the "click chemistry" concept gave the field a major boost. The flagship reaction, a modified Hüisgen cycloaddition, allowed researchers greater freedom in designing and building dendrimers. In the last five years, advances in click chemistry saw a wider use of other click reactions and a notable increase in the complexity of the reported structures. This review covers key developments in the click chemistry field applied to dendrimer synthesis from 2010 to 2015. Even though this is an expert review, basic notions and references have been included to help newcomers to the field. PMID:26007183

  4. Two Dimensional Aggregation Behaviors of Quinoxaline Dendrimers.

    PubMed

    Choi, Soyoung; Lee, Hoik; Kim, Hwan Kyu; Lee, Sang Uck; Sohn, Daewon

    2015-02-01

    This study focuses on the molecular behavior of two dendrimers containing a hydrophilic core group (carboxyl group) and hydrophobic branches (quinoxaline and methoxyphenyl groups), 2,3-bis(4-(2,3- bis(4-methoxyphenyl)quinoxalin-6-yloxy)phenyl)quinoxaline-6-carb-oxylic acid (G2) and 2,3-bis(4-(2,3-bis(4-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yloxy)phe-nyl)quinoxalin-6-y-oxy)phenyl) quin oxaline-6-carboxylic acid (G3) at the air-water interface. To understand the mechanism of the self-assembly of these molecules, we measured the surface pressure-area (III-A) isotherm and investigated the surface morphology of Langmuir-Blodgett films transferred onto hydrophilic silicon wafers using atomic force microscopy (AFM). Upon compression, G2 molecules stand up and steadily make close-packed monolayer whereas G3 molecules form circular domains and gradually make aggregates of domains. These results were confirmed by the X-ray Reflectivity (XRR) profiles of G2 and G3 monolayers transferred onto silicon substrates. PMID:26353682

  5. Elastic Light Tunable Tissue Adhesive Dendrimers.

    PubMed

    Feng, Gao; Djordjevic, Ivan; Mogal, Vishal; O'Rorke, Richard; Pokholenko, Oleksandr; Steele, Terry W J

    2016-07-01

    Development of bioadhesive formulations for tissue fixation remains a challenge. The major drawbacks of available bioadhesives are low adhesion strength, toxic byproducts, and complexity of application onto affected tissues. In order to address these problems, this study has developed a hydrogel bioadhesive system based on poly amido amine (PAMAM) dendrimer, grafted (conjugated) with UV-sensitive, 4-[3-(trifluoromethyl)-3H-diazirin-3-yl] benzyl bromide (PAMAM-g-diazirine). This particular diazirine molecule can be grafted to the surface amine groups of PAMAM in a one-pot synthesis. Diazirine functionalities are carbene precursors that form covalent crosslinks with hydrated tissues after low-power UV activation without necessity of free-radical initiators. The rheological properties and adhesion strength to ex vivo tissues are highly controllable depending on diazirine grafting, hydrogel concentration, and UV dose intensity fitting variety types of tissues. Covalent bonds at the tissue/bioadhesive interface provide robust adhesive and mechanical strength in a highly hydrated environment. The free flowing hydrogel conversion to elastic adhesive after UV activation allows intimate contact with the ex vivo swine tissue surfaces with low in vitro cytotoxicity observed, making it a promising bioadhesive formulation toward clinical applications. PMID:27061355

  6. Exciton localization-delocalization transition in an extended dendrimer

    SciTech Connect

    Pouthier, Vincent

    2013-12-21

    Exciton-mediated quantum state transfer between the periphery and the core of an extended dendrimer is investigated numerically. By mapping the dynamics onto that of a linear chain, it is shown that a localization-delocalization transition arises for a critical value of the generation number G{sub c} ≈ 5. This transition originates in the quantum interferences experienced by the excitonic wave due to the multiple scatterings that arise each time the wave tunnels from one generation to another. These results suggest that only small-size dendrimers could be used for designing an efficient quantum communication protocol.

  7. Disorder-enhanced exciton delocalization in an extended dendrimer.

    PubMed

    Pouthier, Vincent

    2014-08-01

    The exciton dynamics in a disordered extended dendrimer is investigated numerically. Because a homogeneous dendrimer exhibits few highly degenerate energy levels, a dynamical localization arises when the exciton is initially located on the periphery. However, it is shown that the disorder lifts the degeneracy and favors a delocalization-relocalization transition. Weak disorder enhances the delocalized nature of the exciton and improves any quantum communication, whereas strong disorder prevents the exciton from propagating in accordance with the well-known Anderson theory. PMID:25215792

  8. Coarse-grained simulations of poly(propylene imine) dendrimers in solution.

    PubMed

    Smeijers, A F; Markvoort, A J; Pieterse, K; Hilbers, P A J

    2016-02-21

    The behavior of poly(propylene imine) (PPI) dendrimers in concentrated solutions has been investigated using molecular dynamics simulations containing up to a thousand PPI dendrimers of generation 4 or 5 in explicit water. To deal with large system sizes and time scales required to study the solutions over a wide range of dendrimer concentrations, a previously published coarse-grained model was applied. Simulation results on the radius of gyration, structure factor, intermolecular spacing, dendrimer interpenetration, and water penetration are compared with available experimental data, providing a clear concentration dependent molecular picture of PPI dendrimers. It is shown that with increasing concentration the dendrimer volume diminishes accompanied by a reduction of internalized water, ultimately resulting in solvent filled cavities between stacked dendrimers. Concurrently dendrimer interpenetration increases only slightly, leaving each dendrimer a separate entity also at high concentrations. Moreover, we compare apparent structure factors, as calculated in experimental studies relying on the decoupling approximation and the constant atomic form factor assumption, with directly computed structure factors. We demonstrate that these already diverge at rather low concentrations, not because of small changes in form factor, but rather because the decoupling approximation fails as monomer positions of separate dendrimers become correlated at concentrations well below the overlap concentration. PMID:26896998

  9. Zwitterionic Chitosan-Polyamidoamine Dendrimer Complex Nanoparticles as a pH-Sensitive Drug Carrier

    PubMed Central

    Liu, Karen C.; Yeo, Yoon

    2013-01-01

    Polyamidoamine (PAMAM) dendrimers have been widely explored as carriers of therapeutics and imaging agents. However, amine-terminated PAMAM dendrimers is rarely utilized in systemic applications due to its cytotoxicity and risk of opsonization, caused by its cationic charges. Such undesirable effects may be mitigated by shielding the PAMAM dendrimer surface with polymers that reduce the charges. However, this shielding may also interfere with PAMAM dendrimers’ ability to interact with target cells, thus reducing cellular uptake and overall efficacy of the delivery system. Therefore, we propose to use zwitterionic chitosan (ZWC), a new chitosan derivative, which has a unique pH-sensitive charge profile, as an alternative biomaterial to modify the cationic surface of PAMAM dendrimers. Stable electrostatic complex of ZWC and PAMAM dendrimers was formed at pH 7.4, where the PAMAM dendrimer surface was covered with ZWC, as demonstrated by fluorescence spectroscopy and transmission electron microscopy. The presence of ZWC coating protected red blood cells and fibroblast cells from hemolytic and cytotoxic activities of PAMAM dendrimers, respectively. Confocal microscopy showed that the protective effect of ZWC disappeared at low pH as the complex dissociated due to the charge conversion of ZWC, allowing PAMAM dendrimers to enter cells. These results demonstrate that ZWC is able to provide a surface coverage of PAMAM dendrimers in a pH-dependent manner and, thus, enhance the utility of PAMAM dendrimers as a drug carrier to solid tumors with acidifying microenvironment. PMID:23510114

  10. Fabrication of dendrimer-releasing lipidic nanoassembly for cancer drug delivery.

    PubMed

    Sun, Qihang; Ma, Xinpeng; Zhang, Bo; Zhou, Zhuxian; Jin, Erlei; Shen, Youqing; Van Kirk, Edward A; Murdoch, William J; Radosz, Maciej; Sun, Weilin

    2016-06-24

    An inherent dilemma in the use of nanomedicines for cancer drug delivery is their limited penetration into tumors due to their large size. We have demonstrated that dendrimer/lipid nanoassemblies can solve this problem by means of tumor-triggered disassembly and the release of small (several nanometers) dendrimers to facilitate tumor penetration. Herein, we report a general strategy for the fabrication of nanoassemblies from hydrophobic and hydrophilic dendrimers with phospholipids. Hydrophobic dendrimers could assemble with lipids via hydrophobic interactions, whereas hydrophilic dendrimers could only assemble with lipids in the presence of anionic surfactants via both electrostatic and hydrophobic interactions. The nanoassemblies of hydrophobic dendrimers/lipids were found to be capable of stripping off their lipid layers via fusion with the cell membrane and then intracellular or extracellular release of dendrimers, whereas the nanoassemblies of hydrophilic dendrimers/lipids were internalized via endocytosis and then released their dendrimers inside the cells. Therefore, these dendrimer/lipid nanoassemblies could be used for the delivery of different cancer drugs. PMID:27087640

  11. Effect of electron donating groups on polyphenol-based antioxidant dendrimers.

    PubMed

    Lee, Choon Young; Nanah, Cyprien N; Held, Rich A; Clark, Amanda R; Huynh, Uyen G T; Maraskine, Marina C; Uzarski, Rebecca L; McCracken, John; Sharma, Ajit

    2015-04-01

    Numerous studies have reported the beneficial effects of antioxidants in human diseases. Among their biological effects, a majority of antioxidants scavenge reactive radicals in the body, thereby reducing oxidative stress that is associated with the pathogenesis of many diseases. Antioxidant dendrimers are a new class of potent antioxidant compounds reported recently. In this study, six polyphenol-based antioxidant dendrimers with or without electron donating groups (methoxy group) were synthesized in order to elucidate the influence of electron donating groups (EDG) on their antioxidant activities. Syringaldehyde (2 ortho methoxy groups), vanillin (1 ortho methoxy group), and 4-hydroxybenzaldehyde (0 methoxy group) were derivatized with propargylamine to form building blocks for the dendrimers. All the six dendrimers contain polyether cores, which were synthesized by attaching pentaerythritol and methyl α-d-glucopyranoside to in-house prepared spacer units. To prepare generation 1 antioxidant dendrimers, microwave energy and granulated metallic copper catalyst were used to link the cores and building blocks together via alkyne-azide 1,3-cycloaddition click chemistry. These reaction conditions resulted in high yields of the target dendrimers that were free from copper contamination. Based on DPPH antioxidant assay, antioxidant dendrimers decorated with syringaldehyde and vanillin exhibited over 70- and 170-fold increase in antioxidant activity compared to syringaldehyde and vanillin, respectively. The antioxidant activity of dendrimers increased with increasing number of EDG groups. Similar results were obtained when the dendrimers were used to protect DNA and human LDL against organic carbon and nitrogen-based free radicals. In addition, the antioxidant dendrimers did not show any pro-oxidant activity on DNA in the presence of physiological amounts of copper. Although the dendrimers showed potent antioxidant activities against carbon and nitrogen free radicals

  12. Effect of Electron Donating Groups on Polyphenol-based Antioxidant Dendrimers

    PubMed Central

    Lee, Choon Young; Nanah, Cyprien; Held, Rich; Clark, Amanda; Huynh, Uyen; Maraskine, Marina C.; Uzarski, Rebecca L.; McCracken, John; Sharma, Ajit

    2015-01-01

    Numerous studies have reported the beneficial effects of antioxidants in human diseases. Among their biological effects, a majority of antioxidants scavenge reactive radicals in the body, thereby reducing oxidative stress that is associated with the pathogenesis of many diseases. Antioxidant dendrimers are a new class of potent antioxidant compounds reported recently. In this study, six polyphenol-based antioxidant dendrimers with or without electron donating groups (methoxy group) were synthesized in order to elucidate the influence of electron donating groups (EDG) on their antioxidant activities. Syringaldehyde (2 ortho methoxy groups), vanillin (1 ortho methoxy group), and 4-hydroxybenzaldehyde (0 methoxy group) were derivatized with propargylamine to form building blocks for the dendrimers. All the six dendrimers contain polyether cores, which were synthesized by attaching pentaerythritol and methyl α-D-glucopyranoside to in-house prepared spacer units. To prepare generation 1 antioxidant dendrimers, microwave energy and granulated metallic copper catalyst were used to link the cores and building blocks together via alkyne-azide 1,3-cycloaddition click chemistry. These reaction conditions resulted in high yields of the target dendrimers that were free from copper contamination. Based on DPPH antioxidant assay, antioxidant dendrimers decorated with syringaldehyde and vanillin exhibited over 70- and 170-fold increase in antioxidant activity compared to syringaldehyde and vanillin, respectively. The antioxidant activity of dendrimers increased with increasing number of EDG groups. Similar results were obtained when the dendrimers were used to protect DNA and human LDL against organic carbon and nitrogen-based free radicals. In addition, the antioxidant dendrimers did not show any pro-oxidant activity on DNA in the presence of physiological amounts of copper. Although the dendrimers showed potent antioxidant activities against carbon and nitrogen free radicals

  13. Modular peripheral functionalization of thiophene dendrons and dendrimers.

    PubMed

    Deng, Suxiang; Sriwichai, Saengrawee; Taranekar, Prasad; Krueger, Greg; Mays, Jimmy W; Advincula, Rigoberto C

    2011-08-21

    A series of thiophene dendrons and dendrimers with peripheral functional groups were designed and synthesized. Two methodologies using thiophene dendrons and dendrons as synthetic building blocks, namely, (1) periphery functionalization; (2) a combination of focal and periphery functionalization have been demonstrated. PMID:21735024

  14. Dendrimers and methods of preparing same through proportionate branching

    SciTech Connect

    Yu, Yihua; Yue, Xuyi

    2015-09-15

    The present invention provides for monodispersed dendrimers having a core, branches and periphery ends, wherein the number of branches increases exponentially from the core to the periphery end and the length of the branches increases exponentially from the periphery end to the core, thereby providing for attachment of chemical species at the periphery ends without exhibiting steric hindrance.

  15. Designing Dendrimers to Offer Micelle-Type Nanocontainers

    ERIC Educational Resources Information Center

    King, Angela G.

    2005-01-01

    The properties of a dendrimer with hydrophobic and hydrophilic substituents on an orthogonal plane is synthesized and studied. The resulting polymer contains one of the substituents in its concave interior and the other at the convex surface and the design promotes micelle-like behavior in polar solvent and inverted micelle arrangement in…

  16. HIV-1 antiviral behavior of anionic PPI metallo-dendrimers with EDA core.

    PubMed

    García-Gallego, Sandra; Díaz, Laura; Jiménez, José Luis; Gómez, Rafael; de la Mata, F Javier; Muñoz-Fernández, M Ángeles

    2015-06-15

    The development of novel strategies to prevent HIV-1 infection is of outstanding relevance. Metal complexes of Cu(2+), Ni(2+), Co(2+) and Zn(2+) derived from sulfonated and carboxylated poly(propylene imine) dendrimers with ethylenediamine core were evaluated as tunable antiviral agents against HIV-1. After demonstrating their biocompatibility, specific trends in the antiviral properties were found, related to both the dendritic scaffold (peripheral group, generation) and the bound metal ions (sort, amount). In HEC-1A and VK-2 cell lines, as model of the first barrier against HIV-1 infection, a high preventive inhibitory action was found, which also avoided virus internalization inside cells and inhibited both CCR5 and CXCR4 HIV-1 strains. In peripheral blood mononuclear cells (PBMC), as model of the second barrier, a dual preventive and therapeutic behavior was observed. A rational design of such metallodendrimers opens new avenues for the production of versatile and efficient treatments against HIV-1 infection. PMID:26005027

  17. A Foldamer-Dendrimer Conjugate Neutralizes Synaptotoxic β-Amyloid Oligomers

    PubMed Central

    Fülöp, Lívia; Mándity, István M.; Juhász, Gábor; Szegedi, Viktor; Hetényi, Anasztázia; Wéber, Edit; Bozsó, Zsolt; Simon, Dóra; Benkő, Mária; Király, Zoltán; Martinek, Tamás A.

    2012-01-01

    Background and Aims Unnatural self-organizing biomimetic polymers (foldamers) emerged as promising materials for biomolecule recognition and inhibition. Our goal was to construct multivalent foldamer-dendrimer conjugates which wrap the synaptotoxic β-amyloid (Aβ) oligomers with high affinity through their helical foldamer tentacles. Oligomeric Aβ species play pivotal role in Alzheimer's disease, therefore recognition and direct inhibition of this undruggable target is a great current challenge. Methods and Results Short helical β-peptide foldamers with designed secondary structures and side chain chemistry patterns were applied as potential recognition segments and their binding to the target was tested with NMR methods (saturation transfer difference and transferred-nuclear Overhauser effect). Helices exhibiting binding in the µM region were coupled to a tetravalent G0-PAMAM dendrimer. In vitro biophysical (isothermal titration calorimetry, dynamic light scattering, transmission electron microscopy and size-exclusion chromatography) and biochemical tests (ELISA and dot blot) indicated the tight binding between the foldamer conjugates and the Aβ oligomers. Moreover, a selective low nM interaction with the low molecular weight fraction of the Aβ oligomers was found. Ex vivo electrophysiological experiments revealed that the new material rescues the long-term potentiation from the toxic Aβ oligomers in mouse hippocampal slices at submicromolar concentration. Conclusions The combination of the foldamer methodology, the fragment-based approach and the multivalent design offers a pathway to unnatural protein mimetics that are capable of specific molecular recognition, and has already resulted in an inhibitor for an extremely difficult target. PMID:22859942

  18. Development of water-soluble polyanionic carbosilane dendrimers as novel and highly potent topical anti-HIV-2 microbicides.

    PubMed

    Briz, Verónica; Sepúlveda-Crespo, Daniel; Diniz, Ana Rita; Borrego, Pedro; Rodes, Berta; de la Mata, Francisco Javier; Gómez, Rafael; Taveira, Nuno; Muñoz-Fernández, Ma Ángeles

    2015-09-21

    The development of topical microbicide formulations for vaginal delivery to prevent HIV-2 sexual transmission is urgently needed. Second- and third-generation polyanionic carbosilane dendrimers with a silicon atom core and 16 sulfonate (G2-S16), napthylsulfonate (G2-NS16) and sulphate (G3-Sh16) end-groups have shown potent and broad-spectrum anti-HIV-1 activity. However, their antiviral activity against HIV-2 and mode of action have not been probed. Cytotoxicity, anti-HIV-2, anti-sperm and antimicrobial activities of dendrimers were determined. Analysis of combined effects of triple combinations with tenofovir and raltegravir was performed by using CalcuSyn software. We also assessed the mode of antiviral action on the inhibition of HIV-2 infection through a panel of different in vitro antiviral assays: attachment, internalization in PBMCs, inactivation and cell-based fusion. Vaginal irritation and histological analysis in female BALB/c mice were evaluated. Our results suggest that G2-S16, G2-NS16 and G3-Sh16 exert anti-HIV-2 activity at an early stage of viral replication inactivating the virus, inhibiting cell-to-cell HIV-2 transmission, and blocking the binding of gp120 to CD4, and the HIV-2 entry. Triple combinations with tenofovir and raltegravir increased the anti-HIV-2 activity, consistent with synergistic interactions (CIwt: 0.33-0.66). No vaginal irritation was detected in BALB/c mice after two consecutive applications for 2 days with 3% G2-S16. Our results have clearly shown that G2-S16, G2-NS16 and G3-Sh16 have high potency against HIV-2 infection. The modes of action confirm their multifactorial and non-specific ability, suggesting that these dendrimers deserve further studies as potential candidate microbicides to prevent vaginal/rectal HIV-1/HIV-2 transmission in humans. PMID:26274532

  19. Development of water-soluble polyanionic carbosilane dendrimers as novel and highly potent topical anti-HIV-2 microbicides

    NASA Astrophysics Data System (ADS)

    Briz, Verónica; Sepúlveda-Crespo, Daniel; Diniz, Ana Rita; Borrego, Pedro; Rodes, Berta; de La Mata, Francisco Javier; Gómez, Rafael; Taveira, Nuno; Muñoz-Fernández, Mª Ángeles

    2015-08-01

    The development of topical microbicide formulations for vaginal delivery to prevent HIV-2 sexual transmission is urgently needed. Second- and third-generation polyanionic carbosilane dendrimers with a silicon atom core and 16 sulfonate (G2-S16), napthylsulfonate (G2-NS16) and sulphate (G3-Sh16) end-groups have shown potent and broad-spectrum anti-HIV-1 activity. However, their antiviral activity against HIV-2 and mode of action have not been probed. Cytotoxicity, anti-HIV-2, anti-sperm and antimicrobial activities of dendrimers were determined. Analysis of combined effects of triple combinations with tenofovir and raltegravir was performed by using CalcuSyn software. We also assessed the mode of antiviral action on the inhibition of HIV-2 infection through a panel of different in vitro antiviral assays: attachment, internalization in PBMCs, inactivation and cell-based fusion. Vaginal irritation and histological analysis in female BALB/c mice were evaluated. Our results suggest that G2-S16, G2-NS16 and G3-Sh16 exert anti-HIV-2 activity at an early stage of viral replication inactivating the virus, inhibiting cell-to-cell HIV-2 transmission, and blocking the binding of gp120 to CD4, and the HIV-2 entry. Triple combinations with tenofovir and raltegravir increased the anti-HIV-2 activity, consistent with synergistic interactions (CIwt: 0.33-0.66). No vaginal irritation was detected in BALB/c mice after two consecutive applications for 2 days with 3% G2-S16. Our results have clearly shown that G2-S16, G2-NS16 and G3-Sh16 have high potency against HIV-2 infection. The modes of action confirm their multifactorial and non-specific ability, suggesting that these dendrimers deserve further studies as potential candidate microbicides to prevent vaginal/rectal HIV-1/HIV-2 transmission in humans.

  20. Multivalency in the gas phase: H/D exchange reactions unravel the dynamic "rock 'n' roll" motion in dendrimer-dendrimer complexes.

    PubMed

    Qi, Zhenhui; Schlaich, Christoph; Schalley, Christoph A

    2013-10-25

    Noncovalent dendrimer-dendrimer complexes were successfully ionized by electrospray ionization of partly protonated amino-terminated polypropylene amine (POPAM) and POPAM dendrimers fully functionalized with benzo[21]crown-7 on all branches. Hydrogen/deuterium exchange (HDX) experiments conducted on dendrimer-dendrimer complexes in the high vacuum of a mass spectrometer give rise to a complete exchange of all labile NH hydrogen atoms. As crown ethers represent noncovalent protective groups against HDX reactions on the ammonium group to which they are coordinated, this result provides evidence for a very dynamic binding situation: each crown is mobile enough to move from one ammonium binding site to another. Schematically, one might compare this motion with two rock 'n' roll dancers that swirl around each other without completely losing all contact at any time. Although the multivalent attachment certainly increases the overall affinity, the "microdynamics" of individual site binding and dissociation remains fast. PMID:24105808

  1. Molecular dynamics study of charged dendrimers in salt-free solution: Effect of counterions

    NASA Astrophysics Data System (ADS)

    Gurtovenko, Andrey A.; Lyulin, Sergey V.; Karttunen, Mikko; Vattulainen, Ilpo

    2006-03-01

    Polyamidoamine dendrimers, being protonated under physiological conditions, represent a promising class of nonviral, nanosized vectors for drug and gene delivery. We performed extensive molecular dynamics simulations of a generic model dendrimer in a salt-free solution with dendrimer's terminal beads positively charged. Solvent molecules as well as counterions were explicitly included as interacting beads. We find that the size of the charged dendrimer depends nonmonotonically on the strength of electrostatic interactions demonstrating a maximum when the Bjerrum length equals the diameter of a bead. Many other structural and dynamic characteristics of charged dendrimers are also found to follow this pattern. We address such a behavior to the interplay between repulsive interactions of the charged terminal beads and their attractive interactions with oppositely charged counterions. The former favors swelling at small Bjerrum lengths and the latter promotes counterion condensation. Thus, counterions can have a dramatic effect on the structure and dynamics of charged dendrimers and, under certain conditions, cannot be treated implicitly.

  2. pH controlled gating of toxic protein pores by dendrimers

    NASA Astrophysics Data System (ADS)

    Mandal, Taraknath; Kanchi, Subbarao; Ayappa, K. G.; Maiti, Prabal K.

    2016-06-01

    Designing effective nanoscale blockers for membrane inserted pores formed by pore forming toxins, which are expressed by several virulent bacterial strains, on a target cell membrane is a challenging and active area of research. Here we demonstrate that PAMAM dendrimers can act as effective pH controlled gating devices once the pore has been formed. We have used fully atomistic molecular dynamics (MD) simulations to characterize the cytolysin A (ClyA) protein pores modified with fifth generation (G5) PAMAM dendrimers. Our results show that the PAMAM dendrimer, in either its protonated (P) or non-protonated (NP) states can spontaneously enter the protein lumen. Protonated dendrimers interact strongly with the negatively charged protein pore lumen. As a consequence, P dendrimers assume a more expanded configuration efficiently blocking the pore when compared with the more compact configuration adopted by the neutral NP dendrimers creating a greater void space for the passage of water and ions. To quantify the effective blockage of the protein pore, we have calculated the pore conductance as well as the residence times by applying a weak force on the ions/water. Ionic currents are reduced by 91% for the P dendrimers and 31% for the NP dendrimers. The preferential binding of Cl- counter ions to the P dendrimer creates a zone of high Cl- concentration in the vicinity of the internalized dendrimer and a high concentration of K+ ions in the transmembrane region of the pore lumen. In addition to steric effects, this induced charge segregation for the P dendrimer effectively blocks ionic transport through the pore. Our investigation shows that the bio-compatible PAMAM dendrimers can potentially be used to develop therapeutic protocols based on the pH sensitive gating of pores formed by pore forming toxins to mitigate bacterial infections.Designing effective nanoscale blockers for membrane inserted pores formed by pore forming toxins, which are expressed by several virulent

  3. Synthesis and self-assembly of PAMAM/PAA Janus dendrimers

    NASA Astrophysics Data System (ADS)

    Gao, Chunmei; Liu, Mingzhu; Lü, Shaoyu; Zhang, Xinjie; Chen, Yuanmou

    2014-03-01

    Janus dendrimers have two differently functionalized segments which are located on opposite sides. They have many excellent properties and broad application prospects. In this study, poly(amido amine)/poly(acrylic acid) (PAMAM/PAA) Janus dendrimers were prepared by click chemistry. One of the first steps taken was the synthesis of N-Boc-G3.0 PAMAM dendrimers with primary amine groups at the periphery. Second, by amide coupling between propargylic acid and N-Boc-G3.0 PAMAM, PAMAM dendrimers with alkyne were successfully synthesized. After being dissolved in aqueous solutions with different pH, Janus dendrimers spontaneously form flowerlike micellar, Janus particles, and spherical micelles due to primary amino, tertiary amino, and carboxyl groups in the dendrimers. This self-assembly behavior depending on pH changes has a number of potential applications in the field of materials.

  4. Visual observation and characterization of fluorescent poly(amido amine) dendrimer in film state.

    PubMed

    Saravanan, Govindachetty; Imae, Toyoko

    2011-06-01

    The fluorescent property of PAMAM dendrimers were examined at film state rather than in solution. The O2-treated PAMAM dendrimer displayed strong blue fluorescence due to its conservation of luminance in the film state and diminished its intensity with degas. The fluorescent property of PAMAM dendrimers was utilized as a fluorescent probe on functional patterned substrates for visual observation by a fluorescence microscope. G4 and G4.5 PAMAM dendrimers having peripheral groups of functional amine and carboxylate, respectively, were adsorbed selectively by electrostatic interactions on patterned carboxylic acid and amine terminated surfaces, respectively resulting in strong fluorescent patterns. This suggests the possible application of fluorescent PAMAM dendrimers as a fluorophor for the visualizable reactions. It was confirmed from an X-ray photoelectron spectroscopy that O2 molecules interact with tertiary amine moiety in PAMAM dendrimers but not amide group. These results give us an important support for the principle of fluorescence phenomenon. PMID:21770112

  5. Click dendrimers and triazole-related aspects: catalysts, mechanism, synthesis, and functions. A bridge between dendritic architectures and nanomaterials.

    PubMed

    Astruc, Didier; Liang, Liyuan; Rapakousiou, Amalia; Ruiz, Jaime

    2012-04-17

    One of the primary recent improvements in molecular chemistry is the now decade-old concept of click chemistry. Typically performed as copper-catalyzed azide-alkyne (CuAAC) Huisgen-type 1,3-cycloadditions, this reaction has many applications in biomedicine and materials science. The application of this chemistry in dendrimer synthesis beyond the zeroth generation and in nanoparticle functionalization requires stoichiometric use of the most common click catalyst, CuSO(4)·5H(2)O with sodium ascorbate. Efforts to develop milder reaction conditions for these substrates have led to the design of polydentate nitrogen ligands. Along these lines, we have described a new, efficient, practical, and easy-to-synthesize catalytic complex, [Cu(I)(hexabenzyltren)]Br, 1 [tren = tris(2-aminoethyl)amine], for the synthesis of relatively large dendrimers and functional gold nanoparticles (AuNPs). This efficient catalyst can be used alone in 0.1% mol amounts for nondendritic click reactions or with the sodium-ascorbate additive, which inhibits aerobic catalyst oxidation. Alternatively, catalytic quantities of the air-stable compounds hexabenzyltren and CuBr added to the click reaction medium can provide analogously satisfactory results. Based on this catalyst as a core, we have also designed and synthesized analogous Cu(I)-centered dendritic catalysts that are much less air-sensitive than 1 and are soluble in organic solvents or in water (depending on the nature of the terminal groups). These multivalent catalysts facilitate efficient click chemistry and exert positive dendritic effects that mimic enzyme activity. We propose a monometallic CuAAC click mechanism for this process. Although the primary use of click chemistry with dendrimers has been to decorate dendrimers with a large number of molecules for medicinal or materials purposes, we are specifically interested in the formation of intradendritic [1,2,3]-triazole heterocycles that coordinate to transition-metal ions via their

  6. pH controlled gating of toxic protein pores by dendrimers.

    PubMed

    Mandal, Taraknath; Kanchi, Subbarao; Ayappa, K G; Maiti, Prabal K

    2016-07-14

    Designing effective nanoscale blockers for membrane inserted pores formed by pore forming toxins, which are expressed by several virulent bacterial strains, on a target cell membrane is a challenging and active area of research. Here we demonstrate that PAMAM dendrimers can act as effective pH controlled gating devices once the pore has been formed. We have used fully atomistic molecular dynamics (MD) simulations to characterize the cytolysin A (ClyA) protein pores modified with fifth generation (G5) PAMAM dendrimers. Our results show that the PAMAM dendrimer, in either its protonated (P) or non-protonated (NP) states can spontaneously enter the protein lumen. Protonated dendrimers interact strongly with the negatively charged protein pore lumen. As a consequence, P dendrimers assume a more expanded configuration efficiently blocking the pore when compared with the more compact configuration adopted by the neutral NP dendrimers creating a greater void space for the passage of water and ions. To quantify the effective blockage of the protein pore, we have calculated the pore conductance as well as the residence times by applying a weak force on the ions/water. Ionic currents are reduced by 91% for the P dendrimers and 31% for the NP dendrimers. The preferential binding of Cl(-) counter ions to the P dendrimer creates a zone of high Cl(-) concentration in the vicinity of the internalized dendrimer and a high concentration of K(+) ions in the transmembrane region of the pore lumen. In addition to steric effects, this induced charge segregation for the P dendrimer effectively blocks ionic transport through the pore. Our investigation shows that the bio-compatible PAMAM dendrimers can potentially be used to develop therapeutic protocols based on the pH sensitive gating of pores formed by pore forming toxins to mitigate bacterial infections. PMID:27328315

  7. Optical manipulation of the nematic director field around microspheres covered with an azo-dendrimer monolayer.

    PubMed

    Hirankittiwong, Pemika; Chattham, Nattaporn; Limtrakul, Jumras; Haba, Osamu; Yonetake, Koichiro; Eremin, Alexey; Stannarius, Ralf; Takezoe, Hideo

    2014-08-25

    We report here the optical manipulation of the director and topological defect structures of nematic liquid crystals around a silica microparticle with azobenzene-containing dendrimers (azo-dendrimers) on its surface. We successfully demonstrate the successive switching processes from hedgehog, to boojum, and further to Saturn ring configurations by ultraviolet (UV) light irradiation and termination. The switching time between these defect structures depends on the UV light intensity and attains about 50 ms. Since the pretreatment of microparticles is not necessary and the surface modification is spontaneously performed just by dissolving the azo-dendrimers in liquid crystals, this dendrimer supplies us with a variety of possible applications. PMID:25321218

  8. Efficient Transfer of Genetic Material into Mammalian Cells Using Starburst Polyamidoamine Dendrimers

    NASA Astrophysics Data System (ADS)

    Kukowska-Latallo, Jolanta F.; Bielinska, Anna U.; Johnson, Jennifer; Spindler, Ralph; Tomalia, Donald A.; Baker, James R.

    1996-05-01

    Starburst polyamidoamine dendrimers are a new class of synthetic polymers with unique structural and physical characteristics. These polymers were investigated for the ability to bind DNA and enhance DNA transfer and expression in a variety of mammalian cell lines. Twenty different types of polyamidoamine dendrimers were synthesized, and the polymer structure was confirmed using well-defined analytical techniques. The efficiency of plasmid DNA transfection using dendrimers was examined using two reporter gene systems: firefly luciferase and bacterial β -galactosidase. The transfections were performed using various dendrimers, and levels of expression of the reporter protein were determined. Highly efficient transfection of a broad range of eukaryotic cells and cell lines was achieved with minimal cytotoxicity using the DNA/dendrimer complexes. However, the ability to transfect cells was restricted to certain types of dendrimers and in some situations required the presence of additional compounds, such as DEAE-dextran, that appeared to alter the nature of the complex. A few cell lines demonstrated enhanced transfection with the addition of chloroquine, indicating endosomal localization of the complexes. The capability of a dendrimer to transfect cells appeared to depend on the size, shape, and number of primary amino groups on the surface of the polymer. However, the specific dendrimer most efficient in achieving transfection varied between different types of cells. These studies demonstrate that Starburst dendrimers can transfect a wide variety of cell types in vitro and offer an efficient method for producing permanently transfected cell lines.

  9. Dendronylation: Residue-specific chemoselective attachment of oligoglycerol dendrimers on proteins with noncanonical amino acids.

    PubMed

    Ma, Ying; Thota, Bala N S; Haag, Rainer; Budisa, Nediljko

    2015-11-15

    Polyglycerol dendrimers as an important class of polymeric materials especially attractive for covalent attachment to therapeutic proteins as a useful alternative to traditional PEGylation procedures. Herein, we combine in vivo noncanonical amino acid (ncAA) incorporation and chemoselective conjugation in vitro to produce novel hybrid protein-dendrimer conjugates with the defined architectures. We incorporated Azidohomoalanine (Aha) as methionine substitute in vivo into various protein scaffolds to allow non-invasive dendrimer conjugations (dendronylation). Our approach makes recombinant proteins accessible for the design of multivalent dendrimer conjugates since it enables the preparation of many sequences with various positions for regioselective dendronylation. PMID:26483199

  10. Preparation and Biophysical Characterization of Poly(amidoamine) Dendrimer-Poly(acrylic acid) Graft.

    PubMed

    Dung, Tran Huu; Do, Le Thanh; Loan, Ta Thi; Yoo, Hoon

    2015-01-01

    A series of PAMAM dendrimer generation 5-poly(acrylic acid) grafts were prepared to evaluate the potential use of dendritic grafts as a drug encapsulated nanocarrier. The structural features of the synthesized polymer graft were identified by FT-IR and 1H-NMR spectra and the biophysical properties were characterized by measuring its particle size and zeta potential. The prepared dendrimer G5-PAA grafts had particle size in the range of 600 to 900 nm and the size increased proportionally with the number of PAA on dendrimer surface. The electrostatic property of the dendrimer G5-PAA, carried out by HPLC reversed phase column analysis and the measurement of zeta potential, revealed that both migration time and zeta potential were dependent on the number of grafted PAA. The number of free amino groups on dendrimer G5-PAA, determined quantitatively by fluorescamine assay, was in a reverse order with the reaction mole ratio of dendrimer to PAA. In addition, dendrimer G5-PAA showed a pH-dependent solubility in aqueous solution with characteristic pH region of solubility, depending on the dendrimer generation. The observed biophysical properties indicate that PAMAM dendrimer G5-PAA is promising as a drug encapsulated nanocarrier. PMID:26328427

  11. Transcorneal iontophoresis of dendrimers: PAMAM corneal penetration and dexamethasone delivery.

    PubMed

    Souza, Joel G; Dias, Karina; Silva, Silas A M; de Rezende, Lucas C D; Rocha, Eduardo M; Emery, Flavio S; Lopez, Renata F V

    2015-02-28

    Iontophoresis of nanocarriers in the eye has been proposed to sustain drug delivery and maintain therapeutic concentrations. Fourth generation polyamidoamine (PAMAM) dendrimers are semi-rigid nanoparticles with surface groups that are easily modified. These dendrimers are known to modulate tight junctions, increase paracellular transport of small molecules and be translocated across epithelial barriers, exhibiting high uptake by different cell lines. The first aim of this study was to investigate the effect of iontophoresis on PAMAM penetration and distribution into the cornea. The second aim was to evaluate, ex vivo and in vivo, the effect of these dendrimers in dexamethasone (Dex) transcorneal iontophoresis. Anionic (PAMAM G3.5) and cationic (PAMAM G4) dendrimers were labeled with fluorescein isothiocyanate (FITC), and their distribution in the cornea was investigated using confocal microscopy after ex vivo anodal and cathodal iontophoresis for various application times. The particle size distribution and zeta potential of the dendrimers in an isosmotic solution were determined using dynamic light scattering and Nanoparticle Tracking Analysis (NTA), where the movement of small particles and the formation of large aggregates, from 5 to 100 nm, could be observed. Transcorneal iontophoresis increased the intensity and depth of PAMAM-FITC fluorescence in the cornea, suggesting improved transport of the dendrimers across the epithelium toward the stroma. PAMAM complexes with Dex were characterized by (13)C-NMR, (1)H-NMR and DOSY. PAMAM G3.5 and PAMAM G4 increased the aqueous solubility of Dex by 10.3 and 3.9-fold, respectively; however, the particle size distribution and zeta potential remained unchanged. PAMAM G3.5 decreased the Dex diffusion coefficient 48-fold compared with PAMAM G4. The ex vivo studies showed that iontophoresis increased the amount of Dex that penetrated into the cornea by 2.9, 5.6 and 3.0-fold for Dex, Dex-PAMAM G4 and Dex-PAMAM G3

  12. Interaction studies reveal specific recognition of an anti-inflammatory polyphosphorhydrazone dendrimer by human monocytes

    NASA Astrophysics Data System (ADS)

    Ledall, Jérémy; Fruchon, Séverine; Garzoni, Matteo; Pavan, Giovanni M.; Caminade, Anne-Marie; Turrin, Cédric-Olivier; Blanzat, Muriel; Poupot, Rémy

    2015-10-01

    Dendrimers are nano-materials with perfectly defined structure and size, and multivalency properties that confer substantial advantages for biomedical applications. Previous work has shown that phosphorus-based polyphosphorhydrazone (PPH) dendrimers capped with azabisphosphonate (ABP) end groups have immuno-modulatory and anti-inflammatory properties leading to efficient therapeutic control of inflammatory diseases in animal models. These properties are mainly prompted through activation of monocytes. Here, we disclose new insights into the molecular mechanisms underlying the anti-inflammatory activation of human monocytes by ABP-capped PPH dendrimers. Following an interdisciplinary approach, we have characterized the physicochemical and biological behavior of the lead ABP dendrimer with model and cell membranes, and compared this experimental set of data to predictive computational modelling studies. The behavior of the ABP dendrimer was compared to the one of an isosteric analog dendrimer capped with twelve azabiscarboxylate (ABC) end groups instead of twelve ABP end groups. The ABC dendrimer displayed no biological activity on human monocytes, therefore it was considered as a negative control. In detail, we show that the ABP dendrimer can bind both non-specifically and specifically to the membrane of human monocytes. The specific binding leads to the internalization of the ABP dendrimer by human monocytes. On the contrary, the ABC dendrimer only interacts non-specifically with human monocytes and is not internalized. These data indicate that the bioactive ABP dendrimer is recognized by specific receptor(s) at the surface of human monocytes.Dendrimers are nano-materials with perfectly defined structure and size, and multivalency properties that confer substantial advantages for biomedical applications. Previous work has shown that phosphorus-based polyphosphorhydrazone (PPH) dendrimers capped with azabisphosphonate (ABP) end groups have immuno-modulatory and anti

  13. Self-assembling DNA dendrimers: a numerical study.

    PubMed

    Largo, Julio; Starr, Francis W; Sciortino, Francesco

    2007-05-22

    DNA is increasingly used as a specific linker to template nanostructured materials. We present a molecular dynamics simulation study of a simple DNA-dendrimer model designed to capture the basic characteristics of the biological interactions, where selectivity and strong cooperativity play an important role. Exploring a large set of densities and temperatures, we follow the progressive formation of a percolating large-scale network whose connectivity can be described by random percolation theory. We identify the relative regions of network formation and kinetic arrest versus phase separation and show that the location of the two-phase region can be interpreted in the same framework as reduced valency models. This correspondence provides guidelines for designing stable, equilibrium self-assembled low-density networks. Finally, we demonstrate a relation between bonding and dynamics, by showing that the temperature dependence of the diffusion constant is controlled by the number of fully unbonded dendrimers. PMID:17439252

  14. Design, synthesis, characterization and drug release kinetics of PAMAM dendrimer based drug formulations

    NASA Astrophysics Data System (ADS)

    Kurtoglu, Yunus Emre

    The drug release characteristics of G4-polyamidoamine (PAMAM) dendrimer-ibuprofen conjugates with ester, amide, and peptide linkers were investigated, in addition to a linear PEG-ibuprofen conjugate to understand the effect of architecture and linker on drug release. Ibuprofen was directly conjugated to NH2 -terminated dendrimer by an amide bond and OH-terminated dendrimer by an ester bond. A tetra-peptide linked dendrimer conjugate and a linear mPEG-ibuprofen conjugate were also studied for comparison to direct linked dendrimer conjugates. It is demonstrated that the 3-D nanoscale architecture of PAMAM dendrimer-drug conjugates, along with linking chemistry govern the drug release mechanisms as well as kinetics. Understanding these structural effects on their drug release characteristics is crucial for design of dendrimer conjugates with high efficacy such as poly(amidoamine) dendrimer-N-Acetylcysteine conjugates with disulfide linkages. N-Acetylcysteine (NAC) is an anti-inflammatory agent with significant potential for clinical use in the treatment of neuroinflammation, stroke and cerebral palsy. A poly(amidoamine) dendrimer-NAC conjugate that contains a disulfide linkage was synthesized and evaluated for its release kinetics in the presence of glutathione (GSH), Cysteine (Cys), and bovine serum albumin (BSA) at both physiological and lysosomal pH. FITC-labeled conjugates showed that they enter cells rapidly and localize in the cytoplasm of lipopolysaccharide (LPS)-activated microglial cells. The efficacy of the dendrimer-NAC conjugate was measured in activated microglial cells using reactive oxygen species (ROS) assays. The conjugates showed an order of magnitude increase in anti-oxidant activity compared to free drug. When combined with intrinsic and ligand-based targeting with dendrimers, these types of GSH sensitive nanodevices can lead to improved drug release profiles and in vivo efficacy.

  15. Solid-State NMR Reveals the Hydrophobic-Core Location of Poly(amidoamine) Dendrimers in Biomembranes

    PubMed Central

    Smith, Pieter E. S.; Brender, Jeffrey R.; Dürr, Ulrich H. N.; Xu, Jiadi; Mullen, Douglas G.; Banaszak Holl, Mark M.; Ramamoorthy, Ayyalusamy

    2010-01-01

    Poly(amidoamine) (PAMAM) dendrimer nanobiotechnology shows great promise in targeted drug delivery and gene therapy. Because of the involvement of cell membrane lipids with the pharmacological activity of dendrimer nanomedicines, the interactions between dendrimers and lipids are of particular relevance to the pharmaceutical applications of dendrimers. In this study, solid-state NMR was used to obtain a molecular image of the complex of generation 5 PAMAM dendrimer with the lipid bilayer. Using 1H radio frequency driven dipolar recoupling (RFDR) and 1H magic angle spinning (MAS) nuclear Overhauser effect spectroscopy (NOESY) techniques, we show that dendrimers are thermodynamically stable when inserted into zwitterionic lipid bilayers. 14N and 31P NMR experiments on static samples and measurements of the mobility of C–H bonds using a 2D proton detected local field protocol under MAS corroborate these results. The localization of dendrimers in the hydrophobic core of lipid bilayers restricts the motion of bilayer lipid tails, with the smaller G5 dendrimer having more of an effect than the larger G7 dendrimer. Fragmentation of the membrane does not occur at low dendrimer concentrations in zwitterionic membranes. Because these results show that the amphipathic dendrimer molecule can be stably incorporated in the interior of the bilayer (as opposed to electrostatic binding at the surface), they are expected to be useful in the design of dendrimer-based nanobiotechnologies. PMID:20481633

  16. Dendrimers as synthetic gene vectors: Cell membrane attachment

    NASA Astrophysics Data System (ADS)

    Voulgarakis, N. K.; Rasmussen, K. Ø.; Welch, P. M.

    2009-04-01

    We present molecular-level simulations of dendrimer/DNA complexes in the presence of a model cell membrane. We determine the required conditions for the complex to arrive intact at the membrane, and the lifetime of the complex as it resides attached to the membrane. Our simulations directly pertain to critical issues arising in emerging gene delivery therapeutic applications, where a molecular carrier is required to deliver DNA segments to the interior of living cells.

  17. Dendrimers Based on [1,3,5]-Triazines

    PubMed Central

    STEFFENSEN, MACKAY B.; HOLLINK, EMILY; KUSCHEL, FRANK; BAUER, MONIKA; SIMANEK, ERIC E.

    2009-01-01

    A comprehensive and chronological account of dendrimers based on [1,3,5]-triazines is provided. Synthetic strategies to install the triazine through cycloaddition, cyclotrimerization, and nucleophilic aromatic substitution of cyanuric chloride are discussed. Motivations and applications of these architectures are surveyed, including the preparation of supra-molecular assemblies in the solution and solid states and their use in medicines, advanced materials, and separations when anchored to solid supports. PMID:19953202

  18. Dendrimer-mediated approaches for the treatment of brain tumor.

    PubMed

    Dwivedi, Nitin; Shah, Jigna; Mishra, Vijay; Mohd Amin, Mohd Cairul Iqbal; Iyer, Arun K; Tekade, Rakesh Kumar; Kesharwani, Prashant

    2016-05-01

    Worldwide, the cancer appeared as one of the most leading cause of morbidity and mortality. Among the various cancer types, brain tumors are most life threatening with low survival rate. Every year approximately 238,000 new cases of brain and other central nervous system tumors are diagnosed. The dendrimeric approaches have a huge potential for diagnosis and treatment of brain tumor with targeting abilities of molecular cargoes to the tumor sites and the efficiency of crossing the blood brain barrier and penetration to brain after systemic administration. The various generations of dendrimers have been designed as novel targeted drug delivery tools for new therapies including sustained drug release, gene therapy, and antiangiogenic activities. At present era, various types of dendrimers like PAMAM, PPI, and PLL dendrimers validated them as milestones for the treatment and diagnosis of brain tumor as well as other cancers. This review highlights the recent research, opportunities, advantages, and challenges involved in development of novel dendrimeric complex for the therapy of brain tumor. PMID:26928261

  19. Biodegradable Polydisulfide Dendrimer Nanoclusters as MRI Contrast Agents

    PubMed Central

    Huang, Ching-Hui; Nwe, Kido; Zaki, Ajlan Al; Brechbiel, Martin W.; Tsourkas, Andrew

    2012-01-01

    Gd-conjugated dendrimer nanoclusters (DNCs) are a promising platform for the early detection of disease; however, their clinical utility is potentially limited due to safety concerns related to nephrogenic systemic fibrosis (NSF). In this paper, biodegradable DNCs were prepared with polydisulfide linkages between the individual dendrimers to facilitate excretion. Further, DNCs were labeled with pre-metalated Gd chelates to eliminate the risk of free Gd becoming entrapped in dendrimer cavities. The biodegradable polydisulfide DNCs possessed a circulation half-life of > 1.6 h in mice and produced significant contrast enhancement in the abdominal aorta and kidneys for as long as 4 h. The DNCs were reduced in circulation as a result of thiol-disulfide exchange and the degradation products were rapidly excreted via renal filtration. These agents demonstrated effective and prolonged in vivo contrast enhancement and yet minimized Gd tissue retention. Biodegradable polydisulfide DNCs represent a promising biodegradable macromolecular MRI contrast agent for magnetic resonance angiography and can potentially be further developed into target specific MRI contrast agents. PMID:23098069

  20. Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer

    PubMed Central

    Shukla, Nikunj M.; Salunke, Deepak B.; Balakrishna, Rajalakshmi; Mutz, Cole A.; Malladi, Subbalakshmi S.; David, Sunil A.

    2012-01-01

    Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen. PMID:22952720

  1. Conformations and dynamics of dendrimers and cascade macromolecules

    NASA Astrophysics Data System (ADS)

    La Ferla, Roberto

    1997-01-01

    The Rouse-Zimm discrete hydrodynamic model is extended to acyclic macromolecules of any topology, and particular attention is devoted to starlike dendrimers and other symmetric cascade structures. As a first approximation, freely rotating models are built for branched structures by means of appropriate choices of topology-dependent stiffness parameters. Relevant dynamic observables (depending on the spectrum of viscoelastic relaxation rates) are studied as functions of local stiffness, of branching topology, and of dendrimer generational growth. The present results show that a moderate increase of local stiffness accounts for the molecular dimensions of dendrimers as previously calculated by Mansfield and Klushin [J. Phys. Chem. 96, 3994 (1992)] by Monte Carlo methods, and reproduces with good precision their results for the intrinsic viscosity (upper-bound calculations). Thus omission of excluded-volume interactions within the present models can be at least partially compensated for by suitable choices of local stiffness parameters, provided that the chain portions between branching points are not very long. In addition, the inaccuracy caused by preaveraging of hydrodynamic interactions (as estimated by computing exact and preaveraged first cumulant of the structure factor) does not seem to obscure the essential conclusions.

  2. Antitumor effect and safety profile of systemically delivered oncolytic adenovirus complexed with EGFR-targeted PAMAM-based dendrimer in orthotopic lung tumor model.

    PubMed

    Yoon, A-Rum; Kasala, Dayananda; Li, Yan; Hong, Jinwoo; Lee, Wonsig; Jung, Soo-Jung; Yun, Chae-Ok

    2016-06-10

    Adenovirus (Ad)-mediated cancer gene therapy has been proposed as a promising alternative to conventional therapy for cancer. However, success of systemically administered naked Ad has been limited due to the immunogenicity of Ad and the induction of hepatotoxicity caused by Ad's native tropism. In this study, we synthesized an epidermal growth factor receptor (EGFR)-specific therapeutic antibody (ErbB)-conjugated and PEGylated poly(amidoamine) (PAMAM) dendrimer (PPE) for complexation with Ad. Transduction of Ad was inhibited by complexation with PEGylated PAMAM (PP) dendrimer due to steric hindrance. However, PPE-complexed Ad selectively internalized into EGFR-positive cells with greater efficacy than either naked Ad or Ad complexed with PP. Systemically administered PPE-complexed oncolytic Ad elicited significantly reduced immunogenicity, nonspecific liver sequestration, and hepatotoxicity than naked Ad. Furthermore, PPE-complexed oncolytic Ad demonstrated prolonged blood retention time, enhanced intratumoral accumulation of Ad, and potent therapeutic efficacy in EGFR-positive orthotopic lung tumors in comparison with naked Ad. We conclude that ErbB-conjugated and PEGylated PAMAM dendrimer can efficiently mask Ad's capsid and retarget oncolytic Ad to be efficiently internalized into EGFR-positive tumor while attenuating toxicity induced by systemic administration of naked oncolytic Ad. PMID:26951927

  3. Unexpected Temperature Behavior of Polyethylene Glycol Spacers in Copolymer Dendrimers in Chloroform

    NASA Astrophysics Data System (ADS)

    Markelov, Denis A.; Matveev, Vladimir V.; Ingman, Petri; Nikolaeva, Marianna N.; Penkova, Anastasia V.; Lahderanta, Erkki; Boiko, Natalia I.; Chizhik, Vladimir I.

    2016-04-01

    We have studied copolymer dendrimer structure: carbosilane dendrimers with terminal phenylbenzoate mesogenic groups attached by poly(ethylene) glycol (PEG) spacers. In this system PEG spacers are additional tuning to usual copolymer structure: dendrimer with terminal mesogenic groups. The dendrimer macromolecules were investigated in a dilute chloroform solution by 1H NMR methods (spectra and relaxations). It was found that the PEG layer in G = 5 generations dendrimer is “frozen” at high temperatures (above 260 K), but it unexpectedly becomes “unfrozen” at temperatures below 250 K (i.e., melting when cooling). The transition between these two states occurs within a small temperature range (~10 K). Such a behavior is not observed for smaller dendrimer generations (G = 1 and 3). This effect is likely related to the low critical solution temperature (LCST) of PEG and is caused by dendrimer conformations, in which the PEG group concentration in the layer increases with growing G. We suppose that the unusual behavior of PEG fragments in dendrimers will be interesting for practical applications such as nanocontainers or nanoreactors.

  4. Radionuclide (131)I-labeled multifunctional dendrimers for targeted SPECT imaging and radiotherapy of tumors.

    PubMed

    Zhu, Jingyi; Zhao, Lingzhou; Cheng, Yongjun; Xiong, Zhijuan; Tang, Yueqin; Shen, Mingwu; Zhao, Jinhua; Shi, Xiangyang

    2015-11-21

    We report the synthesis, characterization, and utilization of radioactive (131)I-labeled multifunctional dendrimers for targeted single-photon emission computed tomography (SPECT) imaging and radiotherapy of tumors. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5·NH2) were sequentially modified with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO) and folic acid (FA) linked with polyethylene glycol (PEG), followed by acetylation modification of the dendrimer remaining surface amines and labeling of radioactive iodine-131 ((131)I). The generated multifunctional (131)I-G5·NHAc-HPAO-PEG-FA dendrimers were characterized via different methods. We show that prior to (131)I labeling, the G5·NHAc-HPAO-PEG-FA dendrimers conjugated with approximately 9.4 HPAO moieties per dendrimer are noncytotoxic at a concentration up to 20 μM and are able to target cancer cells overexpressing FA receptors (FAR), thanks to the modified FA ligands. In the presence of a phenol group, radioactive (131)I is able to be efficiently labeled onto the dendrimer platform with good stability and high radiochemical purity, and render the platform with an ability for targeted SPECT imaging and radiotherapy of an FAR-overexpressing xenografted tumor model in vivo. The designed strategy to use the facile dendrimer nanotechnology may be extended to develop various radioactive theranostic nanoplatforms for targeted SPECT imaging and radiotherapy of different types of cancer. PMID:26477402

  5. Small cell foams containing a modified dense star polymer or dendrimer as a nucleating agent

    DOEpatents

    Hedstrand, D.M.; Tomalia, D.A.

    1995-02-28

    A small cell foam having a modified dense star polymer or dendrimer is described. This modified dense star polymer or dendrimer has a highly branched interior of one monomeric composition and an exterior structure of a different monomeric composition capable of providing a hydrophobic outer shell and a particle diameter of from about 5 to about 1,000 nm with a matrix polymer.

  6. Effect of dendrimers on selected enzymes--Evaluation of nano carriers.

    PubMed

    Ionov, Maksim; Ihnatsyeu-Kachan, Aliaksei; Michlewska, Sylwia; Shcharbina, Natallia; Shcharbin, Dzmitry; Majoral, Jean-Pierre; Bryszewska, Maria

    2016-02-29

    In the field of nanotechnology, dendrimers represent a new class of highly branched macromolecules that is receiving a stimulating and rising interest. The structural organization of these synthetic macromolecules provides promising opportunities for using them as nano-carriers of drugs or gene material to be delivered to the target cells. For applications of dendrimers as drug carriers, analysis of their specific interactions with biological structures at molecular level is very important. This paper describes the molecular interactions between cationic phosphorus dendrimers of third and fourth generation (CPD G3 and CPD G4) and 3 plasma regulatory proteins, namely aspartate transaminase, alkaline phosphatase and l-lactic dehydrogenase. Dendrimer-protein interactions were studied using spectrofluorimetric, circular dichroism and dynamic light scattering techniques. Their morphology in the presence or absence of dendrimers was examined by transmission electron microscopy. The results suggest that both dendrimers form positively charged complexes with HIV-derived peptides. The circular dichroism spectra show that these dendrimers can significantly change the secondary structure of proteins, indicating formation of protein/dendrimer complexes. PMID:26724219

  7. Expand classical drug administration ways by emerging routes using dendrimer drug delivery systems: a concise overview.

    PubMed

    Mignani, Serge; El Kazzouli, Saïd; Bousmina, Mosto; Majoral, Jean-Pierre

    2013-10-01

    Drugs are introduced into the body by numerous routes such as enteral (oral, sublingual and rectum administration), parenteral (intravascular, intramuscular, subcutaneous and inhalation administration), or topical (skin and mucosal membranes). Each route has specific purposes, advantages and disadvantages. Today, the oral route remains the preferred one for different reasons such as ease and compliance by patients. Several nanoformulated drugs have been already approved by the FDA, such as Abelcet®, Doxil®, Abraxane® or Vivagel®(Starpharma) which is an anionic G4-poly(L-lysine)-type dendrimer showing potent topical vaginal microbicide activity. Numerous biochemical studies, as well as biological and pharmacological applications of both dendrimer based products (dendrimers as therapeutic compounds per se, like Vivagel®) and dendrimers as drug carriers (covalent conjugation or noncovalent encapsulation of drugs) were described. It is widely known that due to their outstanding physical and chemical properties, dendrimers afforded improvement of corresponding carried-drugs as dendrimer-drug complexes or conjugates (versus plain drug) such as biodistribution and pharmacokinetic behaviors. The purpose of this manuscript is to review the recent progresses of dendrimers as nanoscale drug delivery systems for the delivery of drugs using enteral, parenteral and topical routes. In particular, we focus our attention on the emerging and promising routes such as oral, transdermal, ocular and transmucosal routes using dendrimers as delivery systems. PMID:23415951

  8. Photosensitizer and peptide-conjugated PAMAM dendrimer for targeted in vivo photodynamic therapy

    PubMed Central

    Narsireddy, Amreddy; Vijayashree, Kurra; Adimoolam, Mahesh G; Manorama, Sunkara V; Rao, Nalam M

    2015-01-01

    Challenges in photodynamic therapy (PDT) include development of efficient near infrared-sensitive photosensitizers (5,10,15,20-tetrakis(4-hydroxyphenyl)-21H,23H-porphine [PS]) and targeted delivery of PS to the tumor tissue. In this study, a dual functional dendrimer was synthesized for targeted PDT. For targeting, a poly(amidoamine) dendrimer (G4) was conjugated with a PS and a nitrilotriacetic acid (NTA) group. A peptide specific to human epidermal growth factor 2 was expressed in Escherichia coli with a His-tag and was specifically bound to the NTA group on the dendrimer. Reaction conditions were optimized to result in dendrimers with PS and the NTA at a fractional occupancy of 50% and 15%, respectively. The dendrimers were characterized by nuclear magnetic resonance, matrix-assisted laser desorption/ionization, absorbance, and fluorescence spectroscopy. Using PS fluorescence, cell uptake of these particles was confirmed by confocal microscopy and fluorescence-activated cell sorting. PS-dendrimers are more efficient than free PS in PDT-mediated cell death assays in HER2 positive cells, SK-OV-3. Similar effects were absent in HER2 negative cell line, MCF-7. Compared to free PS, the PS-dendrimers have shown significant tumor suppression in a xenograft animal tumor model. Conjugation of a PS with dendrimers and with a targeting agent has enhanced photodynamic therapeutic effects of the PS. PMID:26604753

  9. Molecular dynamics simulation of coarse-grained poly(L-lysine) dendrimers.

    PubMed

    Rahimi, Ali; Amjad-Iranagh, Sepideh; Modarress, Hamid

    2016-03-01

    Poly(L-lysine) (PLL) dendrimer are amino acid based macromolecules and can be used as drug delivery agents. Their branched structure allows them to be functionalized by various groups to encapsulate drug agents into their structure. In this work, at first, an attempt was made on all-atom simulation of PLL dendrimer of different generations. Based on all-atom results, a course-grained model of this dendrimer was designed and its parameters were determined, to be used for simulation of three generations of PLL dendrimer, at two pHs. Similar to the all-atom, the coarse-grained results indicated that by increasing the generation, the dendrimer becomes more spherical. At pH 7, the dendrimer had larger size, whereas at pH 12, due to back folding of branching chains, they had the tendency to penetrate into the inner layers. The calculated radial probability and radial distribution functions confirm that at pH 7, the PLL dendrimer has more cavities and as a result it can encapsulate more water molecules into its inner structure. By calculating the moment of inertia and the aspect ratio, the formation of spherical structure for PLL dendrimer was confirmed. PMID:26885845

  10. Small cell foams containing a modified dense star polymer or dendrimer as a nucleating agent

    DOEpatents

    Hedstrand, David M.; Tomalia, Donald A.

    1995-01-01

    A small cell foam having a modified dense star polymer or dendrimer is described. This modified dense star polymer or dendrimer has a highly branched interior of one monomeric composition and an exterior structure of a different monomeric composition capable of providing a hydrophobic outer shell and a particle diameter of from about 5 to about 1,000 nm with a matrix polymer.

  11. Pegylated dendrimer and its effect in fluorouracil loading and release for enhancing antitumor activity.

    PubMed

    Ly, Tu Uyen; Tran, Ngoc Quyen; Hoang, Thi Kim Dung; Phan, Kim Ngoc; Truong, Hai Nhung; Nguyen, Cuu Khoa

    2013-02-01

    Dendrimer, a new class of hyper-branched polymer with predetermined molecular weight, is being received much attention in nano biomedical applications such as anticancer drug delivery, gene therapy, disease diagnosis and etc. In this study, polyamidoamine (PAMAM)-based dendrimer generation 3.0 (G 3.0) was synthesized and subsequently pegylated. Obtained results showed that pegylation degree of the dendrimer was around 31% for its external amine groups. TEM image of the pegylated dendrimer exhibited spherical shape and nano sizes ranging from 30 to 40 nm. The fluorouracil (5-FU)-loaded pegylated dendrimer showed a slow release profile of the drug. In vitro study, at the primary screening concentration of 100 microg/mL, the PAMAM dendrimer presented higher toxicity in MCF-7 cells as compared to its pegylated counterpart. Meanwhile, the (5-FU)-loaded pegylated dendrimer exhibited the antiproliferative activity against the cell line with the IC50 of 9.92 +/- 0.19 microg/mL. In vivo tumor xenograft study, we succeeded in generating MCF-7 cells-derived cancer tumors on mice that was well-confirmed by using flow cytometer assay. The 5-FU encapsulated pegylated dendrimer exhibited a significant decrement in volume of the tumors which was generated by MCF-7 cancer cells. PMID:23627047

  12. Unexpected Temperature Behavior of Polyethylene Glycol Spacers in Copolymer Dendrimers in Chloroform.

    PubMed

    Markelov, Denis A; Matveev, Vladimir V; Ingman, Petri; Nikolaeva, Marianna N; Penkova, Anastasia V; Lahderanta, Erkki; Boiko, Natalia I; Chizhik, Vladimir I

    2016-01-01

    We have studied copolymer dendrimer structure: carbosilane dendrimers with terminal phenylbenzoate mesogenic groups attached by poly(ethylene) glycol (PEG) spacers. In this system PEG spacers are additional tuning to usual copolymer structure: dendrimer with terminal mesogenic groups. The dendrimer macromolecules were investigated in a dilute chloroform solution by (1)H NMR methods (spectra and relaxations). It was found that the PEG layer in G = 5 generations dendrimer is "frozen" at high temperatures (above 260 K), but it unexpectedly becomes "unfrozen" at temperatures below 250 K (i.e., melting when cooling). The transition between these two states occurs within a small temperature range (~10 K). Such a behavior is not observed for smaller dendrimer generations (G = 1 and 3). This effect is likely related to the low critical solution temperature (LCST) of PEG and is caused by dendrimer conformations, in which the PEG group concentration in the layer increases with growing G. We suppose that the unusual behavior of PEG fragments in dendrimers will be interesting for practical applications such as nanocontainers or nanoreactors. PMID:27052599

  13. Photosensitizer and peptide-conjugated PAMAM dendrimer for targeted in vivo photodynamic therapy.

    PubMed

    Narsireddy, Amreddy; Vijayashree, Kurra; Adimoolam, Mahesh G; Manorama, Sunkara V; Rao, Nalam M

    2015-01-01

    Challenges in photodynamic therapy (PDT) include development of efficient near infrared-sensitive photosensitizers (5,10,15,20-tetrakis(4-hydroxyphenyl)-21H,23H-porphine [PS]) and targeted delivery of PS to the tumor tissue. In this study, a dual functional dendrimer was synthesized for targeted PDT. For targeting, a poly(amidoamine) dendrimer (G4) was conjugated with a PS and a nitrilotriacetic acid (NTA) group. A peptide specific to human epidermal growth factor 2 was expressed in Escherichia coli with a His-tag and was specifically bound to the NTA group on the dendrimer. Reaction conditions were optimized to result in dendrimers with PS and the NTA at a fractional occupancy of 50% and 15%, respectively. The dendrimers were characterized by nuclear magnetic resonance, matrix-assisted laser desorption/ionization, absorbance, and fluorescence spectroscopy. Using PS fluorescence, cell uptake of these particles was confirmed by confocal microscopy and fluorescence-activated cell sorting. PS-dendrimers are more efficient than free PS in PDT-mediated cell death assays in HER2 positive cells, SK-OV-3. Similar effects were absent in HER2 negative cell line, MCF-7. Compared to free PS, the PS-dendrimers have shown significant tumor suppression in a xenograft animal tumor model. Conjugation of a PS with dendrimers and with a targeting agent has enhanced photodynamic therapeutic effects of the PS. PMID:26604753

  14. Quantitative evaluation of the effect of poly(amidoamine) dendrimers on the porosity of epithelial monolayers

    NASA Astrophysics Data System (ADS)

    Lin, Yen-Ling; Khanafer, Khalil; El-Sayed, Mohamed E. H.

    2010-05-01

    Poly(amidoamine) (PAMAM) dendrimers are a family of water-soluble polymers with a characteristic tree-like branching architecture and a large number of surface groups, which have been used to immobilize a variety of therapeutic molecules for targeted drug delivery. Earlier studies showed that small cationic PAMAM-NH2 and selected anionic PAMAM-COOH dendrimers permeate across in vitro models of the small intestinal epithelium by paracellular and transcellular transport mechanisms. The focus of this research is to mathematically calculate the effect of cationic, anionic, and neutral PAMAM dendrimers on the porosity of epithelial tight junctions as a function of dendrimers concentration, incubation time, generation number, and charge density. Results show that the increase in the concentration, incubation time and generation number of cationic G0-G2 PAMAM-NH2 and anionic G2.5 and G3.5 PAMAM-COOH dendrimers caused a corresponding increase in the porosity of Caco-2 cell monolayers. Neutral G2-G4 PAMAM-OH dendrimers had no effect on the porosity of intestinal cells. These results provide quantitative evidence that the observed increase in permeability of PAMAM dendrimers across Caco-2 cell monolayers is due to their effect on the organization of the tight junctions and the associated increase in membrane porosity. Furthermore, these results emphasize the potential of cationic PAMAM-NH2 and anionic PAMAM-COOH dendrimers to function as carriers for controlled oral drug delivery.

  15. Monofunctionalization of Dendrimers Using Microwave–Assisted 1,3 Dipolar Cycloadditions

    PubMed Central

    Yoon, Kunsang; Goyal, Poorva; Weck, Marcus

    2008-01-01

    Monofunctionalized polyamide-based dendrimers containing either a terminal azide or alkyne moiety have been designed and synthesized via a convergent synthetic approach. The monofunctionalization allows for the single attachment of a functional moiety in quantitative yields using 1,3 dipolar cycloadditions thereby opening the possibility for targeted dendrimer functionalization. PMID:17472392

  16. Unexpected Temperature Behavior of Polyethylene Glycol Spacers in Copolymer Dendrimers in Chloroform

    PubMed Central

    Markelov, Denis A.; Matveev, Vladimir V.; Ingman, Petri; Nikolaeva, Marianna N.; Penkova, Anastasia V.; Lahderanta, Erkki; Boiko, Natalia I.; Chizhik, Vladimir I.

    2016-01-01

    We have studied copolymer dendrimer structure: carbosilane dendrimers with terminal phenylbenzoate mesogenic groups attached by poly(ethylene) glycol (PEG) spacers. In this system PEG spacers are additional tuning to usual copolymer structure: dendrimer with terminal mesogenic groups. The dendrimer macromolecules were investigated in a dilute chloroform solution by 1H NMR methods (spectra and relaxations). It was found that the PEG layer in G = 5 generations dendrimer is “frozen” at high temperatures (above 260 K), but it unexpectedly becomes “unfrozen” at temperatures below 250 K (i.e., melting when cooling). The transition between these two states occurs within a small temperature range (~10 K). Such a behavior is not observed for smaller dendrimer generations (G = 1 and 3). This effect is likely related to the low critical solution temperature (LCST) of PEG and is caused by dendrimer conformations, in which the PEG group concentration in the layer increases with growing G. We suppose that the unusual behavior of PEG fragments in dendrimers will be interesting for practical applications such as nanocontainers or nanoreactors. PMID:27052599

  17. Synthesis of Polyamidoamine Dendrimer for Encapsulating Tetramethylscutellarein for Potential Bioactivity Enhancement

    PubMed Central

    Shadrack, Daniel M.; Mubofu, Egid B.; Nyandoro, Stephen S.

    2015-01-01

    The biomedical potential of flavonoids is normally restricted by their low water solubility. However, little has been reported on their encapsulation into polyamidoamine (PAMAM) dendrimers to improve their biomedical applications. Generation four (G4) PAMAM dendrimer containing ethylenediaminetetraacetic acid core with acrylic acid and ethylenediamine as repeating units was synthesized by divergent approach and used to encapsulate a flavonoid tetramethylscutellarein (TMScu, 1) to study its solubility and in vitro release for potential bioactivity enhancement. The as-synthesized dendrimer and the dendrimer–TMScu complex were characterized by spectroscopic and spectrometric techniques. The encapsulation of 1 into dendrimer was achieved by a co-precipitation method with the encapsulation efficiency of 77.8% ± 0.69% and a loading capacity of 6.2% ± 0.06%. A phase solubility diagram indicated an increased water solubility of 1 as a function of dendrimer concentration at pH 4.0 and 7.2. In vitro release of 1 from its dendrimer complex indicated high percentage release at pH 4.0. The stability study of the TMScu-dendrimer at 0, 27 and 40 °C showed the formulations to be stable when stored in cool and dark conditions compared to those stored in light and warmer temperatures. Overall, PAMAM dendrimer-G4 is capable of encapsulating 1, increasing its solubility and thus could enhance its bioactivity. PMID:26556337

  18. Probing the binding of cationic lipids with dendrimers.

    PubMed

    Mandeville, J S; Bourassa, P; Tajmir-Riahi, H A

    2013-01-14

    Polycationic polymers are used extensively in biology to disrupt cell membranes and thus enhance the transport of materials into the cell. We report the bindings of several lipids cholesterol (Chol), 1,2-dioleoyl-3-trimethylammonium-propane(DOTAP), dioctadecyldimethylammoniumbromide (DDAB), and dioleoylphosphatidylethanolamine (DOPE) to dendrimers of different compositions such as mPEG-PAMAM (G3), mPEG-PAMAM (G4), and PAMAM (G4) under physiological conditions. FTIR, UV-visible spectroscopic, methods and molecular modeling were used to analyze the lipid binding mode, the binding constant, and the effects of lipid complexation on the dendrimer structure. The structural analysis showed that lipids bind dendrimers through both hydrophilic and hydrophobic contacts with overall binding constants of K(chol-mPEG-G3) = 1.7 × 10(3) M(-1), K(chol-mPEG-PAMAM-G4) = 2.7 × 10(3) M(-1), K(chol-PAMAM-G4) = 1.0 × 10(3) M(-1), K(DOPE-mPEG-G3) = 1.5 × 10(3) M(-1), K(DOPE-mPEG-PAMAM-G4) = 1.6 × 10(3) M(-1), K(DOPE-PAMAM-G4) = 5.3 × 10(2) M(-1), K(DDAB-mPEG-G3) = 1.5 × 10(3) M(-1), K(DDAB-mPEG-PAMAM-G4) = 1.9 × 10(2) M(-1), K(DDAB-PAMAM-G4) = 7.0 × 10(2) M(-1), K(DOTAP-mPEG-G3) = 1.9 × 10(3) M(-1), K(DOTAP-mPEG-PAMAM-G4) = 1.5 × 10(3) M(-1), and K(DOTAP-PAMAM-G4) = 5.7 × 10(2) M(-1). Weaker interaction was observed as dendrimer cationic charges increased. The free binding energies from docking were -5.15 (cholesterol), -5.79 (DDAB), and -5.36 kcal/mol (DOTAP) with the order of stability DDAB-PAMAM-G-4 > DOTAP-PAMAM-G4 > cholesterol-PAMAM-G4, consistent with the spectroscopic results. Dendrimers might act as carriers to transport lipids in vitro. PMID:23130659

  19. Thermoregulated Coacervation, Metal-Encapsulation and Nanoparticle Synthesis in Novel Triazine Dendrimers.

    PubMed

    Ramírez-Crescencio, Fermín; Enciso, Alan E; Hasan, Mirza; da Costa, Viviana C P; Annunziata, Onofrio; Redón, Rocío; Coffer, Jeffery L; Simanek, Eric E

    2016-01-01

    The synthesis and solubility behaviors of four generation five (G5) triazine dendrimers are studied. While the underivatized cationic dendrimer is soluble in water, the acetylated and propanoylated derivatives undergo coacervation in water upon increasing temperature. Occurring around room temperature, this behavior is related to a liquid-liquid phase transition with a lower critical solution temperature (LCST) and is explained by differences in composition, notably, the hydrophobic nature of the terminal groups. Interestingly, the water solubility of the acetylated dendrimer is affected by the addition of selected metal ions. Titrating solutions of acetylated dendrimer at temperatures below the LCST with gold or palladium ions promoted precipitation, but platinum, iridium, and copper did not. Gold nanoparticles having diameters of 2.5 ± 0.8 nm can be obtained from solutions of the acetylated dendrimer at concentrations of gold less than that required to induce precipitation by treating the solution with sodium borohydride. PMID:27187331

  20. Antimicrobial Organometallic Dendrimers with Tunable Activity against Multidrug-Resistant Bacteria.

    PubMed

    Abd-El-Aziz, Alaa S; Agatemor, Christian; Etkin, Nola; Overy, David P; Lanteigne, Martin; McQuillan, Katherine; Kerr, Russell G

    2015-11-01

    Multidrug-resistant pathogens are an increasing threat to public health. In an effort to curb the virulence of these pathogens, new antimicrobial agents are sought. Here we report a new class of antimicrobial organometallic dendrimers with tunable activity against multidrug-resistant Gram-positive bacteria that included methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Mechanistically, these redox-active, cationic organometallic dendrimers induced oxidative stress on bacteria and also disrupted the microbial cell membrane. The minimum inhibitory concentrations, which provide a quantitative measure of the antimicrobial activity of these dendrimers, were in the low micromolar range. AlamarBlue cell viability assay also confirms the antimicrobial activity of these dendrimers. Interestingly, these dendrimers were noncytotoxic to epidermal cell lines and to mammalian red blood cells, making them potential antimicrobial platforms for topical applications. PMID:26452022

  1. Fourier transform infrared spectroscopy (FTIR) characterization of the interaction of anti-cancer photosensitizers with dendrimers.

    PubMed

    Dabrzalska, Monika; Benseny-Cases, Nuria; Barnadas-Rodríguez, Ramon; Mignani, Serge; Zablocka, Maria; Majoral, Jean-Pierre; Bryszewska, Maria; Klajnert-Maculewicz, Barbara; Cladera, Josep

    2016-01-01

    The systemic or local administration of a photosensitizer for photodynamic therapy is highly limited by poor selectivity, rapid deactivation and long-lasting skin toxicity due to unfavorable biodistribution. Drug delivery systems based on nanocarriers may help specific and effective delivery of photosensitizers. In the present paper, the interaction of two photosensitizers, methylene blue and rose bengal, with phosphorous cationic and anionic dendrimers as potential nanocarriers, has been characterized. A novel method is presented based on the analysis of the infrared spectra of mixtures of photosensitizer and dendrimer. The capacity of dendrimers to bind the photosensitizers has been evaluated by obtaining the corresponding binding curves. It is shown that methylene blue interacts with both cationic and anionic dendrimers, whereas rose bengal only binds to the cationic ones. Dendrimers are shown to be potential nanocarriers for a specific delivery of both photosensitizers. PMID:26507333

  2. Contribution of hydrophobicity, DNA and proteins to the cytotoxicity of cationic PAMAM dendrimers.

    PubMed

    Halets, Inessa; Shcharbin, Dzmitry; Klajnert, Barbara; Bryszewska, Maria

    2013-09-15

    In most articles, cytotoxicity of cationic polyamidoamine (PAMAM) dendrimers toward red blood cells has been exclusively explained by their surface charge. We have focused on dendrimer hydrophobicity as a second possible factor that determines this cytotoxicity. Using PAMAM-NH2 dendrimers from the 3rd to the 6th generations and PAMAM-NH2-C12(25%) dendrimer of the 4th generation bearing 25% acyl groups, these induced hemolysis that increased with their surface charge and hydrophobicity. Interaction of PAMAM-NH2-C12(25%) G4 dendrimer with blood proteins (γ-globulin, α-thrombin, human serum albumin) and calf thymus DNA (ctDNA) significantly reduced their cytotoxicity toward red blood cells. PMID:23831196

  3. A fluorinated dendrimer achieves excellent gene transfection efficacy at extremely low nitrogen to phosphorus ratios

    NASA Astrophysics Data System (ADS)

    Wang, Mingming; Liu, Hongmei; Li, Lei; Cheng, Yiyun

    2014-01-01

    Polymers have shown great promise in the design of high efficient and low cytotoxic gene vectors. Here we synthesize fluorinated dendrimers for use as gene vectors. Fluorinated dendrimers achieve excellent gene transfection efficacy in several cell lines (higher than 90% in HEK293 and HeLa cells) at extremely low N/P ratios. These polymers show superior efficacy and biocompatibility compared with several commercial transfection reagents such as Lipofectamine 2000 and SuperFect. Fluorination enhances the cellular uptake of the dendrimer/DNA polyplexes and facilitates their endosomal escape. In addition, the fluorinated dendrimer shows excellent serum resistance and exhibits high gene transfection efficacy even in medium containing 50% FBS. The results suggest that fluorinated dendrimers are a new class of highly efficient gene vectors and fluorination is a promising strategy to design gene vectors without involving sophisticated syntheses.

  4. A new microscopic insight into membrane penetration and reorganization by PETIM dendrimers.

    PubMed

    Bhattacharya, R; Kanchi, Subbarao; C, Roobala; Lakshminarayanan, A; Seeck, Oliver H; Maiti, Prabal K; Ayappa, K G; Jayaraman, N; Basu, J K

    2014-10-14

    Dendrimers are highly branched polymeric nanoparticles whose structure and topology, largely, have determined their efficacy in a wide range of studies performed so far. An area of immense interest is their potential as drug and gene delivery vectors. Realizing this potential, depending on the nature of cell surface-dendrimer interactions, here we report controlled model membrane penetration and reorganization, using a model supported lipid bilayer and poly(ether imine) (PETIM) dendrimers of two generations. By systematically varying the areal density of the lipid bilayers, we provide a microscopic insight, through a combination of high resolution scattering, atomic force microscopy and atomistic molecular dynamics simulations, into the mechanism of PETIM dendrimer membrane penetration, pore formation and membrane re-organization induced by such interactions. Our work represents the first systematic observation of a regular barrel-like membrane spanning pore formation by dendrimers, tunable through lipid bilayer packing, without membrane disruption. PMID:25115726

  5. Dendrimers as a promising tool in ocular therapeutics: Latest advances and perspectives.

    PubMed

    Rodríguez Villanueva, Javier; Navarro, Manuel Guzmán; Rodríguez Villanueva, Laura

    2016-09-10

    Dendrimers have called the attention of scientists in the area of drug and gene delivery over the last two decades for their versatility, complexity and multibranching properties. Some strategies for optimizing drug pharmacokinetics and site-specific targeting using dendrimers have been proposed. Among them, those related to treating and managing ocular diseases are of special interest. Ocular therapies suffer from significant disadvantages, including frequent administration, poor penetration and/or rapid elimination. This review provides an overview of the recent and promising progress in the dendrimers field, focusing on both the anterior and posterior segments of the eye ocular targets, the use of dendrimers as a strategy for overcoming obstacles to the traditional treatment of ocular diseases and an outlook on future directions. Finally, a first approach to ocular safety with dendrimers is intended that accounts for the state-of-the-art science to date. PMID:27436708

  6. Evaluation of the activity of new cationic carbosilane dendrimers on trophozoites and cysts of Acanthamoeba polyphaga.

    PubMed

    Heredero-Bermejo, Irene; Copa-Patiño, Jose Luis; Soliveri, Juan; Fuentes-Paniagua, Elena; de la Mata, Francisco Javier; Gomez, Rafael; Perez-Serrano, Jorge

    2015-02-01

    Dendrimers are repetitively branched molecules with a broad spectrum of applications, mainly for their antimicrobial properties and as nanocarriers for other molecules. Recently, our research group have synthesized and studied their activity against Acanthamoeba sp., causative agent of a severe ocular disease in humans: Acanthamoeba keratitis. New cationic carbosilane dendrimers were tested against the protozoa forms at different concentrations and for different incubation times. Trophozoite viability was determined by manual counting and cyst viability by observing excystment in microplates with fresh culture medium. Cytotoxicity was checked on HeLa cells using the microculture tetrazolium assay. Alterations were observed by optical microscopy and by flow cytometry staining with propidium iodide. Six out of the 18 dendrimers tested were non-cytotoxic and effective against the trophozoite form, having one of them (dendrimer 14 with an IC50 of 2.4 + 0.1 mg/L) a similar activity to chlorhexidine digluconate (IC50 1.7 + 0.1 mg/L). This dendrimer has a polyphenoxo core and a sulphur atom close to the six -NH3+ terminal groups. On the other hand, only two dendrimers showed some effect against cysts (dendrimers 14 and 17). However, their minimum cysticidal concentrations were cytotoxic and less effective than the control drug. The alterations on the amoeba morphology produced by the treatment with dendrimers were size reduction, increased complexity, loss of acanthopodia and cell membrane disruption. In conclusion, these results suggest that some dendrimers may be studied in animal models to test their effect and that new dendrimers with similar features should be synthesized. PMID:25358240

  7. Carbosilane dendrimer 2G-NN16 represses Tc17 differentiation in primary T CD8+ lymphocytes.

    PubMed

    Gras, Rafael; García, María I; Gómez, Rafael; de la Mata, F Javier; Muñoz-Fernández, M Angeles; López-Fernández, Luís A

    2012-01-01

    We studied changes in gene expression induced by the carbosilane dendrimer 2G-NN16 to evaluate their potential as a vehicle for gene therapy and as medication. Global gene expression profiles on CD8+ T lymphocytes reveal that ribosomal proteins are induced in the presence of 2G-NN16. IL17A and IL17F, the principal interleukins secreted by Tc17 cells, a subset of CD8+ T lymphocytes, were down-regulated when cultured in the presence of this dendrimer. Microarray results were confirmed by real time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). 2G-NN16 also showed a high potential for in vitro inhibition of Tc17 differentiation of CD8+ T lymphocytes in the presence of the Tc17 differentiation molecules IL6 and TGF-B1. These findings suggest that 2G-NN16 could facilitate drug delivery and may be used to treat inflammatory processes driven by Tc17 cells. PMID:22023154

  8. Synthesis and characterization of a PAMAM dendrimer nanocarrier functionalized by SRL peptide for targeted gene delivery to the brain.

    PubMed

    Zarebkohan, Amir; Najafi, Farhood; Moghimi, Hamid Reza; Hemmati, Mohammad; Deevband, Mohammad Reza; Kazemi, Bahram

    2015-10-12

    Blood-brain barrier inhibits most of drugs and genetic materials from reaching the brain. So, developing high efficiency carriers for gene and drug delivery to the brain, is the challenging area in pharmaceutical sciences. This investigation aimed to target DNA to brain using Serine-Arginine-Leucine (SRL) functionalized PAMAM dendrimers as a novel gene delivery system. The SRL peptide was linked on G4 PAMAM dendrimers using bifunctional PEG. DNA was then loaded in these functionalized nanoparticles and their physicochemical properties and cellular uptake/distribution evaluated by AFM, NMR, FTIR and fluorescence and confocal microscopy. Also, biodistribution and brain localization of nanoparticles were studied after IV injection of nanoparticles into rat tail. Unmodified nanoparticles were used as control in all evaluations. In vitro studies showed that SRL-modified nanoparticles have good transfection efficacy and low toxicity. Results also showed that SRL is a LRP ligand and SRL-modified nanoparticles internalized by clathrin/caveolin energy-dependent endocytosis to brain capillary endothelial cells. After intravenous administration, the SRL-modified nanoparticles were able to cross the blood-brain barrier and enter the brain parenchyma. Our result showed that, SRL-modified nanoparticles provide a safe and effective nanocarrier for brain gene delivery. PMID:26118442

  9. Inter- and intra-molecular energy transfers of encapsulate dyes in dendrimers

    NASA Astrophysics Data System (ADS)

    Otomo, Akira; Zhou, Minniu; Furumi, Seiichi; Yokoyama, Shiyoshi; Mashiko, Shinro

    2002-12-01

    Dendrimers are capable to encapsulate small molecules inside them. Because three-dimensional structures of dendrimers are highly controllable, energy transfers among dye molecules encapsulated inside them can be controlled precisely. Electronic energy transfers from optical excited molecules are categorized into two classes, Forster and Dexter types. Inter-molecular interactions between encapsulated dyes can be expressed as the Forster (singlet-singlet) energy transfer, because the size of dendrimers extends to a few nanometers. We have evaluated time resolved optical responses in rhodamine-cored dendrimer films. Fast decay in fluorescent lifetime is observed and it depends on the dendrimer size. A low generation dendrimer shows lifetime as short as 10 psec without severe quenching of fluorescence. A quadratic dependence of the emission intensity on density of molecules indicates that the origin of the short lifetime is not only energy transfer, but also super-radiance. Since the Dexter (triplet-triplet) energy transfer occurs in short range of 1.0 nm, we attached both donor and acceptor molecules to a dendrimer for investigation. We demonstrated photocrosslinking via triplet-triplet energy transfer from donor molecules encapsulated to acceptors attached at the surface. This procedure of triplet-triplet energy transfer in dendritic molecules opens up way to design novel optical and electrical molecular devices.

  10. Promoting siRNA delivery via enhanced cellular uptake using an arginine-decorated amphiphilic dendrimer

    NASA Astrophysics Data System (ADS)

    Liu, Xiaoxuan; Liu, Cheng; Zhou, Jiehua; Chen, Chao; Qu, Fanqi; Rossi, John J.; Rocchi, Palma; Peng, Ling

    2015-02-01

    RNA interference (RNAi) with small interfering RNA (siRNA) is expected to offer an attractive means to specifically and efficiently silence disease-associated genes for treating various diseases provided that safe and efficient delivery systems are available. In this study, we have established an arginine-decorated amphiphilic dendrimer composed of a hydrophobic alkyl chain and a hydrophilic PAMAM dendron bearing arginine terminals as nonviral vector for siRNA delivery. Indeed, this dendrimer proved to be very effective at delivering siRNAs in human prostate cancer PC-3 cells and in human hematopoietic CD34+ stem cells, leading to improved gene silencing compared to the corresponding nonarginine decorated dendrimer. Further investigation confirmed that this dendrimer was granted with the capacity to form stable nanoparticles with siRNA and significantly enhance cellular uptake of siRNA. In addition, this dendrimer revealed no discernible cytotoxicity. All these findings demonstrate that decoration of the dendrimer surface with arginine residues is indeed a useful strategy to improve the delivery ability of dendrimers.

  11. Prolonged drug delivery system of an antifungal drug by association with polyamidoamine dendrimers

    PubMed Central

    Jose, Jobin; Charyulu, R Narayana

    2016-01-01

    Introduction: The potent antifungal agent amphotericin B (AmB) is not freely soluble in water. The clinical use of AmB is limited by nephrotoxicity and poor water solubility. Polyamidoamine (PAMAM) dendrimer offers an identical carrier for drug binding that has the capacity to attach and discharge drugs in numerous ways. Materials and methods: In this research work, we explored the potential of PAMAM dendrimers to improve the solubility of AmB. Results and discussion: The experimental results indicated that the solubility of AmB was greatly enhanced in the presence of PAMAM dendrimer solutions. Results indicated that the solubility of AmB enhanced with increase in dendrimer generations as well as concentration. In vitro release studies of AmB in the presence of the third generation of PAMAM dendrimers was performed by the dialysis method. Our research work revealed that binding of drug into dendrimers led to sustained release of AmB in vitro. Conclusion: Based on the stability studies, it was concluded that the drug dendrimer complex should be stored in a dark place at a cool temperature. PMID:27051632

  12. Synthesis, Radiolabeling, and In Vivo Imaging of PEGylated High-Generation Polyester Dendrimers.

    PubMed

    McNelles, Stuart A; Knight, Spencer D; Janzen, Nancy; Valliant, John F; Adronov, Alex

    2015-09-14

    A fifth generation aliphatic polyester dendrimer was functionalized with vinyl groups at the periphery and a dipicolylamine Tc(I) chelate at the core. This structure was PEGylated with three different molecular weight mPEGs (mPEG160, mPEG350, and mPEG750) using thiol-ene click chemistry. The size of the resulting macromolecules was evaluated using dynamic light scattering, and it was found that the dendrimer functionalized with mPEG750 was molecularly dispersed in water, exhibiting a hydrodynamic diameter of 9.2 ± 2.1 nm. This PEGylated dendrimer was subsequently radiolabeled using [(99m)Tc(CO)3(H2O)3](+) and purified to high (>99%) radiochemical purity. Imaging studies were initially performed on healthy rats to allow comparison to previous Tc-labeled dendrimers and then on xenograft murine tumor models, which collectively showed that the dendrimers circulated in the blood for an extended period of time (up to 24 h). Furthermore, the radiolabeled dendrimer accumulated in H520 xenograft tumors, which could be visualized by single-photon emission computed tomography (SPECT). The reported PEGylated aliphatic polyester dendrimers represent a new platform for developing tumor-targeted molecular imaging probes and therapeutics. PMID:26295201

  13. Rational design of dendrimer/lipid nanoassemblies in drug delivery for cancer chemotherapy

    NASA Astrophysics Data System (ADS)

    Sun, Qihang

    Nanocarriers can minimize the side effects and improve therapeutic efficacy of anticancer drugs. Although some success has been achieved via active or passive drug delivery to tumor cells, the known nanocarriers are far from satisfying therapeutic efficacy expectations. This is because they usually fail in one of the four crucial requirements, that is, to retain drug in blood circulation but release it reliably in tumor cells and to be stealthy in transport in circulation and tumor tissue but sticky upon arrival at the tumor cell. Therefore, the goal of this work is to fabricate nanoassemblies of dendrimers and lipids to address all these challenges. Particularly, nanoassemblies designed and prepared in this work are illustrated to improve the tumor tissue penetration. Examples of dendrimers synthesized in this work are water-insoluble, pH-dependent water-insoluble and water-soluble biodegradable polyester dendrimers. These dendrimers are shown to be encapsulated by commonly used fusogenic and long-circulating lipids to form reliable nanoassemblies. The dendrimer/lipid nanocarriers are used to demonstrate a cascade drug delivery. They are expected to be stable in circulation, due to their appropriately large size, but to release the drug-loaded dendrimers in tumor tissue. The released dendrimers carrying drugs are much smaller and hence expected to have a much deeper penetration throughout the tumor tissue.

  14. Transepithelial Transport of PAMAM Dendrimers across Isolated Rat Jejunal Mucosae in Ussing Chambers

    PubMed Central

    2015-01-01

    Oral delivery remains a challenge for poorly permeable hydrophilic macromolecules. Poly(amido amine) (PAMAM) dendrimers have shown potential for their possible oral delivery. Transepithelial transport of carboxyl-terminated G3.5 and amine-terminated G4 PAMAM dendrimers was assessed using isolated rat jejunal mucosae mounted in Ussing chambers. The 1 mM FITC-labeled dendrimers were added to the apical side of mucosae. Apparent permeability coefficients (Papp) from the apical to the basolateral side were significantly increased for FITC when conjugated to G3.5 PAMAM dendrimer compared to FITC alone. Minimal signs of toxicity were observed when mucosae were exposed to both dendrimers with respect to transepithelial electrical resistance changes, carbachol-induced short circuit current stimulation, and histological changes. [14C]-mannitol fluxes were not altered in the presence of 1 mM dendrimers, suggesting that the paracellular pathway was not affected at this concentration in this model. These results give insight into the mechanism of PAMAM dendrimer transepithelial rat jejunal transport, as well as toxicological considerations important for oral drug delivery. PMID:24992090

  15. Electron injection from graphene quantum dots to poly(amido amine) dendrimers

    NASA Astrophysics Data System (ADS)

    Lin, T. N.; Inciong, M. R.; Santiago, S. R.; Kao, C. W.; Shu, G. W.; Yuan, C. T.; Shen, J. L.; Yeh, J. M.; Chen-Yang, Y. W.

    2016-04-01

    The steady-state and time-resolved photoluminescence (PL) are used to study the electron injection from graphene quantum dots (GQDs) to poly(amido amine) (PAMAM) dendrimers. The PL is enhanced by depositing GQDs on the surfaces of the PAMAM dendrimers. The maximum enhancement of PL with a factor of 10.9 is achieved at a GQD concentration of 0.9 mg/ml. The dynamics of PL in the GQD/PAMAM composite are analyzed, evidencing the existence of electron injection. On the basis of Kelvin probe measurements, the electron injection from the GQDs to the PAMAM dendrimers is accounted for by the work function difference between them.

  16. Mesoporous silica nanoparticles with controlled loading of cationic dendrimer for gene delivery

    NASA Astrophysics Data System (ADS)

    Lin, Jian-Tao; Wang, Chao; Zhao, Yi; Wang, Guan-Hai

    2014-09-01

    In this work, a series of polyamidoamine (PAMAM) dendrimer-functionalized mesoporous silica nanoparticles (MSNs) with predictable and adjustable cationic charge densities for gene delivery were designed, synthesized and characterized. The ‘clickable’ MSNs with controlled and randomly distributed azide groups were synthesized by co-condensation method, and PAMAM dendrimer was conjugated to MSNs via quantitative click modification. The structures of PAMAM-functionalized MSNs were characterized by FTIR, XRD and TEM analyses. Dendrimer-functionalized MSNs formed complexes with plasmid DNA (pDNA), and the complexes were successfully transfected into human kidney cell 293 T. The in vitro cytotoxicity and gene transfection efficacy were also investigated.

  17. A novel fluorescent sensor for Cr 3+ based on rhodamine-cored poly (amidoamine) dendrimer

    NASA Astrophysics Data System (ADS)

    Lei, Yonglin; Su, Yuanqiang; Huo, Jichuan

    2011-12-01

    A novel poly (amidoamine) (PAMAM) dendrimer, comprising rhodamine B unit in the core and 1-phenyl-3-methyl-5-pyrazolone unit at the periphery, has been synthesized and characterized. The dendrimer shows dramatic increase in its fluorescence intensity in the presence of proton and metal cations, especially in the presence of Cr 3+. The complex formed by dendrimer and Cr 3+ in ethanol solution has also been studied, considering the potential application for Cr 3+ fluorescent sensor. The influence of the unique chemical structure and resulted photoinduced electron transfer, as well as spirolactam ring-opening on the photophysical properties of the product has been investigated.

  18. Charge-Dependent Dynamics of Polyelectrolyte Dendrimer and Its Correlation with Invasive Water

    SciTech Connect

    Chen, Wei-Ren; Hong, Kunlun; Li, Xin; Liu, Emily; Liu, Yun; Porcar, L.; Smith, Gregory Scott; Wu, Bin; Mamontov, Eugene; Egami, T.; Kolesnikov, Alexander I; Diallo, Souleymane Omar

    2013-01-01

    Atomistic molecular dynamics (MD) simulations were carried out to investigate the local dynamics of polyelectrolyte dendrimers dissolved in deuterium oxide (D2O) and its dependence on molecular charge. Enhanced segmental dy-namics upon increase in molecular charge is observed, consistent with quasielastic neutron scattering (QENS) measurements. A strong coupling between the intra-dendrimer local hydration level and segmental dynamics is also revealed. Compelling evidence shows these findings originate from the electrostatic interaction between the hydrocarbon components of dendrimer and invasive water. This combined study provides fundamental insight into the dynamics of charged polyelectrolytes and the solvating water molecules.

  19. Photoinduced Electron Transfer of PAMAM Dendrimer-Zinc(II) Porphyrin Associates at Polarized Liquid|Liquid Interfaces.

    PubMed

    Nagatani, Hirohisa; Sakae, Hiroki; Torikai, Taishi; Sagara, Takamasa; Imura, Hisanori

    2015-06-01

    The heterogeneous photoinduced electron-transfer reaction of the ion associates between NH2-terminated polyamidoamine (PAMAM) dendrimers and 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato zinc(II) (ZnTPPS(4-)) was studied at the polarized water|1,2-dichloroethane (DCE) interface. The positive photocurrent arising from the photoreduction of ZnTPPS(4-) by a lipophilic quencher, decamethylferrocene, in the interfacial region was significantly enhanced by the ion association with the PAMAM dendrimers. The photocurrent response of the dendrimer-ZnTPPS(4-) associates was dependent on the pH condition and on the generation of dendrimer. A few cationic additives such as polyallylamine and n-octyltrimethyammonium were also examined as alternatives to the PAMAM dendrimer, but the magnitude of the photocurrent enhancement was rather small. The high photoreactivity of the dendrimer-ZnTPPS(4-) associates was interpreted mainly as a result of the high interfacial concentration of photoreactive porphyrin units associated stably with the dendrimer which was preferably adsorbed at the polarized water|DCE interface. The photochemical data observed in the second and fourth generation PAMAM dendrimer systems demonstrated that the higher generation dendrimer which can incorporate a porphyrin molecule more completely in the interior is less efficient for the photocurrent enhancement at the interface. These results indicated that the photoreactivity of ionic reactant at a polarized liquid|liquid interface can readily be modified via ion association with the charged dendrimer. PMID:25989445

  20. Interactions of dendrimers with biological drug targets: reality or mystery - a gap in drug delivery and development research.

    PubMed

    Ahmed, Shaimaa; Vepuri, Suresh B; Kalhapure, Rahul S; Govender, Thirumala

    2016-07-21

    Dendrimers have emerged as novel and efficient materials that can be used as therapeutic agents/drugs or as drug delivery carriers to enhance therapeutic outcomes. Molecular dendrimer interactions are central to their applications and realising their potential. The molecular interactions of dendrimers with drugs or other materials in drug delivery systems or drug conjugates have been extensively reported in the literature. However, despite the growing application of dendrimers as biologically active materials, research focusing on the mechanistic analysis of dendrimer interactions with therapeutic biological targets is currently lacking in the literature. This comprehensive review on dendrimers over the last 15 years therefore attempts to identify the reasons behind the apparent lack of dendrimer-receptor research and proposes approaches to address this issue. The structure, hierarchy and applications of dendrimers are briefly highlighted, followed by a review of their various applications, specifically as biologically active materials, with a focus on their interactions at the target site. It concludes with a technical guide to assist researchers on how to employ various molecular modelling and computational approaches for research on dendrimer interactions with biological targets at a molecular level. This review highlights the impact of a mechanistic analysis of dendrimer interactions on a molecular level, serves to guide and optimise their discovery as medicinal agents, and hopes to stimulate multidisciplinary research between scientific, experimental and molecular modelling research teams. PMID:27100841

  1. Transcriptomic response of zebrafish embryos to polyaminoamine (PAMAM) dendrimers.

    PubMed

    Oliveira, Eva; Casado, Marta; Faria, Melissa; Soares, Amadeu M V M; Navas, José María; Barata, Carlos; Piña, Benjamin

    2014-08-01

    The progressive practical applications of engineered nanoparticles results in their ever-increasing release into the environment. Accurate assessment of their environmental and health risks requires the development of methods allowing their monitoring in different environmental compartments and the evaluation of their potential toxicity at different levels of organization. Toxic effects of third-generation (G3) and fourth-generation (G4) poly(amidoamine) dendrimers (ethylenediamine cored, imine-terminated) were assessed on zebrafish embryos during the first two days post-fertilization. Particle characterization by dynamic light scattering showed no tendency to form aggregates in the assay conditions. G3 particles showed somewhat a higher acute toxicity than G4 particles, with LC50 values of 1.8 and 2.3 mg/L, respectively. At sublethal concentrations, both particles affected the zebrafish transcriptome following similar patterns, suggesting a similar mode of action. About 700 transcripts were affected by at least one of the treatments, following a pattern with significant correlations to the effects of bacterial infection in zebrafish embryos. We concluded that the response to G3 and G4 dendrimers was consistent with the activation of the innate immune response, a still unreported potential effect of these particles. These data may contribute to the characterization of hazards of these nanomaterials for both human health and the environment. PMID:24266889

  2. Organometallic Silicon-Containing Dendrimers and Their Electrochemical Applications

    NASA Astrophysics Data System (ADS)

    Cuadrado, Isabel

    Dendrimers constitute a unique class of macromolecular architectures that differs from all other synthetic macromolecules in its perfectly branched topology, which is constructed from a multifunctional central core and expands to the periphery that becomes denser with increasing generation number (see Chapter 1) [1-5]. Since the pioneering works published in the late 1970s and the mid-1980s [6-8], the design and synthesis of these tree-like, well-defined molecules, which exhibit a unique combination of chemical and physical properties, is a field which has sustained dramatic growth and has generated enthusiastic studies at the frontiers of organic, inorganic, supramolecular and polymer chemistry, and more recently in the fields of nanoscience, biotechnology and medicine [1-5, 9, 10]. Whereas the initial interest in dendrimers was focused on the synthetic and structural characterization challenges that pose their fractal geometries, nanometer sizes and monodisperse nature, in the last decade the emphasis has been placed mainly on modification of the properties of dendritic molecules by their functionalization

  3. From structure to function via complex supramolecular dendrimer systems.

    PubMed

    Sun, Hao-Jan; Zhang, Shaodong; Percec, Virgil

    2015-06-21

    This tutorial review summarizes strategies elaborated for the discovery and prediction of programmed primary structures derived from quasi-equivalent constitutional isomeric libraries of self-assembling dendrons, dendrimers and dendronized polymers. These libraries demonstrate an 82% predictability, defined as the percentage of similar primary structures resulting in at least one conserved supramolecular shape with internal order. A combination of structural and retrostructural analysis that employs methodologies transplanted from structural biology, adapted to giant supramolecular assemblies was used for this process. A periodic table database of programmed primary structures was elaborated and used to facilitate the emergence of a diversity of functions in complex dendrimer systems via first principles. Assemblies generated by supramolecular and covalent polymer backbones were critically compared. Although by definition complex functional systems cannot be designed, this tutorial hints to a methodology based on database analysis principles to facilitate design principles that may help to mediate an accelerated emergence of chemical, physical and most probably also societal, political and economic complex systems on a shorter time scale and lower cost than by the current methods. This tutorial review is limited to the simplest, synthetically most accessible self-assembling minidendrons, minidendrimers and polymers dendronized with minidendrons that are best analyzed and elucidated at molecular, supramolecular and theoretical levels, and most used in other laboratories. These structures are all interrelated, and their principles expand in a simple way to their higher generations. PMID:25325787

  4. Enzyme-linked DNA dendrimer nanosensors for acetylcholine

    PubMed Central

    Walsh, Ryan; Morales, Jennifer M.; Skipwith, Christopher G.; Ruckh, Timothy T.; Clark, Heather A.

    2015-01-01

    It is currently difficult to measure small dynamics of molecules in the brain with high spatial and temporal resolution while connecting them to the bigger picture of brain function. A step towards understanding the underlying neural networks of the brain is the ability to sense discrete changes of acetylcholine within a synapse. Here we show an efficient method for generating acetylcholine-detecting nanosensors based on DNA dendrimer scaffolds that incorporate butyrylcholinesterase and fluorescein in a nanoscale arrangement. These nanosensors are selective for acetylcholine and reversibly respond to levels of acetylcholine in the neurophysiological range. This DNA dendrimer architecture has the potential to overcome current obstacles to sensing in the synaptic environment, including the nanoscale size constraints of the synapse and the ability to quantify the spatio-temporal fluctuations of neurotransmitter release. By combining the control of nanosensor architecture with the strategic placement of fluorescent reporters and enzymes, this novel nanosensor platform can facilitate the development of new selective imaging tools for neuroscience. PMID:26442999

  5. Record Multiphoton Absorption Cross-Sections by Dendrimer Organometalation.

    PubMed

    Simpson, Peter V; Watson, Laurance A; Barlow, Adam; Wang, Genmiao; Cifuentes, Marie P; Humphrey, Mark G

    2016-02-12

    Large increases in molecular two-photon absorption, the onset of measurable molecular three-photon absorption, and record molecular four-photon absorption in organic π-delocalizable frameworks are achieved by incorporation of bis(diphosphine)ruthenium units with alkynyl linkages. The resultant ruthenium alkynyl-containing dendrimers exhibit strong multiphoton absorption activity through the biological and telecommunications windows in the near-infrared region. The ligated ruthenium units significantly enhance solubility and introduce fully reversible redox switchability to the optical properties. Increasing the ruthenium content leads to substantial increases in multiphoton absorption properties without any loss of optical transparency. This significant improvement in multiphoton absorption performance by incorporation of the organometallic units into the organic π-framework is maintained when the relevant parameters are scaled by molecular weights or number of delocalizable π-electrons. The four-photon absorption cross-section of the most metal-rich dendrimer is an order of magnitude greater than the previous record value. PMID:26797727

  6. Enzyme-linked DNA dendrimer nanosensors for acetylcholine

    NASA Astrophysics Data System (ADS)

    Walsh, Ryan; Morales, Jennifer M.; Skipwith, Christopher G.; Ruckh, Timothy T.; Clark, Heather A.

    2015-10-01

    It is currently difficult to measure small dynamics of molecules in the brain with high spatial and temporal resolution while connecting them to the bigger picture of brain function. A step towards understanding the underlying neural networks of the brain is the ability to sense discrete changes of acetylcholine within a synapse. Here we show an efficient method for generating acetylcholine-detecting nanosensors based on DNA dendrimer scaffolds that incorporate butyrylcholinesterase and fluorescein in a nanoscale arrangement. These nanosensors are selective for acetylcholine and reversibly respond to levels of acetylcholine in the neurophysiological range. This DNA dendrimer architecture has the potential to overcome current obstacles to sensing in the synaptic environment, including the nanoscale size constraints of the synapse and the ability to quantify the spatio-temporal fluctuations of neurotransmitter release. By combining the control of nanosensor architecture with the strategic placement of fluorescent reporters and enzymes, this novel nanosensor platform can facilitate the development of new selective imaging tools for neuroscience.

  7. Direct Synthesis and Morphological Characterization of Gold-Dendrimer Nanocomposites Prepared Using PAMAM Succinamic Acid Dendrimers: Preliminary Study of the Calcification Potential

    PubMed Central

    Vasile, E.; Serafim, A.; Petre, D.; Giol, D.; Dubruel, P.; Iovu, H.; Stancu, I. C.

    2014-01-01

    Gold-dendrimer nanocomposites were obtained for the first time by a simple colloidal approach based on the use of polyamidoamine dendrimers with succinamic acid terminal groups and dodecanediamine core. Spherical and highly crystalline nanoparticles with dimensions between 3 nm and 60 nm, and size-polydispersity depending on the synthesis conditions, have been generated. The influence of the stoichiometric ratio and the structural and architectural features of the dendrimers on the properties of the nanocomposites has been described. The self-assembling behaviour of these materials produces gold-dendrimer nanostructured porous networks with variable density, porosity, and composition. The investigations of the reaction systems, by TEM, at two postsynthesis moments, allowed to preliminary establish the control over the properties of the nanocomposite products. Furthermore, this study allowed better understanding of the mechanism of nanocomposite generation. Impressively, in the early stages of the synthesis, the organization of gold inside the dendrimer molecules has been evidenced by micrographs. Growth and ripening mechanisms further lead to nanoparticles with typical characteristics. The potential of such nanocomposite particles to induce calcification when coating a polymer substrate was also investigated. PMID:24600316

  8. Oral Absorption Enhancement of Probucol by PEGylated G5 PAMAM Dendrimer Modified Nanoliposomes

    PubMed Central

    Ma, Qian; Han, Yingchun; Chen, Cong; Cao, Yini; Wang, Siling; Shen, Wenwen; Zhang, Huayu; Li, Yanzhi; van Dongen, Mallory A.; He, Bing; Yu, Maomao; Xu, Lu; Banaszak Holl, Mark M.; Liu, George; Zhang, Qiang; Qi, Rong

    2016-01-01

    Probucol (PB), an antioxidant drug, is commonly used as a lipid concentration lowering drug to reduce blood plasma cholesterol levels in the clinic. However, the therapeutic effects of this drug are negatively impacted by its poor water solubility and low oral absorption efficiency. In this study, a PEGylated G5 PAMAM dendrimer (G5-PEG) modified nanoliposome was employed to increase water solubility, transepithelial transport, and oral absorption of PB. The uptake mechanism was explored in vitro in Caco-2 cells with the results suggesting that the absorption improvement of G5-PEG modified PB-liposome (PB-liposome/G5-PEG) was related to P-glycoprotein (P-gp) efflux pump, but was independent of caveolae endocytosis pathways. Additionally, plasma lipid concentration lowering effects of PB-liposome/G5-PEG were evaluated in vivo in a LDLR−/− hyperlipidemia mouse model. Compared with saline treated group, treatment with PB-liposome/G5-PEG significantly inhibited the increase of plasma total cholesterol (TC) and triglyceride (TG) of mice induced by a high fat diet. Moreover, its lipid concentration lowering effects and plasma drug concentration were greater than PB alone or commercial PB tablets. Our results demonstrated that PB-liposome/G5-PEG significantly increased the oral absorption of PB and therefore, significantly improved its pharmacodynamic effects. PMID:25587935

  9. Transdermal delivery of therapeutic agents using dendrimers (US20140018435A1): a patent evaluation.

    PubMed

    Yang, Jiepin; Hu, Jingjing; He, Binwei; Cheng, Yiyun

    2015-01-01

    Transdermal drug delivery offers a number of advantages over systematic administrations such as oral administration and intravenous injection. However, most therapeutic agents are limited in transdermal delivery due to the presence of a stratum corneum barrier. A number of chemical penetration enhancers were used to facilitate the penetration of drugs with poor skin permeability across the barrier, but these enhancers are usually associated with safety concerns such as skin irritation and immune response. The current patent application by Hong et al. provides the potential use of surface-engineered dendrimers for transdermal delivery of therapeutic agents. It systemically demonstrates the effect of dendrimer generation, surface chemistry and hydrophobicity on the skin permeability of dendrimers. The most efficient dendrimer shows nearly 30% skin permeation when its surface was conjugated with endoxifen, a drug widely used for the treatment of breast cancers. The described technique provides an efficient and safe method for the delivery of therapeutic agents, especially chemopreventive compounds and anticancer drugs. PMID:26150049

  10. Salicylic Acid Conjugated Dendrimers Are a Tunable, High Performance CEST MRI NanoPlatform.

    PubMed

    Lesniak, Wojciech G; Oskolkov, Nikita; Song, Xiaolei; Lal, Bachchu; Yang, Xing; Pomper, Martin; Laterra, John; Nimmagadda, Sridhar; McMahon, Michael T

    2016-04-13

    Chemical exchange saturation transfer (CEST) is a novel MRI contrast mechanism that is well suited for imaging, however, existing small molecule CEST agents suffer from low sensitivity. We have developed salicylic acid conjugated dendrimers as a versatile, high performance nanoplatform. In particular, we have prepared nanocarriers based on generation 5-poly(amidoamine) (PAMAM) dendrimers with salicylic acid covalently attached to their surface. The resulting conjugates produce strong CEST contrast 9.4 ppm from water with the proton exchange tunable from ∼1000 s(-1) to ∼4500 s(-1) making these dendrimers well suited for sensitive detection. Furthermore, we demonstrate that these conjugates can be used for monitoring convection enhanced delivery into U87 glioblastoma bearing mice, with the contrast produced by these nanoparticles persisting for over 1.5 h and distributed over ∼50% of the tumors. Our results demonstrate that SA modified dendrimers present a promising new nanoplatform for medical applications. PMID:26910126

  11. Dendrimers as tunable vectors of drug delivery systems and biomedical and ocular applications

    PubMed Central

    Kalomiraki, Marina; Thermos, Kyriaki; Chaniotakis, Nikos A

    2016-01-01

    Dendrimers are large polymeric structures with nanosize dimensions (1–10 nm) and unique physicochemical properties. The major advantage of dendrimers compared with linear polymers is their spherical-shaped structure. During synthesis, the size and shape of the dendrimer can be customized and controlled, so the finished macromolecule will have a specific “architecture” and terminal groups. These characteristics will determine its suitability for drug delivery, diagnostic imaging, and as a genetic material carrier. This review will focus initially on the unique properties of dendrimers and their use in biomedical applications, as antibacterial, antitumor, and diagnostic agents. Subsequently, emphasis will be given to their use in drug delivery for ocular diseases. PMID:26730187

  12. A functionalized fluorescent dendrimer as a pesticide nanocarrier: application in pest control

    NASA Astrophysics Data System (ADS)

    Liu, Xiaoxia; He, Bicheng; Xu, Zejun; Yin, Meizhen; Yang, Wantai; Zhang, Huaijiang; Cao, Jingjun; Shen, Jie

    2014-12-01

    We report the delivery of a hydrophobic pesticide, thiamethoxam, by water-soluble nanosized cationic dendrimers that contain hydrophobic dendritic polyesters and peripheral amines, demonstrated by DLS, spectral analysis and ITC. The dendrimer-based nanocarrier can efficiently deliver the pesticide into the live cells and largely increase the cytotoxicity of the drug.We report the delivery of a hydrophobic pesticide, thiamethoxam, by water-soluble nanosized cationic dendrimers that contain hydrophobic dendritic polyesters and peripheral amines, demonstrated by DLS, spectral analysis and ITC. The dendrimer-based nanocarrier can efficiently deliver the pesticide into the live cells and largely increase the cytotoxicity of the drug. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr05733c

  13. Poly(amidoamine) Dendrimers with Carbonic Anhydrase Inhibitory Activity and Antiglaucoma Action.

    PubMed

    Carta, Fabrizio; Osman, Sameh M; Vullo, Daniela; Gullotto, Antonella; Winum, Jean-Yves; AlOthman, Zeid; Masini, Emanuela; Supuran, Claudiu T

    2015-05-14

    Four generations of poly(amidoamine) (PAMAM) dendrimers decorated with benzenesulfonamide moieties were prepared by derivatizing the amino groups of the dendrimer with 4-carboxy-benzenesulfonamide functionalities. Compounds incorporating 4, 8, 16, and 32 sulfonamide moieties were thus obtained, which showed an increasing carbonic anhydrase (CA, EC 4.2.1.1) inhibitory action with the increase of the number of sulfamoyl groups in the dendrimer. Best inhibitory activity (in the low nanomolar-subnanomolar range) was observed for isoforms CA II and XII, involved among others in glaucoma. In an animal model of this disease, the chronic administration of such dendrimers for 5 days led to a much more efficient drop of intraocular pressure compared to the standard drug dorzolamide. PMID:25849626

  14. High-boron-content porphyrin-cored aryl ether dendrimers: controlled synthesis, characterization, and photophysical properties.

    PubMed

    Cabrera-González, Justo; Xochitiotzi-Flores, Elba; Viñas, Clara; Teixidor, Francesc; García-Ortega, Héctor; Farfán, Norberto; Santillan, Rosa; Parella, Teodor; Núñez, Rosario

    2015-05-18

    The synthesis and characterization of a set of poly(aryl ether) dendrimers with tetraphenylporphyrin as the core and 4, 8, 16, or 32 closo-carborane clusters are described. A regioselective hydrosilylation reaction on the allyl-terminated functions with carboranylsilanes in the presence of Karstedt's catalyst leads to different generations of boron-enriched dendrimers. This versatile approach allows the incorporation of a large number of boron atoms in the dendrimers' periphery. Translational diffusion coefficients (D) determined by DOSY NMR experiments permit estimation of the hydrodynamic radius (RH) and molecular size for each dendrimer. Furthermore, a notable correlation between D and the molecular weight (MW) is found and can be used to predict their overall size and folding properties. The UV-vis and emission behavior are not largely affected by the functionalization, therefore implying that the presence of carboranes does not alter their photoluminescence properties. PMID:25920702

  15. Radionuclide 131I-labeled multifunctional dendrimers for targeted SPECT imaging and radiotherapy of tumors

    NASA Astrophysics Data System (ADS)

    Zhu, Jingyi; Zhao, Lingzhou; Cheng, Yongjun; Xiong, Zhijuan; Tang, Yueqin; Shen, Mingwu; Zhao, Jinhua; Shi, Xiangyang

    2015-10-01

    We report the synthesis, characterization, and utilization of radioactive 131I-labeled multifunctional dendrimers for targeted single-photon emission computed tomography (SPECT) imaging and radiotherapy of tumors. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) were sequentially modified with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO) and folic acid (FA) linked with polyethylene glycol (PEG), followed by acetylation modification of the dendrimer remaining surface amines and labeling of radioactive iodine-131 (131I). The generated multifunctional 131I-G5.NHAc-HPAO-PEG-FA dendrimers were characterized via different methods. We show that prior to 131I labeling, the G5.NHAc-HPAO-PEG-FA dendrimers conjugated with approximately 9.4 HPAO moieties per dendrimer are noncytotoxic at a concentration up to 20 μM and are able to target cancer cells overexpressing FA receptors (FAR), thanks to the modified FA ligands. In the presence of a phenol group, radioactive 131I is able to be efficiently labeled onto the dendrimer platform with good stability and high radiochemical purity, and render the platform with an ability for targeted SPECT imaging and radiotherapy of an FAR-overexpressing xenografted tumor model in vivo. The designed strategy to use the facile dendrimer nanotechnology may be extended to develop various radioactive theranostic nanoplatforms for targeted SPECT imaging and radiotherapy of different types of cancer.We report the synthesis, characterization, and utilization of radioactive 131I-labeled multifunctional dendrimers for targeted single-photon emission computed tomography (SPECT) imaging and radiotherapy of tumors. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH2) were sequentially modified with 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO) and folic acid (FA) linked with polyethylene glycol (PEG), followed by acetylation modification of the dendrimer remaining surface amines and

  16. Brain Targeting of a Water Insoluble Antipsychotic Drug Haloperidol via the Intranasal Route Using PAMAM Dendrimer.

    PubMed

    Katare, Yogesh K; Daya, Ritesh P; Sookram Gray, Christal; Luckham, Roger E; Bhandari, Jayant; Chauhan, Abhay S; Mishra, Ram K

    2015-09-01

    Delivery of therapeutics to the brain is challenging because many organic molecules have inadequate aqueous solubility and limited bioavailability. We investigated the efficiency of a dendrimer-based formulation of a poorly aqueous soluble drug, haloperidol, in targeting the brain via intranasal and intraperitoneal administration. Aqueous solubility of haloperidol was increased by more than 100-fold in the developed formulation. Formulation was assessed via different routes of administration for behavioral (cataleptic and locomotor) responses, and for haloperidol distribution in plasma and brain tissues. Dendrimer-based formulation showed significantly higher distribution of haloperidol in the brain and plasma compared to a control formulation of haloperidol administered via intraperitoneal injection. Additionally, 6.7 times lower doses of the dendrimer-haloperidol formulation administered via the intranasal route produced behavioral responses that were comparable to those induced by haloperidol formulations administered via intraperitoneal injection. This study demonstrates the potential of dendrimer in improving the delivery of water insoluble drugs to brain. PMID:26226403

  17. Converting Nonliquid Crystals into Liquid Crystals by N-Methylation in the Central Linker of Triazine-Based Dendrimers.

    PubMed

    Tsai, Meng-Jung; Hsieh, Jei-Way; Lai, Long-Li; Cheng, Kung-Lung; Liu, Shih-Hsien; Lee, Jey-Jau; Hsu, Hsiu-Fu

    2016-06-17

    Two triazine-based dendrimers were successfully prepared in 60-75% yields. These newly prepared dendrimers 2a and 2b containing the -NMe(CH2)2NMe- and the -NMe(CH2)4NMe- linkers between two G3 dendrons, respectively, exhibit columnar phases during the thermal process. However, the corresponding dendrimers 1a and 1b containing the -NH(CH2)2NH- and the -NH(CH2)4NH- linkers between two G3 dendrons, respectively, do not show any LC phases on thermal treatment. Computational investigations on molecular conformations reveal that N-methylation of the dendritic central linker leads dendrimers to possess more isomeric conformations and thus successfully converts non-LC dendrimers (1a and 1b) into LC dendrimers (2a and 2b). PMID:27203100

  18. High-Resolution Imaging of Polyethylene Glycol Coated Dendrimers via Combined Atomic Force and Scanning Tunneling Microscopy

    PubMed Central

    Zhong, Qian; Yin, Nai-Ning; Karsai, Arpad; da Rocha, Sandro R. P.; Liu, Gang-yu

    2015-01-01

    Dendrimers have shown great promise as drug delivery vehicles in recent years because they can be synthesized with designed size and functionalities for optimal transportation, targeting, and biocompatibility. One of the most well-known termini used for biocompatibility is polyethylene glycol (PEG), whose performance is affected by its actual conformation. However, the conformation of individual PEG bound to soft materials such as dendrimers has not been directly observed. Using atomic force microscopy (AFM) and scanning tunneling microscopy (STM), this work characterizes the structure adopted by PEGylated dendrimers with the highest resolution reported to date. AFM imaging enables visualization of the individual dendrimers, as well as the differentiation and characterization of the dendrimer core and PEG shell. STM provides direct imaging of the PEG extensions with high-resolution. Collectively, this investigation provides important insight into the structure of coated dendrimers, which is crucial for the design and development of better drug delivery vehicles. PMID:25685559

  19. Interaction study between maltose-modified PPI dendrimers and lipidic model membranes.

    PubMed

    Wrobel, Dominika; Appelhans, Dietmar; Signorelli, Marco; Wiesner, Brigitte; Fessas, Dimitrios; Scheler, Ulrich; Voit, Brigitte; Maly, Jan

    2015-07-01

    The influence of maltose-modified poly(propylene imine) (PPI) dendrimers on dimyristoylphosphatidylcholine (DMPC) or dimyristoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DMPC/DMPG) (3%) liposomes was studied. Fourth generation (G4) PPI dendrimers with primary amino surface groups were partially (open shell glycodendrimers - OS) or completely (dense shell glycodendrimers - DS) modified with maltose residues. As a model membrane, two types of 100nm diameter liposomes were used to observe differences in the interactions between neutral DMPC and negatively charged DMPC/DMPG bilayers. Interactions were studied using fluorescence spectroscopy to evaluate the membrane fluidity of both the hydrophobic and hydrophilic parts of the lipid bilayer and using differential scanning calorimetry to investigate thermodynamic parameter changes. Pulsed-filed gradient NMR experiments were carried out to evaluate common diffusion coefficient of DMPG and DS PPI in D2O when using below critical micelle concentration of DMPG. Both OS and DS PPI G4 dendrimers show interactions with liposomes. Neutral DS dendrimers exhibit stronger changes in membrane fluidity compared to OS dendrimers. The bilayer structure seems more rigid in the case of anionic DMPC/DMPG liposomes in comparison to pure and neutral DMPC liposomes. Generally, interactions of dendrimers with anionic DMPC/DMPG and neutral DMPC liposomes were at the same level. Higher concentrations of positively charged OS dendrimers induced the aggregation process with negatively charged liposomes. For all types of experiments, the presence of NaCl decreased the strength of the interactions between glycodendrimers and liposomes. Based on NMR diffusion experiments we suggest that apart from electrostatic interactions for OS PPI hydrogen bonds play a major role in maltose-modified PPI dendrimer interactions with anionic and neutral model membranes where a contact surface is needed for undergoing multiple H-bond interactions between

  20. Synthesis of Novel Peptide Dendrimers PDL-GB2 and PDL-G2

    PubMed Central

    Yunzhu, Lin; Lingling, Weng; Qingrong, Qi

    2015-01-01

    Peptide dendrimers are a novel type of macromolecules with precise structure, which can be used as drug target vector and controlled-release carrier. So it is valuable to study. In this paper, novel peptide dendrimers PDL-GB2 and PDL-G2 were prepared according to divergent procedure with four-orientation molecule as the core and L-lysine as the branch unit. And the structures were identified by 1HNMR, 13CNMR, MS, and elemental analysis. PMID:25874261

  1. Photoinduced water oxidation sensitized by a tetranuclear Ru(II) dendrimer.

    PubMed

    La Ganga, Giuseppina; Nastasi, Francesco; Campagna, Sebastiano; Puntoriero, Fausto

    2009-12-01

    A multimetallic ruthenium(II) dendrimer is used for the first time to photosensitize dioxygen production from water by IrO2 nanoparticles; the system is more efficient than an analogous system based on the more commonly used [Ru(bpy)3]2+-type photosensitizers, in particular for the ability of the dendrimer to take advantage of the red portion of the solar spectrum. PMID:19904425

  2. Advantages of Monodisperse and Chemically Robust "SpheriCal" Polyester Dendrimers as a "Universal" MS Calibrant

    NASA Astrophysics Data System (ADS)

    Grayson, Scott M.; Myers, Brittany K.; Bengtsson, Jonas; Malkoch, Michael

    2014-03-01

    The utilization of dendrimer calibrants as an alternative to peptides and proteins for high mass calibration is explored. These synthetic macromolecules exhibited a number of attractive advantages, including exceptional shelf-lives, broad compatibility with a wide range of matrices and solvents, and evenly spaced calibration masses across the mass range examined, 700-30,000 u. The exceptional purity of these dendrimers and the technical simplicity of this calibration platform validate their broad relevance for high molecular weight mass spectrometry.

  3. Dendrimers Target the Ischemic Lesion in Rodent and Primate Models of Nonarteritic Anterior Ischemic Optic Neuropathy

    PubMed Central

    Guo, Yan; Johnson, Mary A.; Mehrabian, Zara; Mishra, Manoj K.; Kannan, Rangaramanujam; Miller, Neil R.; Bernstein, Steven L.

    2016-01-01

    Introduction Polyamidoamine dendrimer nanoparticles (~ 4 nanometers) are inert polymers that can be linked to biologically active compounds. These dendrimers selectively target and accumulate in inflammatory cells upon systemic administration. Dendrimer-linked compounds enable sustained release of therapeutic compounds directly at the site of damage. The purpose of this study was to determine if dendrimers can be used to target the optic nerve (ON) ischemic lesion in our rodent and nonhuman primate models of nonarteritic anterior ischemic optic neuropathy (NAION), a disease affecting >10,000 individuals in the US annually, and for which there currently is no effective treatment. Methods NAION was induced in male Long-Evans rats (rNAION) and in one adult male rhesus monkey (pNAION) using previously described procedures. Dendrimers were covalently linked to near-infrared cyanine-5 fluorescent dye (D-Cy5) and injected both intravitreally and systemically (in the rats) or just systemically (in the monkey) to evaluate D-Cy5 tissue accumulation in the eye and optic nerve following induction of NAION. Results Following NAION induction, Cy-5 dendrimers selectively accumulated in astrocytes and circulating macrophages. Systemic dendrimer administration provided the best penetration of the ON lesion site when injected shortly after induction. Systemic administration 1 day post-induction in the pNAION model gave localization similar to that seen in the rats. Conclusions Dendrimers selectively target the ischemic ON lesion after induction of both rNAION and pNAION. Systemic nanoparticle-linked therapeutics thus may provide a powerful, targeted and safe approach to NAION treatment by providing sustained and focused treatment of the cells directly affected by ischemia. PMID:27128315

  4. Highly effective poly(ethylene glycol) architectures for specific inhibition of immune receptor activation.

    PubMed

    Baird, Emily J; Holowka, David; Coates, Geoffrey W; Baird, Barbara

    2003-11-11

    Architectural features of synthetic ligands were systematically varied to optimize inhibition of mast cell degranulation initiated by multivalent crossing of IgE-receptor complexes. A series of ligands were generated by end-capping poly(ethylene glycol) (PEG) polymers and amine-based dendrimers with the hapten 2,4-dinitrophenyl (DNP). These were used to explore the influence of polymeric backbone length, valency, and hapten presentation on binding to anti-DNP IgE and inhibition of stimulated activation of RBL cells. Monovalent MPEG(5000)-DNP (IC(50) = 50 nM), bivalent DNP-PEG(3350)-DNP (IC(50) = 8 nM), bismonovalent MPEG(5000)-DNP(2) (IC(50) = 20 nM), bisbivalent DNP(2)-PEG(3350)-DNP(2) (IC(50) = 3nM) and DNP(4)-dendrimer ligands (IC(50) = 50 nM) all effectively inhibit cellular activation caused by multivalent antigen, DNP-bovine serum albumin. For different DNP ligands, we provide evidence for more effective inhibition due to (i) preferential formation of intra-IgE cross-links by bivalent ligands of sufficient length, (ii) self-association of monovalent ligands with longer tails, and (iii) higher probability of binding for bisvalent ligands. We also show that larger DNP(16)-dendrimers of higher valency trigger degranulation by cross-linking IgE-receptor complexes, whereas smaller DNP-dendrimers are inhibitory. Thus, features of synthetic ligands can be manipulated to control receptor occupation, aggregation, and inhibition of the cellular response. PMID:14596588

  5. Molecular Determinants of the Cellular Entry of Asymmetric Peptide Dendrimers and Role of Caveolae

    PubMed Central

    Rewatkar, Prarthana V.; Parekh, Harendra S.; Parat, Marie-Odile

    2016-01-01

    Caveolae are flask-shaped plasma membrane subdomains abundant in most cell types that participate in endocytosis. Caveola formation and functions require membrane proteins of the caveolin family, and cytoplasmic proteins of the cavin family. Cationic peptide dendrimers are non-vesicular chemical carriers that can transport pharmacological agents or genetic material across the plasma membrane. We prepared a panel of cationic dendrimers and investigated whether they require caveolae to enter into cells. Cell-based studies were performed using wild type or caveola-deficient i.e. caveolin-1 or PTRF gene-disrupted cells. There was a statistically significant difference in entry of cationic dendrimers between wild type and caveola-deficient cells. We further unveiled differences between dendrimers with varying charge density and head groups. Our results show, using a molecular approach, that (i) expression of caveola-forming proteins promotes cellular entry of cationic dendrimers and (ii) dendrimer structure can be modified to promote endocytosis in caveola-forming cells. PMID:26788849

  6. In vitro PAMAM, phosphorus and viologen-phosphorus dendrimers prevent rotenone-induced cell damage.

    PubMed

    Milowska, Katarzyna; Szwed, Aleksandra; Zablocka, Maria; Caminade, Anne-Marie; Majoral, Jean-Pierre; Mignani, Serge; Gabryelak, Teresa; Bryszewska, Maria

    2014-10-20

    We have investigated whether polyamidoamine (PAMAM), phosphorus (pd) and viologen-phosphorus (vpd) dendrimers can prevent damage to embryonic mouse hippocampal cells (mHippoE-18) caused by rotenone, which is used as a pesticide, insecticide, and as a nonselective piscicide, that works by interfering with the electron transport chain in mitochondria. Several basic aspects, such as cell viability, production of reactive oxygen species and changes in mitochondrial transmembrane potential, were analyzed. mHippoE-18 cells were treated with these structurally different dendrimers at 0.1μM. A 1h incubation with dendrimers was followed by the addition of rotenone at 1μM, and a further 24h incubation. PAMAM, phosphorus and viologen-phosphorus dendrimers all increased cell viability (reduced cell death-data need to be compared with untreated controls). A lower level of reactive oxygen species and a favorable effect on mitochondrial system were found with PAMAM and viologen-phosphorus dendrimers. These results indicate reduced toxicity in the presence of dendrimers. PMID:25108046

  7. Dendrimer Nanoscaffolds for Potential Theranostics of Prostate Cancer with a Focus on Radiochemistry

    PubMed Central

    Lo, Su-Tang; Kumar, Amit; Hsieh, Jer-Tsong; Sun, Xiankai

    2013-01-01

    Dendrimers are a class of structurally defined macromolecules featured with a central core, a low-density interior formed by repetitive branching units, and a high-density exterior terminated with surface functional groups. In contrast to their polymeric counterparts, dendrimers are nano-sized and symmetrically shaped, which can be reproducibly synthesized in a large scale with monodispersity. These unique features have made dendrimers of increasing interest for drug delivery and other biomedical applications as a nanoscaffold system. Intended to address the potential use of dendrimers for the development of theranostic agents, which combines therapeutics and diagnostics in a single entity for personalized medicine, this review focuses on the reported methodologies of using dendrimer nanoscaffolds for targeted imaging and therapy of prostate cancer. Of particular interest, relevant chemistry strategies are discussed due to their important roles in the design and synthesis of diagnostic and therapeutic dendrimer-based nanoconjugates and potential theranostic agents, targeted or non-targeted. Given the developing status of nanoscaffolded theranostics, major challenges and potential hurdles are discussed along with the examples representing current advances. PMID:23294202

  8. The effect of fluorination on the transfection efficacy of surface-engineered dendrimers.

    PubMed

    Wang, Mingming; Cheng, Yiyun

    2014-08-01

    Dendrimers have shown great promise in the design of high efficient and low cytotoxic gene vectors. In this study, we synthesized a list of fluorobenzoic acid-modified dendrimers by a facile synthetic route and explored their potential applications as non-viral gene vectors. Fluorination on the aromatic rings significantly improves the transfection efficacy of benzoic acid-modified dendrimers. The transfection efficacy increases with increasing number of fluorine atoms on the aromatic rings of the conjugated benzoic acid. The most efficient conjugate shows superior efficacy to polymer-based commercial reagents such as SuperFect and PolyFect, and comparable efficacy to lipid-based commercial reagents such as Lipofectamine 2000. In addition, the fluorobenzoic acid-modified dendrimers show low cytotoxicity on the transfected cells. The improved transfection efficacy of fluorobenzoic acid-modified dendrimers is due to enhanced cellular uptake and/or easier DNA unpacking behavior compared to non-modified dendrimers. These results provide a new fluorination strategy to generate a library of highly efficient and non-cytotoxic polymeric gene vectors. PMID:24818889

  9. Copper Granule-Catalyzed Microwave-Assisted Click Synthesis of Polyphenol Dendrimers

    PubMed Central

    Lee, Choon Young; Held, Rich; Sharma, Ajit; Baral, Rom; Nanah, Cyprien; Dumas, Dan; Jenkins, Shannon; Upadhaya, Samik; Du, Wenjun

    2013-01-01

    Syringaldehyde and vanillin-based antioxidant dendrimers were synthesized via microwave-assisted alkyne-azide 1,3-dipolar cycloaddition using copper granules as a catalyst. The use of Cu(I) as a catalyst resulted in copper contaminated dendrimers. In order to produce copper-free antioxidant dendrimers for biological applications, Cu(I) was substituted with copper granules. Copper granules were ineffective at both room temperature and under reflux conditions (< 5% yield). However, it was an excellent catalyst when dendrimer synthesis was performed under microwave irradiation, giving yields up to 94% within 8 h. ICP-mass analysis of the antioxidant dendrimers obtained with this method showed virtually no copper contamination (9 ppm), which was the same as background level. The synthesized antioxidants, free from copper contamination, demonstrated potent radical scavenging with IC50 values of less than 3 µM in the DPPH assay. In comparison, dendrimers synthesized from Cu(I)-catalyzed Click chemistry showed a high level of copper contamination (4800 ppm) and no detectable antioxidant activity. PMID:24127771

  10. Copper-granule-catalyzed microwave-assisted click synthesis of polyphenol dendrimers.

    PubMed

    Lee, Choon Young; Held, Rich; Sharma, Ajit; Baral, Rom; Nanah, Cyprien; Dumas, Dan; Jenkins, Shannon; Upadhaya, Samik; Du, Wenjun

    2013-11-15

    Syringaldehyde- and vanillin-based antioxidant dendrimers were synthesized via microwave-assisted alkyne-azide 1,3-dipolar cycloaddition using copper granules as a catalyst. The use of Cu(I) as a catalyst resulted in copper contaminated dendrimers. To produce copper-free antioxidant dendrimers for biological applications, Cu(I) was substituted with copper granules. Copper granules were ineffective at both room temperature and under reflux conditions (<5% yield). However, they were an excellent catalyst when dendrimer synthesis was performed under microwave irradiation, giving yields up to 94% within 8 h. ICP-mass analysis of the antioxidant dendrimers obtained with this method showed virtually no copper contamination (9 ppm), which was the same as the background level. The synthesized antioxidants, free from copper contamination, demonstrated potent radical scavenging with IC50 values of less than 3 μM in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. In comparison, dendrimers synthesized from Cu(I)-catalyzed click chemistry showed a high level of copper contamination (4800 ppm) and no detectable antioxidant activity. PMID:24127771

  11. Doxorubicin-conjugated dendrimer/collagen hybrid gels for metastasis-associated drug delivery systems.

    PubMed

    Kojima, Chie; Suehiro, Tomoyuki; Watanabe, Kenji; Ogawa, Mikako; Fukuhara, Ayano; Nishisaka, Eiko; Harada, Atsushi; Kono, Kenji; Inui, Takashi; Magata, Yasuhiro

    2013-03-01

    Metastasis is a characteristic property of cancer cells, which degrade extracellular matrix containing collagen. We prepared a polymer prodrug-embedded collagen gel for metastasis-associated drug delivery. A collagen peptide-modified dendrimer that attached doxorubicin (Dox) via a pH-degradable linkage was synthesized as a polymer prodrug. Compared with free Dox, the diffusion of the dendrimer prodrug from the collagen gel was suppressed. Highly invasive MDA-MB-231 cells were more sensitive to the prodrug-hybrid collagen gel than poorly invasive MCF-7 cells, even though the cytotoxicity of the dendrimer prodrug by itself against these cells was almost identical. The cytotoxicity against MDA-MB-231 cells decreased in the presence of a matrix metalloproteinase (MMP) inhibitor, suggesting that the dendrimer prodrug/collagen hybrid gel was affected by MMP activity. The dendrimer prodrug/collagen hybrid gel not only suppressed tumor growth but also attenuated metastatic activity in vivo. Therefore, the dendrimer prodrug-embedded collagen gel is useful for cancer chemotherapy. PMID:23164946

  12. Preparation and characterization of dense films of poly(amidoamine) dendrimers on indium tin oxide.

    PubMed

    Schlapak, Robert; Armitage, David; Saucedo-Zeni, Nadia; Latini, Gianluca; Gruber, Hermann J; Mesquida, Patrick; Samotskaya, Yulia; Hohage, Michael; Cacialli, Franco; Howorka, Stefan

    2007-08-14

    Indium tin oxide (ITO) substrates were modified with a layer of poly(amidoamine) (PAMAM) dendrimers to change their surface properties and, in particular, the substrates' work function. The functionalization procedure involved the electrostatic adsorption of positively charged PAMAM dendrimers of generation five onto negatively polarized ITO surfaces. Three different PAMAM dendrimers were used: PAMAM-NH2 and PAMAM-OH with terminal amine and hydroxyl groups, respectively, as well as Q-PAMAM-NH2, which had been prepared from PAMAM-NH2 by quaternization of the dendrimer's terminal and internal amine groups with methyl iodide. The resulting organic films were analyzed by contact angle goniometry, X-ray photoelectron spectroscopy, ellipsometry, and Kelvin probe force microscopy to confirm the presence of a dense layer. A Langmuir isotherm was derived from surface densities of fluorescence-labeled PAMAM-NH2 dendrimers from which we deduced an equilibrium binding constant, K(eq), of (1.3 +/- 0.3) x 10(5) M(-1). Kelvin probe measurements of the contact potential difference revealed a high reduction of the work function from 4.9 eV for bare ITO to 4.3 eV for ITO with a dense film of PAMAM-NH2 of generation five. PAMAM-OH and Q-PAMAM-NH2 resulted in slightly smaller work function changes. This study illustrates that the work function of ITO can be tuned by adlayers composed of PAMAM dendrimers. PMID:17636991

  13. Macromolecular and Dendrimer Based Magnetic Resonance Contrast Agents

    PubMed Central

    Bumb, Ambika; Brechbiel, Martin W.; Choyke, Peter

    2010-01-01

    Magnetic resonance imaging (MRI) is a powerful imaging modality that can provide an assessment of function or molecular expression in tandem with anatomic detail. Over the last 20–25 years, a number of gadolinium based MR contrast agents have been developed to enhance signal by altering proton relaxation properties. This review explores a range of these agents from small molecule chelates, such as Gd-DTPA and Gd-DOTA, to macromolecular structures composed of albumin, polylysine, polysaccharides (dextran, inulin, starch), poly(ethylene glycol), copolymers of cystamine and cystine with GD-DTPA, and various dendritic structures based on polyamidoamine and polylysine (Gadomers). The synthesis, structure, biodistribution and targeting of dendrimer-based MR contrast agents are also discussed. PMID:20590365

  14. Charge Transport in Dendrimer Melts Using Multiscale Modeling Simulation.

    PubMed

    Bag, Saientan; Jain, Manish; Maiti, Prabal K

    2016-09-01

    In this article, we present a theoretical calculation of the charge carrier mobility in two different dendrimeric melt systems (dendritic phenylazomethine with a triphenyl amine core and dendritic carbazole with cyclic phenylazomethine as the core), which have recently been reported1 to increase the efficiency of dye-sensitized solar cells by interface modification. Our mobility calculation, which is a combination of molecular dynamics simulation, first-principles calculation, and kinetic Monte Carlo simulation, leads to mobilities that are in quantitative agreement with available experimental data. We also show how the mobility depends on dendrimer generation. Furthermore, we examine the variation of mobility with an external electric field and external reorganization energy. Physical mechanisms behind the observed electric field and generation dependencies of mobility are also explored. PMID:27479077

  15. Light-fuelled transport of large dendrimers and proteins.

    PubMed

    Koskela, Jenni E; Liljeström, Ville; Lim, Jongdoo; Simanek, Eric E; Ras, Robin H A; Priimagi, Arri; Kostiainen, Mauri A

    2014-05-14

    This work presents a facile water-based supramolecular approach for light-induced surface patterning. The method is based upon azobenzene-functionalized high-molecular weight triazine dendrimers up to generation 9, demonstrating that even very large globular supramolecular complexes can be made to move in response to light. We also demonstrate light-fuelled macroscopic movements in native biomolecules, showing that complexes of apoferritin protein and azobenzene can effectively form light-induced surface patterns. Fundamentally, the results establish that thin films comprising both flexible and rigid globular particles of large diameter can be moved with light, whereas the presented material concepts offer new possibilities for the yet marginally explored biological applications of azobenzene surface patterning. PMID:24785836

  16. Hydroxyl PAMAM dendrimer-based gene vectors for transgene delivery to human retinal pigment epithelial cells

    NASA Astrophysics Data System (ADS)

    Mastorakos, Panagiotis; Kambhampati, Siva P.; Mishra, Manoj K.; Wu, Tony; Song, Eric; Hanes, Justin; Kannan, Rangaramanujam M.

    2015-02-01

    Ocular gene therapy holds promise for the treatment of numerous blinding disorders. Despite the significant progress in the field of viral and non-viral gene delivery to the eye, significant obstacles remain in the way of achieving high-level transgene expression without adverse effects. The retinal pigment epithelium (RPE) is involved in the pathogenesis of retinal diseases and is a key target for a number of gene-based therapeutics. In this study, we addressed the inherent drawbacks of non-viral gene vectors and combined different approaches to design an efficient and safe dendrimer-based gene-delivery platform for delivery to human RPE cells. We used hydroxyl-terminated polyamidoamine (PAMAM) dendrimers functionalized with various amounts of amine groups to achieve effective plasmid compaction. We further used triamcinolone acetonide (TA) as a nuclear localization enhancer for the dendrimer-gene complex and achieved significant improvement in cell uptake and transfection of hard-to-transfect human RPE cells. To improve colloidal stability, we further shielded the gene vector surface through incorporation of PEGylated dendrimer along with dendrimer-TA for DNA complexation. The resultant complexes showed improved stability while minimally affecting transgene delivery, thus improving the translational relevance of this platform.Ocular gene therapy holds promise for the treatment of numerous blinding disorders. Despite the significant progress in the field of viral and non-viral gene delivery to the eye, significant obstacles remain in the way of achieving high-level transgene expression without adverse effects. The retinal pigment epithelium (RPE) is involved in the pathogenesis of retinal diseases and is a key target for a number of gene-based therapeutics. In this study, we addressed the inherent drawbacks of non-viral gene vectors and combined different approaches to design an efficient and safe dendrimer-based gene-delivery platform for delivery to human RPE

  17. Use of carbosilane dendrimer to switch macrophage polarization for the acquisition of antitumor functions

    NASA Astrophysics Data System (ADS)

    Perisé-Barrios, Ana J.; Gómez, Rafael; Corbí, Angel L.; de La Mata, Javier; Domínguez-Soto, Angeles; Muñoz-Fernandez, María A.

    2015-02-01

    Tumor microenvironment favors the escape from immunosurveillance by promoting immunosuppression and blunting pro-inflammatory responses. Since most tumor-associated macrophages (TAM) exhibit an M2-like tumor cell growth promoting polarization, we have studied the role of 2G-03NN24 carbosilane dendrimer in M2 macrophage polarization to evaluate the potential application of dendrimers in tumor immunotherapy. We found that the 2G-03NN24 dendrimer decreases LPS-induced IL-10 production from in vitro generated monocyte-derived M2 macrophages, and also switches their gene expression profile towards the acquisition of M1 polarization markers (INHBA, SERPINE1, FLT1, EGLN3 and ALDH1A2) and the loss of M2 polarization-associated markers (EMR1, IGF1, FOLR2 and SLC40A1). Furthermore, 2G-03NN24 dendrimer decreases STAT3 activation. Our results indicate that the 2G-03NN24 dendrimer can be a useful tool for antitumor therapy by virtue of its potential ability to limit the M2-like polarization of TAM.Tumor microenvironment favors the escape from immunosurveillance by promoting immunosuppression and blunting pro-inflammatory responses. Since most tumor-associated macrophages (TAM) exhibit an M2-like tumor cell growth promoting polarization, we have studied the role of 2G-03NN24 carbosilane dendrimer in M2 macrophage polarization to evaluate the potential application of dendrimers in tumor immunotherapy. We found that the 2G-03NN24 dendrimer decreases LPS-induced IL-10 production from in vitro generated monocyte-derived M2 macrophages, and also switches their gene expression profile towards the acquisition of M1 polarization markers (INHBA, SERPINE1, FLT1, EGLN3 and ALDH1A2) and the loss of M2 polarization-associated markers (EMR1, IGF1, FOLR2 and SLC40A1). Furthermore, 2G-03NN24 dendrimer decreases STAT3 activation. Our results indicate that the 2G-03NN24 dendrimer can be a useful tool for antitumor therapy by virtue of its potential ability to limit the M2-like polarization of TAM

  18. Aqueous synthesis of ZnTe/dendrimer nanocomposites and their antimicrobial activity: implications in therapeutics

    NASA Astrophysics Data System (ADS)

    Ghosh, S.; Ghosh, D.; Bag, P. K.; Bhattacharya, S. C.; Saha, A.

    2011-03-01

    The present strategy proposes a simple and single step aqueous route for synthesizing stable, fluorescent ZnTe/dendrimer nanocomposites with varying dendrimer terminal groups. In these hybrid materials, the fluorescence of the semiconductor combines with the biomimetic properties of the dendrimer making them suitable for various biomedical applications. The ZnTe nanocomposites thus obtained demonstrate bactericidal activity against enteropathogenic bacteria without having toxic effects on the human erythrocytes. The average size of the ZnTe nanoparticles within the dendrimer matrix was in the range of 2.9-6.0 nm, and they have a good degree of crystallinity with a hexagonal crystal phase. The antibacterial activities of the ZnTe/dendrimer nanocomposites (ZnTe DNCs) as well other semiconductor nanocomposites were evaluated against enteropathogenic bacteria including multi-drug resistant Vibrio cholerae serogroup O1 and enterotoxigenic Escherichia coli (ETEC). ZnTe DNCs had significant antibacterial activity against strains of V. cholerae and ETEC with minimum inhibitory concentrations ranging from 64 to 512 μg ml-1 and minimum bactericidal concentrations ranging from 128 to 1000 μg ml-1. Thus, the observed results suggest that these water-soluble active nanocomposites have potential for the treatment of enteric diseases like diarrhoea and cholera.The present strategy proposes a simple and single step aqueous route for synthesizing stable, fluorescent ZnTe/dendrimer nanocomposites with varying dendrimer terminal groups. In these hybrid materials, the fluorescence of the semiconductor combines with the biomimetic properties of the dendrimer making them suitable for various biomedical applications. The ZnTe nanocomposites thus obtained demonstrate bactericidal activity against enteropathogenic bacteria without having toxic effects on the human erythrocytes. The average size of the ZnTe nanoparticles within the dendrimer matrix was in the range of 2.9-6.0 nm, and they

  19. The Architecture and Biological Function of Dual Antibody-Coated Dendrimers: Enhanced Control of Circulating Tumor cells and Their Hetero-Adhesion to Endothelial Cells for Metastasis Prevention

    PubMed Central

    Xie, Jingjing; Zhao, Rongli; Gu, Songen; Dong, Haiyan; Wang, Jichuang; Lu, Yusheng; Sinko, Patrick J.; Yu, Ting; Xie, Fangwei; Wang, Lie; Shao, Jingwei; Jia, Lee

    2014-01-01

    Dissemination of circulating tumor cells (CTCs) in blood and their hetero-adhesion to vascular endothelial bed of distant metastatic secondary organs are the critical steps to initiate cancer metastasis. The rarity of CTCs made their in vivo capture technically challenging. Current techniques by virtue of nanostructured scaffolds monovalently conjugated with a single antibody and/or drug seem less efficient and specific in capturing CTCs. Here, we report a novel platform developed to re-engineer nanoscale dendrimers for capturing CTCs in blood and interfering their adhesion to vascular endothelial bed to form micrometastatic foci. The nanoscale dendrimers were spatiotemporally accommodated with dual antibodies to target two surface biomarkers of colorectal CTCs. Physiochemical characterization, including spectra, fluorescence, electron microscope, dynamic light scattering, electrophoresis, and chromatography analyses, was conducted to demonstrate the successful conjugation of dual antibodies to dendrimer surface. The dual antibody conjugates were able to specifically recognize and bind CTCs, moderately down-regulate the activity of the captured CTCs by arresting them in S phase. The related adhesion assay displayed that the dual antibody conjugates interfered the hetero-adhesion of CTCs to fibronectin (Fn)-coated substrates and human umbilical vein endothelial cells (HUVECs). The dual antibody conjugates also showed the enhanced specificity and efficiency in vitro and in vivo in restraining CTCs in comparison with their single antibody counterparts. The present study showed a novel means to effectively prevent cancer metastatic initiation by binding, restraining CTCs and inhibiting their hetero-adhesion to blood vessels, not by traditional cytotoxic-killing of cancer cells. PMID:25285173

  20. Synthesis and Characterization of Photocurable Polyamidoamine Dendrimer Hydrogels as a Versatile Platform for Tissue Engineering and Drug Delivery

    PubMed Central

    Desai, Pooja N.; Yuan, Quan; Yang, Hu

    2010-01-01

    In this work, we describe a novel polyamidoamine (PAMAM) dendrimer hydrogel (DH) platform with potential for tissue engineering and drug delivery. With PAMAM dendrimer G3.0 being the underlying carrier, polyethylene glycol (PEG) chains of various lengths (MW=1500, 6000, or 12000 gmol−1) were coupled to the dendrimer to different extents, and the resulting PEGylated PAMAM dendrimers were further coupled with acrylate groups to yield photoreactive dendrimer macromonomers for gel formation. It was found that gelation based on photoreactive PAMAM G3.0 macromonomers was restricted by the degree of PEGylation, PEG chain length, and the distribution of acrylate groups on the dendrimer surface. Further, the architecture of the photoreactive macromonomers affects the structural stability and swelling of the resultant networks. A completely crosslinked network (DH-G3.0–12000H) with a high water swelling ratio was created by UV-curing of PAMAM dendrimer G3.0 coupled with 28 PEG 12000 chains in the presence of the eosin Y-based photoinitiating system. The disintegration of DH-G3.0–12000H was pH-insensitive. DH-G3.0–12000H was found to have similar cytocompatibility to uncrosslinked G3.0–12000H but have a significantly lower cellular uptake by macrophages. With PAMAM dendrimer G3.5 being the underlying carrier, the dendrimer modified with 43 PEG 1500 chains was able to form a completely crosslinked network (DH-G3.50–1500H) by UV-curing in the presence of the eosin Y-based photoinitiating system. DH-G3.50–1500H exhibited pH-dependent disintegration. Its disintegration ratio increased with pH. PAMAM dendrimer hydrogels uniquely express the structural characteristics of both PEG hydrogel and PAMAM dendrimer and have potential for various applications in tissue engineering and drug delivery. PMID:20108892

  1. Liquid-crystalline octopus dendrimers: block molecules with unusual mesophase morphologies.

    PubMed

    Gehringer, Lionel; Bourgogne, Cyril; Guillon, Daniel; Donnio, Bertrand

    2004-03-31

    The synthesis and the mesomorphic properties of several new main-chain liquid-crystalline dendrimers, thereafter designated as octopus dendrimers in accordance with their eight sidearms, are reported. In these dendritic systems, the arborescence is ensured by anisotropic segments, acting as branching cells with a double multiplicity, which are incorporated at every node of the dendritic architecture. In such a way, these compounds radically differ from the classical end-functionalized liquid-crystalline dendrimers, the most commonly reported systems. Following our previous report on purely homolithic systems, that is, the building blocks constituting the dendritic matrix are all identical, several heterolithic systems made of different anisotropic blocks have been prepared. The dendritic branches and corresponding dendrimers were synthesized using a modular construction. Polarized optical microscopy and X-ray diffraction studies showed that all of these new octopus dendrimers exhibit either smectic-like or columnar phases with novel morphologies, the nature of the mesophases depending on the number of terminal chains attached to the peripheral groups. The mesomorphism of these heterolithic dendrimers is discussed in terms of their intrinsic architecture and compared to the analogous homolithic octopus systems. Models for the molecular organizations within both the smectic and the columnar phases are proposed on the basis of small Bragg angle X-ray diffraction studies and are supported by molecular modelizations. Moreover, this study showed that the mesophase stability is very sensitive to the nature and to the mutual arrangement (the spatial location) of the mesogenic segments within the dendritic matrix, illustrating the intimate relationships existing between the mesomorphic properties and the molecular architecture of these dendrimers. PMID:15038740

  2. Investigation of silver binding to polyamidoamine (PAMAM) dendrimers by ESI tandem mass spectrometry.

    PubMed

    Mazzitelli, Carolyn L; Brodbelt, Jennifer S

    2006-05-01

    Electrospray ionization tandem mass spectrometry (ESI-MS/MS) was used to probe the binding of silver ions and reduced silver species with polyamidoamine generation 1 amine-terminated (PAMAMG1NH2) and generation 2 hydroxyl-terminated (PAMAMG2OH) dendrimers. At Ag(+)/PAMAMG2OH molar ratios of 1, 2:1 and low abundance 3:1 complexes emerge. Similar results were observed for PAMAMG1NH2. The collisional activated dissociation (CAD) patterns of the dendrimer ions are characterized by losses of amidoamine branches resulting largely from hydrogen migration and cleavage reactions. Ag+/dendrimer complexes are characterized by the loss of a dendrimer branch from the complex, with the silver ion remaining bound to a dendrimer fragment. When the Ag+-bound dendrimer complexes are reduced by hydrazine, low abundance complexes, whose m/z values are consistent with ones containing zerovalent silver species, are observed in the mass spectra. Complexes with three silver atoms are observed in the spectrum containing PAMAMG1NH2, and complexes with four and five silver atoms are observed with PAMAMG2OH. The CAD fragmentation patterns of the complexes formed after the silver reduction are different than those observed for complexes containing one silver ion and are characterized by the ejection of all silver species, possibly as a cluster, leaving the intact dendrimer ion. Experiments with Cu+, Cu2+, and Pt2+ binding to PAMAMG2OH were also done, but reduced metal clusters were not observed in the mass spectra after the addition of hydrazine. PMID:16516486

  3. Development and characterization of sulfasalazine loaded fucosylated PPI dendrimer for the treatment of cytokine-induced liver damage.

    PubMed

    Gupta, Richa; Mehra, Neelesh Kumar; Jain, Narendra Kumar

    2014-04-01

    The present investigation was aimed at exploring the targeting potential of sulfasalazine (NF-κB inhibitor drug) loaded fucose tethered poly (propylene imine) (PPI) dendritic nanoarchitecture (SSZ-FUCO-PPID) to Kupffer cells for effective management of cytokine-induced liver damage. The SSZ-FUCO-PPID formulation was characterized for entrapment efficiency, in vitro release, stability, toxicological investigations, macrophage uptake, NF-κB inhibition, and in vivo studies. In cell uptake assay the uptake of SSZ-FUCO-PPID was found to be higher and preferentially by J774 macrophage cell line. Cytokine assay suggested that the SSZ-FUCO-PPID potentially inhibited the IL-12 p40 production in LPS activated macrophages. Western blot analysis clearly suggested that SSZ-FUCO-PPID inhibited the activation of NF-κB as indicated by the absence of p-IκB band. Pharmacokinetic study revealed improved bioavailability, half-life and mean residence time of SSZ upon fucosylation of dendrimers. The biodistribution pattern clearly established the higher amount of SSZ-FUCO-PPID in liver. Hematological data suggest that the fucosylated formulations are less immunogenic as compared to unconjugated formulations. The results suggest that the SSZ-FUCO-PPID formulation holds targeting potential to Kupffer cells for the treatment of cytokine-induced liver damage. PMID:24189499

  4. Complexation Between Weakly Basic Dendrimers and Linear Polyelectrolytes: Effects of Chain Stiffness, Grafts, and pOH

    NASA Astrophysics Data System (ADS)

    Lewis, Thomas; Pandav, Gunja; Omar, Ahmad; Ganesan, Venkat

    2013-03-01

    The unique architecture and high charge density of dendrimer molecules have attracted interest for their utilization in gene delivery applications. The strong binding affinity of cationic dendrimers to genetic materials make them effective gene delivery vectors not only by shielding the nucleic acid (NA) material from degradative enzymes in the blood stream, but also by reducing the overall negative charge of the dendrimer-NA material complex, which in turn creates more favorable interaction with the anionic cell membrane. However, the high cytotoxicities of cationic dendrimers have motivated the development of polyethylene glycol (PEG) conjugated dendrimer molecules, which have been shown to reduce dendrimer cytotoxicity while still retaining transfection ability. In order to gain insight into how the addition of neutral grafts affects the binding affinity and conformations of dendrimer-NA material complexes, we have developed and numerically solved a Self-Consistent Field Theory approach for both grafted and non-grafted annealed charged dendrimer molecules in the presence of linear polyelectrolyte molecules. Specifically, this work examines the effect of linear polyelectrolyte stiffness, grafting chain length, and solution pOH.

  5. Two for the Price of One: PAMAM-Dendrimers with Mixed Phosphoryl Choline and Oligomeric Poly(Caprolactone) Surfaces.

    PubMed

    Svenningsen, Søren Wedel; Janaszewska, Anna; Ficker, Mario; Petersen, Johannes Fabritius; Klajnert-Maculewicz, Barbara; Christensen, Jørn Bolstad

    2016-06-15

    The application of dendrimers for biological and medical purposes is highly dependent on the type of surface group in relation to cytotoxicity. Since amine terminated PAMAM dendrimers have been shown to have toxic properties and thereby limited applications in the medical field, the discovery of a new nontoxic surface coating is of great interest. In the present work, amine terminated DAB-PAMAM dendrimers from generation zero to four have been coated with statistical surface functionalization giving a dendrimer surface consisting of an approximately 1:1 mixture of zwitterionic phosphoryl choline hexanamide and 6-((6-hydroxyhexanoyl)oxy)hexanamide. The cytotoxic properties of generation two to four were tested on three different human cancer cell lines, SKBR3 human breast cancer cells, HeLa human cervical cancer cells, and Hep G2 human hepatocellular liver carcinoma cells and compared to the toxicity of amine terminated PAMAM dendrimers. In addition to lower cytotoxicity than observed for amine terminated dendrimers, the coated dendrimers showed minor cytotoxicity against all three human cell lines, negligible influence on ROS generation and mitochondrial membrane potential. These observations support the conclusion that the analyzed group of phosphorylcholine dendrimers may be suitable for medical applications. PMID:27244598

  6. Charge-dependent conformations and dynamics of pamam dendrimers revealed by neutron scattering and molecular dynamics

    NASA Astrophysics Data System (ADS)

    Wu, Bin

    Neutron scattering and fully atomistic molecular dynamics (MD) are employed to investigate the structural and dynamical properties of polyamidoamine (PAMAM) dendrimers with ethylenediamine (EDA) core under various charge conditions. Regarding to the conformational characteristics, we focus on scrutinizing density profile evolution of PAMAM dendrimers as the molecular charge of dendrimer increases from neutral state to highly charged condition. It should be noted that within the context of small angle neutron scattering (SANS), the dendrimers are composed of hydrocarbon component (dry part) and the penetrating water molecules. Though there have been SANS experiments that studied the charge-dependent structural change of PAMAM dendrimers, their results were limited to the collective behavior of the aforementioned two parts. This study is devoted to deepen the understanding towards the structural responsiveness of intra-molecular polymeric and hydration parts separately through advanced contrast variation SANS data analysis scheme available recently and unravel the governing principles through coupling with MD simulations. Two kinds of acids, namely hydrochloric and sulfuric acids, are utilized to tune the pH condition and hence the molecular charge. As far as the dynamical properties, we target at understanding the underlying mechanism that leads to segmental dynamic enhancement observed from quasielstic neutron scattering (QENS) experiment previously. PAMAM dendrimers have a wealth of potential applications, such as drug delivery agency, energy harvesting medium, and light emitting diodes. More importantly, it is regarded as an ideal system to test many theoretical predictions since dendrimers conjugate both colloid-like globular shape and polymer-like flexible chains. This Ph.D. research addresses two main challenges in studying PAMAM dendrimers. Even though neutron scattering is an ideal tool to study this PAMAM dendrimer solution due to its matching temporal and

  7. Transfer of PAMAM Dendrimers across Human Placenta: Prospects of Its Use as Drug Carrier During Pregnancy

    PubMed Central

    Menjoge, Anupa R.; Rinderknecht, Amber; Navath, Raghavendra S.; Faridnia, Masoud; Kim, Chong J.; Romero, Roberto; Miller, Richard K.; Kannan, Rangaramanujam M.

    2011-01-01

    Dendrimers offer significant potential as nanocarriers for targeted delivery of drugs and imaging agents. The objectives of this study were to evaluate the transplacental transport, kinetics and biodistribution of PAMAM dendrimers ex-vivo across the human placenta in comparison with antipyrine, a freely diffusible molecule, using dually perfused re-circulating term human placental lobules. The purpose of this study is to determine if dendrimers as drug carriers can be used to design drug delivery systems directed at selectively treating either the mother or the fetus. The transplacental transfers of fluorescently (Alexa 488) tagged PAMAM dendrimer (16 kDa) and antipyrine (188 Da) from maternal to fetal circulation were measured using HPLC/dual UV and fluorescent detector (sensitivity of 10 ng / mL for dendrimer and 100 ng /mL for antipyrine respectively). Cmax for the dendrimer-Alexa (DA) in maternal perfusate (Tmax = 15min) was 18 times higher than in the fetal perfusate and never equilibrated with the maternal perfusate during 5.5 hours of perfusion (n=4). DA exhibited a significant but low transplacental transport of ~2.26 ± 0.12 μg / mL during 5.5 hours, where the mean transplacental transfer was 0.84 ±0.11 % of the total maternal concentration and the feto-maternal ratio as percent was 0.073% ± 0.02. The biochemical and physiological analysis of the placentae perfused with DA demonstrated normal function throughout the perfusion. The immunofluorescence histochemistry confirmed that the biodistribution of DA in perfused placenta was sparsely dispersed, and when noted was principally seen in the inter-villous spaces and outer rim of the villous branches. In a few cases, DA was found internalized and localized in nuclei and cytoplasm of syncytiotrophoblast and inside the villous core; however, DA was mostly absent from the villous capillaries. In conclusion, the PAMAM dendrimers exhibited a low rate of transfer from maternal to the fetal side across the

  8. Enhancement of immunogenicity and efficacy of a plasmid DNA rabies vaccine by nanoformulation with a fourth-generation amine-terminated poly(ether imine) dendrimer

    PubMed Central

    Ullas, Padinjaremattathil Thankappan; Madhusudana, Shampur Narayan; Desai, Anita; Sagar, Bhadravathi Kenchappa Chandrasekhar; Jayamurugan, Govindasamy; Rajesh, Yamajala Bhaskara Rama Durga; Jayaraman, Narayanaswami

    2014-01-01

    Purpose Delayed onset of, and low magnitude of, protective immune responses are major drawbacks limiting the practical utility of plasmid vaccination against rabies. In this study we evaluated whether nanoformulation with the novel poly(ether imine) (PETIM) dendrimer can enhance the immunogenicity and efficacy of a plasmid-based rabies vaccine. Materials and methods A plasmid vaccine construct (pIRES-Rgp) was prepared by cloning the full-length rabies virus glycoprotein gene into pIRES vector. Drawing upon the results of our previous study, a dendriplex (dendrimer-DNA complex) of pIRES-Rgp was made with PETIM dendrimer (10:1 w/w, PETIM:pIRES-Rgp). In vitro transfection was done on baby hamster kidney (BHK)-21 cells to evaluate expression of glycoprotein gene from pIRES-Rgp and PETIM-pIRES-Rgp. Subsequently, groups of Swiss albino mice were immunized intramuscularly with pIRES-Rgp or PETIM-pIRES-Rgp. A commercially available cell culture rabies vaccine was included for comparison. Rabies virus neutralizing antibody (RVNA) titers in the immune sera were evaluated on days 14, 28, and 90 by rapid fluorescent focus inhibition test. Finally, an intracerebral challenge study using a challenge virus standard strain of rabies virus was done to evaluate the protective efficacy of the formulations. Results Protective levels of RVNA titer (≥0.5 IU/mL) were observed by day 14 in animals immunized with pIRES-Rgp and its dendriplex. Notably, PETIM-pIRES-Rgp produced 4.5-fold higher RVNA titers compared to pIRES-Rgp at this time point. All mice immunized with the PETIM-pIRES-Rgp survived the intracerebral rabies virus challenge, compared with 60% in the group which received pIRES-Rgp. Conclusion Our results suggest that nanoformulation with PETIM dendrimer can produce an earlier onset of a high-titered protective antibody response to a plasmid-based rabies vaccine. PETIM dendriplexing appears to be an efficacious nonviral delivery strategy to enhance genetic vaccination. PMID

  9. Gene delivery efficiency and cytotoxicity of heterocyclic amine-modified PAMAM and PPI dendrimers.

    PubMed

    Hashemi, Maryam; Tabatabai, Seyed Meghdad; Parhiz, Hamideh; Milanizadeh, Soroush; Amel Farzad, Sara; Abnous, Khalil; Ramezani, Mohammad

    2016-04-01

    Poly-(amidoamine) (PAMAM) and poly-(propylenimine) (PPI) are the two most widely investigated dendrimers for drug and gene delivery. In order to enhance DNA transfection activity of these dendrimers, generation 3 and 4 PAMAM and generation 4 and 5 PPI were modified by partial substitution of surface primary amines with histidine, pyridine, and piperazine, which have buffering capacity properties. It was shown that higher dendrimer generations and higher grafting percentages (30% and 50% of primary amines) were associated with higher transfection activity. Pyridine was the most effective substituent for PPI, while piperazine-modified PAMAM dendrimers showed the best transfection efficiency among PAMAM-based vectors in murine neuroblastoma (Neuro-2a) cells. None of the modified carriers showed remarkable cytotoxicity in vitro. Pretreatment of cells with bafilomycin A indicated that endosomal buffering capacity is the main mechanism of endosomal escape. In conclusion, PAMAM and PPI may exhibit different gene delivery efficiency and cytotoxicity profiles with the same chemical modifications. These modified dendrimers could be considered as efficient and safe gene carriers in neuroblastoma cells in vitro. PMID:26838910

  10. Macromolecular delivery of 5-aminolaevulinic acid for photodynamic therapy using dendrimer conjugates.

    PubMed

    Battah, Sinan; Balaratnam, Sherina; Casas, Adriana; O'Neill, Sophie; Edwards, Christine; Batlle, Alcira; Dobbin, Paul; MacRobert, Alexander J

    2007-03-01

    Intracellular porphyrin generation following administration of 5-aminolaevulinic acid (5-ALA) has been widely used in photodynamic therapy. However, cellular uptake of 5-ALA is limited by its hydrophilicity, and improved means of delivery are therefore being sought. Highly branched polymeric drug carriers known as dendrimers present a promising new approach to drug delivery because they have a well-defined structure capable of incorporating a high drug payload. In this work, a dendrimer conjugate was investigated, which incorporated 18 aminolaevulinic acid residues attached via ester linkages to a multipodent aromatic core. The ability of the dendrimer to deliver and release 5-ALA intracellularly for metabolism to the photosensitizer, protoporphyrin IX, was studied in the transformed PAM 212 murine keratinocyte and A431 human epidermoid carcinoma cell lines. Up to an optimum concentration of 0.1 mmol/L, the dendrimer was significantly more efficient compared with 5-ALA for porphyrin synthesis. The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, together with minimal dark toxicity. Cellular uptake of the dendrimer occurs through endocytic routes predominantly via a macropinocytosis pathway. In conclusion, macromolecular dendritic derivatives are capable of delivering 5-ALA efficiently to cells for sustained porphyrin synthesis. PMID:17363482

  11. Reactive Landing of Dendrimer Ions onto Activated Self-assembled Monolayer Surfaces

    SciTech Connect

    Hu, Qichi; Laskin, Julia

    2014-02-06

    The reactivity of gaseous, amine-terminated polyamidoamine (PAMAM) dendrimer ions with activated self-assembled monolayer (SAM) surfaces terminated with N-hydroxysuccinimidyl ester groups (NHS-SAM) is examined using mass-selected ion deposition combined with in situ infrared reflection absorption spectroscopy (IRRAS). The reaction extent is determined from depletion of the infrared band at 1753 cm-1, corresponding to the stretching vibration of the NHS carbonyl groups following ion deposition. For reaction yields below 10%, NHS band depletion follows a linear dependence on the ion dose. By comparing the kinetics plots obtained for 1,12-dodecanediamine and different generations of dendrimer ions (G0–G3) containing 4, 8, 16, and 32 terminal amino group, we demonstrate that the relative reaction efficiency increases linearly with the number of NH2 groups in the molecule. This finding is rationalized assuming the formation of multiple amide bonds upon collision of higher-generation dendrimers with NHS-SAM. Furthermore, by comparing the NHS band depletion following deposition of [M+4H]4+ ions of the G2 dendrimer at 30, 80, and 120 eV, we demonstrate that the ion’s kinetic energy has no measurable effect on reaction efficiency. Similarly, the ion’s charge state only has a minor effect on the reactive landing efficiency of dendrimer ions. Our results indicate that reactive landing is an efficient approach for highly selective covalent immobilization of complex multifunctional molecules onto organic surfaces terminated with labile functional groups.

  12. Synthesis, radiolabeling, and bio-imaging of high-generation polyester dendrimers.

    PubMed

    Parrott, Matthew C; Benhabbour, S Rahima; Saab, Chantal; Lemon, Jennifer A; Parker, Shannon; Valliant, John F; Adronov, Alex

    2009-03-01

    A series of aliphatic polyester dendrons, generations 1 through 8, were prepared with a core p-toluenesulfonyl ethyl (TSe) ester as an easily removable protecting group that can be efficiently replaced with a variety of nucleophiles. Using amidation chemistry, a tridentate bis(pyridyl)amine ligand which is known to form stable complexes with both Tc(I) and Re(I) was introduced at the dendrimer core. Metalation of the core ligand with (99m)Tc was accomplished for generations 5 through 7, and resulted in regioselective radiolabeling of the dendrimers. The distribution of the radiolabeled dendrimers was evaluated in healthy adult Copenhagen rats using dynamic small-animal single photon emission computed tomography (SPECT). The labeled dendrimers were cleanly and rapidly eliminated from the bloodstream via the kidneys with negligible nonspecific binding to organs or tissues being observed. These data were corroborated by a quantitative biodistribution study on the generation 7 dendrimer following necropsy. The quantitative biodistribution results were in excellent agreement with the data obtained from the dynamic SPECT images. PMID:19239268

  13. Drug complexation, in vitro release and cellular entry of dendrimers and hyperbranched polymers.

    PubMed

    Kolhe, Parag; Misra, Ekta; Kannan, Rangaramanujam M; Kannan, Sujatha; Lieh-Lai, Mary

    2003-06-18

    Highly branched, functionalized polymers have potential to act as efficient drug carrier systems. Dendrimers are ideal candidates among model hyperbranched polymers because of their well-defined structure and high density of functional groups. Using ibuprofen as a model drug, we studied the interaction between the drug and Polyamidoamine (PAMAM) dendrimers (generations 3 and 4 with --NH2 functionality) and Perstrop Polyol (generation 5, hyperbranched polyester with --OH functionality). FTIR and NMR studies suggest that ibuprofen predominantly forms a complex with PAMAM dendrimers because of the ionic interaction between the --NH2 end groups and the carboxyl group of ibuprofen. On an average, up to 78 molecules of ibuprofen could be incorporated into one molecule of PAMAM-G4-NH2 with 64 end groups. This complex is stable in deionized water and methanol. The in vitro release of ibuprofen from drug-dendrimer complex is appreciably slower compared to pure ibuprofen. The complexed drug enters A549 cells much more rapidly than pure drug suggesting that dendrimers may be able to carry the complexed drug inside cells efficiently. Hyperbranched Polyol (with 128 --OH end groups) appears to encapsulate approximately 24 drug molecules. Perhaps the lack of strong interactions between the --OH end groups and the drugs prevents complex formation. PMID:12787643

  14. Experimental and Theoretical Investigations in Stimuli Responsive Dendrimer-based Assemblies

    PubMed Central

    Molla, Mijanur Rahaman; Rangadurai, Poornima

    2014-01-01

    Stimuli-responsive macromolecular assemblies are of great interest in drug delivery applications, as it holds the promise to keep the drug molecules sequestered under one set of conditions and release them under another. The former set of conditions could represent circulation, while the latter could represent a disease location. Over the past two decades, sizeable contributions to this field have come from dendrimers, which along with their monodispersity, provide great scope for structural modifications at the molecular level. In this paper, we briefly discuss the various synthetic strategies that have been developed so far to obtain a range of functional dendrimers. We then discuss the design strategies utilized to introduce stimuli responsive elements within the dendritic architecture. The stimuli itself are broadly classified into two categories, viz. extrinsic and intrinsic. Extrinsic stimuli are externally induced such as temperature and light variations, while intrinsic stimuli involve physiological aberrations such as variations in pH, redox conditions, proteins and enzyme concentrations in pathological tissues. Furthermore, the unique support from molecular dynamics (MD) simulations has been highlighted. MD simulations have helped back many of the observations made from assembly formation properties to rationalized the mechanism of drug release and this has been illustrated with discussions on G4 PPI (Poly propylene imine) dendrimers and biaryl facially amphiphilic dendrimers. The synergy that exists between experimental and theoretical studies open new avenues for the use of dendrimers as versatile drug delivery systems. PMID:25260107

  15. Molecular dynamics and neutron scattering study of the dependence of polyelectrolyte dendrimer conformation on counterion behavior

    SciTech Connect

    Chen, Wei-Ren; Do, Changwoo; Egami, T; Hong, Kunlun; Li, Xin; Liu, Emily; Liu, Yun; Porcar, L.; Smith, Gregory Scott; Smith, Sean C; Wu, Bin

    2012-01-01

    Atomistic molecular dynamics (MD) simulations and contrast variation small angle neutron scattering (SANS) technique have been used to investigate the generation-5 (G5) polyelectrolyte polyamidoamine (PAMAM) starburst dendrimer with respect to its conformational dependence on counterion behavior at different levels of molecular charge. Satisfactory agreement is seen between the simulated results, such as the excess intra-dendrimer scattering length density (SLD) distribution and hydration level, and their experimental counterparts. The conformational evolution of charged dendrimer appears to be highly dependent on the association behavior of counterion. We explore the nature of the distribution of counterions around charged amines and qualitatively account for its sensitivity to the counterion valency on the difference of excess free energy. Moreover, via extending the concept of electrical double layer for compact charged colloids, we define an effective radius of charged dendrimer based on the spatial distribution of counterions in its vicinity. Within the same framework, the correlation between the strength of intra-dendrimer electrostatic repulsion and counterion valency and dynamics is also addressed.

  16. Dendrimer-coupled sonophoresis-mediated transdermal drug-delivery system for diclofenac

    PubMed Central

    Huang, Bin; Dong, Wei-Jiang; Yang, Gao-Yi; Wang, Wei; Ji, Cong-Hua; Zhou, Fei-Ni

    2015-01-01

    The purpose of the present study was to develop a novel transdermal drug-delivery system comprising a polyamidoamine dendrimer coupled with sonophoresis to enhance the permeation of diclofenac (DF) through the skin. The novel transdermal drug-delivery system was developed by using a statistical Plackett–Burman design. Hairless male Wistar rat skin was used for the DF-permeation study. Coupling media concentration, ultrasound-application time, duty cycle, distance from probe to skin, and a third-generation polyamidoamine-dendrimer concentration were selected as independent variables, while in vitro drug release was selected as a dependent variable. Independent variables were found to be statistically significant (P<0.05). DF gel without dendrimer and ultrasound treatment to skin (passive delivery, run 13) showed 56.69 µg/cm2 cumulative drug permeated through the skin, while the DF-dendrimer gel without sonophoresis treatment (run 14) showed 257.3 µg/cm2 cumulative drug permeated through the skin after 24 hours. However, when the same gel was applied to sonophoresis-treated skin, drastic permeation enhancement was observed. In the case of run 3, the cumulative drug that permeated through the skin was 935.21 µg/cm2. It was concluded that dendrimer-coupled sonophoresis-mediated transdermal drug delivery system has the potential to enhance the permeation of DF through the skin. PMID:26229447

  17. Use of Poly (Amidoamine) Dendrimer for Dentinal Tubule Occlusion: A Preliminary Study

    PubMed Central

    Wang, Tianda; Yang, Sheng; Wang, Lei; Feng, Hailan

    2015-01-01

    The occlusion of dentinal tubules is an effective method to alleviate the symptoms caused by dentin hypersensitivity, a significant health problem in dentistry and daily life. The in situ mineralization within dentinal tubules is a promising treatment for dentin hypersensitivity as it induces the formation of mineral on the sensitive regions and occludes the dentinal tubules. This study was carried out to evaluate the in vitro effect of a whole generation poly(amidoamine) (PAMAM) dendrimer (G3.0) on dentinal tubule occlusion by inducing mineralization within dentinal tubules. Dentin discs were treated with PAMAM dendrimers using two methods, followed by the in vitro characterization using Attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR), X-ray diffraction (XRD), Field emission scanning electron microscopy (FE-SEM) and Energy-Dispersive X-ray Spectroscopy (EDS). These results showed that G3.0 PAMAM dendrimers coated on dentin surface and infiltrated in dentinal tubules could induce hydroxyapatite formation and resulted in effective dentinal tubule occlusion. Moreover, crosslinked PAMAM dendrimers could induce the remineralization of demineralized dentin and thus had the potential in dentinal tubule occlusion. In this in vitro study, dentinal tubules occlusion could be achieved by using PAMAM dendrimers. This could lead to the development of a new therapeutic technique for the treatment of dentin hypersensitivity. PMID:25885090

  18. Dendrimer-Capped Gold Nanoparticles for Highly Reliable and Robust Surface Enhanced Raman Scattering.

    PubMed

    Kim, Kwanghyun; Lee, Jeongyeop; Jo, Gyeongcheon; Shin, Seungmin; Kim, Jin-Baek; Jang, Ji-Hyun

    2016-08-10

    Dendrimer-stabilized gold nanoparticles (Au-Den) were prepared by a facile solution based method for a highly reliable and robust surface enhanced Raman scattering (SERS) substrate. Au-Den was selectively attached on the surface of reduced graphene oxide (rGO) by noncovalent interactions between the Au capping dendrimer and the graphene surface. Au-Den/rGO exhibits the outstandingly stable and highly magnified Raman signal with an enhancement factor (EF) of 3.9 × 10(7) that enables detection of R6G dyes with concentration as low as 10 nM, retaining 95% of the Raman signal intensity after 1 year. The remarkable stability and enhancement originated not only from a simple combination of the electromagnetic and chemical mechanism of SERS but also from intensified packing density of stable Au-Den on the graphene substrate due to the firm binding between the dendrimer capped metal nanoparticles and the graphene substrate. This method is not limited to the gold nanoparticles and G4 dendrimer used herein, but also can be applied to other dendrimers and metal nanoparticles, which makes the material platform suggested here superior to other SERS substrates. PMID:27403733

  19. Use of poly (amidoamine) dendrimer for dentinal tubule occlusion: a preliminary study.

    PubMed

    Wang, Tianda; Yang, Sheng; Wang, Lei; Feng, Hailan

    2015-01-01

    The occlusion of dentinal tubules is an effective method to alleviate the symptoms caused by dentin hypersensitivity, a significant health problem in dentistry and daily life. The in situ mineralization within dentinal tubules is a promising treatment for dentin hypersensitivity as it induces the formation of mineral on the sensitive regions and occludes the dentinal tubules. This study was carried out to evaluate the in vitro effect of a whole generation poly(amidoamine) (PAMAM) dendrimer (G3.0) on dentinal tubule occlusion by inducing mineralization within dentinal tubules. Dentin discs were treated with PAMAM dendrimers using two methods, followed by the in vitro characterization using Attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR), X-ray diffraction (XRD), Field emission scanning electron microscopy (FE-SEM) and Energy-Dispersive X-ray Spectroscopy (EDS). These results showed that G3.0 PAMAM dendrimers coated on dentin surface and infiltrated in dentinal tubules could induce hydroxyapatite formation and resulted in effective dentinal tubule occlusion. Moreover, crosslinked PAMAM dendrimers could induce the remineralization of demineralized dentin and thus had the potential in dentinal tubule occlusion. In this in vitro study, dentinal tubules occlusion could be achieved by using PAMAM dendrimers. This could lead to the development of a new therapeutic technique for the treatment of dentin hypersensitivity. PMID:25885090

  20. Nanoparticle size and surface charge determine effects of PAMAM dendrimers on human platelets in vitro

    PubMed Central

    Dobrovolskaia, Marina A.; Patri, Anil K.; Simak, Jan; Hall, Jennifer B.; Semberova, Jana; De Paoli Lacerda, Silvia H.; McNeil, Scott E.

    2013-01-01

    Blood platelets are essential in maintaining hemostasis. Various materials can activate platelets and cause them to aggregate. Platelet aggregation in vitro is often used as a marker for materials’ thrombogenic properties and studying nanomaterial interaction with platelets is an important step toward understanding their hematocompatibility. Here we report evaluation of 12 formulations of PAMAM dendrimers varying in size and surface charge. Using a cell counter based method, light transmission aggregometry and scanning electron microscopy, we show that only large cationic dendrimers, but not anionic, neutral or small cationic dendrimers, induce aggregation of human platelets in plasma in vitro. The aggregation caused by large cationic dendrimers was proportional to the number of surface amines. The observed aggregation was not associated with membrane microparticle release, and was insensitive to a variety of chemical and biological inhibitors known to interfere with various pathways of platelet activation. Taken in context with previously reported studies, our data suggest that large cationic PAMAM dendrimers induce platelet aggregation through disruption of membrane integrity. PMID:22026635

  1. Hydroxyl PAMAM dendrimer-based gene vectors for transgene delivery to human retinal pigment epithelial cells†

    PubMed Central

    Mastorakos, Panagiotis; Kambhampati, Siva P.; Mishra, Manoj K.; Wu, Tony; Song, Eric; Hanes, Justin

    2016-01-01

    Ocular gene therapy holds promise for the treatment of numerous blinding disorders. Despite the significant progress in the field of viral and non-viral gene delivery to the eye, significant obstacles remain in the way of achieving high-level transgene expression without adverse effects. The retinal pigment epithelium (RPE) is involved in the pathogenesis of retinal diseases and is a key target for a number of gene-based therapeutics. In this study, we addressed the inherent drawbacks of non-viral gene vectors and combined different approaches to design an efficient and safe dendrimer-based gene-delivery platform for delivery to human RPE cells. We used hydroxyl-terminated polyamidoamine (PAMAM) dendrimers functionalized with various amounts of amine groups to achieve effective plasmid compaction. We further used triamcinolone acetonide (TA) as a nuclear localization enhancer for the dendrimer-gene complex and achieved significant improvement in cell uptake and transfection of hard-to-transfect human RPE cells. To improve colloidal stability, we further shielded the gene vector surface through incorporation of PEGylated dendrimer along with dendrimer-TA for DNA complexation. The resultant complexes showed improved stability while minimally affecting transgene delivery, thus improving the translational relevance of this platform. PMID:25213606

  2. Experimental and theoretical investigations in stimuli responsive dendrimer-based assemblies

    NASA Astrophysics Data System (ADS)

    Molla, Mijanur Rahaman; Rangadurai, Poornima; Pavan, Giovanni M.; Thayumanavan, S.

    2015-02-01

    Stimuli-responsive macromolecular assemblies are of great interest in drug delivery applications, as it holds the promise to keep the drug molecules sequestered under one set of conditions and release them under another. The former set of conditions could represent circulation, while the latter could represent a disease location. Over the past two decades, sizeable contributions to this field have come from dendrimers, which along with their monodispersity, provide great scope for structural modifications at the molecular level. In this paper, we briefly discuss the various synthetic strategies that have been developed so far to obtain a range of functional dendrimers. We then discuss the design strategies utilized to introduce stimuli responsive elements within the dendritic architecture. The stimuli itself are broadly classified into two categories, viz. extrinsic and intrinsic. Extrinsic stimuli are externally induced such as temperature and light variations, while intrinsic stimuli involve physiological aberrations such as variations in pH, redox conditions, proteins and enzyme concentrations in pathological tissues. Furthermore, the unique support from molecular dynamics (MD) simulations has been highlighted. MD simulations have helped back many of the observations made from assembly formation properties to rationalized the mechanism of drug release and this has been illustrated with discussions on G4 PPI (Poly propylene imine) dendrimers and biaryl facially amphiphilic dendrimers. The synergy that exists between experimental and theoretical studies open new avenues for the use of dendrimers as versatile drug delivery systems.

  3. α-Conotoxin dendrimers have enhanced potency and selectivity for homomeric nicotinic acetylcholine receptors.

    PubMed

    Wan, Jingjing; Huang, Johnny X; Vetter, Irina; Mobli, Mehdi; Lawson, Joshua; Tae, Han-Shen; Abraham, Nikita; Paul, Blessy; Cooper, Matthew A; Adams, David J; Lewis, Richard J; Alewood, Paul F

    2015-03-11

    Covalently attached peptide dendrimers can enhance binding affinity and functional activity. Homogenous di- and tetravalent dendrimers incorporating the α7-nicotinic receptor blocker α-conotoxin ImI (α-ImI) with polyethylene glycol spacers were designed and synthesized via a copper-catalyzed azide-alkyne cycloaddition of azide-modified α-ImI to an alkyne-modified polylysine dendron. NMR and CD structural analysis confirmed that each α-ImI moiety in the dendrimers had the same 3D structure as native α-ImI. The binding of the α-ImI dendrimers to binding protein Ac-AChBP was measured by surface plasmon resonance and revealed enhanced affinity. Quantitative electrophysiology showed that α-ImI dendrimers had ∼100-fold enhanced potency at hα7 nAChRs (IC50 = 4 nM) compared to native α-ImI (IC50 = 440 nM). In contrast, no significant potency enhancement was observed at heteromeric hα3β2 and hα9α10 nAChRs. These findings indicate that multimeric ligands can significantly enhance conotoxin potency and selectivity at homomeric nicotinic ion channels. PMID:25710197

  4. Intermolecular forces between low generation PAMAM dendrimer condensed DNA helices: role of cation architecture.

    PubMed

    An, Min; Parkin, Sean R; DeRouchey, Jason E

    2014-01-28

    In recent years, dendriplexes, complexes of cationic dendrimers with DNA, have become attractive DNA delivery vehicles due to their well-defined chemistries. To better understand the nature of the forces condensing dendriplexes, we studied low generation poly(amidoamine) (PAMAM) dendrimer-DNA complexes and compared them to comparably charged linear arginine peptides. Using osmotic stress coupled with X-ray scattering, we have investigated the effect of molecular chain architecture on DNA-DNA intermolecular forces that determine the net attraction and equilibrium interhelical distance within these polycation condensed DNA arrays. In order to compact DNA, linear cations are believed to bind in DNA grooves and to interact with the phosphate backbone of apposing helices. We have previously shown a length dependent attraction resulting in higher packaging densities with increasing charge for linear cations. Hyperbranched polycations, such as polycationic dendrimers, presumably would not be able to bind to DNA and correlate their charges in the same manner as linear cations. We show that attractive and repulsive force amplitudes in PAMAM-DNA assemblies display significantly different trends than comparably charged linear arginines resulting in lower DNA packaging densities with increasing PAMAM generation. The salt and pH dependencies of packaging in PAMAM dendrimer-DNA and linear arginine-DNA complexes were also investigated. Significant differences in the force curve behaviour and salt and pH sensitivities suggest that different binding modes may be present in DNA condensed by dendrimers when compared to linear polycations. PMID:24651934

  5. Dendrimers as Carriers for siRNA Delivery and Gene Silencing: A Review

    PubMed Central

    Huang, Weizhe; He, Ziying

    2013-01-01

    RNA interference (RNAi) was first literaturally reported in 1998 and has become rapidly a promising tool for therapeutic applications in gene therapy. In a typical RNAi process, small interfering RNAs (siRNA) are used to specifically downregulate the expression of the targeted gene, known as the term “gene silencing.” One key point for successful gene silencing is to employ a safe and efficient siRNA delivery system. In this context, dendrimers are emerging as potential nonviral vectors to deliver siRNA for RNAi purpose. Dendrimers have attracted intense interest since their emanating research in the 1980s and are extensively studied as efficient DNA delivery vectors in gene transfer applications, due to their unique features based on the well-defined and multivalent structures. Knowing that DNA and RNA possess a similar structure in terms of nucleic acid framework and the electronegative nature, one can also use the excellent DNA delivery properties of dendrimers to develop effective siRNA delivery systems. In this review, the development of dendrimer-based siRNA delivery vectors is summarized, focusing on the vector features (siRNA delivery efficiency, cytotoxicity, etc.) of different types of dendrimers and the related investigations on structure-activity relationship to promote safe and efficient siRNA delivery system. PMID:24288498

  6. Design, Synthesis and Study of Dendrimers as Nanoscaffolds for Solar Energy Harvest

    SciTech Connect

    Sankaran Thayumanavan

    2008-01-25

    Designing molecules in which the vectorial motions of charges can be controlled has been of significant research interest in the recent past. Covalent linear arrays of chromophores or other molecular assemblies such as liquid crystals, zeolites, polymers, peptides, and amphiphiles have all been used as components for this purpose. Significant amount of this effort also involved the use of dendrimers as the molecular architecture. The structural feature in which multiple functionalities are present in the periphery that decreases gradually as one moves towards the core renders dendrimers obvious candidates for light harvesting antenna. Most of the efforts reported in the literature are directed towards energy funneling from a chromophore in the periphery to another chromophore at the core of the dendrimer. There are relatively few reports that utilize the dendritic architecture for photoinduced charge separation, an important step in designing materials for photovoltaics. These reports focus mostly on conjugated molecular backbones. Since non-conjugated dendrimer backbones provide the possibility of independently tuning the electronic characteristics of the chromophore and the charge transfer unit and therefore carry out a systematic structure-property relationship study, we have designed and synthesized dendrimers

  7. Design, Synthesis and Study of Dendrimers as Nanoscaffolds for Solar Energy Harvest

    SciTech Connect

    Sankaran Thayumanavan

    2008-01-25

    Designing molecules in which the vectorial motions of charges can be controlled has been of significant research interest in the recent past. Covalent linear arrays of chromophores or other molecular assemblies such as liquid crystals, zeolites, polymers, peptides, and amphiphiles have all been used as components for this purpose. Significant amount of this effort also involved the use of dendrimers as the molecular architecture. The structural feature in which multiple functionalities are present in the periphery that decreases gradually as one moves towards the core renders dendrimers obvious candidates for light harvesting antenna. Most of the efforts reported in the literature are directed towards energy funneling from a chromophore in the periphery to another chromophore at the core of the dendrimer. There are relatively few reports that utilize the dendritic architecture for photoinduced charge separation, an important step in designing materials for photovoltaics. These reports focus mostly on conjugated molecular backbones. Since non-conjugated dendrimer backbones provide the possibility of independently tuning the electronic characteristics of the chromophore and the charge transfer unit and therefore carry out a systematic structure-property relationship study, we have designed and synthesized dendrimers.

  8. Carbazole dendrimers as solution-processable thermally activated delayed-fluorescence materials.

    PubMed

    Albrecht, Ken; Matsuoka, Kenichi; Fujita, Katsuhiko; Yamamoto, Kimihisa

    2015-05-01

    Recently, thermally activated delayed fluorescence (TADF) materials have received increasing attention as effective emitters for organic light-emitting diodes (OLEDs). However, most of them are usually employed as dopants in a host material. In this report, carbazole dendrimers with a triphenyl-s-triazine core are reported, which are the first solution-processable, non-doped, high-molecular-weight TADF materials. The dendrimers were obtained by a new and facile synthetic route using the tert-butyldimethylsilyl moiety as a protecting group. All dendrimers showed TADF in toluene. Measurements of the temperature-dependent luminescence lifetime revealed that spin-coated neat films also showed TADF with moderate quantum yields. OLED devices incorporating these dendrimers as spin-coated emitting layers gave external quantum efficiencies of up to a 3.4 %, which suggests that this device is harvesting triplet excitons. This result indicates that carbazole dendrimers with attached acceptors are potential TADF materials owing to their polarized electronic structure (with HOMO-LUMO separation). PMID:25753430

  9. Dendrimer mediated clustering of bacteria: improved aggregation and evaluation of bacterial response and viability.

    PubMed

    Leire, Emma; Amaral, Sandra P; Louzao, Iria; Winzer, Klaus; Alexander, Cameron; Fernandez-Megia, Eduardo; Fernandez-Trillo, Francisco

    2016-06-24

    Here, we evaluate how cationic gallic acid-triethylene glycol (GATG) dendrimers interact with bacteria and their potential to develop new antimicrobials. We demonstrate that GATG dendrimers functionalised with primary amines in their periphery can induce the formation of clusters in Vibrio harveyi, an opportunistic marine pathogen, in a generation dependent manner. Moreover, these cationic GATG dendrimers demonstrate an improved ability to induce cluster formation when compared to poly(N-[3-(dimethylamino)propyl]methacrylamide) [p(DMAPMAm)], a cationic linear polymer previously shown to cluster bacteria. Viability of the bacteria within the formed clusters and evaluation of quorum sensing controlled phenotypes (i.e. light production in V. harveyi) suggest that GATG dendrimers may be activating microbial responses by maintaining a high concentration of quorum sensing signals inside the clusters while increasing permeability of the microbial outer membranes. Thus, the reported GATG dendrimers constitute a valuable platform for the development of novel antimicrobial materials that can target microbial viability and/or virulence. PMID:27127812

  10. Biomimetics: From Bioinformatics to Rational Design of Dendrimers as Gene Carriers

    PubMed Central

    Araya-Durán, Ingrid; Varas-Concha, Ignacio; Almonacid, Daniel Eduardo; González-Nilo, Fernando Danilo

    2015-01-01

    Biomimetics, or the use of principles of Nature for developing new materials, is a paradigm that could help Nanomedicine tremendously. One of the current challenges in Nanomedicine is the rational design of new efficient and safer gene carriers. Poly(amidoamine) (PAMAM) dendrimers are a well-known class of nanoparticles, extensively used as non-viral nucleic acid carriers, due to their positively charged end-groups. Yet, there are still several aspects that can be improved for their successful application in in vitro and in vivo systems, including their affinity for nucleic acids as well as lowering their cytotoxicity. In the search of new functional groups that could be used as new dendrimer-reactive groups, we followed a biomimetic approach to determine the amino acids with highest prevalence in protein-DNA interactions. Then we introduced them individually as terminal groups of dendrimers, generating a new class of nanoparticles. Molecular dynamics studies of two systems: PAMAM-Arg and PAMAM-Lys were also performed in order to describe the formation of complexes with DNA. Results confirmed that the introduction of amino acids as terminal groups in a dendrimer increases their affinity for DNA and the interactions in the complexes were characterized at atomic level. We end up by briefly discussing additional modifications that can be made to PAMAM dendrimers to turned them into promising new gene carriers. PMID:26382062

  11. Simulations reveal that the HIV-1 gp120-CD4 complex dissociates via complex pathways and is a potential target of the polyamidoamine (PAMAM) dendrimer

    NASA Astrophysics Data System (ADS)

    Nandy, Bidisha; Bindu, D. Hima; Dixit, Narendra M.; Maiti, Prabal K.

    2013-07-01

    The polyamidoamine (PAMAM) dendrimer prevents HIV-1 entry into target cells in vitro. Its mechanism of action, however, remains unclear and precludes the design of potent dendrimers targeting HIV-1 entry. We employed steered molecular dynamics simulations to examine whether the HIV-1 gp120-CD4 complex is a target of PAMAM. Our simulations mimicked single molecule force spectroscopy studies of the unbinding of the gp120-CD4 complex under the influence of a controlled external force. We found that the complex dissociates via complex pathways and defies the standard classification of adhesion molecules as catch and slip bonds. When the force loading rate was large, the complex behaved as a slip bond, weakening gradually. When the loading rate was small, the complex initially strengthened, akin to a catch bond, but eventually dissociated over shorter separations than with large loading rates. PAMAM docked to gp120 and destabilized the gp120-CD4 complex. The rupture force of the complex was lowered by PAMAM. PAMAM disrupted salt bridges and hydrogen bonds across the gp120-CD4 interface and altered the hydration pattern of the hydrophobic cavity in the interface. In addition, intriguingly, PAMAM suppressed the distinction in the dissociation pathways of the complex between the small and large loading rate regimes. Taken together, our simulations reveal that PAMAM targets the gp120-CD4 complex at two levels: it weakens the complex and also alters its dissociation pathway, potentially inhibiting HIV-1 entry.

  12. Simulations reveal that the HIV-1 gp120-CD4 complex dissociates via complex pathways and is a potential target of the polyamidoamine (PAMAM) dendrimer.

    PubMed

    Nandy, Bidisha; Bindu, D Hima; Dixit, Narendra M; Maiti, Prabal K

    2013-07-14

    The polyamidoamine (PAMAM) dendrimer prevents HIV-1 entry into target cells in vitro. Its mechanism of action, however, remains unclear and precludes the design of potent dendrimers targeting HIV-1 entry. We employed steered molecular dynamics simulations to examine whether the HIV-1 gp120-CD4 complex is a target of PAMAM. Our simulations mimicked single molecule force spectroscopy studies of the unbinding of the gp120-CD4 complex under the influence of a controlled external force. We found that the complex dissociates via complex pathways and defies the standard classification of adhesion molecules as catch and slip bonds. When the force loading rate was large, the complex behaved as a slip bond, weakening gradually. When the loading rate was small, the complex initially strengthened, akin to a catch bond, but eventually dissociated over shorter separations than with large loading rates. PAMAM docked to gp120 and destabilized the gp120-CD4 complex. The rupture force of the complex was lowered by PAMAM. PAMAM disrupted salt bridges and hydrogen bonds across the gp120-CD4 interface and altered the hydration pattern of the hydrophobic cavity in the interface. In addition, intriguingly, PAMAM suppressed the distinction in the dissociation pathways of the complex between the small and large loading rate regimes. Taken together, our simulations reveal that PAMAM targets the gp120-CD4 complex at two levels: it weakens the complex and also alters its dissociation pathway, potentially inhibiting HIV-1 entry. PMID:23862963

  13. Influence of PPH dendrimers' surface functions on the activation of human monocytes: a study of their interactions with pure lipid model systems.

    PubMed

    Ielasi, F; Ledall, J; Anes, A Perez; Fruchon, S; Caminade, A-M; Poupot, R; Turrin, C-O; Blanzat, M

    2016-08-01

    The influence of surface functions on the interactions between Poly(PhosphorHydrazone) PPH dendrimers and human monocytes is discussed on the basis of complementary biological and physicochemical studies on membrane models (monolayers and multi-lamellar vesicles). The studies were performed on both an active and non-toxic phosphonic acid capped dendrimer and a non-active but toxic carboxylic acid capped one. On the one hand, comparative studies of the behaviour of DPPC monolayers in the presence or absence of PPH dendrimers in the subphase showed differences in the phase transitions, highlighting interactions between both dendrimers and phospholipid monolayers, with a larger incidence for the carboxylic acid capped dendrimer (negative control), validating its cellular toxicity. On the other hand, comparative biological studies (activation of human monocytes and binding of fluorescent dendrimers on human monocytes) show the pre-eminence of phosphonic acid capped dendrimers towards specific binding and subsequent activation of human monocytes. PMID:27435630

  14. Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery

    PubMed Central

    Kesharwani, Prashant; Iyer, Arun K.

    2015-01-01

    Advances in the application of nanotechnology in medicine have given rise to multifunctional smart nanocarriers that can be engineered with tunable physicochemical characteristics to deliver one or more therapeutic agent(s) safely and selectively to cancer cells, including intracellular organelle-specific targeting. Dendrimers having properties resembling biomolecules, with well-defined 3D nanopolymeric architectures, are emerging as a highly attractive class of drug and gene delivery vector. The presence of numerous peripheral functional groups on hyperbranched dendrimers affords efficient conjugation of targeting ligands and biomarkers that can recognize and bind to receptors overexpressed on cancer cells for tumor-cell-specific delivery. The present review compiles the recent advances in dendrimer-mediated drug and gene delivery to tumors by passive and active targeting principles with illustrative examples. PMID:25555748

  15. Novel perfluorocyclobutane (PFCB)-containing polymers and dendrimers for photonic devices

    NASA Astrophysics Data System (ADS)

    Ma, Hong; Wong, Sharon; Kang, Seok H.; Luo, Jingdong; Haller, Marnie; Jen, Alex K. Y.; Barto, Richard R.; Frank, Curtis W.

    2002-11-01

    A wide variety of aromatic trifluorovinyl ether monomers and highly fluorinated crosslinkable dendrimers have been developed via novel synthetic strategies. Through the thermal dimerization of trifluorovinyl ether moieties on the monomers or on the periphery of dendrimers, these monomers or dendrimers can be melt or solution polymerized to form perfluorocyclobutane(PFCB)-containing prepolymers with good processability for optical waveguide fabrication. By further thermal crosslinking, the resulting thermoset materials possess low optical loss (0.3-0.4 dB/cm at 1310 nm with 1% of DR-1 or DCM doping), high thermal stability (Tg: 100-400 °C), good thermo-optic property, high solvent and humid resistance, and excellent mechanical flexibility. The combination of processability and performance in these PFCB-containing thermoset materials make them as ideal candidates for the fabrication of high-performance polymeric planar lightwave circuit components with the applications in the telecom and datacom optical networks.

  16. Dendrimer-Encapsulated Ruthenium Nanoparticles as Catalysts for Lithium-O2 Batteries

    SciTech Connect

    Bhattacharya, Priyanka; Nasybulin, Eduard N.; Engelhard, Mark H.; Kovarik, Libor; Bowden, Mark E.; Li, Shari; Gaspar, Daniel J.; Xu, Wu; Zhang, Jiguang

    2014-12-01

    Dendrimer-encapsulated ruthenium nanoparticles (DEN-Ru) have been used as catalysts in lithium-O2 batteries for the first time. Results obtained from UV-vis spectroscopy, electron microscopy and X-ray photoelectron spectroscopy show that the nanoparticles synthesized by the dendrimer template method are ruthenium oxide instead of metallic ruthenium reported earlier by other groups. The DEN-Ru significantly improve the cycling stability of lithium (Li)-O2 batteries with carbon black electrodes and decrease the charging potential even at low catalyst loading. The monodispersity, porosity and large number of surface functionalities of the dendrimer template prevent the aggregation of the ruthenium nanoparticles making their entire surface area available for catalysis. The potential of using DEN-Ru as stand-alone cathode materials for Li-O2 batteries is also explored.

  17. Targeting of follicle stimulating hormone peptide-conjugated dendrimers to ovarian cancer cells

    NASA Astrophysics Data System (ADS)

    Modi, Dimple A.; Sunoqrot, Suhair; Bugno, Jason; Lantvit, Daniel D.; Hong, Seungpyo; Burdette, Joanna E.

    2014-02-01

    Ovarian cancer is the most lethal gynecological malignancy. Current treatment modalities include a combination of surgery and chemotherapy, which often lead to loss of fertility in premenopausal women and a myriad of systemic side effects. To address these issues, we have designed poly(amidoamine) (PAMAM) dendrimers to selectively target the follicle stimulating hormone receptor (FSHR), which is overexpressed by tumorigenic ovarian cancer cells but not by immature primordial follicles and other non-tumorigenic cells. Fluorescein-labeled generation 5 (G5) PAMAM dendrimers were conjugated with the binding peptide domain of FSH (FSH33) that has a high affinity to FSHR. The targeted dendrimers exhibited high receptor selectivity to FSHR-expressing OVCAR-3 cells, resulting in significant uptake and downregulation of an anti-apoptotic protein survivin, while showing minimal interactions with SKOV-3 cells that do not express FSHR. The selectivity of the FSH33-targeted dendrimers was further validated in 3D organ cultures of normal mouse ovaries. Immunostaining of the conjugates revealed their selective binding and uptake by ovarian surface epithelium (OSE) cells that express FSHR, while sparing the immature primordial follicles. In addition, an in vivo study monitoring tissue accumulation following a single intraperitoneal (i.p.) injection of the conjugates showed significantly higher accumulation of FSH33-targeted dendrimers in the ovary and oviduct compared to the non-targeted conjugates. These proof-of-concept findings highlight the potential of these FSH33-targeted dendrimers to serve as a delivery platform for anti-ovarian cancer drugs, while reducing their systemic side effects by preventing nonspecific uptake by the primordial follicles.Ovarian cancer is the most lethal gynecological malignancy. Current treatment modalities include a combination of surgery and chemotherapy, which often lead to loss of fertility in premenopausal women and a myriad of systemic side

  18. Structured water in polyelectrolyte dendrimers: Understanding small angle neutron scattering results through atomistic simulation

    SciTech Connect

    Chen, Wei-Ren; Do, Changwoo; Hong, Kunlun; Liu, Emily; Liu, Yun; Porcar, L.; Smith, Gregory Scott; Wu, Bin; Egami, T; Smith, Sean C

    2012-01-01

    Based on atomistic molecular dynamics (MD) simulations, the small angle neutron scattering (SANS) intensity behavior of a single generation-4 (G4) polyelectrolyte polyamidoamine (PAMAM) starburst dendrimer is investigated at different levels of molecular protonation. The SANS form factor, P(Q), and Debye autocorrelation function, (r), are calculated from the equilibrium MD trajectory based on a mathematical approach proposed in this work which provides a link between the neutron scattering experiment and MD computation. The simulations enable scattering calculations of not only the hydrocarbons, but also the contribution to the scattering length density fluctuations caused by structured, confined water within the dendrimer. Based on our computational results, we question the validity of using radius of gyration RG for microstructure characterization of a polyelectrolyte dendrimer from the scattering perspective.

  19. Quantitative analysis of generation and branch defects in G5 poly(amidoamine) dendrimer

    PubMed Central

    van Dongen, Mallory A.; Desai, Ankur; Orr, Bradford G.; Baker, James R.; Holl, Mark M. Banaszak

    2013-01-01

    Although methods have been developed to synthesize and isolate generation 5 (G5) PAMAM dendrimers containing precise numbers of ligands per polymer particle, the presence of skeletal and generational defects in this material can substantially hamper the process. Here we provide a quantitative analysis of G5 PAMAM dendrimer defects via high performance liquid chromatography, potentiometric titration, mass spectrometry, size exclusion chromatography, and nuclear magnetic resonance. We identified, isolated, and characterized the major structural defects of G5 dendrimer, trailing generations, and dimer, trimer, and tetramer species. We determine that the G5 material present in the as-received mixture contains 93 arms on average. We have developed two model systems capable of generating the experimentally observed mass range and polydispersity at defect rates of 8–15%. PMID:24058210

  20. Elucidation of the Interaction Mechanism with Liposomes of gH625-Peptide Functionalized Dendrimers

    PubMed Central

    Falanga, Annarita; Tarallo, Rossella; Carberry, Thomas; Galdiero, Massimiliano; Weck, Marcus; Galdiero, Stefania

    2014-01-01

    We have demonstrated that amide-based dendrimers functionalized with the membrane-interacting peptide gH625 derived from the herpes simplex virus type 1 (HSV-1) envelope glycoprotein H enter cells mainly through a non-active translocation mechanism. Herein, we investigate the interaction between the peptide-functionalized dendrimer and liposomes composed of PC/Chol using fluorescence spectroscopy, isothermal titration calorimetry, and surface plasmon resonance to get insights into the mechanism of internalization. The affinity for the membrane bilayer is very high and the interaction between the peptide-dendrimer and liposomes took place without evidence of pore formation. These results suggest that the presented peptidodendrimeric scaffold may be a promising material for efficient drug delivery. PMID:25423477

  1. Hyperbranched polymers and dendrimers as templates for organic/inorganic hybrid nanomaterials.

    PubMed

    Huang, Xinhua; Zheng, Sudan; Kim, Il

    2014-02-01

    This paper reviews the recent research and development of hyperbranched polymers (HPs) and dendrimers, and their use as templates for organic-inorganic hybrid nanomaterials. Hyperbranched polymers (HPs) are highly branched macromolecules with three-dimensional globular structures featuring unique properties such as low viscosity, high solubility, and a large number of terminal functional groups compared to their linear analogs. They are easily prepared by (1) condensation polymerization, (2) self-condensing vinyl copolymerization (SCVCP), and (3) ring-opening multibranch polymerization methods. Organic-inorganic hybrid nanomaterials are synthesized by a template approach using HPs/dendrimers. Monometallic, bimetallic (alloy and core/shell), semiconductor, and metal oxide nanoparticles have been prepared by this route. The dendrimer component of these composites serves not only as a template for preparing the nanoparticles but also as a stabilizer for the nanoparticles. PMID:24749446

  2. Effects of catalyst introduction methods using PAMAM dendrimers on selective electroless nickel deposition on polyelectrolyte multilayers.

    PubMed

    Hendricks, Troy R; Dams, Erin E; Wensing, Steven T; Lee, Ilsoon

    2007-06-19

    We studied the effects of catalyst introduction methods using poly(amidoamine) (PAMAM) dendrimers on the nickel patterning of polyelectrolyte multilayer (PEM)-coated substrates. Three different approaches to palladium catalyst introduction using microcontact printing as the patterning technique were utilized and compared. The catalyst introduction methods are (1) direct catalyst stamping, (2) directed assembly using PAMAM dendrimer stamping, and (3) catalyst encapsulation and reduction to nanoparticles within PAMAM dendrimers before stamping. After patterning, the sample surfaces were placed in an electroless bath where nickel was selectively plated onto the patterns. The patterned surfaces were characterized using optical microscopy, atomic force microscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. The metal plating rates on different homogeneous surfaces that simulate the patterned surfaces were measured using a quartz crystal microbalance. In addition, the effect of PEM film thickness (i.e., number of bilayers) on the selectivity of nickel patterning was investigated. PMID:17523692

  3. Properties of mixed alkanethiol-dendrimer layers and their applications in biosensing.

    PubMed

    Svobodová, L; Snejdárková, M; Tóth, K; Gyurcsanyi, R E; Hianik, T

    2004-06-01

    We studied the properties of mixed alkanethiol-dendrimer layers on a gold support and their application in biosensing. We showed that properties of glucose sensor can be modified using a different ratio of 1-hexadecanethiol (HDT) and poly(amidoamine) dendrimer of first generation (G1). The cyclic voltammetry in the presence of the redox couple, Fe(CN)(6)(3-)/Fe(CN)(6)(4-), was used for estimating how effectively the layer blocks the redox probe's access to the electrode surface. A scanning electrochemical microscope (SECM) was used to image the resulting distribution of the organic compounds. We found that with increasing content of dendrimers, the integrity of the layers was improved. PMID:15110289

  4. The key role of the scaffold on the efficiency of dendrimer nanodrugs.

    PubMed

    Caminade, Anne-Marie; Fruchon, Séverine; Turrin, Cédric-Olivier; Poupot, Mary; Ouali, Armelle; Maraval, Alexandrine; Garzoni, Matteo; Maly, Marek; Furer, Victor; Kovalenko, Valeri; Majoral, Jean-Pierre; Pavan, Giovanni M; Poupot, Rémy

    2015-01-01

    Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs. Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks. On the contrary, it is generally believed that the properties of dendrimers are essentially related to their terminal groups, and that the internal structure plays the minor role of an 'innocent' scaffold. Here we show that such an assertion is misleading, using convergent information from biological data (human monocytes activation) and all-atom molecular dynamics simulations on seven families of dendrimers (13 compounds) that we have synthesized, possessing identical terminal groups, but different internal structures. This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins. PMID:26169490

  5. The key role of the scaffold on the efficiency of dendrimer nanodrugs

    PubMed Central

    Caminade, Anne-Marie; Fruchon, Séverine; Turrin, Cédric-Olivier; Poupot, Mary; Ouali, Armelle; Maraval, Alexandrine; Garzoni, Matteo; Maly, Marek; Furer, Victor; Kovalenko, Valeri; Majoral, Jean-Pierre; Pavan, Giovanni M.; Poupot, Rémy

    2015-01-01

    Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs. Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks. On the contrary, it is generally believed that the properties of dendrimers are essentially related to their terminal groups, and that the internal structure plays the minor role of an ‘innocent' scaffold. Here we show that such an assertion is misleading, using convergent information from biological data (human monocytes activation) and all-atom molecular dynamics simulations on seven families of dendrimers (13 compounds) that we have synthesized, possessing identical terminal groups, but different internal structures. This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins. PMID:26169490

  6. Ethylendiamine core PAMAM dendrimers/siRNA complexes as in vitro silencing agents.

    PubMed

    Perez, A P; Romero, E L; Morilla, M J

    2009-10-01

    We have screened the formation of complexes between ethylendiamine (EDA) core polyamidoamine (PAMAM) dendrimers (D) and a short interfering RNA (siRNA) as a function of three variables: the ionic strength of the medium (lacking or containing 150 mM NaCl), the D generation (G4, G5, G6 and G7) and the N/P ratio (nitrogen amines in D/phosphate in siRNA). It was observed that all D formed complexes with siRNA, being the size of the complexes strictly dependent on the ionic strength of the media. The strong electrostatic interactions occurring in NaCl lacking medium made siRNA-D complexes (siRNA-D) smaller than those obtained in NaCl containing medium (30-130 nm, +25 mV zeta potential vs. several microm-800 nm, 0 zeta potential, respectively). Not surprisingly, both the uptake and inhibition of EGFP expression in cell culture, resulted dependent on siRNA-D size. siRNA-D prepared in NaCl containing medium were poorly captured and presented a basal activity on phagocytic (J-774-EGFP) cells, being inactive on non-phagocytic cells (T98G-EGFP). However, the smaller siRNA-D prepared in NaCl lacking medium were massively captured, exhibiting the highest inhibition of EGFP expression at 50 nM siRNA (non-cytotoxic concentration). Remarkably, siRNA-G7 produced the highest inhibition of EGFP expression both in T98G-EGFP (35%) and J-774-EGFP (45%) cells, in spite of inducing a lower protection of siRNA against RNase A degradation. Taken together, our results showed that modifying the chemical structure of D is not the only way of achieving siRNA-D suitable for silencing activity. The simple use of a low ionic strength preparation media has been critical to get small siRNA-D that could be captured by cells and in particular, siRNA-G7 but not those formed by lower generation D, possessed structural constraints other than size that could favor its silencing activity. PMID:19577619

  7. Multifunctional dendrimer/combretastatin A4 inclusion complexes enable in vitro targeted cancer therapy

    PubMed Central

    Zhang, Mengen; Guo, Rui; Wang, Yin; Cao, Xueyan; Shen, Mingwu; Shi, Xiangyang

    2011-01-01

    Background We report here a unique approach to using multifunctional dendrimer/combretastatin A4 (CA4) inclusion complexes for targeted cancer therapeutics. Methods Amine-terminated generation 5 polyamidoamine dendrimers were first partially acetylated to neutralize a significant portion of the terminal amines, and then the remaining dendrimer terminal amines were sequentially modified with fluorescein isothiocyanate as an imaging agent and folic acid as a targeting ligand. The multifunctional dendrimers formed (G5.NHAc-FI-FA) were utilized to encapsulate the anticancer drug, CA4, for targeted delivery into cancer cells overexpressing folic acid receptors. Results The inclusion complexes of G5.NHAc-FI-FA/CA4 formed were stable and are able to significantly improve the water solubility of CA4 from 11.8 to 240 μg/mL. In vitro release studies showed that the multifunctional dendrimers complexed with CA4 could be released in a sustained manner. Both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and morphological cell observation showed that the inhibitory effect of the G5.NHAc-FI-FA/CA4 complexes was similar to that of free CA4 at the same selected drug concentration. More importantly, the complexes were able to target selectively and display specific therapeutic efficacy to cancer cells overexpressing high-affinity folic acid receptors. Conclusion Multifunctional dendrimers may serve as a valuable carrier to form stable inclusion complexes with various hydrophobic anticancer drugs with improved water solubility, for targeting chemotherapy to different types of cancer. PMID:22072871

  8. Biodistribution of Fluorescently Labeled PAMAM Dendrimers in Neonatal Rabbits: Effect of Neuroinflammation

    PubMed Central

    Lesniak, Wojciech G.; Mishra, Manoj K.; Jyoti, Amar; Balakrishnan, Bindu; Zhang, Fan; Nance, Elizabeth; Romero, Roberto; Kannan, Sujatha; Kannan, Rangaramanujam M.

    2014-01-01

    Dendrimers are being explored in many preclinical studies as drug, gene, and imaging agent delivery systems. Understanding their detailed organ, tissue, cellular uptake, and retention can provide valuable insights into their effectiveness as delivery vehicles and the associated toxicity. This work explores a fluorescence-quantification based assay that enables simultaneous quantitative biodistribution and imaging of dendrimers with a single agent. We have labeled an ethylenediamine-core generation-4 hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimer using the fluorescent photostable, near-IR cyanine dye (Cy5) and performed quantitative and qualitative biodistribution of the dendrimer-Cy5 conjugates (D-Cy5) in healthy neonatal rabbits and neonatal rabbits with cerebral palsy (CP). The biodistribution of D-Cy5 and free Cy5 dye was evaluated in newborn rabbits, based on the developed quantification methods using fluorescence spectroscopy, high-performance liquid chromatography (HPLC), and size exclusion chromatography (SEC) and supported by microscopic imaging. The uptake was assessed in the brain, heart, liver, lungs, kidneys, blood serum, and urine. Results obtained based on these three independent methods are in good agreement and indicate the fast renal clearance of D-Cy5 and free Cy5 with relatively higher organs accumulation of the D-Cy5 conjugate. Following systemic administration, the D-Cy5 mainly accumulated in kidneys and bladder at 24 h. The quantitative biodistribution is in good agreement with previous studies based on radiolabeling. These methods for dendrimers quantification are easier and more practical, provide excellent sensitivity (reaching 0.1 ng per gram of tissue), and allow for quantification of dendrimers in different organs over longer time periods without concerns for radioactive decay, while also enabling tissue and cellular imaging in the same animal. In kits with fetal-neuroinflammation induced CP, there was a significantly higher

  9. Evaluation of polyamidoamine dendrimers as potential carriers for quercetin, a versatile flavonoid.

    PubMed

    Madaan, Kanika; Lather, Viney; Pandita, Deepti

    2016-01-01

    The aim of the present research work was to investigate the potential of polyamidoamine (PAMAM) dendrimers as oral drug delivery carriers for quercetin, a Biopharmaceutical Classification System (BCS) class II molecule. The aqueous solubility of quercetin was investigated in different generations of dendrimers, i.e. G0, G1, G2 and G3, with varying concentrations (0.1, 0.5, 1, 2 and 4 µM). Then, it was successfully incorporated in PAMAM dendrimers and they were characterized for incorporation efficacy, nature of nanoformulations, size, size distribution, surface morphology and stability. In vitro release characteristics of quercetin from all quercetin-PAMAM complexes were studied at 37 °C in phosphate buffer saline (PBS; pH 7.4). Furthermore, the efficacy of quercetin-loaded PAMAM dendrimer was assessed by pharmacodynamic experiment, namely, a carrageenan-induced paw edema model to evaluate the acute activity of this nanocarrier in response to inflammation. It was observed that both generation and the respective concentrations of PAMAM dendrimers showed potential positive effects on solubility enhancement of quercetin. All the quercetin-PAMAM complexes were found to be in nanometeric range (<100 nm) with narrow polydispersity index. In vitro study revealed a biphasic release pattern of quercetin which was characterized by an initial faster release followed by sustained release phase and pharmacodynamic study provided the preliminary proof of concept about the potential of quercetin-PAMAM complexes. The study concludes that the dendrimer-based drug delivery system for quercetin has enormous potential to resolve the drug delivery issues associated with it. PMID:24845475

  10. Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury.

    PubMed

    Nance, Elizabeth; Porambo, Michael; Zhang, Fan; Mishra, Manoj K; Buelow, Markus; Getzenberg, Rachel; Johnston, Michael; Kannan, Rangaramanujam M; Fatemi, Ali; Kannan, Sujatha

    2015-09-28

    Extreme prematurity is a major risk factor for perinatal and neonatal brain injury, and can lead to white matter injury that is a precursor for a number of neurological diseases, including cerebral palsy (CP) and autism. Neuroinflammation, mediated by activated microglia and astrocytes, is implicated in the pathogenesis of neonatal brain injury. Therefore, targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes in models of perinatal white matter injury. In this work, we use a mouse model of ischemia-induced neonatal white matter injury to study the biodistribution of generation 4, hydroxyl-functionalized polyamidoamine dendrimers. Following systemic administration of the Cy5-labeled dendrimer (D-Cy5), we demonstrate dendrimer uptake in cells involved in ischemic injury, and in ongoing inflammation, leading to secondary injury. The sub-acute response to injury is driven by astrocytes. Within five days of injury, microglial proliferation and migration occurs, along with limited differentiation of oligodendrocytes and oligodendrocyte death. From one day to five days after injury, a shift in dendrimer co-localization occurred. Initially, dendrimer predominantly co-localized with astrocytes, with a subsequent shift towards microglia. Co-localization with oligodendrocytes reduced over the same time period, demonstrating a region-specific uptake based on the progression of the injury. We further show that systemic administration of a single dose of dendrimer-N-acetyl cysteine conjugate (D-NAC) at either sub-acute or delayed time points after injury results in sustained attenuation of the 'detrimental' pro-inflammatory response up to 9days after injury, while not impacting the 'favorable' anti-inflammatory response. The D-NAC therapy also led to improvement in myelination, suggesting reduced white matter injury. Demonstration of treatment efficacy at later time points in the postnatal period provides a greater understanding of how

  11. Fourier-transform infrared and Raman difference spectroscopy studies of the phosphorus-containing dendrimers

    NASA Astrophysics Data System (ADS)

    Furer, V. L.; Vandyukov, A. E.; Majoral, J. P.; Caminade, A. M.; Kovalenko, V. I.

    2004-06-01

    FT IR and Raman spectra of 12 generations of the phosphorus-containing starburst dendrimers containing PS and PO bonds with terminal aldehyde and PCl groups were compared. The influence of the encirclement on the band frequencies and intensity is studied and due to the predictable, controlled and reproducible structure of the dendrimers the information usually inaccessible is obtained. Bands in the IR difference ( G2'(PO) G2'(PS)) spectra have characteristic EPR-like form. The strong band at 1600 cm -1 show marked changes of the optical density in dependence of the aldehyde (CHO) or azomethyne (CHN) substituents in the aromatic ring. The analysis of difference spectra enables one to assign the characteristic bands ν(PS) and ν(PO) for the bonds in the core, in the repeating unit and in the terminal groups of the dendrimers. This assignment is supported by the calculation of the absorption curves of the different fragments of dendrimer with the force constants and electro-optical parameters. The IR and Raman spectra of dendrimers are depended on the ratio of number terminal groups to a number of repeating units, which in its turn is strictly determined by the generation number. Thus, the marked differences in the vibrational spectra of the first successive generations aspire to zero for the higher ones. The rather rigid repeated units with little conformational flexibility define the perfect microstructure of the studied phosphorus-containing dendrimers up to the eleventh generation.

  12. Novel 3-Dimensional Dendrimer Platform for Glycolipid Microarray

    PubMed Central

    Zhang, Jian; Zhou, Xichun

    2011-01-01

    Glycolipids are important biological molecules that modulate cellular recognitions and pathogen adhesions. In this paper, we report a sensitive glycolipid microarray for non-covalently immobilizing glycolipids on a microarray substrate and we perform a set of immunoassays to explore glycolipid-protein interactions. This substrate utilizes a three-dimensional hydrazide-functionalized dendrimer monolayer attached onto a microscopic glass surface, which possesses the characteristics to adsorb glycoliplids non-covalently and facilitates multivalent attributes on the substrate surface. In the proof-of-concept experiments, gangliosides such as GM1, FucGM1, GM3, GD1b, GT1b, and GQ1b, and a lipoarabinomannan were tested on the substrate and interrogated with toxins and antibodies. The resulting glycolipid microarrays exhibited hypersensitivity and specificity for detection of glycolipid-protein interactions. In particular, a robust and specific binding of a pentameric cholera toxin B subunit to the GM1 glycolipid spotted on the array has demonstrated its superiority in sensitivity and specificity. In addition, this glycolipid microarray substrate was used to detect lipoarabinomannan in buffer within a limit-of-detection of 125 ng/mL. Furthermore, Mycobacterium tuberculosis (Mtb) Lipoarabinomannan was tested in human urine specimens on this platform, which can effectively identify urine samples either infected or not infected with Mtb. The results of this work suggest the possibility of using this glycolipid microarray platform to fabricate glycoconjugate microarrays, which includes free glycans and glycolipids and potential application in detection of pathogen and toxin. PMID:21820887

  13. Dendrimer-like hybrid particles with tunable hierarchical pores

    NASA Astrophysics Data System (ADS)

    Du, Xin; Li, Xiaoyu; Huang, Hongwei; He, Junhui; Zhang, Xueji

    2015-03-01

    Dendrimer-like silica particles with a center-radial dendritic framework and a synergistic hierarchical porosity have attracted much attention due to their unique open three-dimensional superstructures with high accessibility to the internal surface areas; however, the delicate regulation of the hierarchical porosity has been difficult to achieve up to now. Herein, a series of dendrimer-like amino-functionalized silica particles with tunable hierarchical pores (HPSNs-NH2) were successfully fabricated by carefully regulating and optimizing the various experimental parameters in the ethyl ether emulsion systems via a one-pot sol-gel reaction. Interestingly, the simple adjustment of the stirring rate or reaction temperature was found to be an easy and effective route to achieve the controllable regulation towards center-radial large pore sizes from ca. 37-267 (148 +/- 45) nm to ca. 8-119 (36 +/- 21) nm for HPSNs-NH2 with particle sizes of 300-700 nm and from ca. 9-157 (52 +/- 28) nm to ca. 8-105 (30 +/- 16) nm for HPSNs-NH2 with particle sizes of 100-320 nm. To the best of our knowledge, this is the first successful regulation towards center-radial large pore sizes in such large ranges. The formation of HPSNs-NH2 may be attributed to the complex cross-coupling of two processes: the dynamic diffusion of ethyl ether molecules and the self-assembly of partially hydrolyzed TEOS species and CTAB molecules at the dynamic ethyl ether-water interface of uniform small quasi-emulsion droplets. Thus, these results regarding the elaborate regulation of center-radial large pores and particle sizes not only help us better understand the complicated self-assembly at the dynamic oil-water interface, but also provide a unique and ideal platform as carriers or supports for adsorption, separation, catalysis, biomedicine, and sensor.Dendrimer-like silica particles with a center-radial dendritic framework and a synergistic hierarchical porosity have attracted much attention due to their

  14. Optimizing the Multivalent Binding of the Bacterial Lectin LecA by Glycopeptide Dendrimers for Therapeutic Purposes.

    PubMed

    Bouvier, Benjamin

    2016-06-27

    Bacterial lectins are nonenzymatic sugar-binding proteins involved in the formation of biofilms and the onset of virulence. The weakness of individual sugar-lectin interactions is compensated by the potentially large number of simultaneous copies of such contacts, resulting in high overall sugar-lectin affinities and marked specificities. Therapeutic compounds functionalized with sugar residues can compete with the host glycans for binding to lectins only if they are able to take advantage of this multivalent binding mechanism. Glycopeptide dendrimers, featuring treelike topologies with sugar moieties at their leaves, have already shown great promise in this regard. However, optimizing the dendrimers' amino acid sequence is necessary to match the dynamics of the lectin active sites with that of the multivalent ligands. This work combines long-time-scale coarse-grained simulations of dendrimers and lectins with a reasoned exploration of the dendrimer sequence space in an attempt to suggest sequences that could maximize multivalent binding to the galactose-specific bacterial lectin LecA. These candidates are validated by simulations of mixed dendrimer/lectin solutions, and the effects of the dendrimers on lectin dynamics are discussed. This approach is an attractive first step in the conception of therapeutic compounds based on the dendrimer scaffold and contributes to the understanding of the various classes of multivalency that underpin the ubiquitous "sugar code". PMID:27223679

  15. Anti-Human Immunodeficiency Virus Activity of Thiol-Ene Carbosilane Dendrimers and Their Potential Development as a Topical Microbicide.

    PubMed

    Sánchez-Rodríguez, Javier; Díaz, Laura; Galán, Marta; Maly, Marek; Gómez, Rafael; Javier de la Mata, F; Jiménez, José L; Muñoz-Fernández, M Angeles

    2015-10-01

    The concept of a "microbicide" was born out of the lack of a vaccine against HIV and the difficulty of women in ensuring the use of preventive prophylaxis by their partners, especially in developing countries. Approaches using polyanionic carbosilane dendrimers have shown promise in the development of new microbicides. We have developed and evaluated two anionic carbosilane dendrimers with sulfonate and carboxylate terminal groups, G2-STE16 and G2-CTE16. Both dendrimers showed high biosafety in human epithelial cell lines derived from the vagina and in primary blood human cells (PBMCs). The dendrimers not only have a greater capacity to block the entry of different X4- and R5-HIV-1 isolates into epithelial cells but also prevent the HIV-1 infection of activated PBMCs. The treatment of epithelial cells with different carbosilane dendrimers did not produce changes in the activation or proliferation of PBMCs or in the expression of CD4, CCR5 or CXCR4. Computational modeling showed significantly higher affinities for the complexes G2-STE16/gp120 and G2-CTE16/gp120. Moreover, no irritation or vaginal lesions were detected in female BALB/c mice after vaginal administration of the dendrimers. Summing up, G2-STE16 and G2-CTE16 are easy to synthesize and compatible with functional groups, and the purification steps are easy and short. Our results have clearly demonstrated that these dendrimers have high potency as a topical microbicide against HIV-1 infection. PMID:26502641

  16. Development of (177)Lu-DOTA-Dendrimer and Determination of Its Effect on Metal and Ion Levels in Tumor Tissue.

    PubMed

    Kovacs, Luciana; Tassano, Marcos; Cabrera, Mirel; Zamboni, Cibele B; Fernández, Marcelo; Anjos, Roberto M; Cabral, Pablo

    2015-12-01

    Dendrimers are synthetic nanomolecules with well-defined chemical structures. Different strategies have been used for radiolabeling dendrimers with different radioisotopes. In this study, the aim was to conjugate dendrimers with (177)Lu, to observe the in vivo behavior of the labeled compound and to measure the elementary changes in tumor tissue that could be caused by ionizing radiation. PAMAM G4 dendrimers conjugated with DOTA were labeled with (177)Lu. The radiolabeled compound was characterized and its stability was evaluated by reverse phase high performance liquid chromatography. Radiolabeling yield was >98% and stable for 24 hours. Biodistribution studies of (177)Lu-DOTA-dendrimers in C57BL/6 melanoma-bearing mice showed blood clearance with hepatic and renal depuration and tumor uptake. The concentrations of Br, Ca, Cl, Fe, K, Mg, Na, Rb, S, and Zn were determined in tumor tissues of C57BL/6 mice treated with (177)Lu-DOTA-dendrimers and in untreated mice. The results showed decreased concentrations of Br (62%), Ca (24%), Cl (51%), K (12%) and Na (60%) and increased concentrations of Fe (8%), Mg (28%), Rb (100%), S (6%) and Zn (4%) in tumor tissues of mice treated with (177)Lu-DOTA-dendrimers. These data may be useful to evaluate changes in tumor tissues as indicators of damage that could be caused by ionizing radiation. PMID:26625257

  17. Intra-molecular Structural Change of PAMAM Dendrimers in Aqueous Solutions Revealed by Small Angle Neutron Scattering

    SciTech Connect

    Porcar, L.; Hong, Kunlun; Butler, Paul D; Herwig, Kenneth W; Smith, Gregory Scott; Liu, Yun; Chen, Wei-Ren

    2010-01-01

    Small-angle neutron scattering (SANS) experiments were carried out to investigate the structure of aqueous (D2O) G4 PAMAM dendrimer solutions as a function of molecular protonation and dendrimer concentration. Our results indicate unambiguously that, although the radius of gyration RG remains nearly invariant, the dendrimer radial density profile (r) decreases in the dendrimer core with a continuous increase in protonation. This discovery also suggests that RG, which is commonly adopted by numerous simulation and experimental works in describing the global dendrimer size, is not suitable as the index parameter to characterize the dendrimer conformation change. We also found that RG and (r), for dendrimers dissolved in both neutral and acidified solutions, remain nearly constant over the studied concentration range. We further demonstrate that the outcome of the widely used Guinier method is questionable for extracting RG in the concentration range studied. Our results reveal the polymer colloid structural duality as benchmarks for future experimental and theoretical studies and provide a critical step toward understanding drug encapsulation by ionic bonds.

  18. Trastuzumab-grafted PAMAM dendrimers for the selective delivery of anticancer drugs to HER2-positive breast cancer

    PubMed Central

    Kulhari, Hitesh; Pooja, Deep; Shrivastava, Shweta; Kuncha, Madhusudana; Naidu, V. G. M.; Bansal, Vipul; Sistla, Ramakrishna; Adams, David J.

    2016-01-01

    Approximately 20% of breast cancer cases are human epidermal growth factor receptor 2 (HER2)-positive. This type of breast cancer is more aggressive and tends to reoccur more often than HER2-negative breast cancer. In this study, we synthesized trastuzumab (TZ)-grafted dendrimers to improve delivery of docetaxel (DTX) to HER2-positive breast cancer cells. Bioconjugation of TZ on the surface of dendrimers was performed using a heterocrosslinker, MAL-PEG-NHS. For imaging of cancer cells, dendrimers were also conjugated to fluorescein isothiocyanate. Comparative in vitro studies revealed that these targeted dendrimers were more selective, and had higher antiproliferation activity, towards HER2-positive MDA-MB-453 human breast cancer cells than HER2-negative MDA-MB-231 human breast cancer cells. When compared with unconjugated dendrimers, TZ-conjugated dendrimers also displayed higher cellular internalization and induction of apoptosis against MDA-MB-453 cells. Binding of TZ to the dendrimer surface could help site-specific delivery of DTX and reduce systemic toxicity resulting from its lack of specificity. In addition, in vivo studies revealed that the pharmacokinetic profile of DTX was significantly improved by the conjugated nanosystem. PMID:27052896

  19. Spatial distribution of intra-molecular water and polymeric components in polyelectrolyte dendrimers revealed by small angle scattering investigations

    SciTech Connect

    Chen, Chun-Yu; Chen, Wei-Ren; Herwig, Kenneth W; Hong, Kunlun; Li, Xin; Liu, Emily; Liu, Yun; Smith, Gregory Scott; Wu, Bin; Yang, Jun; Do, Changwoo

    2011-01-01

    An experimental scheme using contrast variation small angle neutron scattering technique (SANS), is developed to investigate the structural characteristics of amine-terminated poly(amidoamine) dendrimers (PAMAM) solutions. The focus is placed on understanding the dependence of intra-dendrimer water and polymer distribution on molecular protonation, which can be precisely adjusted by tuning the pH value of solution. Assuming the spherical symmetry in the spatial arrangement of the constituent component of dendrimer, and the atomic ratio of hydrogen-to-deuterium for the solvent residing within the cavities of dendrimer is identical to that for the solvent outside dendrimer, the intra-dendrimer water distribution along the radial direction can be determined based on the model of coherent scattering cross section developed in this work. Moreover, our result clearly reveals an outward relocation of the peripheral groups, as well as the enhanced intra-dendrimer hydration, upon increasing the molecular protonation and therefore allows the determination of segmental backfolding in a quantitative manner. The connection between these charge-induced structural changes and our recently observed progressively active segmental dynamics is also discussed.

  20. Poly(amidoamine) dendrimers: A new class of high capacity chelating agents for Cu(II) ions

    SciTech Connect

    Diallo, M.S. |; Balogh, L.; Shafagati, A.; Johnson, J.H. Jr.; Goddard, W.A. III; Tomalia, D.A. |

    1999-03-01

    This communication describes preliminary results of an experimental investigation of the binding of Cu(II) ions to poly(amidoamine) (PAMAM) dendrimers in aqueous solutions. Dendrimers are highly branched polymers with controlled composition and architecture consisting of three structural components: a core, interior branch cells, and terminal branch cells. PAMAM dendrimers possess functional nitrogen and amide groups arranged in regular branched upon branched patterns which are displayed in geometrically progressive numbers as a function of generation level. Terminal groups of PAMAM dendrimers may be any organic substituent such as primary amines, carboxylic groups, etc. In aqueous solutions, PAMAM dendrimers can serve as high capacity nanoscale containers for toxic metal ions such as Cu(II). Compared to traditional chelating agents with nitrogen donors, which can typically bind only one Cu(II) ion per molecule, a generation eight (G8) PAMAM dendrimer can bind up 153 {+-} 20 Cu(II) ions per molecule. This clearly illustrates a distinct advantage of dendrimers over traditional chelating agents and macrocycles; that is the covalent attachment of nitrogen ligands to conformationally flexible PAMAM chains enclosed within a nanoscopic structure results in a substantial increase in binding capacity.

  1. X-ray computed tomography contrast agents prepared by seeded growth of gold nanoparticles in PEGylated dendrimer

    NASA Astrophysics Data System (ADS)

    Kojima, Chie; Umeda, Yasuhito; Ogawa, Mikako; Harada, Atsushi; Magata, Yasuhiro; Kono, Kenji

    2010-06-01

    Gold nanoparticles (Au NPs) are a potential x-ray computed tomography (CT) contrast agent. A biocompatible and bioinactive surface is necessary for application of gold nanoparticle to CT imaging. Polyethylene glycol (PEG)-attached dendrimers have been used as a drug carrier with long blood circulation. In this study, the Au NPs were grown in the PEGylated dendrimer to produce a CT contrast agent. The Au NPs were grown by adding gold ions and ascorbic acid at various equivalents to the Au NP-encapsulated dendrimer solution. Both size and surface plasmon absorption of the grown Au NPs increased with adding a large number of gold ions. The x-ray attenuation of the Au NPs also increased after the seeded growth. The Au NPs grown in the PEG-attached dendrimer at the maximum under our conditions exhibited a similar CT value to a commercial iodine agent, iopamidol, in vitro. The Au NP-loaded PEGylated dendrimer and iopamidol were injected into mice and CT images were obtained at different times. The Au NP-loaded PEGylated dendrimer achieved a blood pool imaging, which was greater than a commercial iodine agent. Even though iopamidol was excreted rapidly, the PEGylated dendrimer loading the grown Au NP was accumulated in the liver.

  2. Bilayer Charge Reversal and Modification of Lipid Organization by Dendrimers as Observed by Sum-Frequency Vibrational Spectroscopy.

    PubMed

    Keszthelyi, Tamás; Holló, Gábor; Nyitrai, Gabriella; Kardos, Julianna; Héja, László

    2015-07-21

    Polyamidoamine (PAMAM) dendrimers are hyperbranched, nanosized polymers with promising biomedical applications as nanocarriers in targeted drug delivery and gene therapy. For the development of safe dendrimer-based biomedical applications it is necessary to gain an understanding of the detailed mechanism of the interactions of both cationic and anionic dendrimers with cell membranes. To characterize dendrimer-membrane interactions we applied solid-supported lipid bilayers as biomembrane models and utilized infrared-visible sum-frequency vibrational spectroscopy to independently probe the interactions of cationic G5-NH2 and anionic G4.5-COONa dendrimers with the two leaflets of the lipid bilayers. Interaction with both dendrimers led to changes in the interfacial water structure and charge density as evidenced by the changes in the OH band intensities in the sum-frequency spectra of the bilayers. Interaction with the G5-NH2 dendrimer also led to a unique inversion of the sign of the OH-stretch amplitudes, in addition to a decrease in their absolute values. We suggest that the positively charged amino groups on the G5-NH2 dendrimer surface bind to the negatively charged bilayer, while uncompensated positive charges not involved in the binding cause a reversal of the electric field and thus an opposite orientation of the interfacial water molecules. More subtle but nonetheless significant changes were seen in the relative magnitudes of the CH amplitudes. The methyl antisymmetric to symmetric stretch amplitude ratios are altered, implying changes in the tilt angles of the phospholipid alkyl chains. The conformational order of the phospholipid alkyl chains of both leaflets is also influenced by the G5-NH2 dendrimer while G4.5-COONa has no effect on the alkyl chain conformation. PMID:26099064

  3. 64Cu-Labeled LyP-1-Dendrimer for PET-CT Imaging of Atherosclerotic Plaque

    PubMed Central

    2015-01-01

    The ability to detect and quantify macrophage accumulation can provide important diagnostic and prognostic information for atherosclerotic plaque. We have previously shown that LyP-1, a cyclic 9-amino acid peptide, binds to p32 proteins on activated macrophages, facilitating the visualization of atherosclerotic plaque with PET. Yet, the in vivo plaque accumulation of monomeric [18F]FBA-LyP-1 was low (0.31 ± 0.05%ID/g). To increase the avidity of LyP-1 constructs to p32, we synthesized a dendritic form of LyP-1 on solid phase using lysine as the core structural element. Imaging probes (FAM or 6-BAT) were conjugated to a lysine or cysteine on the dendrimer for optical and PET studies. The N-terminus of the dendrimer was further modified with an aminooxy group in order to conjugate LyP-1 and ARAL peptides bearing a ketone. Oxime ligation of peptides to both dendrimers resulted in (LyP-1)4- and (ARAL)4-dendrimers with optical (FAM) and PET probes (6-BAT). For PET-CT studies, (LyP-1)4- and (ARAL)4-dendrimer-6-BAT were labeled with 64Cu (t1/2 = 12.7 h) and intravenously injected into the atherosclerotic (ApoE–/–) mice. After two hours of circulation, PET-CT coregistered images demonstrated greater uptake of the (LyP-1)4-dendrimer-64Cu than the (ARAL)4-dendrimer-64Cu in the aortic root and descending aorta. Ex vivo images and the biodistribution acquired at three hours after injection also demonstrated a significantly higher uptake of the (LyP-1)4-dendrimer-64Cu (1.1 ± 0.26%ID/g) than the (ARAL)4-dendrimer-64Cu (0.22 ± 0.05%ID/g) in the aorta. Similarly, subcutaneous injection of the LyP-1-dendrimeric carriers resulted in preferential accumulation in plaque-containing regions over 24 h. In the same model system, ex vivo fluorescence images within aortic plaque depict an increased accumulation and penetration of the (LyP-1)4-dendrimer-FAM as compared to the (ARAL)4-dendrimer-FAM. Taken together, the results suggest that the (LyP-1)4-dendrimer can be applied for in

  4. Nanomanufacturing of Gold Nanoparticle Arrays Using Peptide-Derivatized Block Copolymer Templates

    NASA Astrophysics Data System (ADS)

    Rao, Tingling; Singh, Gurpreet; Xie, Sibai; Karim, Alamgir; Becker, Matthew

    2013-03-01

    Collective surface plasmons (SPs) displayed by two-dimensional (2-D) Au nanostructures are important for applications such as plasmonics and plasmonic sensing. However, methods for fabricating programmable highly-ordered arrays of Au nanoparticles with nanoscale precision are limited. Here, we report a peptide--derivated block copolymer based rout towards continuous fabrication of Au nanoparticle superlatice with tunable structures. We successfully obtain discrete, hexagonally-packed Au nanoparticle hierarchical structures where Au-to-Au nanoparticle spacing is precisely controlled by the underlying PMMA cylindrical phase of the block copolymer (BCP). Dynamic thermal field processing techniques offer a facile and continuous rout to tune the BCP assembly, thus enabling versatile arrangement of Au nanostructures from Au-dots to Au-lines. Our method may open a cost-effective way towards assembly of 2-D Au nanoparticles with tunable structures by carefully tuning molecular parameters - a promising step to novel nanodevices. Akron Functional Materials Center (AFMC) and The University of Akron Research Foundation

  5. Electrochemical aptasensor of cellular prion protein based on modified polypyrrole with redox dendrimers.

    PubMed

    Miodek, A; Castillo, G; Hianik, T; Korri-Youssoufi, H

    2014-06-15

    This work consists of the development of an electrochemical aptasensor based on polyprrole modified with redox dendrimers, able to detect human cellular prions PrP(C) with high sensitivity. The gold surface was modified by conductive polypyrrole film coupled to polyamidoamine dendrimers of fourth generation (PAMAM G4) and ferrocenyl group as redox marker. The aptamers were immobilized on the surface via biotin/streptavidin chemistry. Electrochemical signal was detected by ferrocenyl group incorporated between dendrimers and aptamers layers. We demonstrated that the interaction between aptamer and prion protein led to variation in electrochemical signal of the ferrocenyl group. The kinetics parameters (diffusion coefficient D and heterogeneous constant transfer ket) calculated from electrochemical signals demonstrate that the variation in redox signal results from the lower diffusion process of ions during redox reaction after prion interaction due to bulk effect of larger protein. The association of redox dendrimers with conducting polypyrrole leads to high sensitivity of PrP(C) determination with detection limit of 0.8 pM, which is three orders of magnitude lower, compared to flat ferrocene-functionalized polypyrrole. Detection of PrP(C) in spiked blood plasma has been achieved and demonstrated a recovery up to 90%. PMID:24480126

  6. A theoretical investigation of symmetry-origin unidirectional energy gradient in light-harvesting dendrimers

    NASA Astrophysics Data System (ADS)

    Koda, Shin-ichi

    2016-03-01

    We theoretically investigate a possibility that the symmetry of the repetitively branched structure of light-harvesting dendrimers creates the energy gradient descending toward inner generations (layers of pigment molecules) of the dendrimers. In the first half of this paper, we define a model system using the Frenkel exciton Hamiltonian that focuses only on the topology of dendrimers and numerically show that excitation energy tends to gather at inner generations of the model system at a thermal equilibrium state. This indicates that an energy gradient is formed in the model system. In the last half, we attribute this result to the symmetry of the model system and propose two symmetry-origin mechanisms creating the energy gradient. The present analysis and proposition are based on the theory of the linear chain (LC) decomposition [S. Koda, J. Chem. Phys. 142, 204112 (2015)], which equivalently transforms the model system into a set of one-dimensional systems on the basis of the symmetry of dendrimers. In the picture of the LC decomposition, we find that energy gradient is formed both in each linear chain and among linear chains, and these two mechanisms explain the numerical results well.

  7. PAMAM Dendrimer/pDNA Functionalized-Magnetic Iron Oxide Nanoparticles for Gene Delivery.

    PubMed

    Xiao, Shili; Castro, Rita; Rodrigues, João; Shi, Xiangyang; Tomás, Helena

    2015-08-01

    Herein, we report an easy and ingenious method to functionalize magnetic iron oxide nanoparticles (MNPs) with plasmid DNA (pDNA) to obtain nanohybrid systems suitable for nucleic acid therapy. The nanohybrids were prepared by combining complexes of dendrimers and pDNA (dendriplexes) and poly(styrene) sulfonate-coated MNPs through electrostatic interactions. The effects of the dendrimer generation (generations 2, 4 and 6) and the amine to phosphate group (N/P) ratio on the hydrodynamic diameter, zeta potential, cell viability, cellular internalization and transfection efficiency of the nanohybrids were systematically investigated at different transfection conditions (including incubation time, pDNA concentration, presence or absence of an external magnetic field, and presence or absence of fetal bovine serum). The results confirmed that the nanohybrids were able to transfect NIH 3T3 cells, and that the level of gene expression (the luciferase protein reporter gene was used) was strongly dependent on the dendrimer generation, the N/P ratio, and the pDNA concentration. The best system was based on dendriplex-coated MNPs formed by generation 6 dendrimers at an N/P ratio of 10 that, at optimized conditions, led to a gene expression level which was not significantly different from that obtained only using dendriplexes. In summary, a coherent set of results was reached indicating the potential of the developed nanohybrids as effective gene delivery nanomaterials. PMID:26295139

  8. Antimicrobial Efficacy of Synthesized Quaternary Ammonium Polyamidoamine Dendrimers and Dendritic Polymer Network.

    PubMed

    Zainul Abid, C K V; Jackeray, Richa; Jain, Swati; Chattopadhyay, Sruti; Asif, S; Singh, Harpal

    2016-01-01

    Water treatment to mitigate microbial contaminants is a major challenge across globe paving the way to develop novel antimicrobial compounds. We aim at architecting antibacterial moiety eventually catering to vast water treatment industry. In this research study, quaternary ammonium functionalized polyamidoamine (PAMAM) dendrimer and PAMAM-ethyleneglycol dimethacrylate (EGDMA) dendritic polymer network were synthesized. These materials were characterized by various analytical techniques like ATR-FTIR, 1HNMR, DSC etc. Water soluble generation (G) 1.0 PAMAM dendrimer and water insoluble PAMAM G1.0 EGDMA dendritic polymer network were quaternized by reacting with dilute hydrochloric acid (HCI) and octyl iodide (01) respectively. Both quaternary ammonium dendrimer products were found to exhibit potent bactericidal activity against a group of common Gram-negative and Gram-positive bacteria. 10 mg/L concentration of liquid PAMAM G1.0 QHCI was efficient to kill 100% bacteria rapidly within an incubation time of just 2 minutes. In addition, quaternary ammonium dendritic polymer network PAMAM G1.0-EGDMA Q OI demonstrated good contact killing antimicrobial property without releasing any active molecule into the surrounding medium and disinfected contaminated water within 5 minutes. Both quaternary ammonium dendrimer and dendritic polymer network showed negligible cytotoxicity in MTT assay indicating their potential as a viable antimicrobial agent. PMID:27398560

  9. Mechanistic studies of in vitro cytotoxicity of poly(amidoamine) dendrimers in mammalian cells

    SciTech Connect

    Mukherjee, Sourav Prasanna; Lyng, Fiona M.; Garcia, Amaya; Davoren, Maria; Byrne, Hugh J.

    2010-11-01

    Poly(amidoamine) (PAMAM) dendrimer nanoparticles have been demonstrated to elicit a well defined cytotoxicological response from mammalian cell lines, the response increasing systematically with dendrimer generation and number of surface amino groups. In this work, using generation G4, G5, and G6 dendrimers, this systematic response is furthermore demonstrated for the generation of reactive oxygen species, lysosomal activity, and the onset of apoptosis and levels of DNA damage. The results are consistent with a pathway of localisation of PAMAM dendrimers in the mitochondria leading to ROS production causing oxidative stress, apoptosis and DNA damage. ROS production is co-located in the mitochondria, and both generated levels and timescales are systematically generation dependent (G4 < G5 < G6). Flow cytometry confirms that with increasing dose, the percentage of healthy and early apoptotic cells decreases, whereas the late apoptotic and necrotic cell populations increase. This process is again systematically generation dependent. DNA damage as measured using the TUNEL assay further demonstrates a systematic trend, G4, G5 and G6 showing 4.69%, 25.87% and 89.63% DNA breakage respectively. Increases in lysosomal activity at timescales of {approx} 24 h are observed in HaCaT but not SW480 cells upon low concentration PAMAM exposure. Overall, significant differences are observed between the responses of the dermal cell line, HaCaT, and the colon cell line, SW480, and it is suggested that these can be understood in terms of differing intrinsic antioxidant levels.

  10. Comparison of MRI properties between derivatized DTPA and DOTA gadolinium-dendrimer conjugates

    PubMed Central

    Nwe, K.; Bernardo, M; Regino, C. A. S.; Williams, M; Brechbiel, M. W.

    2010-01-01

    In this report we directly compare the in vivo and in vitro MRI properties of gadolinium-dendrimer conjugates of derivatized acyclic diethylenetriamine-N,N’,N’,N’’, N’’-pentaacetic acid (1B4M-DTPA) and macrocyclic 1,4,7,10-tetraazacyclododecane-N,N’,N’’,N’’’-tetraacetic acid (C-DOTA). The metal-ligand chelates were pre-formed in alcohol prior to conjugation to the generation 4 PAMAM dendrimer (G4D), and the dendrimer-based agents were purified by Sephadex® G-25 column. The analysis and SE-HPLC data indicated chelate to dendrimer ratios of 30:1 and 28:1 respectively. Molar relaxivity measured at pH 7.4, 22°C, and 3T are comparable (29.5 vs. 26.9 mM−1s−1), and both conjugates are equally viable as MRI contrast agents based on the images obtained. The macrocyclic agent however exhibits a faster rate of clearance in vivo (t1/2 = 16 vs. 29 min.). Our conclusion is that the macrocyclic-based agent is the more suitable agent for in vivo use for these reasons combined with kinetic inertness associated with the Gd(III) DOTA complex stability properties. PMID:20663676

  11. Artificial Golgi apparatus: globular protein-like dendrimer facilitates fully automated enzymatic glycan synthesis.

    PubMed

    Matsushita, Takahiko; Nagashima, Izuru; Fumoto, Masataka; Ohta, Takashi; Yamada, Kuriko; Shimizu, Hiroki; Hinou, Hiroshi; Naruchi, Kentaro; Ito, Takaomi; Kondo, Hirosato; Nishimura, Shin-Ichiro

    2010-11-24

    Despite the growing importance of synthetic glycans as tools for biological studies and drug discovery, a lack of common methods for the routine synthesis remains a major obstacle. We have developed a new method for automated glycan synthesis that employs the enzymatic approach and a dendrimer as an ideal support within the chemical process. Recovery tests using a hollow fiber ultrafiltration module have revealed that monodisperse G6 (MW = 58 kDa) and G7 (MW = 116 kDa) poly(amidoamine) dendrimers exhibit a similar profile to BSA (MW = 66 kDa). Characteristics of the globular protein-like G7 dendrimer with high solubility and low viscosity in water greatly enhanced throughput and efficiency in automated synthesis while random polyacrylamide-based supports entail significant loss during the repetitive reaction/separation step. The present protocol allowed for the fully automated enzymatic synthesis of sialyl Lewis X tetrasaccharide derivatives over a period of 4 days in 16% overall yield from a simple N-acetyl-d-glucosamine linked to an aminooxy-functionalized G7 dendrimer. PMID:21033706

  12. Modification of cotton fabric with a dendrimer to improve ink-jet printing process.

    PubMed

    Soleimani-Gorgani, Atasheh; Najafi, Farhood; Karami, Zohreh

    2015-10-20

    In this study, the cotton fabrics were modified with different polyamidoamine (PAMAM) dendrimer concentrations to yield antimicrobial and efficient polymeric materials for ink-jet printing. PAMAM dendrimer has been covalently grafted on cotton fabric via the reaction of cellulosate anion with the cynuric chloride. The obtained modified cotton fabrics were characterized by FTIR and TGA. The morphology and yellowness of modified cotton fabrics were analysed by SEM and UV spectroscopy. The ink-jet printing onto modified cotton fabrics were evaluated at different pHs. The results at optimum pH indicated that by increasing the PAMAM dendrimer concentration in modified cotton fabric not only the colour strength of reactive ink-jet printed fabric increased but also the antimicrobial cotton fabric produced. A comparision between printing modified and unmodified cottons suggest that the PAMAM dendrimer has the potential for using in single-phase ink-jet printing. The yielded prints demonstrate excellent colour fastness for washing and dry/wet crocking properties. PMID:26256173

  13. Interfacial Interaction between Transmembrane Ocular Mucins and Adhesive Polymers and Dendrimers Analyzed by Surface Plasmon Resonance

    PubMed Central

    Noiray, M.; Briand, E.; Woodward, A. M.; Argüeso, P.; Molina Martínez, I. T.; Herrero-Vanrell, R.; Ponchel, G.

    2013-01-01

    Purpose Development of the first in vitro method based on biosensor chip technology designed for probing the interfacial interaction phenomena between transmembrane ocular mucins and adhesive polymers and dendrimers intended for ophthalmic administration. Methods The surface plasmon resonance (SPR) technique was used. A transmembrane ocular mucin surface was prepared on the chip surface and characterized by QCM-D (Quartz Crystal Microbalance with Dissipation) and XPS (X-ray photoelectron spectroscopy). The mucoadhesive molecules tested were: hyaluronic acid (HA), carboxymethyl cellulose (CMC), hydroxypropylmethyl cellulose (HPMC), chitosan (Ch) and polyamidoamine dendrimers (PAMAM). Results While Ch originated interfacial interaction with ocular transmembrane mucins, for HA, CMC and HPMC, chain interdiffusion seemed to be mandatory for bioadherence at the concentrations used in ophthalmic clinical practise. Interestingly, PAMAM dendrimers developed permanent interfacial interactions with transmembrane ocular mucins whatever their surface chemical groups, showing a relevant importance of co-operative effect of these multivalent systems. Polymers developed interfacial interactions with ocular membrane-associated mucins in the following order: Ch(1 %) > G4PAMAM-NH2(2 %) = G4PAMAM-OH(2 %) > G3.5PAMAM-COOH(2 %)≫ CMC(0.5 %) = HA(0.2 %) = HPMC(0.3 %). Conclusions The method proposed is useful to discern between the mucin-polymer chemical interactions at molecular scale. Results reinforce the usefulness of chitosan and den-drimers as polymers able to increase the retention time of drugs on the ocular surface and hence their bioavailability. PMID:22565639

  14. Theoretical evaluation of the nanocarrier properties of two families of functionalized dendrimers

    NASA Astrophysics Data System (ADS)

    Evangelista-Lara, Aurelio; Guadarrama, Patricia

    Two families of dendrimers, denamide (oxy-amide) and denurea (oxy-urea), of second and third generation were designed as possible nanocarriers for high-spectral parasiticide drugs of the family of macrocyclic lactones. Their geometric description was carried out by Connolly's algorithm, obtaining molecular volumes and sizes of cavities. According to these calculations, about 50% of the total dendrimeric molecular volume in both families corresponds to cavities that are able to shelter guest drugs, forming complexes in ratios higher than 1:1. The molecular shape suffers more notorious changes, going through higher dendrimeric generations; therefore, third-generation dendrimers with two carbon atoms in their fractal patterns are more spherical than second-generation dendrimers with six carbon atoms in their fractal patterns. The experimentally studied host-guest system formed by PAMAM and ibuprofen (analgesic drug) was taken as a reference in the present study. Molecular dynamics and mechanics calculations were able to reproduce some experimental observations. Nevertheless, the interaction energies of some of the 1:1 complexes were calculated at the density functional theory (DFT) level. Comparing the fractal patterns of the denamide and denurea families with polyamidoamine dendrimers (PAMAM), the observed order of efficiency, in terms of favorable interactions with guest molecules, is as follows: denamide > PAMAM > denurea. The differences in functionalization are responsible for such behavior. Content:text/plain; charset="UTF-8"

  15. Water-soluble polyelectrolyte complexes of Astramol poly(propyleneimine) dendrimers with poly(methacrylate) anion.

    PubMed

    Zhiryakova, Marina V; Izumrudov, Vladimir A

    2014-11-26

    Water-soluble complexes formed by pyrenyl-tagged poly(methacrylate) anion with cationic DAB-dendr-(NH2)x of five generations, x = 4, 8, 16, 32, and 64 were prepared and studied. The ability of the dendrimers to quench the pyrenyl fluorescence was used to monitor formation/dissociation of the complexes by fluorescence quenching technique. In salt-free solutions, dissociation of the complexes occurred in highly acidic and highly alkaline media independently on the dendrimer generation, whereas stability of the complexes against destruction by added salt (NaCl) enhanced markedly with x increase. Phase separations were dependent on pH and charged ratio of the components, but independent of a dendrimer generation. By contrast, in water-salt solutions the generation had a profound impact on phase diagram manifested by a considerable extension of a heterogeneity region as x increased. These findings strongly suggest that the complexes obey the main regularities ascertained for polyelectrolyte complexes of oppositely charged polyions. The revealed possibility of preparing negatively charged and positively charged complexes with controllable stability and solubility demonstrates potentialities of Astramol dendrimers for design self-assembled and self-adjusted systems attractive for biotechnological and biomedical applications. PMID:25369241

  16. PAMAM dendrimers and graphene: materials for removing aromatic contaminants from water.

    PubMed

    DeFever, Ryan S; Geitner, Nicholas K; Bhattacharya, Priyanka; Ding, Feng; Ke, Pu Chun; Sarupria, Sapna

    2015-04-01

    We present results from experiments and atomistic molecular dynamics simulations on the remediation of naphthalene by polyamidoamine (PAMAM) dendrimers and graphene oxide (GrO). Specifically, we investigate 3rd-6th generation (G3-G6) PAMAM dendrimers and GrO with different levels of oxidation. The work is motivated by the potential applications of these emerging nanomaterials in removing polycyclic aromatic hydrocarbon contaminants from water. Our experimental results indicate that GrO outperforms dendrimers in removing naphthalene from water. Molecular dynamics simulations suggest that the prominent factors driving naphthalene association to these seemingly disparate materials are similar. Interestingly, we find that cooperative interactions between the naphthalene molecules play a significant role in enhancing their association to the dendrimers and GrO. Our findings highlight that while selection of appropriate materials is important, the interactions between the contaminants themselves can also be important in governing the effectiveness of a given material. The combined use of experiments and molecular dynamics simulations allows us to comment on the possible factors resulting in better performance of GrO in removing polyaromatic contaminants from water. PMID:25786141

  17. Identification of surface domain structure on enamel crystals using polyamidoamine dendrimer

    NASA Astrophysics Data System (ADS)

    Chen, Haifeng; Clarkson, Brian H.; Orr, Bradford; Majoros, Istvan; Banaszak Holl, Mark M.

    2002-03-01

    The control of hydroxyapatite crystal nucleation and crystal growth is central to the mineralization and remineralization of enamel and dentin of teeth. However, the precise biomolecular mechanisms involved remain obscure. The intimate association between the crystal's surface and extracellular protein components implies a modulating role for organic crystal interactions probably mediated via specific crystal surface domains. These include lattice defects and specific stereochemical arrays on associated organic molecules. The nature of protein-crystal interaction depends upon the physical forces of attraction / repulsion between specific biomolecular groups and crystal surface domains. The proposed study is to utilize specific polyamidoamine (PAMAM) dendrimers, also known as “artificial proteins”, acting as nanoprobe. These will be used to probe specific surface domain on the surface of the naturally derived crystals of hydroxyapatite and to determine how control of growth and dissolution may be affected at the biomolecular level. The hydroxyapatite crystals are extracted from the maturation stage enamel of rats. Three types of PAMAM dendrimers, respectively with amine-, carboxylic acid and methyl-capped surface, will be applied in the study. The dendrimer binding on the surface of the hydoxyapatite crystals will be characterized using atomic force microscopy (AFM). The different dendrimer binding on the crystals will disclose the specific surface domain structure on the crystals, which is assumed to be important in binding the extracellular protein.

  18. Optical coherence tomography to delineate the interactions of PAMAM dendrimers with the porcine skin surface

    NASA Astrophysics Data System (ADS)

    Judd, Amy M.; Moss, Gary P.; Heylings, Jon; Wan, Ka-Wai; Yang, Ying

    2013-02-01

    Polyamidoamine (PAMAM) dendrimers have been topically applied to the skin and utilised as a permeation enhancer for a range of therapeutic compounds. However, very little is known about the mechanism of enhancement. This study used optical coherence tomography (OCT) to investigate the influence of PAMAM dendrimers to alter surface refractive index (RI) in excised porcine skin. It is revealed that PAMAM dendrimers caused a sporadic disruption and disappearance of the white hyper-reflective band on the skin surface using OCT. Following the decontamination of the treated skin specimens, the entrance signal, resulting in the polarised light reflecting off the keratin of the upper skin strata, returned to normal. Further, PAMAM-induced changes in skin RI was benchmarked against glycerol, a known permeation enhancer and skin clearing agent. Changes in RI with PAMAM were only observed on the skin surface, suggesting that the dendrimer only modulates the outer layers of the stratum corneum. This is substantially different to the observed effect of glycerol, which permeated more deeply into the skin. The non-invasive and non-destructive OCT imaging technique may provide a convenient tool to investigate the mechanism of permeation enhancement and transdermal drug delivery.

  19. Anti-angiogenic poly-L-lysine dendrimer binds heparin and neutralizes its activity.

    PubMed

    Al-Jamal, Khuloud T; Al-Jamal, Wafa T; Kostarelos, Kostas; Turton, John A; Florence, Alexander T

    2012-01-01

    The interaction between heparin, a polyanion, and a polycationic dendrimer with a glycine core and lysine branches Gly-Lys63(NH2)64 has been investigated. Complexation was assessed by transmission electron microscopy, size and zeta potential measurements, methylene blue spectroscopy, and measuring the anti-coagulant activity of heparin in vitro and in vivo. Complete association between the heparin and the dendrimer occurred a 1:1 mass ratio (2:1 molar ratio or +/-charge ratio) with formation of quasi-spherical complexes in the size range of 99-147 nm with a negative zeta potential (-47 mV). Heparin-dendrimer (dendriplex) formation led to a concentration-dependent neutralization of the anticoagulant activity of heparin in human plasma in vitro, with complete loss of activity at a 1:1 mass ratio. The anticoagulant activity of the dendriplexes in Sprague-Dawley rats was also evaluated after subcutaneous administration with uncomplexed heparin as a comparator. The in vivo anticoagulant activity of heparin in plasma, evaluated using an antifactor Xa assay, was abolished after complexation. Measurement of [(3)H]-heparin showed that both free heparin and dendriplexes were present in plasma and in organs. Such data confirmed stably the formation of dendriplexes, which could be essential in developing novel dendrimer-based anti-angiogenic therapeutics suitable in combinatory therapeutics and theranostics. PMID:25755989

  20. Photocontrolled reversible morphology conversion of protein nanowires mediated by an azobenzene-cored dendrimer.

    PubMed

    Sun, Hongcheng; Zhao, Linlu; Wang, Tingting; An, Guo; Fu, Shuang; Li, Xiumei; Deng, Xiaoli; Liu, Junqiu

    2016-05-21

    A novel strategy to construct photocontrolled protein nanowires with reversible morphology was reported through photoisomerizable azobenzene-cored dendrimer evoked protein self-assembly. Furthermore, the curvature of the protein nanowires could be switched by alternatively irradiating with visible light and ultraviolet light. PMID:27062988

  1. Expanding the structural diversity of self-assembling dendrons and supramolecular dendrimers via complex building blocks.

    PubMed

    Percec, Virgil; Won, Betty C; Peterca, Mihai; Heiney, Paul A

    2007-09-12

    The design and synthesis of the first examples of AB4 and AB5 dendritic building blocks with complex architecture are reported. Structural and retrostructural analysis of supramolecular dendrimers self-assembled from hybrid dendrons based on different combinations of AB4 and AB5 building blocks with AB2 and AB3 benzyl ether dendrons demonstrated that none of these new hybrid dendrons exhibit the previously encountered conformations of libraries of benzyl ether dendrons. These hybrid dendrons enabled the discovery of some highly unusual tapered and conical dendrons generated by the intramolecular back-folding of their repeat units and of their apex. The new back-folded tapered dendrons have double thickness and self-assemble into pine-tree-like columns exhibiting a long-range 7/2 helical order. The back-folded conical dendrons self-assemble into spherical dendrimers. Non-back-folded truncated conical dendrons were also discovered. They self-assemble into spherical dendrimers with a less densely packed center. The discovery of dendrons displaying a novel crown-like conformation is also reported. Crown-like dendrons self-assemble into long-range 5/1 helical pyramidal columns. The long-range 7/2 and 5/1 helical structures were established by applying, for the first time, the helical diffraction theory to the analysis of X-ray patterns obtained from oriented fibers of supramolecular dendrimers. PMID:17705390

  2. PAMAM dendrimers and graphene: Materials for removing aromatic contaminants from water

    SciTech Connect

    DeFever, Ryan S.; Geitner, Nicholas K.; Bhattacharya, Priyanka; Ding, Feng; Ke, Pu Chun; Sarupria, Sapna

    2015-04-07

    We present results from experiments and atomistic molecular dynamics simulations on the association of naphthalene with polyamidoamine (PAMAM) dendrimers and graphene oxide (GrO). Specifically, we investigate 3rd-6th generation (G3-G6) PAMAM dendrimers and GrO with different levels of oxidation. The work is motivated by the potential applications of these materials in removing polycyclic aromatic hydrocarbon contaminants from water. Our experimental results indicate that graphene oxide outperforms dendrimers in removing naphthalene from water. Molecular dynamics simulations suggest that the prominent factors driving naphthalene association to these seemingly disparate materials are similar. Interestingly, we find that cooperative interactions between the naphthalene molecules play a significant role in enhancing their association to the dendrimers and graphene oxide. Our findings highlight that while selection of appropriate materials is important, the interactions between the contaminants themselves can also be important in governing the effectiveness of a given material. The combined use of experiments and molecular dynamics simulations allows us to comment on the possible factors resulting in better performance of graphene oxide in removing naphthalene from water.

  3. A novel Ag+ cation sensor based on polyamidoamine dendrimer modified with 1,8-naphthalimide derivatives

    NASA Astrophysics Data System (ADS)

    Dodangeh, Mohammad; Gharanjig, Kamaladin; Arami, Mokhtar

    2016-02-01

    In this study, 4-amino-1,8-naphthalimide-conjugated polyamidoamine dendrimer was synthesized and characterized and its potentiality as a cation sensor was investigated. 4-Amino-1,8-naphthalic anhydride reacted with polyamidoamine dendrimer and the product was characterized using FTIR, 1H NMR, 13C NMR and melting point analysis method. The synthesized compound was applied to detect various cations in water media and N,N-dimethylformamide (DMF) via monitoring the quenching of the fluorescence intensity. Furthermore, various metal cations including Cu2 +, Ni2 +, Zn2 +, Pb2 +,Ca2 +, Ba2 +, Cd2 +, Hg2 +, Fe2 +, Fe3 + and Ag+ were tested. The complexes formed between the synthesized compound and metal cations in solution and their effects on Photoinduced Electron Transfer (PET) process were investigated regarding the potential application of the newly-synthesized dendrimer as a colorimetric and fluorescent sensor for such cations. The results clearly confirmed that the 1,8-naphthalimide groups surrounding the central dendrimer core showed strong green fluorescence emission at 553 nm. This effect considerably decreased with the introduction of all cations, except Ag+ where the fluorescence quenching effect was remarkable and more dominant. Therefore, it can be concluded that the synthesized dye has the potentiality of being a highly sensitive and selective fluorescence sensor for Ag+ cation.

  4. Surface functionality affects the biodistribution and microglia-targeting of intra-amniotically delivered dendrimers.

    PubMed

    Zhang, Fan; Nance, Elizabeth; Zhang, Zhi; Jasty, Venkatasai; Kambhampati, Siva P; Mishra, Manoj K; Burd, Irina; Romero, Roberto; Kannan, Sujatha; Kannan, Rangaramanujam M

    2016-09-10

    Cerebral Palsy (CP) is a chronic childhood disorder with limited therapeutic options. Maternal intrauterine inflammation/infection is a major risk factor in the pathogenesis of CP. In pre-clinical models, dendrimer-based therapies are viable in postnatal period, attenuating inflammation and improving motor function in vivo. However, treatment to the mother, in the prenatal period, may provide the possibility of preventing/resolving inflammation at early stages. Towards this goal, we used a maternal intrauterine inflammation-induced rabbit model of CP to study fetal-maternal transport and neuroinflammation targeting of intra-amniotically administrated dendrimers with neutral/anionic surface functionality. Our study suggested both hydroxyl-terminated 'neutral' (D-OH) and carboxyl-terminated 'anionic' (D-COOH) Polyamidoamine (PAMAM) dendrimers were absorbed by fetuses and demonstrated bi-directional transport between fetuses and mother. D-OH was more effective in crossing the fetal blood-brain barrier, and targeting activated microglia. The cell-specific targeting was associated with the extent of microglia activation. This study demonstrated intra-amniotically administered hydroxyl PAMAM dendrimers could be an effective drug delivery vehicle for targeting fetal inflammation and preventing subsequent neurologic injury associated with chorioamnionitis. PMID:27378700

  5. Thiol-ene crosslinking polyamidoamine dendrimer-hyaluronic acid hydrogel system for biomedical applications.

    PubMed

    Bi, Xiangdong; Liang, Aiye; Tan, Yu; Maturavongsadit, Panita; Higginbothem, Ashley; Gado, Togor; Gramling, Abigail; Bahn, Hanna; Wang, Qian

    2016-06-01

    A series of alkene functionalized polyamidoamine (PAMAM) dendrimers were synthesized to prepare in situ forming hydrogels with varied gelation time and mechanical properties through crosslinking with thiolated hyaluronic acid (HS-HA). By varying the alkenyl groups on the dendrimers, the gelation time displayed a large range from 8 seconds to 18 hours, and the modulus of the hydrogels ranged from 36 to 183 Pa under experimental conditions. Investigation by (1)H-NMR spectroscopy revealed that the gelation time and the stiffness of the hydrogels were governed by the degree of electron deficiency of alkenyl groups on the dendrimers. This research provided a systematic study on the relationship between chemical structures versus gelation time and mechanical properties of hydrogels, which could guide the way to synthesize in situ forming hydrogels with designated gelation time and stiffness for biomedical applications. Further, a RGD peptide was attached to the PAMAM dendrimers to enhance cell attachment and proliferation. Viability assays of Human Umbilical Vein Endothelial Cells (HUVEC) in the synthesized hydrogels demonstrated the biocompatibility of the hydrogels after 48 hours of culturing, and the RGD peptide improved the viability of HUVEC cells in hydrogels. We believe the PAMAM/HA hydrogel system is a tuneable and biocompatible system for diverse biomedical applications. PMID:26923639

  6. Dendrimer-curcumin conjugate: a water soluble and effective cytotoxic agent against breast cancer cell lines.

    PubMed

    Debnath, Shawon; Saloum, Darin; Dolai, Sukanta; Sun, Chong; Averick, Saadyah; Raja, Krishnaswami; Fata, Jimmie E

    2013-12-01

    Curcumin, which is derived from the plant Curcuma longa, has received considerable attention as a possible anti-cancer agent. In cell culture, curcumin is capable of inducing apoptosis in cancer cells at concentrations that do not affect normal cells. One draw-back holding curcumin back from being an effective anti-cancer agent in humans is that it is almost completely insoluble in water and therefore has poor absorption and subsequently poor bioavailability. Here we have generated a number of curcumin derivatives (tetrahydro-curcumin, curcumin mono-carboxylic acid, curcumin mono-galactose, curcumin mono-alkyne and dendrimer-curcumin conjugate) to test whether any of them display both cytotoxicity and water solubility. Of those tested only dendrimer-curcumin conjugate exhibited both water solubility and cytotoxicity against SKBr3 and BT549 breast cancer cells. When compared to curcumin dissolved in DMSO, dendrimer-curcumin conjugate dissolved in water was significantly more effective in inducing cytotoxicity, as measured by the MTT assay and effectively induced cellular apoptosis measured by caspase-3 activation. Since dendrimer-curcumin conjugate is water soluble and capable of inducing potent cytotoxic effects on breast cancer cell lines, it may prove to be an effective anti-cancer therapy to be used in humans. PMID:23387971

  7. Unusual liquid-liquid phase transition in aqueous mixtures of a well-known dendrimer.

    PubMed

    da Costa, Viviana C P; Annunziata, Onofrio

    2015-11-21

    Liquid-liquid phase separation (LLPS) has been extensively investigated for polymer and protein solutions due to its importance in mixture thermodynamics, separation science and self-assembly processes. However, to date, no experimental studies have been reported on LLPS of dendrimer solutions. Here, it is shown that LLPS of aqueous solutions containing a hydroxyl-functionalized poly(amido amine) dendrimer of fourth generation is induced in the presence of sodium sulfate. Both the LLPS temperature and salt-dendrimer partitioning between the two coexisting phases at constant temperature were measured. Interestingly, our experiments show that LLPS switches from being induced by cooling to being induced by heating as the salt concentration increases. The two coexisting phases also show opposite temperature response. Thus, this phase transition exhibits a simultaneous lower and upper critical solution temperature-type behavior. Dynamic light-scattering and dye-binding experiments indicate that no appreciable conformational change occurs as the salt concentration increases. To explain the observed phase behavior, a thermodynamic model based on two parameters was developed. The first parameter, which describes dendrimer-dendrimer interaction energy, was determined by isothermal titration calorimetry. The second parameter describes the salt salting-out strength. By varying the salting-out parameter, it is shown that the model achieves agreement not only with the location of the experimental binodal at 25 °C but also with the slope of this curve around the critical point. The proposed model also predicts that the unusual temperature behavior of this phase transition can be described as the net result of two thermodynamic factors with opposite temperature responses: salt thermodynamic non-ideality and salting-out strength. PMID:26451401

  8. Dendrimer-mediated synthesis of platinum nanoparticles: new insights from dialysis and atomic force microscopy measurements.

    PubMed

    Xie, Hong; Gu, Yunlong; Ploehn, Harry J

    2005-07-01

    In this work, we use AFM measurements in conjunction with dialysis experiments to study the synthesis mechanism and physical state of dendrimer-stabilized platinum nanoparticles. For characterizing particle size distributions by high resolution transmission electron microscopy and AFM, sample preparation by drop evaporation presumably minimizes the risk of sample bias that might be found in spin coating or dip-and-rinse methods. However, residual synthesis by-products (mainly salts) must be removed from solutions of dendrimer-stabilized metal nanoparticles prior to AFM imaging. Purification by dialysis is effective for this purpose. We discovered, by UV-visible spectrophotometry and atomic absorption (AA) spectroscopy, that dialysis using 'regular' cellulose dialysis tubing (12 000 Da cut-off) used in all previous work leads to substantial losses of poly(amidoamine) (PAMAM) dendrimer (G4OH), PAMAM-Pt(+2) complex, and PAMAM-stabilized Pt nanoparticles. Use of benzoylated dialysis tubing (1200 Da cut-off) shows no losses of G4OH or G4OH-Pt mixtures. We use AFM to see whether selective filtration during dialysis introduces sampling bias in the measurement of particle size distributions. We compare results (UV-visible spectra, AA results, and AFM-based particle size distributions) for a sample of G4OH-Pt(40) divided into two parts, one part dialysed with regular dialysis tubing and the other with benzoylated tubing. Exhaustive dialysis using benzoylated tubing may lead to the loss of colloidal Pt nanoparticles stabilized by adsorbed dendrimer, but not Pt nanoparticles encapsulated by the dendrimer. The comparisons also lead to new insights concerning the underlying synthesis mechanisms for PAMAM-stabilized Pt nanoparticles. PMID:21727470

  9. Unbinding forces and energies between a siRNA molecule and a dendrimer measured by force spectroscopy.

    PubMed

    Dumitru, Andra C; Herruzo, Elena T; Rausell, Estrella; Ceña, Valentin; Garcia, Ricardo

    2015-12-21

    We have measured the intermolecular forces between small interference RNA (siRNA) and polyamidoamine dendrimers at the single molecular level. A single molecule force spectroscopy approach has been developed to measure the unbinding forces and energies between a siRNA molecule and polyamidoamine dendrimers deposited on a mica surface in a buffer solution. We report three types of unbinding events which are characterized by forces and free unbinding energies, respectively, of 28 pN, 0.709 eV; 38 pN, 0.722 eV; and 50 pN, 0.724 eV. These events reflect different possible electrostatic interactions between the positive charges of one or two dendrimers and the negatively charged phosphate groups of a single siRNA. We have evidence of a high binding affinity of siRNA towards polyamidoamine dendrimers that leads to a 45% probability of measuring specific unbinding events. PMID:26580848

  10. Unbinding forces and energies between a siRNA molecule and a dendrimer measured by force spectroscopy

    NASA Astrophysics Data System (ADS)

    Dumitru, Andra C.; Herruzo, Elena T.; Rausell, Estrella; Ceña, Valentin; Garcia, Ricardo

    2015-11-01

    We have measured the intermolecular forces between small interference RNA (siRNA) and polyamidoamine dendrimers at the single molecular level. A single molecule force spectroscopy approach has been developed to measure the unbinding forces and energies between a siRNA molecule and polyamidoamine dendrimers deposited on a mica surface in a buffer solution. We report three types of unbinding events which are characterized by forces and free unbinding energies, respectively, of 28 pN, 0.709 eV; 38 pN, 0.722 eV; and 50 pN, 0.724 eV. These events reflect different possible electrostatic interactions between the positive charges of one or two dendrimers and the negatively charged phosphate groups of a single siRNA. We have evidence of a high binding affinity of siRNA towards polyamidoamine dendrimers that leads to a 45% probability of measuring specific unbinding events.

  11. Light-controlled active release of photocaged ciprofloxacin for lipopolysaccharide-targeted drug delivery using dendrimer conjugates.

    PubMed

    Wong, Pamela T; Tang, Shengzhuang; Mukherjee, Jhindan; Tang, Kenny; Gam, Kristina; Isham, Danielle; Murat, Claire; Sun, Rachel; Baker, James R; Choi, Seok Ki

    2016-08-16

    We report an active delivery mechanism targeted specifically to Gram(-) bacteria based on the photochemical release of photocaged ciprofloxacin carried by a cell wall-targeted dendrimer nanoconjugate. PMID:27476878

  12. Differences in toxicity of anionic and cationic PAMAM and PPI dendrimers in zebrafish embryos and cancer cell lines.

    PubMed

    Bodewein, Lambert; Schmelter, Frank; Di Fiore, Stefano; Hollert, Henner; Fischer, Rainer; Fenske, Martina

    2016-08-15

    Dendrimers are an emerging class of polymeric nanoparticles with beneficial biomedical applications like early diagnostics, in vitro gene transfection or controlled drug delivery. However, the potential toxic impact of exposure on human health or the environment is often inadequately defined. Thus, polyamidoamine (PAMAM) dendrimers of generations G3.0, 3.5, 4.0, 4.5 and 5.0 and polypropylenimine (PPI) dendrimers G3.0, 4.0 and 5.0 were tested in zebrafish embryos for 96h and human cancer cell lines for 24h, to assess and compare developmental in vivo toxicity with cytotoxicity. The zebrafish embryo toxicity of cationic PAMAM and PPI dendrimers increased over time, with EC50 values ranging from 0.16 to just below 1.7μM at 24 and 48hpf. The predominant effects were mortality, plus reduced heartbeat and blood circulation for PPI dendrimers. Apoptosis in the embryos increased in line with the general toxicity concentration-dependently. Hatch and dechorionation of the embryos increased the toxicity, suggesting a protective role of the chorion. Lower generation dendrimers were more toxic in the embryos whereas the toxicity in the HepG2 and DU145 cell lines increased with increasing generation of cationic PAMAMs and PPI dendrimers. HepG2 were less sensitive than DU145 cells, with IC50 values≥402μM (PAMAMs) and ≤240μM (PPIs) for HepG2 and ≤13.24μM (PAMAMs) and ≤12.84μM (PPIs) for DU145. Neither in fish embryos nor cells toxicity thresholds were determinable for anionic PAMAM G3.5 and G4.5. The study demonstrated that the cytotoxicity underestimated the in-vivo toxicity of the dendrimers in the fish embryos. PMID:27288734

  13. Supramolecular coordination polymer formed from artificial light-harvesting dendrimer.

    PubMed

    Lee, Hosoowi; Jeong, Young-Hwan; Kim, Joo-Ho; Kim, Inhye; Lee, Eunji; Jang, Woo-Dong

    2015-09-30

    We report the formation of supramolecular coordination polymers formed from multiporphyrin dendrimers (PZnPM; M = FB or Cu), composed of the focal freebase porphyrin (PFB) or cupper porphyrin (PCu) with eight zinc porphyrin (PZn) wings, and multipyridyl porphyrins (PyPM; M = FB or Cu), PFB or PCu with eight pyridyl groups, through multiple axial coordination interactions of pyridyl groups to PZns. UV-vis absorption spectra were recorded upon titration of PyPFB to PZnPFB. Differential spectra, obtained by subtracting the absorption of PZnPFB without guest addition as well as the absorption of PyPFB, exhibited clear isosbestic points with saturation binding at 1 equiv addition of PyPFB to PZnPFB. Job's plot analysis also indicated 1:1 stoichiometry for the saturation binding. The apparent association constant between PZnPFB and PyPFB (2.91 × 10(6) M(-1)), estimated by isothermal titration calorimetry, was high enough for fibrous assemblies to form at micromolar concentrations. The formation of a fibrous assembly from PZnPFB and PyPFB was visualized by atomic force microscopy and transmission electron microscopy (TEM). When a 1:1 mixture solution of PZnPFB and PyPFB (20 μM) in toluene was cast onto mica, fibrous assemblies with regular height (ca. 2 nm) were observed. TEM images obtained from 1:1 mixture solution of PZnPFB and PyPFB (0.1 wt %) in toluene clearly showed the formation of nanofibers with a regular diameter of ca. 6 nm. Fluorescence emission measurement of PZnPM indicated efficient intramolecular energy transfer from PZn to the focal PFB or PCu. By the formation of supramolecular coordination polymers, the intramolecular energy transfer changed to intermolecular energy transfer from PZnPM to PyPM. When the nonfluorescent PyPCu was titrated to fluorescent PZnPFB, fluorescence emission from the focal PFB was gradually decreased. By the titration of fluorescent PyPFB to nonfluorescent PZnPCu, fluorescence emission from PFB in PyPFB was gradually increased

  14. Self-Assembly of Amphiphilic Dendrimers: The Role of Generation and Alkyl Chain Length in siRNA Interaction.

    PubMed

    Márquez-Miranda, Valeria; Araya-Durán, Ingrid; Camarada, María Belén; Comer, Jeffrey; Valencia-Gallegos, Jesús A; González-Nilo, Fernando Danilo

    2016-01-01

    An ideal nucleic-acid transfection system should combine the physical and chemical characteristics of cationic lipids and linear polymers to decrease cytotoxicity and uptake limitations. Previous research described new types of carriers termed amphiphilic dendrimers (ADs), which are based on polyamidoamine dendrimers (PAMAM). These ADs display the cell membrane affinity advantage of lipids and preserve the high affinity for DNA possessed by cationic dendrimers. These lipid/dendrimer hybrids consist of a low-generation, hydrophilic dendron (G2, G1, or G0) bonded to a hydrophobic tail. The G2-18C AD was reported to be an efficient siRNA vector with significant gene silencing. However, shorter tail ADs (G2-15C and G2-13C) and lower generation (G0 and G1) dendrimers failed as transfection carriers. To date, the self-assembly phenomenon of this class of amphiphilic dendrimers has not been molecularly explored using molecular simulation methods. To gain insight into these systems, the present study used coarse-grained molecular dynamics simulations to describe how ADs are able to self-assemble into an aggregate, and, specifically, how tail length and generation play a key role in this event. Finally, explanations are given for the better efficiency of G2/18-C as gene carrier in terms of binding of siRNA. This knowledge could be relevant for the design of novel, safer ADs with well-optimized affinity for siRNA. PMID:27377641

  15. A Controllable Aptamer-Based Self-Assembled DNA Dendrimer for High Affinity Targeting, Bioimaging and Drug Delivery

    PubMed Central

    Zhang, Huimin; Ma, Yanli; Xie, Yi; An, Yuan; Huang, Yishun; Zhu, Zhi; Yang, Chaoyong James

    2015-01-01

    Targeted drug delivery is important in cancer therapy to decrease the systemic toxicity resulting from nonspecific drug distribution and to enhance drug delivery efficiency. We have developed an aptamer-based DNA dendritic nanostructure as a multifunctional vehicle for targeted cancer cell imaging and drug delivery. The multifunctional DNA dendrimer is constructed from functional Y-shaped building blocks with predesigned base-pairing hybridization including fluorophores, targeting DNA aptamers and intercalated anticancer drugs. With controllable step-by-step self-assembly, the programmable DNA dendrimer has several appealing features, including facile modular design, excellent biostability and biocompatibility, high selectivity, strong binding affinity, good cell internalization efficiency, and high drug loading capacity. Due to the unique structural features of DNA dendrimers, multiple copies of aptamers can be incorporated into each dendrimer, generating a multivalent aptamer-tethered nanostructure with enhanced binding affinity. A model chemotherapeutic anticancer drug, doxorubicin, was delivered via these aptamer-based DNA dendrimers and exerted a potent toxicity for target cancer cells (human T cell acute lymphoblastic leukemia cell line) with low side effects for the non-target cells (human Burkitt’s lymphoma cell line). This controllable aptamer-based DNA dendrimer is a promising candidate for biomedical applications. PMID:25959874

  16. Anti-Microbial Dendrimers against Multidrug-Resistant P. aeruginosa Enhance the Angiogenic Effect of Biological Burn-wound Bandages

    PubMed Central

    Abdel-Sayed, Philippe; Kaeppli, Ariane; Siriwardena, Thissa; Darbre, Tamis; Perron, Karl; Jafari, Paris; Reymond, Jean-Louis; Pioletti, Dominique P.; Applegate, Lee Ann

    2016-01-01

    Multi-drug resistant Pseudomonas aeruginosa has increased progressively and impedes further regression in mortality in burn patients. Such wound infections serve as bacterial reservoir for nosocomial infections and are associated with significant morbidity and costs. Anti-microbial polycationic dendrimers G3KL and G3RL, able to kill multi-drug resistant P. aeruginosa, have been previously developed. The combination of these dendrimers with a class of biological bandages made of progenitor skin cells, which secrete growth factors, could positively impact wound-healing processes. However, polycations are known to be used as anti-angiogenic agents for tumor suppression. Since, neovascularization is pivotal in the healing of deep burn-wounds, the use of anti-microbial dendrimers may thus hinder the healing processes. Surprisingly, we have seen in this study that G3KL and G3RL dendrimers can have angiogenic effects. Moreover, we have shown that a dendrimer concentration ranging between 50 and 100 μg/mL in combination with the biological bandages can suppress bacterial growth without altering cell viability up to 5 days. These results show that antimicrobial dendrimers can be used in combination with biological bandages and could potentially improve the healing process with an enhanced angiogenesis. PMID:26912450

  17. Reactive oxygen species (ROS) induced cytokine production and cytotoxicity of PAMAM dendrimers in J774A.1 cells

    SciTech Connect

    Naha, Pratap C.; Davoren, Maria; Lyng, Fiona M.; Byrne, Hugh J.

    2010-07-15

    The immunotoxicity of three generations of polyamidoamine (PAMAM) dendrimers (G-4, G-5 and G-6) was evaluated in mouse macrophage cells in vitro. Using the Alamar blue and MTT assays, a generation dependent cytotoxicity of the PAMAM dendrimers was found whereby G-6 > G-5 > G-4. The toxic response of the PAMAM dendrimers correlated well with the number of surface primary amino groups, with increasing number resulting in an increase in toxic response. An assessment of intracellular ROS generation by the PAMAM dendrimers was performed by measuring the increased fluorescence as a result of intracellular oxidation of Carboxy H{sub 2}DCFDA to DCF both quantitatively using plate reader and qualitatively by confocal laser scanning microscopy. The inflammatory mediators macrophage inflammatory protein-2 (MIP-2), tumour necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6, (IL-6) were measured by the enzyme linked immunosorbant assay (ELISA) following exposure of mouse macrophage cells to PAMAM dendrimers. A generation dependent ROS and cytokine production was found, which correlated well with the cytotoxicological response and therefore number of surface amino groups. A clear time sequence of increased ROS generation (maximum at {approx} 4 h), TNF-{alpha} and IL-6 secretion (maximum at {approx} 24 h), MIP-2 levels and cell death ({approx} 72 h) was observed. The intracellular ROS generation and cytokine production induced cytotoxicity point towards the mechanistic pathway of cell death upon exposure to PAMAM dendrimers.

  18. Self-Assembly of Amphiphilic Dendrimers: The Role of Generation and Alkyl Chain Length in siRNA Interaction

    PubMed Central

    Márquez-Miranda, Valeria; Araya-Durán, Ingrid; Camarada, María Belén; Comer, Jeffrey; Valencia-Gallegos, Jesús A.; González-Nilo, Fernando Danilo

    2016-01-01

    An ideal nucleic-acid transfection system should combine the physical and chemical characteristics of cationic lipids and linear polymers to decrease cytotoxicity and uptake limitations. Previous research described new types of carriers termed amphiphilic dendrimers (ADs), which are based on polyamidoamine dendrimers (PAMAM). These ADs display the cell membrane affinity advantage of lipids and preserve the high affinity for DNA possessed by cationic dendrimers. These lipid/dendrimer hybrids consist of a low-generation, hydrophilic dendron (G2, G1, or G0) bonded to a hydrophobic tail. The G2-18C AD was reported to be an efficient siRNA vector with significant gene silencing. However, shorter tail ADs (G2-15C and G2-13C) and lower generation (G0 and G1) dendrimers failed as transfection carriers. To date, the self-assembly phenomenon of this class of amphiphilic dendrimers has not been molecularly explored using molecular simulation methods. To gain insight into these systems, the present study used coarse-grained molecular dynamics simulations to describe how ADs are able to self-assemble into an aggregate, and, specifically, how tail length and generation play a key role in this event. Finally, explanations are given for the better efficiency of G2/18-C as gene carrier in terms of binding of siRNA. This knowledge could be relevant for the design of novel, safer ADs with well-optimized affinity for siRNA. PMID:27377641

  19. Modulated cellular delivery of anti-VEGF siRNA (bevasiranib) by incorporating supramolecular assemblies of hydrophobically modified polyamidoamine dendrimer in stealth liposomes.

    PubMed

    Golkar, Nasim; Samani, Soliman Mohammadi; Tamaddon, Ali Mohammad

    2016-08-20

    A novel lipopolymer based system was designed and characterized for cellular delivery of anti-VEGF siRNA in SKBR-3 breast tumor cell line. Polyamidoamine (PAMAM) dendrimers of low generations (G1, G2 and G3) were incorporated into polyethylene glycol (PEG)-stabilized liposomes by following the consecutive steps: (a) synthesis of the cholesterol conjugates (40% molar ratio of cholesterol to primary amines of PAMAM), (b) incorporation of the conjugates in liposome by lipid mixing and (c) microencapsulation of the siRNA using the ethanol drop method. The cholesterol conjugates of PAMAM dendrimers (G1-Chol40%, G2-Chol40% and G3-Chol40%) formed self assembly with low CMC values (<11μg/ml). Not only did G2-Chol40% show the highest lipid mixing among the cholesterol conjugates, but also, had the lowest leakage of encapsulated carboxyfluorescein tracer. Various N(amine))/L(lipid)/P(phosphate) mole ratios were investigated for siRNA condensation by ethidium bromide dye exclusion assay. The optimum N/L/P ratio of 20:33:10 was chosen for microencapsulation of anti-VEGF siRNA by ethanol drop method, showing particle size of 130nm, zeta-potential of +4mV, siRNA loading efficiency and capacity of 96% and 13wt%, and high stability against heparin sulfate (extracellular matrix). TEM shows uniform and discrete oligo- or multi-lamellar vesicular structures. The liposome incorporating G2-Chol40% was successfully internalized into SKBR-3 cells mainly through clathrin-mediated endocytosis, which was able to escape from endosomes and showed a significantly higher sequence-specific inhibition of VEGF expression and cell growth than the respective G2-Chol40%/siRNA dendriplexes. Importantly, the cytotoxicity decreased with incorporation of G2-Chol40% in the liposomes. PMID:27291973

  20. Synthesis and Characterization of New Conjugated Fluorenyl-Porphyrin Dendrimers for Optics.

    PubMed

    Yao, Dandan; Zhang, Xu; Mongin, Olivier; Paul, Frédéric; Paul-Roth, Christine O

    2016-04-11

    A new family of conjugated meso-tetraphenylporphyrin-based dendrimers with four (TPP1, TPP2), eight (TPP3, TPP4, TPP5) and up to sixteen (TPP6) fluorenyl groups has been synthesized and fully characterized. These tetraphenylporphyrin-cored dendrimers present peripheral alkynyl π-conjugated dendrons with fluorenyl termini. The meso-aryl rings of these porphyrins are functionalized either in para- (TPP1, TPP2, and TPP3) or meta-positions (TPP4, TPP5, and TPP6). Their detailed luminescence properties are discussed in reference to two porphyrins lacking fluorenyl dendrons (TPP-H1,2,3 and TPP-H4,5,6 ). A strong dependence of their luminescence quantum yield and lifetime on their structures is stated, their nonlinear optical properties were also discussed. PMID:26933931

  1. Dendrimer-Templated Ultrasmall and Multifunctional Photothermal Agents for Efficient Tumor Ablation.

    PubMed

    Zhou, Zhengjie; Wang, Yitong; Yan, Yang; Zhang, Qiang; Cheng, Yiyun

    2016-04-26

    Ultrasmall and multifunctional nanoparticles are highly desirable for photothermal cancer therapy, but the synthesis of these nanoparticles remains a huge challenge. Here, we used a dendrimer as a template to synthesize ultrasmall photothermal agents and further modified them with multifunctional groups. Dendrimer-encapsulated nanoparticles (DENPs) including copper sulfide, platinum, and palladium nanoparticles possessed a sub-5 nm size and exhibited an excellent photothermal effect. DENPs were further modified with TAT or RGD peptides to facilitate their cellular uptake and targeting delivery to tumors. They were also decorated with fluorescent probes for real-time imaging and tracking of the particles' distribution. The in vivo study revealed RGD-modified DENPs efficiently reduced the tumor growth upon near-infrared irradiation. In all, our study provides a facile and flexible scaffold to prepare ultrasmall and multifunctional photothermal agents. PMID:27054555

  2. Determining average path length and average trapping time on generalized dual dendrimer

    NASA Astrophysics Data System (ADS)

    Li, Ling; Guan, Jihong

    2015-03-01

    Dendrimer has wide number of important applications in various fields. In some cases during transport or diffusion process, it transforms into its dual structure named Husimi cactus. In this paper, we study the structure properties and trapping problem on a family of generalized dual dendrimer with arbitrary coordination numbers. We first calculate exactly the average path length (APL) of the networks. The APL increases logarithmically with the network size, indicating that the networks exhibit a small-world effect. Then we determine the average trapping time (ATT) of the trapping process in two cases, i.e., the trap placed on a central node and the trap is uniformly distributed in all the nodes of the network. In both case, we obtain explicit solutions of ATT and show how they vary with the networks size. Besides, we also discuss the influence of the coordination number on trapping efficiency.

  3. Enhancement of cytotoxicity by combining pyrenyl-dendrimers and arene ruthenium metallacages.

    PubMed

    Pitto-Barry, Anaïs; Zava, Olivier; Dyson, Paul J; Deschenaux, Robert; Therrien, Bruno

    2012-07-01

    Three generations of pyrenyl bis-MPA dendrimers with two different end-groups, acetonide (pyr(Gn)) or alcohol (pyr(Gn-OH)) (n = 1-3), were synthesized, and the pyrenyl group of the dendritic molecules was encapsulated in the arene ruthenium metallacages, [Ru(6)(p-cymene)(6)(OO∩OO)(3)(tpt)(2)](6+) (OO∩OO = 5,8-dioxydo-1,4-naphtaquinonato (donq) [1](6+) and 6,11-dioxydo-5,12-naphtacenedionato (dotq) [2](6+); tpt =2,4,6-tri(pyridin-4-yl)-1,3,5-triazine). The host-guest properties of [guest⊂1](6+) and [guest⊂2](6+) were studied in solution by NMR and UV-vis spectroscopic methods, thus allowing the determination of the affinity constants. Moreover, the cytotoxicity of these water-soluble host-guest systems and the pyrenyl-dendrimers was evaluated on human ovarian cancer cells. PMID:22716166

  4. Triclosan-loaded poly(amido amine) dendrimer for simultaneous treatment and remineralization of human dentine.

    PubMed

    Zhou, Yan; Yang, Jiaojiao; Lin, Zaifu; Li, Jiyao; Liang, Kunneng; Yuan, He; Li, Sheyu; Li, Jianshu

    2014-03-01

    In order to treat dental caries of damaged dentine, triclosan-loaded carboxyl-terminated poly(amido amine) dendrimer (PAMAM-COOH) is prepared and characterized. While being incubated in artificial saliva, triclosan-loaded PAMAM-COOH formulation can induce in situ remineralization of hydroxyapatite (HA) on etched dentine, and the regenerated HA has a similar crystal structure with natural dentine. It can also release the encapsulated triclosan for a long period. The interesting drug release profiles are controlled by both dendrimer encapsulation capability and the mineralization degree, which are ideal to obtain multifunctional properties of long-term release of anti-bacterial drug for local treatment during the remineralization process. The triclosan-loaded G4-COOH provides a general strategy to cure dental caries and repair damaged dentine at the same time, which forms a potential restorative material for dental repair. PMID:24362062

  5. A novel nanocomposite material prepared by intercalating photoresponsive dendrimers into a layered double hydroxide

    SciTech Connect

    Tanaka, Toshiyuki; Nishimoto, Shunsuke; Kameshima, Yoshikazu; Matsukawa, Junpei; Fujita, Yasuhiko; Takaguchi, Yutaka; Matsuda, Motohide; Miyake, Michihiro

    2010-02-15

    A novel combination for an inorganic-organic nanocomposite material was demonstrated. Anthryl dendron, i.e., poly(amidoamine) dendron with an anthracene chromophore group at the focal point, was incorporated in the interlayer space of ZnAl-NO{sub 3} type layered double hydroxide (LDH) through an anion-exchange reaction. The photoabsorption and fluorescence properties of the resulting material were different from those of the bare anthryl dendron molecule. It was suggested that the change in photochemical properties was due to the organization and pi-pi interaction of anthracene chromophores within the interlayer of the LDH. - Graphical abstract: A novel inorganic-organic nanocomposite material, a layered double hydroxide (LDH) containing photoresponsive dendrimers in the interlayer space, was successfully prepared through an ion-exchange reaction. The resulting material exhibited unique photochemical properties, compared to those of the bare photoresponsive dendrimer molecule.

  6. A new strategy for assembling multifunctional nanocomposites with iron oxide and amino-terminated PAMAM dendrimers.

    PubMed

    Zhang, Ying; Liu, Jing-Ying; Yang, Fang; Zhang, Ya-Jing; Yao, Qi; Cui, Tie-Yu; Zhao, Xiang; Zhang, Zhi-Dong

    2009-12-01

    A new strategy for assembling multifunctional nanocomposites with magnetic particles and amino dendrimers was reported. In this strategy, the amino terminated PAMAM G5.0 and Fe(3)O(4) NPs prepared by co-deposition method and further modified by aminosilane by two sol-gel processes were combined with the hydrophilic spacer of PEG dicarboxylate by amidation. The nanocomposites were characterized by means of X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), atom force microscopy (AFM), superconducting quantum interference device (SQUID) magnetometer, and hydrophilicity analysis. The results showed that the multifunctional nanocomposites were spherical with the mean diameter of 180 nm and exhibited good dispersion and hydrophilicity. The new strategy put forward here provides an effective route to functionalizing Fe(3)O(4) NPs with various amino dendrimers for drug and gene delivery as well as biological detection. PMID:19578982

  7. Vibrational spectra study of phosphorus dendrimer containing azobenzene, ammonium and carbamate groups

    NASA Astrophysics Data System (ADS)

    Furer, V. L.; Vandyukov, A. E.; Majoral, J. P.; Caminade, A. M.; Kovalenko, V. I.

    2013-06-01

    The FTIR and FT Raman spectra of the first generation dendrimers, possessing carbamate (G1) or ammonium (G2) terminal groups were studied. The structural optimization and normal mode analysis were performed for dendrimers on the basis of the density functional theory (DFT). These calculations of G2 gave the frequencies of vibrations, infrared intensities and Raman scattering activities for the E- and Z-forms of azobenzene unit. The energy difference between the E- and Z-forms of G2 is 27.36 kcal/mol. The calculated geometrical parameters and harmonic vibrational frequencies are predicted in a good agreement with the experimental data. It was found that dendrimers molecules have a concave lens structure with planar -O-C6H4-CHdbnd N-N(CH3)Pdbnd S, and -O-C6H4-Ndbnd N-C6H4-CHdbnd N-NH-Cdbnd O-CH2-N fragments and slightly non-planar cyclotriphosphazene core. The experimental IR and Raman spectra of dendrimers G1 and G2 were interpreted by means of potential energy distributions. Relying on DFT calculations a complete vibrational assignment is proposed. The strong band 1605 cm-1 in the IR spectra show marked changes of the optical density in dependence of substituents in the aromatic ring. The differences in the IR and Raman spectra of G2 for the E- and Z-forms of azobenzene units were cleared up. During structural isomerization of azobenzene units, redistribution of band intensities appears to a much higher extent than frequency shifts.

  8. Design of dendrimer-based drug delivery nanodevices with enhanced therapeutic efficacies

    NASA Astrophysics Data System (ADS)

    Kannan, Rangaramanujam

    2007-03-01

    Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorable, `peripheral' functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug delivery. They have significant potential compared to liposomes and nanoparticles, because of the reduced macrophage update, increased cellular transport, and the ability to modulate the local environment through functional groups. We are developing nanodevices based on dendritic systems for drug delivery, that contain a high drug payload, ligands, and imaging agents, resulting in `smart' drug delivery devices that can target, deliver, and signal. In collaboration with the Children's Hospital of Michigan, Karmanos Cancer Institute, and College of Pharmacy, we are testing the in vitro and in vivo response of these nanodevices, by adapting the chemistry for specific clinical applications such as asthma and cancer. These materials are characterized by UV/Vis spectroscopy, flow cytometry, fluorescence/confocal microscopy, and appropriate animal models. Our results suggest that: (1) We can prepare drug-dendrimer conjugates with drug payloads of greater than 50%, for a variety of drugs; (2) The dendritic polymers are capable of transporting and delivering drugs into cells faster than free drugs, with superior therapeutic efficiency. This can be modulated by the surface functionality of the dendrimer; (3) For chemotherapy drugs, the conjugates are a factor of 6-20 times more effective even in drug-resistant cell lines; (4) For corticosteroidal drugs, the dendritic polymers provide higher drug residence times in the lung, allowing for passive targeting. The ability of the drug-dendrimer-ligand conjugates to target specific asthma and cancer cells is currently being explored using in vitro and in vivo animal models.

  9. Dendrimer-entrapped gold nanoparticles as potential CT contrast agents for blood pool imaging

    PubMed Central

    2012-01-01

    The purpose of this study was to evaluate dendrimer-entrapped gold nanoparticles [Au DENPs] as a molecular imaging [MI] probe for computed tomography [CT]. Au DENPs were prepared by complexing AuCl4- ions with amine-terminated generation 5 poly(amidoamine) [G5.NH2] dendrimers. Resulting particles were sized using transmission electron microscopy. Serial dilutions (0.001 to 0.1 M) of either Au DENPs or iohexol were scanned by CT in vitro. Based on these results, Au DENPs were injected into mice, either subcutaneously (10 μL, 0.007 to 0.02 M) or intravenously (300 μL, 0.2 M), after which the mice were imaged by micro-CT or a standard mammography unit. Au DENPs prepared using G5.NH2 dendrimers as templates are quite uniform and have a size range of 2 to 4 nm. At Au concentrations above 0.01 M, the CT value of Au DENPs was higher than that of iohexol. A 10-μL subcutaneous dose of Au DENPs with [Au] ≥ 0.009 M could be detected by micro-CT. The vascular system could be imaged 5 and 20 min after injection of Au DENPs into the tail vein, and the urinary system could be imaged after 60 min. At comparable time points, the vascular system could not be imaged using iohexol, and the urinary system was imaged only indistinctly. Findings from this study suggested that Au DENPs prepared using G5.NH2 dendrimers as templates have good X-ray attenuation and a substantial circulation time. As their abundant surface amine groups have the ability to bind to a range of biological molecules, Au DENPs have the potential to be a useful MI probe for CT. PMID:22429280

  10. Self-assembly of amphiphilic Janus dendrimers into mechanically robust supramolecular hydrogels for sustained drug release.

    PubMed

    Nummelin, Sami; Liljeström, Ville; Saarikoski, Eve; Ropponen, Jarmo; Nykänen, Antti; Linko, Veikko; Seppälä, Jukka; Hirvonen, Jouni; Ikkala, Olli; Bimbo, Luis M; Kostiainen, Mauri A

    2015-10-01

    Compounds that can gelate aqueous solutions offer an intriguing toolbox to create functional hydrogel materials for biomedical applications. Amphiphilic Janus dendrimers with low molecular weights can readily form self-assembled fibers at very low mass proportion (0.2 wt %) to create supramolecular hydrogels (G'≫G'') with outstanding mechanical properties and storage modulus of G'>1000 Pa. The G' value and gel melting temperature can be tuned by modulating the position or number of hydrophobic alkyl chains in the dendrimer structure; thus enabling exquisite control over the mesoscale material properties in these molecular assemblies. The gels are formed within seconds by simple injection of ethanol-solvated dendrimers into an aqueous solution. Cryogenic TEM, small-angle X-ray scattering, and SEM were used to confirm the fibrous structure morphology of the gels. Furthermore, the gels can be efficiently loaded with different bioactive cargo, such as active enzymes, peptides, or small-molecule drugs, to be used for sustained release in drug delivery. PMID:26134175

  11. EGFR-Targeted Adenovirus Dendrimer Coating for Improved Systemic Delivery of the Theranostic NIS Gene

    PubMed Central

    Grünwald, Geoffrey K; Vetter, Alexandra; Klutz, Kathrin; Willhauck, Michael J; Schwenk, Nathalie; Senekowitsch-Schmidtke, Reingard; Schwaiger, Markus; Zach, Christian; Wagner, Ernst; Göke, Burkhard; Holm, Per S; Ogris, Manfred; Spitzweg, Christine

    2013-01-01

    We recently demonstrated tumor-selective iodide uptake and therapeutic efficacy of combined radiovirotherapy after systemic delivery of the theranostic sodium iodide symporter (NIS) gene using a dendrimer-coated adenovirus. To further improve shielding and targeting we physically coated replication-selective adenoviruses carrying the hNIS gene with a conjugate consisting of cationic poly(amidoamine) (PAMAM) dendrimer linked to the peptidic, epidermal growth factor receptor (EGFR)-specific ligand GE11. In vitro experiments demonstrated coxsackie-adenovirus receptor-independent but EGFR-specific transduction efficiency. Systemic injection of the uncoated adenovirus in a liver cancer xenograft mouse model led to high levels of NIS expression in the liver due to hepatic sequestration, which were significantly reduced after coating as demonstrated by 123I-scintigraphy. Reduction of adenovirus liver pooling resulted in decreased hepatotoxicity and increased transduction efficiency in peripheral xenograft tumors. 124I-PET-imaging confirmed EGFR-specificity by significantly lower tumoral radioiodine accumulation after pretreatment with the EGFR-specific antibody cetuximab. A significantly enhanced oncolytic effect was observed following systemic application of dendrimer-coated adenovirus that was further increased by additional treatment with a therapeutic dose of 131I. These results demonstrate restricted virus tropism and tumor-selective retargeting after systemic application of coated, EGFR-targeted adenoviruses therefore representing a promising strategy for improved systemic adenoviral NIS gene therapy. PMID:24193032

  12. Characterization and evaluation of amphotericin B loaded MDP conjugated poly(propylene imine) dendrimers.

    PubMed

    Jain, Keerti; Verma, Ashwni Kumar; Mishra, Prabhat Ranjan; Jain, Narendra Kumar

    2015-04-01

    This paper describes a novel strategy for targeted delivery of amphotericin B (AmB) to macrophages with muramyl dipeptide (MDP) conjugated multimeric poly(propyleneimine) (PPI) dendrimers. Synergistic antiparasitic activity due to immunostimulation by multimeric presentation of MDP on dendrimers was anticipated. MDP conjugated 5.0G PPI (MdPPI) dendrimers were synthesized and characterized. Therapeutic activity and toxicity of dendrimeric formulation of AmB (MdPPIA) were compared with marketed formulations of AmB. Highly significant (P<0.01) reduction in toxicity was observed in hemolytic toxicity and cytotoxicity studies in erythrocytes and J774A.1 macrophage cells, respectively. Formulation MdPPIA showed appreciable macrophage targeting potential and higher or equivalent antiparasitic activity against parasite infected macrophage cell lines and in vivo infection in Balb/c mice. These results suggest the developed MDP conjugated dendrimeric formulation of AmB as a promising immunostimulant targeted drug delivery system and a safer alternative to marketed formulations. From the clinical editor: Parasitic infections remain a significant issue in the clinical setting. The authors in this article studied the use of ligand anchored dendrimeric formulation of Amphotericin B to target infected macrophages and showed reduced toxicity, high anti-leishmanial activity. This may add another treatment option to available formulations in the future. PMID:25596078

  13. Delivery systems for biopharmaceuticals. Part II: Liposomes, Micelles, Microemulsions and Dendrimers.

    PubMed

    Silva, Ana C; Lopes, Carla M; Lobo, José M S; Amaral, Maria H

    2015-01-01

    Biopharmaceuticals are a generation of drugs that include peptides, proteins, nucleic acids and cell products. According to their particular molecular characteristics (e.g. high molecular size, susceptibility to enzymatic activity), these products present some limitations for administration and usually parenteral routes are the only option. To avoid these limitations, different colloidal carriers (e.g. liposomes, micelles, microemulsions and dendrimers) have been proposed to improve biopharmaceuticals delivery. Liposomes are promising drug delivery systems, despite some limitations have been reported (e.g. in vivo failure, poor long-term stability and low transfection efficiency), and only a limited number of formulations have reached the market. Micelles and microemulsions require more studies to exclude some of the observed drawbacks and guarantee their potential for use in clinic. According to their peculiar structures, dendrimers have been showing good results for nucleic acids delivery and a great development of these systems during next years is expected. This is the Part II of two review articles, which provides the state of the art of biopharmaceuticals delivery systems. Part II deals with liposomes, micelles, microemulsions and dendrimers. PMID:26278524

  14. Synthesis, Characterization, and Biological Evaluation of Integrin αvβ3-Targeted PAMAM Dendrimers

    PubMed Central

    Boswell, C. Andrew; Eck, Peter K.; Regino, Celeste A. S.; Bernardo, Marcelino; Wong, Karen J.; Milenic, Diane E.; Choyke, Peter L.; Brechbiel, Martin W.

    2008-01-01

    Ligand size and valency strongly influence the receptor uptake and clearance of tumor angiogenesis imaging agents. The structures of successful imaging agents exhibit a high degree of variability, encompassing small mono-valent arginine-glycine-aspartic acid (RGD)-containing peptides, multivalent RGD-oligomers, and a monoclonal antibody against integrin alpha-v-beta-3 (αvβ3). We have pursued a nano-scale approach to imaging of angiogenesis using rationally designed polyamidoamine (PAMAM) dendrimers covalently adorned with RGD-cyclopeptides. An orthogonal oxime-ligation strategy was applied to chemoselectively effect conjugation of the PAMAM dendrimers with RGD-cyclopeptides for targeting αvβ3. Fluorescent dyes for optical imaging and chelates for gadolinium-based magnetic resonance (MR) imaging were subsequently appended to create robust multimodal macromolecular imaging agents. Fluorescence microscopy revealed selective binding of the resulting RGD peptide-bearing dendrimer with empty chelates to αvβ3-expressing cells, but somewhat reduced selectivity was observed following Gd(III) complexation. The expected incomplete saturation of chelates with Gd(III) ions permitted radiometal complexation, and an in vivo tissue distribution of the resulting agent in M21 melanoma tumor-bearing mice showed mostly renal and reticuloendothelial accumulation, with the tumor:blood ratio peaking (3.30 ± .03) at 2 hr post-injection. PMID:18537262

  15. Supermolecular columnar liquid-crystalline phosphorus dendrimers decorated with sulfonamide derivatives.

    PubMed

    Hincapié, Cesar Augusto; Sebastián, Rosa María; Barberá, Joaquín; Serrano, José Luis; Sierra, Teresa; Majoral, Jean-Pierre; Caminade, Anne-Marie

    2014-12-15

    A series of supermolecular liquid crystals has been synthesized by combining phosphorus dendrimers of the zero, first, and fourth generations with sulfonamide derivatives, thus generating dendromesogens bearing 6, 12, and 96 mesogenic units on their surfaces. The relevant reactions could be monitored by (1) H, (19) F, and (31) P{(1) H} NMR spectroscopies. The thermal and mesomorphic properties of the products have been studied by optical microscopy, differential scanning calorimetry, and X-ray diffraction. All of the new macromolecules prepared in this work have been found to show mesomorphic properties over a wide temperature range; moreover, for all of the compounds, the columnar mesophases observed were maintained or vitrified at room temperature. On increasing the generation of these dendromesogens, mesophases appear at lower temperatures and remain stable over a wider temperature interval. In all cases, on the basis of X-ray analysis, a cylindrical symmetry of the molecules can be proposed to promote the supramolecular columnar arrangement observed in the mesophases. In this type of model, the height of the dendrimer clearly increases with increasing dendrimer generation, whereas its cross- sectional area increases only slightly, probably due to compression of the highly hyperbranched structures as a consequence of their progressive steric constraints. The mesomorphic arrangement is governed by the peripheral sulfonamide units. PMID:25331036

  16. Polyamidoamine dendrimer and oleic acid-functionalized graphene as biocompatible and efficient gene delivery vectors.

    PubMed

    Liu, Xiahui; Ma, Dongmei; Tang, Hao; Tan, Liang; Xie, Qingji; Zhang, Youyu; Ma, Ming; Yao, Shouzhuo

    2014-06-11

    Functionalized graphene has good potential in biomedical applications. To address a better and multiplex design of graphene-based gene vectors, the graphene-oleate-polyamidoamine (PAMAM) dendrimer hybrids were synthesized by the oleic acid adsorption and covalent linkage of PAMAM dendrimers. The micromorphology, electrical charge property, and amount of free amine groups of the graphene-oleate-PAMAM hybrids were characterized, and the peripheral functional groups were identified. The PAMAM dendrimers could be tethered onto graphene surface in high density. The graphene-oleate-PAMAM hybrids exhibit relatively good dispersity and stability in aqueous solutions. To evaluate the potential application of the hybrids in gene delivery vectors, cytotoxicity to HeLa and MG-63 cells and gene (plasmid DNA of enhanced green fluorescent protein) transfection capacity of the hybrids were investigated in detail. The graphene-oleate-PAMAM hybrids show mammalian cell type- and dose-dependent in vitro cytotoxicity. Under the optimal condition, the hybrids possess good biocompatibility and gene transfection capacity. The surface modification of graphene with oleic acid and PAMAM improves the gene transfection efficiency 13 times in contrast to the ultrasonicated graphene. Moreover, the hybrids show better transfection efficiency than the graphene oxide-PAMAM without the oleic acid modification. PMID:24836601

  17. PAMAM dendrimer generation 5-pluronic F127 nanofilm as a matrix for local metronidazole release.

    PubMed

    Dung, Tran Huu; Do, Le Thanh; Yoo, Hoon

    2013-07-01

    A series of dendrimer G5-pluronic F127 nanofilms (at 1:10, 1:20 and 1:30 mole ratios), loaded with various percent of metronidazole hydrochloride, were prepared by the drug deposition with/without gelatin coating. The nanostructural feature of dendrimer G5-pluronic F127 as a matrix for a sustained drug release was investigated by choosing metronidazole, an antibacterial and antiprotozoal drug as a model drug. The studies on surface morphology, polymer erosion and metronidazole release of the prepared nanofilms revealed unique surface morphology, low film erosion rate and long drug release time. The drug release and the erosion rate of nanofilm were slowed in acidic pH condition and the presence of saliva in medium. The nanofilm of G5-PF127 (1:30 mole ratio) coated with gelatin further prolonged metronidazole release showing G5-PF127 coated with 20% gelatin to be the best suited for a metronidazole release. The nanofilms were stable for up to 9 months at dried condition, while those stored at room temperature with 30% relative humidity were less stable. Our results show that PAMAM dendrimer G5-pluronic F127 nanofilm has a potential to serve as a matrix for the local drug delivery. PMID:23909144

  18. Docosahexaenoic acid triglyceride-based microemulsions with an added dendrimer - Structural considerations.

    PubMed

    Lidich, Nina; Francesca Ottaviani, M; Hoffman, Roy E; Aserin, Abraham; Garti, Nissim

    2016-12-01

    Omega fatty acids, mainly the triglyceride of docosahexaenoic acid (TG-DHA), are considered important nutraceuticals. These compounds are water-insoluble and their transport across membranes depends on their carriers. Dendrimers are known as drug carriers across cell membranes and also as permeation enhancers. The solubilization of TG-DHA and dendrimer into a microemulsion (ME) system serving as a carrier could be used for a targeted delivery in the future. The interactions between TG-DHA and second generation poly(propyleneimine) dendrimers (PPI-G2) and their effect on structural transitions of ME were explored along the water dilution line using electron paramagnetic resonance and pulsed-gradient spin-echo NMR along with other analytical techniques. The microviscosity, order parameter, and micropolarity of all studied systems decrease upon water dilution. Incorporation of TG-DHA reduces the microviscosity, order, and micropolarity, whereas PPI-G2 leads to an increase in these parameters. The effect of PPI-G2 is more pronounced at relative high contents (1 and 5wt%) where PPI-G2 interacts with the hydrophilic headgroups of the surfactants. In the macroscale, the effects of TG-DHA and PPI-G2 differ mostly in the bicontinuous region, where macroviscosity increases upon TG-DHA incorporation and decreases upon solubilization of 5wt% PPI-G2. From DSC measurements it was concluded that in the presence of TG-DHA the PPI-G2 is intercalated easily at the interface. PMID:27571688

  19. Functional dendrimer modified ultra-hydrophilic trapping copolymer network towards highly efficient cell capture.

    PubMed

    Zhang, Peiming; Gao, Mingxia; Zhang, Xiangmin

    2016-06-01

    Highly efficient isolation of living tumor cells possesses great significance in research of cancer. Hence, we have designed the 3-aminophenylboronic acid (APBA) derivative dendrimer-functionalized 3D network polyacrylamide/poly (methyl methacrylate) copolymer as capture substrate which is easily prepared, template free and low-cost. The structure of copolymer is compared to "fishing net" in order to increase the contact between cells and substrates. The application of poly (amidoamine) dendrimers provides abundant amino groups to react with APBA which is just like "baits" that can bond with sialic acid in the cytomembrane to realize cell capture. The 3D network structure trammels cancer cells, offers great reaction space and displays hydrophilic surface, which has immensely improved the contact probability of cells and materials. Due to the 3D network structure and dendrimer, this material can achieve a high capture efficiency of 87±5% in 45min. The viability of captured cells is nearly 100%, as a result of the soft and hydrophilic surface and hypotoxicity of this copolymer. PMID:27130129

  20. An Enzyme-Responsive Nanogel Carrier Based on PAMAM Dendrimers for Drug Delivery.

    PubMed

    Wang, Yao; Luo, Yiyang; Zhao, Qiang; Wang, Zhijian; Xu, Zejun; Jia, Xinru

    2016-08-10

    G4 PAMAM dendrimer molecules were modified via covalently conjugating RGDC, RAADyC, and PEG chains on the periphery (Mac-1), by which a nanogel drug carrier with enzyme-sensitivity (NG-1) was constructed through an oxidation reaction by using NaIO4 to initiate the chemical cross-link of the functional groups on the periphery of dendrimers. Mac-1 and NG-1 both had a spherelike shape with a relatively uniform size of 20 nm for Mac-1 and 50 nm for NG-1 as evidenced by TEM, SEM, and DLS measurements. NG-1 showed much higher drug loading capacity as compared with that of Mac-1 although the cavities in the dendritic structure were used to encapsulate drug molecules as reported in many literatures. In addition, the size of NG-1 with embedded doxorubicin hydrochloride (DOX) decreased significantly to 15 nm in the presence of elastase, which indicated the decomposition of the nanogel triggered by enzyme, leading to drug release in a sustained manner in vitro. The NG-1 carrier was noncytotoxic and biocompatible, and it achieved the same cytotoxicity as free DOX when the drug molecules were loaded inside. From confocal images, the penetrative process of DOX from nanogel could be clearly observed in 8 h. Such a dendrimer-based nanogel may be a potential nanocarrier for drug delivery in cancer therapy. PMID:27420576

  1. Aquatic Self-Assembly of Sixteen Subunits into a 39-kDa Dendrimer

    PubMed Central

    Rivera, Luis R.; Betancourt, José E.; Rivera, José M.

    2010-01-01

    We have developed the 8-(m-acetylphenyl)-2′-deoxyguanosine (mAG) scaffold for the self-assembly of supramolecules in water and for the synthesis of self-assembled dendrimers (SADs) in organic media. Previously, reported mAG assemblies showed promising characteristics for the construction of SADs. Yet, none of these SADs had large enough dendrons to reach a fractal geometry characteristic of high-generation dendrimers. Here we present the synthesis, as well as the molecular and supramolecular characterization of a fourth generation hydrophilic self-assembled hexadecameric dendrimer [mAGD4(OH)16]16•3KI (316) with a size and shape akin to globular proteins. The diameter of 316 (5.0 nm) was measured by Pulsed Field Gradient NMR and Dynamic Light Scattering experiments, which enabled the construction of a computer-generated molecular model. This SAD represents an attractive platform for biomedical applications due to its water solubility, discreteness, well defined structure, thermal stability (Tm= 68 °C), and functional core. PMID:21117678

  2. Piezoelectric sensor for sensitive determination of metal ions based on the phosphate-modified dendrimer

    NASA Astrophysics Data System (ADS)

    Wang, S. H.; Shen, C. Y.; Lin, Y. M.; Du, J. C.

    2016-08-01

    Heavy metal ions arising from human activities are retained strongly in water; therefore public water supplies must be monitored regularly to ensure the timely detection of potential problems. A phosphate-modified dendrimer film was investigated on a quartz crystal microbalance (QCM) for sensing metal ions in water at room temperature in this study. The chemical structures and sensing properties were characterized by Fourier transform infrared spectroscopy and QCM measurement, respectively. This phosphate-modified dendrimer sensor can directly detect metal ions in aqueous solutions. This novel sensor was evaluated for its capacity to sense various metal ions. The sensor exhibited a higher sensitivity level and shorter response time to copper(II) ions than other sensors. The linear detection range of the prepared QCM based on the phosphate-modified dendrimer was 0.0001 ∼ 1 μM Cu(II) ions (R2 = 0.98). The detection properties, including sensitivity, response time, selectivity, reusability, maximum adsorption capacity, and adsorption equilibrium constants, were also investigated.

  3. Dendrimer-magnetic nanoparticles as multiple stimuli responsive and enzymatic drug delivery vehicle

    NASA Astrophysics Data System (ADS)

    Chandra, Sudeshna; Noronha, Glen; Dietrich, Sascha; Lang, Heinrich; Bahadur, Dhirendra

    2015-04-01

    Two different chain lengths of (poly)ethylene glycol-PAMAM dendrimers namely, L6-PEG-PAMAM and S6-PEG-PAMAM with six end-grafted ethylene glycol ether-tentacles of type CH2CH2C(O)O(CH2CH2O)9CH3 and CH2CH2C(O)O(CH2CH2O)2C2H5, respectively, were synthesized. These dendrimers have multiple σ-donor capabilities and therefore, were used for stabilizing the magnetite (Fe3O4) nanoparticles. Both the dendrimer-magnetic nanoparticles (L6-PEG-PAMAM-MNPs and S6-PEG-PAMAM-MNPs) were characterized by different spectroscopic and microstructural techniques. The nanoparticles were mesoporous and superparamagnetic and therefore, explored for their possible use in delivery of cancer drug, doxorubicin (DOX). In the developed drug delivery system, achieving high drug-loading efficiency with controllable release were the main challenges. The change in zeta potential and quenching of fluorescence intensity suggests chemical interaction between DOX and the nanoparticles. The loading efficiency was calculated to be over 95% with a sustained pH and temperature sensitive release. Further, enzyme cathepsin B has also been used to degrade the dendritic shell to trigger sustained drug release in the vicinity of tumor cells.

  4. Regulation of dendrimer/dextran material performance by altered tissue microenvironment in inflammation and neoplasia.

    PubMed

    Oliva, Nuria; Carcole, Maria; Beckerman, Margarita; Seliktar, Sivan; Hayward, Alison; Stanley, James; Parry, Nicola Maria Anne; Edelman, Elazer R; Artzi, Natalie

    2015-01-28

    A "one material fits all" mindset ignores profound differences in target tissues that affect their responses and reactivity. Yet little attention has been paid to the role of diseased tissue on material performance, biocompatibility, and healing capacity. We assessed material-tissue interactions with a prototypical adhesive material based on dendrimer/dextran and colon as a model tissue platform. Adhesive materials have high sensitivity to changes in their environment and can be exploited to probe and quantify the influence of even subtle modifications in tissue architecture and biology. We studied inflammatory colitis and colon cancer and found not only a difference in adhesion related to surface chemical interactions but also the existence of a complex interplay that determined the overall dendrimer/dextran biomaterial compatibility. Compatibility was contextual, not simply a constitutive property of the material, and was related to the extent and nature of immune cells in the diseased environment present before material implantation. We then showed how to use information about local alterations of the tissue microenvironment to assess disease severity. This in turn guided us to an optimal dendrimer/dextran formulation choice using a predictive model based on clinically relevant conditions. PMID:25632035

  5. Dendrimer-based nanocarriers demonstrating a high efficiency for loading and releasing anticancer drugs against cancer cells in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Quyen Tran, Ngoc; Khoa Nguyen, Cuu; Phuong Nguyen, Thi

    2013-12-01

    Dendrimer, a new class of hyper-branched polymer with predetermined molecular weight and well-controlled size, has received much attention in nanobiomedical applications such as drug carrier, gene therapy, disease diagnosis, etc. In this study, pegylated polyamidoamine (PAMAM) dendrimer at generation 3.0 (G 3.0) and carboxylated PAMAM dendrimer G 2.5 were prepared for loading anticancer drugs. For loading cisplatin, carboxylated dendrimer could carry 26.64 wt/wt% of cisplatin. The nanocomplexes have size ranging from 10 to 30 nm in diameter. The drug nanocarrier showed activity against NCI-H460 lung cancer cell line with half maximal inhibitory (IC50) of 23.11 ± 2.08 μg ml-1. Pegylated PAMAM dendrimers (G 3.0) were synthesized below 40 nm in diameter for carrying 5-fluorouracil (5-FU). For 5-FU encapsulation, pegylated dendrimer showed a high drug-loading efficiency of the drug and a slow release profile of 5-FU. The drug nanocarrier system exhibited an antiproliferative activity against MCF-7 cells (breast cancer cell) with a half maximal inhibitory (IC50) of 9.92 ± 0.19 μg ml-1. In vivo tumor xenograft study showed that the 5-FU encapsulated pegylation of dendrimer exhibited a significant decrement in volume of tumor which was generated by MCF-7 cancer cells. These positive results from our studies could pave the ways for further research of drugs dendrimer nanocarriers toward cancer chemotherapy.

  6. Partially Glycosylated Dendrimers Block MD-2 and Prevent TLR4-MD-2-LPS Complex Mediated Cytokine Responses

    PubMed Central

    Barata, Teresa S.; Teo, Ian; Brocchini, Steve; Zloh, Mire; Shaunak, Sunil

    2011-01-01

    The crystal structure of the TLR4-MD-2-LPS complex responsible for triggering powerful pro-inflammatory cytokine responses has recently become available. Central to cell surface complex formation is binding of lipopolysaccharide (LPS) to soluble MD-2. We have previously shown, in biologically based experiments, that a generation 3.5 PAMAM dendrimer with 64 peripheral carboxylic acid groups acts as an antagonist of pro-inflammatory cytokine production after surface modification with 8 glucosamine molecules. We have also shown using molecular modelling approaches that this partially glycosylated dendrimer has the flexibility, cluster density, surface electrostatic charge, and hydrophilicity to make it a therapeutically useful antagonist of complex formation. These studies enabled the computational study of the interactions of the unmodified dendrimer, glucosamine, and of the partially glycosylated dendrimer with TLR4 and MD-2 using molecular docking and molecular dynamics techniques. They demonstrate that dendrimer glucosamine forms co-operative electrostatic interactions with residues lining the entrance to MD-2's hydrophobic pocket. Crucially, dendrimer glucosamine interferes with the electrostatic binding of: (i) the 4′phosphate on the di-glucosamine of LPS to Ser118 on MD-2; (ii) LPS to Lys91 on MD-2; (iii) the subsequent binding of TLR4 to Tyr102 on MD-2. This is followed by additional co-operative interactions between several of the dendrimer glucosamine's carboxylic acid branches and MD-2. Collectively, these interactions block the entry of the lipid chains of LPS into MD-2's hydrophobic pocket, and also prevent TLR4-MD-2-LPS complex formation. Our studies have therefore defined the first nonlipid-based synthetic MD-2 antagonist using both animal model-based studies of pro-inflammatory cytokine responses and molecular modelling studies of a whole dendrimer with its target protein. Using this approach, it should now be possible to computationally design

  7. Janus-Type Dendrimer-like Poly(ethylene oxide)s

    PubMed Central

    Feng, Xiaoshuang; Taton, Daniel; Ibarboure, Emmanuel; Chaikof, Elliot L.; Gnanou, Yves

    2009-01-01

    A straightforward and original methodology allowing the synthesis of Janus-type dendrimer-like poly(ethylene oxide)s (PEOs) carrying orthogonal functional groups on their surface is described. The use of 3-allyloxy-1,2-propanediol (1) as a latent AB2-type heterofunctional initiator of anionic ring-opening polymerization (AROP) of ethylene oxide (EO) and of selective branching agents of PEO chain ends served to construct the two dendrons of these dendrimer-like PEOs, following a divergent pathway. Thus, the first PEO generation of the first dendron was grown by AROP from 1 followed by the reaction of the corresponding α-allyl,ω,ω′-bishydroxy- heterofunctional PEO derivative with 2-(3′-chloromethybenzyloxymethyl)-2-methyl-5,5-dimethyl-1,3-dioxane (2) used as a branching agent. This afforded the dendron A with four latent peripheral hydroxyls protected in the form of two ketal rings. The remaining α-allylic double bond of the PEO thus prepared was transformed into two hydroxyl groups using OsO4 in order to create the first PEO generation of the dendron B by AROP of EO. Allyl chloride (3) was then used as another (latent) branching agent to react with the terminal hydroxyl of the corresponding PEO chains. Deprotection under acidic conditions of the ketal groups of dendron A, followed by AROP of EO, afforded the second PEO generation on this face. This alternate and divergent procedure, combining AROP of EO and selective branching of PEO branches, could be readily iterated, one dendron after the other up to the generation six, leading to a Janus-type dendrimer-like PEO exhibiting a total mass of around 300 kg/mol and possessing 64 peripheral groups on each face. The possibility of orthogonal functionalization of the surfaces of such Janus-type dendritic PEOs was exploited. Indeed, a dendron of generation 4 was functionalized with hydroxyl functions at its periphery, whereas the other was end-capped with either tertiary amino or disulfide groups. In a variant of

  8. Functionalized congeners of P2Y1 receptor antagonists: 2-alkynyl (N)-methanocarba 2'-deoxyadenosine 3',5'-bisphosphate analogues and conjugation to a polyamidoamine (PAMAM) dendrimer carrier.

    PubMed

    de Castro, Sonia; Maruoka, Hiroshi; Hong, Kunlun; Kilbey, S Michael; Costanzi, Stefano; Hechler, Béatrice; Brown, Garth G; Gachet, Christian; Harden, T Kendall; Jacobson, Kenneth A

    2010-07-21

    The P2Y(1) receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y(1) receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N(6)-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y(1) receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K(i) 23 nM) and extended amine congener 15 (K(i) 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended epsilon-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y(1) receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y(1) receptor modeling and ligand docking. Attempted P2Y(1) antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor antagonist to a PAMAM dendrimer to produce a multivalent conjugate

  9. Functionalized Congeners of P2Y1 Receptor Antagonists: 2-Alkynyl (N)-Methanocarba 2′-Deoxyadenosine 3′,5′-Bisphosphate Analogues and Conjugation to a Polyamidoamine (PAMAM) Dendrimer Carrier

    PubMed Central

    de Castro, Sonia; Maruoka, Hiroshi; Hong, Kunlun; Kilbey, S. Michael; Costanzi, Stefano; Hechler, Béatrice; Brown, Garth G.; Gachet, Christian; Harden, T. Kendall; Jacobson, Kenneth A.

    2010-01-01

    The P2Y1 receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3′,5′-bisphosphate antagonists of the P2Y1 receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphates containing extended 2-alkynyl chains was designed and binding affinity at the human (h) P2Y1 receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (Ki 23 nM) and extended amine congener 15 (Ki 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended ε-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y1 receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y1 receptor modeling and ligand docking. Attempted P2Y1 antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor antagonist to a PAMAM dendrimer to produce a multivalent conjugate exhibiting a

  10. Poly(amidoamine) dendrimer-enabled simultaneous stabilization and functionalization of electrospun poly(γ-glutamic acid) nanofibers.

    PubMed

    Wang, Shige; Zhu, Jingyi; Shen, Mingwu; Zhu, Meifang; Shi, Xiangyang

    2014-02-12

    We report a facile and general approach to using generation 2 (G2) poly(amidoamine) (PAMAM) dendrimers for simultaneous stabilization and functionalization of electrospun poly(γ-glutamic acid) nanofibers (γ-PGA NFs). In this study, uniform γ-PGA NFs with a smooth morphology were generated using electrospinning technology. In order to endow the NFs with good water stability, amine-terminated G2.NH2 PAMAM dendrimers were utilized to crosslink the γ-PGA NFs via 1-ethyl-3-(3-dimethylami-nopropyl) carbodiimide coupling chemistry. Under the optimized crosslinking conditions, G2.NH2 dendrimers partially modified with fluorescein isothiocyanate (FI) or folic acid (FA) were used to crosslink γ-PGA NFs. Our results reveal that G2.NH2-FI is able to simultaneously render the NFs with good water stability and fluorescence property, while G2.NH2-FA is able to simultaneously endow the NFs with water stability and the ability to capture FA receptor-overexpressing cancer cells in vitro via ligand-receptor interaction. With the tunable dendrimer surface chemistry, multifunctional water-stable γ-PGA-based NFs may be generated via a dendrimer crosslinking approach, thereby providing diverse applications in the areas of biosensing, tissue engineering, drug delivery, and environmental sciences. PMID:24456208

  11. Dendrimer-based nanoparticles for potential personalized therapy in chronic lymphocytic leukemia: Targeting the BCR-signaling pathway.

    PubMed

    Franiak-Pietryga, Ida; Maciejewski, Henryk; Ostrowska, Kinga; Appelhans, Dietmar; Voit, Brigitte; Misiewicz, Małgorzata; Kowalczyk, Paweł; Bryszewska, Maria; Borowiec, Maciej

    2016-07-01

    Chronic lymphocytic leukemia (CLL) is one of the most prevalent forms of leukemia in western society. Although classic chemoimmune therapy is still the gold standard of care for leukemic patients, effective therapy of CLL is yet to be achieved. The present study examines the influence of poly(propylene)imine (PPI) dendrimers with primary amino surface groups modified with maltotriose residues in approximately 90% (PPI-G4-DS-Mal-III) or 30% (PPI-G4-OS-Mal-III) of cases on CLL cells (MEC-1 cell line with del(17p)), and confirms that the main trigger in this interaction is the induction of the apoptotic mechanism. The efficacy of each dendrimer was compared using fludarabine (FA). Gene expression profiling (GEP) by microarray identified a group of genes in the BCR signaling pathway characterized by different levels of expression directly associated with the tested agent and type of interaction. Network analysis revealed the potential patterns involved in potential personalized therapy of CLL. The expression of most BCR genes decreased under the influence of dendrimers, which might translate into decreased maturation and proliferation of CLL lymphocytes. Moreover, PPI-G4-OS/DS-Mal-III dendrimers affected gene expression and CLL cells in a different way to FA. Thanks to unique properties, dendrimers may be specifically targeted, thus improving the effectiveness of CLL therapy. PMID:26987432

  12. Anionic sulfonated and carboxylated PPI dendrimers with the EDA core: synthesis and characterization of selective metal complexing agents.

    PubMed

    García-Gallego, Sandra; Cangiotti, Michela; Fiorani, Luigi; Fattori, Alberto; Muñoz-Fernández, Ma Ángeles; Gomez, Rafael; Ottaviani, M Francesca; de la Mata, F Javier

    2013-04-28

    Herein we describe the synthesis and characterization of new sulfonated and carboxylated poly(propyleneimino) (PPI) dendrimers with the ethylenediamino (EDA) core, at generations 1, 2 and 3. By means of UV-Vis and EPR spectroscopy, using Cu(2+) as a probe, we concluded that these dendrimers show a specific pattern in the coordination of metal ions. In agreement with the UV-Vis studies, EPR spectra of carboxylated compounds are constituted by 3 different signals which appear and then disappear with increasing copper concentration, corresponding to the saturation of different copper complexation sites. At the lowest copper concentration up to a 1:1 molar ratio between Cu(II) and the dendrimer, the spectrum is characteristic of a CuN2O2 coordination at the core of the dendrimer. The spectrum appearing at higher Cu(II) concentrations indicates a peripheral location of the ions coordinating one nitrogen and 3 oxygen atoms in a square planar geometry in restricted mobility conditions. For the highest concentrations tested, copper ions are confined at the external dendrimer surface with CuO4 coordination. For sulfonate systems, the EPR results are in line with a weaker interaction of Cu(II) with the nitrogen sites and a stronger interaction with the oxygen (SO3(-)) groups with respect to the interactions measured by EPR for carboxylate systems. PMID:23462972

  13. Silica nanoparticles functionalized with polyamidoamine (PAMAM) dendrimers as platforms for photoluminescence (PL) sensing of copper and cyanide ions.

    PubMed

    Gerrans, Kateryna; Luhrs, Alicia; Feider, Clara; Margerum, Lawrence D

    2016-05-15

    Functionalized nanoparticles for photoluminescence (PL) applications are a promising technology for biomedical imaging and as sensors for small molecules. This work presents a new method to modify silica nanoparticles (SNP) using the bifunctional linker 1,1'-carbonyldiimidazole (CDI) with a series of polyamidoamine (PAMAM) dendrimer molecules followed by grafting of fluorescein isothiocyanate (FITC) or rhodamine B isothiocyanate (RITC) to create platforms for photoluminescence (PL) sensors. A dendrimer size and charge-variable response to only copper(II) ions confirmed the prediction of a selective turn-off sensor via proximity quenching. Both dye density and Cu(2+) quenching efficiency peaked with SNP-dendrimer generation 4 (64 terminal amines). In addition, changing the terminal dendrimer arms to carboxylic acid end groups increased the copper quenching suggesting that more metal ion binding sites were created in close proximity to the dyes. Of the small anions tested for a turn-off sensor, only cyanide ion fully restored the PL when reaching a 2:1 CN(-):Cu(2+) ratio, while EDTA was not as effective at the same ratio. Therefore, dendrimer size and surface charge on the nanoparticles controlled the dye loading and copper quenching efficiency, while creating multiple binding sites for cyanide over other metal binding anions. PMID:26962978

  14. Dynamical Interactions of 5-Fluorouracil Drug with Dendritic Peptide Vectors: The Impact of Dendrimer Generation, Charge, Counterions, and Structured Water.

    PubMed

    De Luca, Sergio; Seal, Prasenjit; Ouyang, Defang; Parekh, Harendra S; Kannam, Sridhar Kumar; Smith, Sean C

    2016-06-30

    Molecular dynamics simulations are utilized to investigate the interactions between the skin cancer drug 5-fluorouracil (5FU) and peptide-based dendritic carrier systems. We find that these drug-carrier interactions do not conform to the traditional picture of long-time retention of the drug within a hydrophobic core of the dendrimer carrier. Rather, 5FU, which is moderately soluble in its own right, experiences weak, transient chattering interactions all over the dendrimer, mediated through multiple short-lived hydrogen bonding and close contact events. We find that charge on the periphery of the dendrimer actually has a negative effect on the frequency of drug-carrier interactions due to a counterion screening effect that has not previously been observed. However, charge is nevertheless an important feature since neutral dendrimers are shown to have a significant mutual attraction that can lead to clustering or agglomeration. This clustering is prevented due to charge repulsion for the titrated dendrimers, such that they remain independent in solution. PMID:27267604

  15. Tweaking Dendrimers and Dendritic Nanoparticles for Controlled Nano-bio Interactions: Potential Nanocarriers for Improved Cancer Targeting

    PubMed Central

    Bugno, Jason; Hsu, Hao-Jui; Hong, Seungpyo

    2016-01-01

    Nanoparticles have shown great promise in the treatment of cancer, with a demonstrated potential in targeted drug delivery. Among a myriad of nanocarriers that have been recently developed, dendrimers have attracted a great deal of scientific interests due to their unique chemical and structural properties that allow for precise engineering of their characteristics. Despite this, the clinical translation of dendrimers has been hindered due to their drawbacks, such as scale-up issues, rapid systemic elimination, inefficient tumor accumulation, and limited drug loading. In order to overcome these limitations, a series of reengineered dendrimers have been recently introduced using various approaches, including: i) modifications of structure and surfaces; ii) integration with linear polymers; and iii) hybridization with other types of nanocarriers. Chemical modifications and surface engineering have tailored dendrimers to improve their pharmacokinetics and tissue permeation. Copolymerization of dendritic polymers with linear polymers has resulted in various amphiphilic copolymers with self-assembly capabilities and improved drug loading efficiencies. Hybridization with other nanocarriers integrates advantageous characteristics of both systems, which includes prolonged plasma circulation times and enhanced tumor targeting. This review provides a comprehensive summary of the newly emerging drug delivery systems that involve reengineering of dendrimers in an effort to precisely control their nano-bio interactions, mitigating their inherent weaknesses. PMID:26453160

  16. Ligand-Receptor Interaction-Mediated Transmembrane Transport of Dendrimer-like Soft Nanoparticles: Mechanisms and Complicated Diffusive Dynamics.

    PubMed

    Liang, Junshi; Chen, Pengyu; Dong, Bojun; Huang, Zihan; Zhao, Kongyin; Yan, Li-Tang

    2016-05-01

    Nearly all nanomedical applications of dendrimer-like soft nanoparticles rely on the functionality of attached ligands. Understanding how the ligands interact with the receptors in cell membrane and its further effect on the cellular uptake of dendrimer-like soft nanoparticles is thereby a key issue for their better application in nanomedicine. However, the essential mechanism and detailed kinetics for the ligand-receptor interaction-mediated transmembrane transport of such unconventional nanoparticles remain poorly elucidated. Here, using coarse-grained simulations, we present the very first study of molecular mechanism and kinetics behaviors for the transmembrane transport of dendrimer-like soft nanoparticles conjugated with ligands. A phase diagram of interaction states is constructed through examining ligand densities and membrane tensions that allows us to identify novel endocytosis mechanisms featured by the direct wrapping and the penetration-extraction vesiculation. The results provide an in-depth insight into the diffusivity of receptors and dendrimer in the membrane plane and demonstrate how the ligand density influences receptor diffusion and uptake kinetics. It is interesting to find that the ligand-conjugated dendrimers present superdiffusive behaviors on a membrane, which is revealed to be driven by the random fluctuation dynamics of the membrane. The findings facilitate our understanding of some recent experimental observations and could establish fundamental principles for the future development of such important nanomaterials for widespread nanomedical applications. PMID:27049403

  17. Structure of poly(propyl ether imine) dendrimer from fully atomistic molecular dynamics simulation and by small angle x-ray scattering

    NASA Astrophysics Data System (ADS)

    Jana, Chandan; Jayamurugan, G.; Ganapathy, Rajesh; Maiti, Prabal K.; Jayaraman, N.; Sood, A. K.

    2006-05-01

    We study the structure of carboxylic acid terminated neutral poly(propyl ether imine) (PETIM) dendrimer from generations 1-6 (G1-G6) in a good solvent (water) by fully atomistic molecular dynamics (MD) simulations. We determine as a function of generation the structural properties such as radius of gyration, shape tensor, asphericity, fractal dimension, monomer density distribution, and end-group distribution functions. The sizes obtained from the MD simulations have been validated by small angle x-ray scattering experiment on dendrimer of generations 2-4 (G2-G4). A good agreement between the experimental and theoretical value of radius of gyration has been observed. We find a linear increase in radius of gyration with the generation. In contrast, Rg scales as ˜Nx with the number of monomers. We find two distinct exponents depending on the generations, x =0.47 for G1-G3 and x =0.28 for G3-G6, which reveal their nonspace filling nature. In comparison with the amine terminated poly(amidoamine) (PAMAM) dendrimer, we find that Rg of Gth generation PETIM dendrimer is nearly equal to that of (G +1)th generation of PAMAM dendrimer as observed by Maiti et al. [Macromolecules 38, 979 (2005)]. We find substantial back folding of the outer subgenerations into the interior of the dendrimer. Due to their highly flexible nature of the repeating branch units, the shape of the PETIM dendrimer deviates significantly from the spherical shape and the molecules become more and more spherical as the generation increases. The interior of the dendrimer is quite open with internal cavities available for accommodating guest molecules, suggesting the use of PETIM dendrimer for guest-host applications. We also give a quantitative measure of the number of water molecules present inside the dendrimer.

  18. Fluorescent Phosphorus Dendrimer as a Spectral Nanosensor for Macrophage Polarization and Fate Tracking in Spinal Cord Injury.

    PubMed

    Shakhbazau, Antos; Mishra, Manoj; Chu, Tak-Ho; Brideau, Craig; Cummins, Karen; Tsutsui, Shigeki; Shcharbin, Dzmitry; Majoral, Jean-Pierre; Mignani, Serge; Blanchard-Desce, Mireille; Bryszewska, Maria; Yong, V Wee; Stys, Peter K; van Minnen, Jan

    2015-11-01

    Dendrimers and dendriplexes, highly branched synthetic macromolecules, have gained popularity as new tools for a variety of nanomedicine strategies due to their unique structure and properties. We show that fluorescent phosphorus dendrimers are well retained by bone marrow-derived macrophages and exhibit robust spectral shift in its emission in response to polarization conditions. Fluorescence properties of this marker can also assist in identifying macrophage presence and phenotype status at different time points after spinal cord injury. Potential use of a single dendrimer compound as a drug/siRNA carrier and phenotype-specific cell tracer offers new avenues for enhanced cell therapies combined with monitoring of cell fate and function in spinal cord injury. PMID:26175127

  19. Application of the functionalized congener approach to dendrimer-based signaling agents acting through A(2A) adenosine receptors.

    PubMed

    Kim, Yoonkyung; Klutz, Athena M; Hechler, Béatrice; Gao, Zhan-Guo; Gachet, Christian; Jacobson, Kenneth A

    2009-03-01

    As a continued effort to develop multivalent ligands to enhance the pharmacological effects of monomeric drugs, DITC-APEC, a chemically reactive nucleoside A(2A) adenosine receptor (AR) agonist, was employed to derivatize the surface of third-generation (G3) polyamidoamine (PAMAM) dendrimers. The resulting conjugates carried multiple copies of the agonist attached through a thiourea linkage and differed in the number of attachments and in the presence of a fluorophore or additional surface modification. Computer modeling studies suggested that these DITC-APEC-loaded dendrimers extended the overall diameter of the previously reported PAMAM-CGS21680 dendrimer derivatives (Kim et al., Bioconjugate Chem 2008 19:406-411) by ca. 20 A, potentially increasing the conformational flexibility of the appended ligands to achieve optimal geometry for efficient binding at A(2A) ARs. Increased affinity and selectivity in binding in comparison to the CGS21680 conjugate were envisioned, due to the presence of an extended linker, i.e., a dithioureylenephenyl functionality. In vitro radioligand competition experiments showed effective binding of these PAMAM-DITC-APEC dendrimer conjugates at the human A(2A) and A(3) ARs with submicromolar K (i) values and selectivity in comparison to the human A(1) AR. Furthermore, these nucleoside-loaded dendrimers exhibited an A(2A) AR-mediated inhibitory effect on ADP-induced aggregation of human platelets. The present study demonstrates the potential of applying the functionalized congener concept to engineer dendrimer-based multivalent ligands for G protein-coupled receptors. PMID:18600474

  20. PEGylated dendrimer-entrapped gold nanoparticles for in vivo blood pool and tumor imaging by computed tomography.

    PubMed

    Peng, Chen; Zheng, Linfeng; Chen, Qian; Shen, Mingwu; Guo, Rui; Wang, Han; Cao, Xueyan; Zhang, Guixiang; Shi, Xiangyang

    2012-02-01

    We report the synthesis and characterization of dendrimer-entrapped gold nanoparticles (Au DENPs) modified by polyethylene glycol (PEG) with enhanced biocompatibility for computed tomography (CT) imaging applications. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH(2)) modified by PEG monomethyl ether (G5.NH(2)-mPEG(20)) were used as templates to synthesize Au DENPs, followed by acetylation of the remaining dendrimer terminal amines to generate PEGylated Au DENPs. The partial PEGylation modification of dendrimer terminal amines allows high loading of Au within the dendrimer interior, and consequently by simply varying the Au salt/dendrimer molar ratio, the size of the PEGylated Au DENPs can be controlled at a range of 2-4 nm with a narrow size distribution. The formed PEGylated Au DENPs are water-dispersible, stable in a pH range of 5-8 and a temperature range of 0-50 °C, and non-cytotoxic at a concentration as high as 100 μm. X-ray absorption coefficient measurements show that the attenuation intensity of the PEGylated Au DENPs is much higher than that of Omnipaque with iodine concentration similar to Au. With the sufficiently long half-decay time demonstrated by pharmacokinetics studies, the PEGylated Au DENPs enabled not only X-ray CT blood pool imaging of mice and rats after intravenous injection of the particles, but also effective CT imaging of a xenograft tumor model in nude mice. These findings suggest that the designed PEGylated Au DENPs can be used as a promising contrast agent with enhanced biocompatibility for CT imaging of various biological systems, especially in cancer diagnosis. PMID:22061490

  1. Carboxymethyl Chitosan-Modified Polyamidoamine Dendrimer Enables Progressive Drug Targeting of Tumors via pH-Sensitive Charge Inversion.

    PubMed

    Qi, Xiaole; Qin, Jiayi; Fan, Yuchao; Qin, Xiaoxue; Jiang, Yujie; Wu, Zhenghong

    2016-04-01

    Polyamidoamine dendrimers are potential candidates for drug delivery systems due to their remarkable cell-penetrating power that results from their strong positive surface charge. However, the positively charged surfaces always lead to serious cytotoxicity and the rapid clearance of polyamidoamine in vivo, which limit the application of these dendrimers. To overcome these drawbacks, we developed a carboxymethyl chitosan-modified polyamidoamine dendrimer to achieve progressive drug targeting of tumors via pH-sensitive charge inversion. With the shielding of carboxymethyl chitosan, the complex was negatively charged at physiological conditions (pH 7.4) and prone to enrich at tumor sites due to the enhanced permeation and retention effect; however, it regained a positive charge via the removal of the carboxymethyl chitosan coating under tumor-acidic conditions (pH 6.5) and achieved high intracellular uptake in tumor cells through electrostatic adsorptive endocytosis. In this study, these dendrimers exhibited 1.99- and 1.76-times higher cellular uptake efficiencies at pH 7.4 in MCF-7 or A549 cells, respectively, compared with efficiencies at pH 6.5, indicating an effective pH-dependent accumulation; the fluorescence intensities of these cells exposed to the dendrimers at pH 6.5 were also 16.45- and 9.27-fold greater, respectively, than those of free doxorubicin. After intravenous administration in mice bearing H22 tumors, doxorubicin-loaded dendrimers exhibited a 1.50-fold greater antitumor activity and presented no obvious systematic toxicity based on histological analysis compared with free drugs. Overall, a simple decoration of carboxymethyl chitosan demonstrated to be a promising way for cationic nanocarriers to achieve pH-sensitive drug release and charge conversion response to tumor microenvironment pH and enhance the antitumor therapy efficiency of anticancer drugs. PMID:27301193

  2. Dendrimer-Based Responsive MRI Contrast Agents (G1-G4) for Biosensor Imaging of Redundant Deviation in Shifts (BIRDS).

    PubMed

    Huang, Yuegao; Coman, Daniel; Hyder, Fahmeed; Ali, Meser M

    2015-12-16

    Biosensor imaging of redundant deviation in shifts (BIRDS) is a molecular imaging platform for magnetic resonance that utilizes unique properties of low molecular weight paramagnetic monomers by detecting hyperfine-shifted nonexchangeable protons and transforming the chemical shift information to reflect its microenvironment (e.g., via temperature, pH, etc.). To optimize translational biosensing potential of BIRDS we examined if this detection scheme observed with monomers can be extended onto dendrimers, which are versatile and biocompatible macromolecules with modifiable surface for molecular imaging and drug delivery. Here we report on feasibility of paramagnetic dendrimers for BIRDS. The results show that BIRDS is resilient with paramagnetic dendrimers up to the fourth generation (i.e., G1-G4), where the model dendrimer and chelate were based on poly(amido amine) (PAMAM) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA(4-)) complexed with thulium ion (Tm(3+)). Temperature sensitivities of two prominent signals of Gn-PAMAM-(TmDOTA(-))x (where n = 1-4, x = 6-39) were comparable to that of prominent signals in TmDOTA(-). Transverse relaxation times of the coalesced nonexchangeable protons on Gn-PAMAM-(TmDOTA(-))x were relatively short to provide signal-to-noise ratio that was comparable to or better than that of TmDOTA(-). A fluorescent dye, rhodamine, was conjugated to a G2-PAMAM-(TmDOTA)12 to create a dual-modality nanosized contrast agent. BIRDS properties of the dendrimer were unaltered with rhodamine conjugation. Purposely designed paramagnetic dendrimers for BIRDS in conjunction with novel macromolecular surface modification for functional ligands/drugs could potentially be used for biologically compatible theranostic sensors. PMID:26497087

  3. A New Approach in the Preparation of Dendrimer-Based Bifunctional Diethylenetriaminepentaacetic Acid MR Contrast Agent Derivatives

    PubMed Central

    Nwe, Kido; Xu, Heng; Regino, Celeste Aida S.; Bernardo, Marcelino; Ileva, Lilia; Riffle, Lisa; Wong, Karen J.; Brechbiel, Martin W.

    2009-01-01

    In this paper we report a new method to prepare and characterize a contrast agent based on a fourth-generation (G4) polyamidoamine (PAMAM) dendrimer conjugated to the gadolinium complex of the bifunctional diethylenetriamine pentaacetic acid derivative (1B4M-DTPA). The method involves pre-forming the metal-ligand chelate in alcohol prior to conjugation to the dendrimer. The dendrimer-based agent was purified by a Sephadex® G-25 column and characterized by elemental analysis. The analysis and SEHPLC data gave a chelate to dendrimer ratio of 30:1 suggesting conjugation at approximately every other amine terminal on the dendrimer. Molar relaxivity of the agent measured at pH 7.4 displayed a higher value than that of the analogous G4 dendrimer based agent prepared by the post-metal incorporation method (r1 = 26.9 vs. 13.9 mM-1s-1 at 3T and 22°C). This is hypothesized to be due to the higher hydrophobicity of this conjugate, and the lack of available charged carboxylate groups from non-complexed free ligands that might coordinate to the metal and thus also reduce water exchange sites. Additionally, the distribution populations of compounds that result from the post-metal incorporation route are eliminated from the current product simplifying characterization as quality control issues pertaining to the production of such agents for clinical use as MR contrast agents. In vivo imaging in mice showed a reasonably fast clearance (t1/2 = 24 min) suggesting a viable agent for use in clinical application. PMID:19555072

  4. Dendrimer-Based Responsive MRI Contrast Agents (G1-G4) for Biosensor Imaging of Redundant Deviation in Shifts (BIRDS)

    PubMed Central

    Huang, Yuegao; Coman, Daniel; Hyder, Fahmeed; Ali, Meser M.

    2016-01-01

    Biosensor imaging of redundant deviation in shifts (BIRDS) is a molecular imaging platform for magnetic resonance that utilizes unique properties of low molecular weight paramagnetic monomers by detecting hyperfine-shifted nonexchangeable protons and transforming the chemical shift information to reflect its microenvironment (e.g., via temperature, pH, etc.). To optimize translational biosensing potential of BIRDS we examined if this detection scheme observed with monomers can be extended onto dendrimers, which are versatile and biocompatible macromolecules with modifiable surface for molecular imaging and drug delivery. Here we report on feasibility of paramagnetic dendrimers for BIRDS. The results show that BIRDS is resilient with paramagnetic dendrimers up to the fourth generation (i.e., G1-G4), where the model dendrimer and chelate were based on poly(amido amine) (PAMAM) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA4−) complexed with thulium ion (Tm3+). Temperature sensitivities of two prominent signals of Gn-PAMAM-(TmDOTA−)x (where n = 1–4, x = 6–39) were comparable to that of prominent signals in TmDOTA−. Transverse relaxation times of the coalesced nonexchangeable protons on Gn-PAMAM-(TmDOTA−)x were relatively short to provide signal-to-noise ratio that was comparable to or better than that of TmDOTA−. A fluorescent dye, rhodamine, was conjugated to a G2-PAMAM-(TmDOTA)12 to create a dual-modality nanosized contrast agent. BIRDS properties of the dendrimer were unaltered with rhodamine conjugation. Purposely designed paramagnetic dendrimers for BIRDS in conjunction with novel macromolecular surface modification for functional ligands/drugs could potentially be used for biologically compatible theranostic sensors. PMID:26497087

  5. Selective cytotoxicity of PAMAM G5 core–PAMAM G2.5 shell tecto-dendrimers on melanoma cells

    PubMed Central

    Schilrreff, Priscila; Mundiña-Weilenmann, Cecilia; Romero, Eder Lilia; Morilla, Maria Jose

    2012-01-01

    Background The controlled introduction of covalent linkages between dendrimer building blocks leads to polymers of higher architectural order known as tecto-dendrimers. Because of the few simple steps involved in their synthesis, tecto-dendrimers could expand the portfolio of structures beyond commercial dendrimers, due to the absence of synthetic drawbacks (large number of reaction steps, excessive monomer loading, and lengthy chromatographic separations) and structural constraints of high-generation dendrimers (reduction of good monodispersity and ideal dendritic construction due to de Gennes dense-packing phenomenon). However, the biomedical uses of tecto-dendrimers remain unexplored. In this work, after synthesizing saturated shell core–shell tecto-dendrimers using amine-terminated polyamidoamine (PAMAM) generation 5 (G5) as core and carboxyl-terminated PAMAM G2.5 as shell (G5G2.5 tecto-dendrimers), we surveyed for the first time the main features of their interaction with epithelial cells. Methods Structural characterization of G5G2.5 was performed by polyacrylamide gel electrophoresis, matrix-assisted laser desorption time-of-flight mass spectrometry, and microscopic techniques; their hydrodynamic size and Z-potential was also determined. Cellular uptake by human epidermal keratinocytes, colon adenocarcinoma, and epidermal melanoma (SK-Mel-28) cells was determined by flow cytometry. Cytotoxicity was determined by mitochondrial activity, lactate dehydrogenase release, glutathione depletion, and apoptosis/necrosis measurement. Results The resultant 60%–67% saturated shell, 87,000-dalton G5G2.5 (mean molecular weight) interacted with cells in a significantly different fashion in comparison to their building blocks and to its closest counterpart, PAMAM G6.5. After being actively taken up by epithelial cells, G5G2.5 caused cytotoxicity only on SK-Mel-28 cells, including depletion of intracellular glutathione and fast necrosis that was manifested above 5 μM G5

  6. The SPL7013 dendrimer destabilizes the HIV-1 gp120-CD4 complex

    NASA Astrophysics Data System (ADS)

    Nandy, Bidisha; Saurabh, Suman; Sahoo, Anil Kumar; Dixit, Narendra M.; Maiti, Prabal K.

    2015-11-01

    The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude the CD4 binding site on gp120, suggesting that SPL7013 does not prevent the binding of R5 gp120 to CD4. Using MD simulations to compute binding energies of several docked structures, we find that SPL7013 binding to gp120 significantly weakens the gp120-CD4 complex. Finally, we use steered molecular dynamics (SMD) to study the kinetics of the dissociation of the gp120-CD4 complex in the absence of the dendrimer and with the dendrimer bound in each of the several stable configurations to gp120. We find that SPL7013 significantly lowers the force required to rupture the gp120-CD4 complex and accelerates its dissociation. Taken together, our findings suggest that SPL7013 compromises the stability of the R5 gp120-CD4 complex, potentially preventing the accrual of the requisite number of gp120-CD4 complexes across the virus-cell interface, thereby blocking virus entry.The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude

  7. Development of TRPN dendrimer-modified disordered mesoporous silica for CO{sub 2} capture

    SciTech Connect

    Zhang, Xiaoyun; Zhang, Sisi; Qin, Hongyan; Wu, Wei

    2014-08-15

    Highlights: • A novel series of TRPN dendrimers are synthesized. • Structurally disordered mesoporous silica was used to develop the CO{sub 2} adsorbent. • The CO{sub 2} adsorption capacity is relatively high. • The sorbent exhibits a high stability after 12 cycling runs. • The sorbent achieves complete desorption at low temperature (60 °C). - Abstract: A novel series of tri(3-aminopropyl) amine (TRPN) dendrimers were synthesized and impregnated on structurally disordered mesoporous silica (DMS) to generate CO{sub 2} adsorbents (TS). The physicochemical and adsorption properties of the adsorbents before and after dendrimer modification were characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and N{sub 2} adsorption–desorption (N{sub 2}-BET) techniques. CO{sub 2} adsorption–desorption tests indicated that the sorbent demonstrates high CO{sub 2} adsorption capacity (138.1 mg g{sup −1} for G1 sample TS-G1-3CN-50 and 91.7 mg g{sup −1} for G2 sample TS-G2-6CN-50), and can completely desorb CO{sub 2} under vacuum at 60 °C. Its CO{sub 2} adsorption capacity at 25 °C increases with the amine loading, achieving the highest adsorption capacity (140.6 mg g{sup −1} for TS-G1-3CN) at 60%. The developed TS materials exhibited excellent cycling stability. After 12 consecutive adsorption–desorption runs, TS-G1-3CN-50 shows an adsorption capacity of 136.0 mg g{sup −1}, retaining 98.5% of its original value.

  8. Lyophilized mucoadhesive-dendrimer enclosed matrix tablet for extended oral delivery of albendazole.

    PubMed

    Mansuri, Shakir; Kesharwani, Prashant; Tekade, Rakesh Kumar; Jain, Narendra Kumar

    2016-05-01

    Dendrimers are multifunctional carriers widely employed for delivering drugs in a variety of disease conditions including HIV/AIDS and cancer. Albendazole (ABZ) is a commonly used anthelmintic drug in human as well as veterinary medicine. In this investigation, ABZ was formulated as a "muco-dendrimer" based sustained released tablet. The mucoadhesive complex was synthesized by anchoring chitosan to fifth generation PPI dendrimer (Muco-PPI) and characterized by UV, FTIR, (1)H NMR spectroscopy and electron microscopy. ABZ was entrapped inside Muco-PPI followed by lyophilization and tableting as matrix tablet. A half-life (t1/2) of 8.06±0.15, 8.17±0.47, 11.04±0.73, 11.49±0.92, 12.52±1.04 and 16.9±1.18h was noted for ABZ (free drug), conventional ABZ tablet (F1), conventional ABZ matrix tablet (F2), PPI-ABZ complex, PPI-ABZ matrix tablet (F3) and Muco-PPI-ABZ matrix tablet (F4), respectively. Thus the novel mucoadhesive-PPI based formulation of ABZ (F4) increased the t1/2 of ABZ significantly by almost twofold as compared to the administration of free drug. The in vivo drug release data showed that the Muco-PPI based formulations have a significantly higher Cmax (2.40±0.02μg/mL) compared with orally administered free ABZ (0.19±0.07μg/mL) as well as conventional tablet (0.20±0.05μg/mL). In addition, the Muco-PPI-ABZ matrix tablet displayed increased mean residence time (MRT) and is therefore a potential candidate to appreciably improve the pharmacokinetic profile of ABZ. PMID:26563727

  9. Dendrimer Nanocarriers for Transport Modulation Across Models of the Pulmonary Epithelium

    PubMed Central

    2015-01-01

    The purpose of this study was to determine the effect of PEGylation on the interaction of poly(amidoamine) (PAMAM) dendrimer nanocarriers (DNCs) with in vitro and in vivo models of the pulmonary epithelium. Generation-3 PAMAM dendrimers with varying surface densities of PEG 1000 Da were synthesized and characterized. The results revealed that the apical to basolateral transport of DNCs across polarized Calu-3 monolayers increases with an increase in PEG surface density. DNC having the greatest number of PEG groups (n = 25) on their surface traversed at a rate 10-fold greater than its non-PEGylated counterpart, in spite of their larger size. This behavior was attributed to a significant reduction in charge density upon PEGylation. We also observed that PEGylation can be used to modulate cellular internalization. The total uptake of PEG-free DNC into polarized Calu-3 monolayers was 12% (w/w) vs 2% (w/w) for that with 25 PEGs. Polarization is also shown to be of great relevance in studying this in vitro model of the lung epithelium. The rate of absorption of DNCs administered to mice lungs increased dramatically when conjugated with 25 PEG groups, thus supporting the in vitro results. The exposure obtained for the DNC with 25PEG was determined to be very high, with peak plasma concentrations reaching 5 μg·mL–1 within 3 h. The combined in vitro and in vivo results shown here demonstrate that PEGylation can be potentially used to modulate the internalization and transport of DNCs across the pulmonary epithelium. Modified dendrimers thereby may serve as a valuable platform that can be tailored to target the lung tissue for treating local diseases, or the circulation, using the lung as pathway to the bloodstream, for systemic delivery. PMID:25455560

  10. The SPL7013 dendrimer destabilizes the HIV-1 gp120-CD4 complex.

    PubMed

    Nandy, Bidisha; Saurabh, Suman; Sahoo, Anil Kumar; Dixit, Narendra M; Maiti, Prabal K

    2015-11-28

    The poly (l-lysine)-based SPL7013 dendrimer with naphthalene disulphonate surface groups blocks the entry of HIV-1 into target cells and is in clinical trials for development as a topical microbicide. Its mechanism of action against R5 HIV-1, the HIV-1 variant implicated in transmission across individuals, remains poorly understood. Using docking and fully atomistic MD simulations, we find that SPL7013 binds tightly to R5 gp120 in the gp120-CD4 complex but weakly to gp120 alone. Further, the binding, although to multiple regions of gp120, does not occlude the CD4 binding site on gp120, suggesting that SPL7013 does not prevent the binding of R5 gp120 to CD4. Using MD simulations to compute binding energies of several docked structures, we find that SPL7013 binding to gp120 significantly weakens the gp120-CD4 complex. Finally, we use steered molecular dynamics (SMD) to study the kinetics of the dissociation of the gp120-CD4 complex in the absence of the dendrimer and with the dendrimer bound in each of the several stable configurations to gp120. We find that SPL7013 significantly lowers the force required to rupture the gp120-CD4 complex and accelerates its dissociation. Taken together, our findings suggest that SPL7013 compromises the stability of the R5 gp120-CD4 complex, potentially preventing the accrual of the requisite number of gp120-CD4 complexes across the virus-cell interface, thereby blocking virus entry. PMID:26495445

  11. Functionalization of PAMAM dendrimers with [Ru(III)(edta)(H2O)](-).

    PubMed

    Benini, P G Z; McGarvey, B R; Franco, D W

    2008-11-01

    The anchoring of K[Ru(III)(edta)(Cl)] on poly(amidoamine) dendrimers (PAMAM of three generations G(x)/Ru (x=0, 2 and 3)) through a peptide type bond yielded the aquo species, [Ru(III)(edta)(H2O)] on dendrimer surface, and upon NO exposure, yielded their nitrosyl analogues, G(x)/RuNO. Characterization of these compounds by elemental analysis, and a UV-vis, IR and 13C NMR spectroscopies indicated the immobilization of 4, 12 and 29 molecules of [Ru(III)(edta)(H2O)] or of the nitrosyl complex [Ru(II)(edta)NO] on the dendrimer surface for G(X)=0, 2 and 3, respectively. For each complex the electrochemical spectrum presented only one redox process with redox potential values of -0.20 and -0.32 V(vs SCE) attributed to the Ru(III)/Ru(II) and NO+/NO(0) couples in G(x)/Ru and G(x)/RuNO, respectively. The one-electron reduction of G(x)/RuNO+ generates G(x)/RuNO(0), which undergoes aquation with a k(-NO) of 2.1+/-0.7 x 10(-3)s(-1) (pH 1.0, mu=0.2 mol/L, CF3COOH/NaCF3COO, 25 degrees C). The G(x)/RuNO species induced a relaxing effect in aortic rings denuded of endothelium and exhibited in vitro assay trypanocidal activity. PMID:18503781

  12. Synthesis and In Vivo Antitumor Efficacy of PEGylated Poly(L-lysine) Dendrimer-Camptothecin Conjugates

    PubMed Central

    Fox, Megan E.; Guillaudeu, Steve; Fréchet, Jean M. J.; Jerger, Kat; Macaraeg, Nichole; Szoka, Francis C.

    2009-01-01

    Polymer conjugates of camptothecin (CPT) have been pursued as a solution to the difficulties present in treating cancers with CPT and its derivatives. Covalent attachment of CPT to a polymer can improve solubility, increase blood circulation time, enhance tumor uptake, and significantly improve efficacy of the drug. In this report, we describe a novel polymer conjugate of CPT using a core-functionalized, symmetrically PEGylated poly(L-lysine) (PLL) dendrimer. The PEGylated dendrimer consisted of a lysine dendrimer functionalized with aspartic acid, which was used as an attachment site for poly(ethylene glycol) (PEG) and CPT. The final conjugate had a molecular weight of 40 kDa and was loaded with 4-6 wt% CPT. Polymer-bound CPT was shown to have a long blood circulation half-life of 30.9 ± 8.8 h and a tumor uptake of 4.2 ± 2.3% of the injected dose/g tissue, compared to free CPT in which less than 1% was retained in the blood after 30 min and had a tumor accumulation of 0.29 ± 0.04% of the injected dose/g tissue. The PEGylated PLL-CPT showed superior efficacy in murine (C26) and human colon carcinoma (HT-29) tumor models when compared with no treatment or treatment with irinotecan. In the C26 tumor model, treatment resulted in significantly prolonged survival (P < 0.05) for all mice treated with a single injection of PEGylated PLL-CPT. In the HT-29 tumor model, all mice treated with multiple injections of a low dose survived to the end of the study, with three mice of eight surviving tumor-free. PMID:19588994

  13. Chlorotoxin-Conjugated Multifunctional Dendrimers Labeled with Radionuclide 131I for Single Photon Emission Computed Tomography Imaging and Radiotherapy of Gliomas.

    PubMed

    Zhao, Lingzhou; Zhu, Jingyi; Cheng, Yongjun; Xiong, Zhijuan; Tang, Yueqin; Guo, Lilei; Shi, Xiangyang; Zhao, Jinhua

    2015-09-01

    Chlorotoxin-conjugated multifunctional dendrimers labeled with radionuclide 131I were synthesized and utilized for targeted single photon emission computed tomography (SPECT) imaging and radiotherapy of cancer. In this study, generation five amine-terminated poly(amidoamine) dendrimers were used as a platform to be sequentially conjugated with polyethylene glycol (PEG), targeting agent chlorotoxin (CTX), and 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO). This was followed by acetylation of the remaining dendrimer terminal amines and radiolabeling with 131I to form the targeted theranostic dendrimeric nanoplatform. We show that the dendrimer platform possessing approximately 7.7 CTX and 21.1 HPAO moieties on each dendrimer displays excellent cytocompatibility in a given concentration range (0-20 μM) and can specifically target cancer cells overexpressing matrix metallopeptidase 2 (MMP2) due to the attached CTX. With the attached HPAO moiety having the phenol group, the dendrimer platform can be effectively labeled with radioactive 131I with good stability and high radiochemical purity. Importantly, the 131I labeling renders the dendrimer platform with an ability to be used for targeted SPECT imaging and radiotherapy of an MMP2-overexpressing glioma model in vivo. The developed radiolabeled multifunctional dendrimeric nanoplatform may hold great promise to be used for targeted theranostics of human gliomas. PMID:26291070

  14. Electrogenerated chemiluminescence reactions between the [Ru(bpy)3](2+) complex and PAMAM GX.0 dendrimers in an aqueous medium.

    PubMed

    Jimenez-Ruiz, A; Grueso, E; Perez-Tejeda, P

    2015-10-01

    Electrogenerated chemiluminescence, ECL, reactions between tris(2,2'-bipyridine)ruthenium(II), [Ru(bpy)3](2+), and PAMAM GX.0 (X=1 and 2) dendrimers in an aqueous medium were carried out at pH10 (fully deprotonated dendrimer surface). ECL was detected in the presence of GX.0 dendrimers without addition of any known coreactant. Atomic force microscopy, AFM, measurements for GX.0 dendrimers in the presence of the [Ru(bpy)3](2+) complex were also done. AFM images showed the existence of aggregates (pillars) of globular shape, as well as interdendrimer networks forming fibers in the x-y direction for dendrimer aqueous solutions. ECL and AFM results in cooperation suggest that the coreactant effect of the end amine groups is improved by both the dendritic branched shells and the globular z-type aggregates. The ECL efficiency trends as a function of [GX.0] (whole range) can be interpreted taking into account the coreactant effect modulated by the presence of the z and x-y type aggregates. Importantly, ECL efficiency values can be taken as a measure of the change induced on the dendrimer aggregation in aqueous solutions when their concentrations rise. Redox potentials of the [Ru(bpy)3](3+/2+) couple in the presence of the G1.0 and G2.0 dendrimers were also determined. PMID:26190671

  15. Size and Surface Charge of Engineered Poly(amidoamine) Dendrimers Modulate Tumor Accumulation and Penetration: A Model Study Using Multicellular Tumor Spheroids.

    PubMed

    Bugno, Jason; Hsu, Hao-Jui; Pearson, Ryan M; Noh, Hyeran; Hong, Seungpyo

    2016-07-01

    An enormous effort has been put into designing nanoparticles (NPs) with controlled biodistributions, prolonged plasma circulation times, and/or enhanced tissue targeting. However, little is known about how to design NPs with precise distributions in the target tissues. In particular, understanding NP tumor penetration and accumulation characteristics is crucial to maximizing the therapeutic potential of drug molecules carried by the NPs. In this study, we employed poly(amidoamine) (PAMAM) dendrimers, given their well-controlled size (<10 nm) and surface charge, to understand how the physical properties of NPs govern their tumor accumulation and penetration behaviors. We demonstrate for the first time that the size and surface charge of PAMAM dendrimers control their distributions in both a 3D multicellular tumor spheroid (MCTS) model and a separate extracellular matrix (ECM) model, which mimics the tumor microenvironment. Smaller PAMAM dendrimers not only diffused more rapidly in the ECM model but also efficiently penetrated to the MCTS core compared to their larger counterparts. Furthermore, cationic, amine-terminated PAMAM dendrimers exhibited the greatest accumulation in MCTS compared to either charge-neutral or anionic dendrimers. Our findings indicate that the size and surface charge of PAMAM dendrimers may tailor their tumor accumulation and penetration behaviors. These results suggest that controlled tumor accumulation and distinct intratumoral distributions can be achieved by simply controlling the size and surface charge of dendrimers, which may also be applicable for other similarly sized NPs. PMID:26828309

  16. Dendrimer-capped nanoparticles prepared by picosecond laser ablation in liquid environment.

    PubMed

    Giorgetti, Emilia; Giusti, Anna; Giammanco, Francesco; Marsili, Paolo; Laza, Simona

    2009-01-01

    Fifth generation ethylendiamine-core poly(amidoamine) (PAMAM G5) is presented as an efficient capping agent for the preparation of metal and semiconductor nanoparticles by ps laser ablation in water. In particular, we describe results obtained with the fundamental, second and third harmonic of a ps Nd:YAG laser and the influence of laser wavelength and pulse energy on gold particle production and subsequent photofragmentation. In this framework, the role of the dendrimer and, in particular, its interactions with gold clusters and cations are accounted. PMID:19783955

  17. Partially oxidized iridium clusters within dendrimers: size-controlled synthesis and selective hydrogenation of 2-nitrobenzaldehyde.

    PubMed

    Higaki, Tatsuya; Kitazawa, Hirokazu; Yamazoe, Seiji; Tsukuda, Tatsuya

    2016-06-01

    Iridium clusters nominally composed of 15, 30 or 60 atoms were size-selectively synthesized within OH-terminated poly(amidoamine) dendrimers of generation 6. Spectroscopic characterization revealed that the Ir clusters were partially oxidized. All the Ir clusters efficiently converted 2-nitrobenzaldehyde to anthranil and 2-aminobenzaldehyde under atmospheric hydrogen at room temperature in toluene via selective hydrogenation of the NO2 group. The selectivity toward 2-aminobenzaldehyde over anthranil was improved with the reduction of the cluster size. The improved selectivity is ascribed to more efficient reduction than intramolecular heterocyclization of a hydroxylamine intermediate on smaller clusters that have a higher Ir(0)-phase population on the surface. PMID:27193739

  18. Electrospun Blends of Gelatin and Gelatin-dendrimer Conjugates as a Wound Dressing and Drug Delivery Platform

    PubMed Central

    Dongargaonkar, Alpana A.; Bowlin, Gary L.; Yang, Hu

    2013-01-01

    In this work, we report a new nanofiber construct based on electrospun blends of gelatin and gelatin-dendrimer conjugates. Highly branched star-shaped polyamidoamine (PAMAM) dendrimer G3.5 was covalently conjugated to gelatin via EDC/NHS chemistry. Blends of gelatin and gelatin-dendrimer conjugates mixed with various loading levels of silver acetate (0, 0.83, 1.65, and 3.30% w/w) were successfully electrospun into nanofiber constructs (NCs). The NCs were further converted into semi-interpenetrating networks (sIPNs) with photoreactive polyethylene glycol diacrylate (Mn=575 gmol-1) (PEG DA575). They were characterized in terms of fiber morphology, diameter, pore size, permeability, degradation, and mechanical properties. The resulting sIPN NCs retained nanofiber morphology, possessed similar fiber diameters to counterpart NCs, and gained improved structural stability. The sIPN NCs also showed good swelling capacity owing to porous structures and were permeable to aqueous solutions. Silvercontaining sIPN NCs allowed sustained silver release and showed antimicrobial activity against two common types of pathogens—Staphylococcus aureus and Pseudomonas aeruginosa. Incorporation of dendrimers into the gelatin nanofibers through covalent conjugation not only expands drug loading capacity of nanofiber constructs but provides tremendous flexibility for developing multifunctional electrospun dressing materials. PMID:24127747

  19. A novel Ag⁺ cation sensor based on polyamidoamine dendrimer modified with 1,8-naphthalimide derivatives.

    PubMed

    Dodangeh, Mohammad; Gharanjig, Kamaladin; Arami, Mokhtar

    2016-02-01

    In this study, 4-amino-1,8-naphthalimide-conjugated polyamidoamine dendrimer was synthesized and characterized and its potentiality as a cation sensor was investigated. 4-Amino-1,8-naphthalic anhydride reacted with polyamidoamine dendrimer and the product was characterized using FTIR, (1)H NMR, (13)C NMR and melting point analysis method. The synthesized compound was applied to detect various cations in water media and N,N-dimethylformamide (DMF) via monitoring the quenching of the fluorescence intensity. Furthermore, various metal cations including Cu(2+), Ni(2+), Zn(2+), Pb(2+),Ca(2+), Ba(2+), Cd(2+), Hg(2+), Fe(2+), Fe(3+) and Ag(+) were tested. The complexes formed between the synthesized compound and metal cations in solution and their effects on Photoinduced Electron Transfer (PET) process were investigated regarding the potential application of the newly-synthesized dendrimer as a colorimetric and fluorescent sensor for such cations. The results clearly confirmed that the 1,8-naphthalimide groups surrounding the central dendrimer core showed strong green fluorescence emission at 553 nm. This effect considerably decreased with the introduction of all cations, except Ag(+) where the fluorescence quenching effect was remarkable and more dominant. Therefore, it can be concluded that the synthesized dye has the potentiality of being a highly sensitive and selective fluorescence sensor for Ag(+) cation. PMID:26529637

  20. MECHANICAL PROPERTIES OF BLENDS OF PAMAM DENDRIMERS WITH POLY(VINYL CHLORIDE) AND POLY(VINYL ACETATE)

    EPA Science Inventory

    Hybrid blends of poly(amidoamine) PAMAM dendrimers with two linear high polymers, poly(vinyl chloride), PVC, and poly(vinyl acetate), PVAc, are reported. The interaction between the blend components was studied using dynamic mechanical analysis, xenon nuclear magnetic resonacne ...

  1. Arginine-glycine-aspartic acid-conjugated dendrimer-modified quantum dots for targeting and imaging melanoma.

    PubMed

    Li, Zhiming; Huang, Peng; Lin, Jing; He, Rong; Liu, Bing; Zhang, Xiaomin; Yang, Sen; Xi, Peng; Zhang, Xuejun; Ren, Qiushi; Cui, Daxiang

    2010-08-01

    Angiogenesis is essential for the development of malignant tumors and provides important targets for tumor diagnosis and therapy. Quantum dots have been broadly investigated for their potential application in cancer molecular imaging. In present work, CdSe quantum dots were synthesized, polyamidoamine dendrimers were used to modify surface of quantum dots and improve their solubility in water solution. Then, dendrimer-modified CdSe quantum dots were conjugated with arginine-glycine-aspartic acid (RGD) peptides. These prepared nanoprobes were injected into nude mice loaded with melanoma (A375) tumor xenografts via tail vessels, IVIS imaging system was used to image the targeting and bio-distribution of as-prepared nanoprobes. The dendrimer-modified quantum dots exhibit water-soluble, high quantum yield, and good biocompatibility. RGD-conjugated quantum dots can specifically target human umbilical vein endothelial cells (HUVEC) and A375 melanoma cells, as well as nude mice loaded with A735 melanoma cells. High-performance RGD-conjugated dendrimers modified quantum dot-based nanoprobes have great potential in application such as tumor diagnosis and therapy. PMID:21125820

  2. Spectroscopic and molecular structure investigation of the phosphorus-containing G‧2 dendrimer with terminal aldehyde groups using DFT method

    NASA Astrophysics Data System (ADS)

    Furer, V. L.; Vandyukov, A. E.; Majoral, J. P.; Caminade, A. M.; Kovalenko, V. I.

    2015-02-01

    The FTIR and FT Raman spectra of the second generation dendrimer G‧2 built from thiophosphoryl core with terminal aldehyde groups have been recorded. The structural optimization and normal mode analysis were performed for model compound C, consisting of thiophosphoryl core, one branch with three repeated units, and four 4-oxybenzaldehyde terminal groups on the basis of the density functional theory (DFT) at the PBE/TZ2P level. The vibrational frequencies, infrared and Raman intensities for the t,g,g- and t,-g,g-conformers of the terminal groups were calculated. The t,g,g-conformer is 2.0 kcal/mol less stable compared to t,-g,g-conformer. A reliable assignment of the fundamental bands observed in the experimental IR and Raman spectra of dendrimer was achieved. For the low generations (G‧1 to G‧3) the disk form of studied dendrimer molecules is the most probable. For higher generations, the shape of dendrimer molecules will be that of a cauliflower.

  3. Electrostatics and Flexibility Drive Membrane Recognition and Early Penetration by Antimicrobial Peptide Dendrimer bH1

    SciTech Connect

    Ravi, Harish Kumar; Stach, Michaela; Soares, Thereza A.; Darbre, Tamis; Reymond, Jean-Louis; Cascella, Michele

    2013-08-01

    Molecular dynamics simulation of polycationic antimicrobial peptide dendrimer bH1 (Leu)8(DapLeu)4(DapPhe)2DapLys- NH2 binding to membranes suggest that electrostatic 10 interactions with the polyanionic lipopolysaccharide (LPS) and conformational flexibility of the 2,3-diaminopropanoic acid (Dap) branching units drive its selective insertion into microbial membranes.

  4. Biocompatible Size-Defined Dendrimer-Albumin Binding Protein Hybrid Materials as a Versatile Platform for Biomedical Applications.

    PubMed

    Maly, Jan; Stanek, Ondrej; Frolik, Jan; Maly, Marek; Ennen, Franka; Appelhans, Dietmar; Semeradtova, Alena; Wrobel, Dominika; Stofik, Marcel; Knapova, Tereza; Kuchar, Milan; Stastna, Lucie Cervenkova; Cermak, Jan; Sebo, Peter; Maly, Petr

    2016-04-01

    For the design of a biohybrid structure as a ligand-tailored drug delivery system (DDS), it is highly sophisticated to fabricate a DDS based on smoothly controllable conjugation steps. This article reports on the synthesis and the characterization of biohybrid conjugates based on noncovalent conjugation between a multivalent biotinylated and PEGylated poly(amido amine) (PAMAM) dendrimer and a tetrameric streptavidin-small protein binding scaffold. This protein binding scaffold (SA-ABDwt) possesses nM affinity toward human serum albumin (HSA). Thus, well-defined biohybrid structures, finalized by binding of one or two HSA molecules, are available at each conjugation step in a controlled molar ratio. Overall, these biohybrid assemblies can be used for (i) a controlled modification of dendrimers with the HSA molecules to increase their blood-circulation half-life and passive accumulation in tumor; (ii) rendering dendrimers a specific affinity to various ligands based on mutated ABD domain, thus replacing tedious dendrimer-antibody covalent coupling and purification procedures. PMID:26748571

  5. G2 and G5 carboxyl-terminated polyamidoamine dendrimers interact differently with 1-palmitoyl-2-oleoyl phosphocholine bilayers **1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Limits on non-target tissue exposure and avoidance of metabolic changes to active agents make topical application/delivery of skin active agents highly desirable. Individually, phospholipid liposomes and polyamidoamine dendrimers are effective delivery systems of various active agents. Potentially...

  6. Effect of the Route of Administration and PEGylation of Poly(amidoamine) Dendrimers on Their Systemic and Lung Cellular Biodistribution.

    PubMed

    Zhong, Qian; Merkel, Olivia M; Reineke, Joshua J; da Rocha, Sandro R P

    2016-06-01

    There are many opportunities in the development of oral inhalation (oi) formulations for the delivery of small molecule therapeutics and biologics to and through the lungs. Nanocarriers have the potential to play a key role in advancing oi technologies and pushing the boundary of the pulmonary delivery market. In this work we investigate the effect of the route of administration and PEGylation on the systemic and lung cellular biodistribution of generation 3, amino-terminated poly(amidoamine) (PAMAM) dendrimers (G3NH2). Pharmacokinetic profiles show that the dendrimers reach their peak concentration in systemic circulation within a few hours after pulmonary delivery, independent of their chemistry (PEGylated or not), charge (+24 mV for G3NH2 vs -3.7 mV for G3NH2-24PEG1000), or size (5.1 nm for G3NH2 and 9.9 nm for G3NH2-24PEG1000). However, high density of surface modification with PEG enhances pulmonary absorption and the peak plasma concentration upon pulmonary delivery. The route of administration and PEGylation also significantly impact the whole body and local (lung cellular) distribution of the dendrimers. While ca. 83% of G3NH2 is found in the lungs upon pulmonary delivery at 6.5 h post administration, only 2% reached the lungs upon intravenous (iv) delivery. Moreover, no measurable concentration of either G3NH2 or G3NH2-24PEG1000 is found in the lymph nodes upon iv administration, while these are the tissues with the second highest mass distribution of dendrimers post pulmonary delivery. Dendrimer chemistry also significantly impacts the (cellular) distribution of the nanocarriers in the lung tissue. Upon pulmonary delivery, approximately 20% of the lung endothelial cells are seen to internalize G3NH2-24PEG1000, compared to only 6% for G3NH2. Conversely, G3NH2 is more readily taken up by lung epithelial cells (35%) when compared to its PEGylated counterpart (24%). The results shown here suggest that both the pulmonary route of administration and dendrimer

  7. Homogeneous alignment of liquid crystalline dendrimers confined in a slit-pore. A simulation study

    NASA Astrophysics Data System (ADS)

    Workineh, Zerihun G.; Vanakaras, Alexandros G.

    2016-03-01

    In this work we present results from isobaric-isothermal (NPT) Monte Carlo simulation studies of model liquid crystalline dendrimer (LCDr) systems confined in a slit-pore made of two parallel flat walls. The dendrimers are modelled as a collection of spherical and ellipsoidal particles corresponding to the junction points of the dendritic core and to the mesogenic units respectively. Assuming planar uniform (unidirectional) soft anchoring of the mesogenic units on the substrates we investigate the conformational and alignment properties of the LCDr system at different thermodynamic state points. Tractable coarse grained force fields have been used from our previous work. At low pressures the interior of the pore is almost empty, since almost all LCDrs are anchored to the substrates forming two-dimensional smectic-like structures with the mesogens aligned along the aligning direction of the substrates. As the pressure grows the LCDrs occupy the whole pore. However, even at low temperatures, the smectic organization does not transmit in the interior of the pore and is preserved for distances of 2-3 mesogenic diameters from the walls. For this reason, the global orientational order decreases with increasing pressure (density). In the vicinity (2-3 mesogenic diameters) of the pore walls, mesogenic units preserve the smectic structure whose layers are separated by layers of spherical beads. In this region individual LCDrs possess a rod like shape.

  8. Mean first passage time for random walk on dual structure of dendrimer

    NASA Astrophysics Data System (ADS)

    Li, Ling; Guan, Jihong; Zhou, Shuigeng

    2014-12-01

    The random walk approach has recently been widely employed to study the relations between the underlying structure and dynamic of complex systems. The mean first-passage time (MFPT) for random walks is a key index to evaluate the transport efficiency in a given system. In this paper we study analytically the MFPT in a dual structure of dendrimer network, Husimi cactus, which has different application background and different structure (contains loops) from dendrimer. By making use of the iterative construction, we explicitly determine both the partial mean first-passage time (PMFT, the average of MFPTs to a given target) and the global mean first-passage time (GMFT, the average of MFPTs over all couples of nodes) on Husimi cactus. The obtained closed-form results show that PMFPT and EMFPT follow different scaling with the network order, suggesting that the target location has essential influence on the transport efficiency. Finally, the impact that loop structure could bring is analyzed and discussed.

  9. Ligand anchored poly(propyleneimine) dendrimers for brain targeting: Comparative in vitro and in vivo assessment.

    PubMed

    Patel, Hemant K; Gajbhiye, Virendra; Kesharwani, Prashant; Jain, Narendra K

    2016-11-15

    The present investigation was aimed at developing various ligands-anchored dendrimers and comparing their brain targeting potential at one platform. Sialic acid (S), glucosamine (G) and concanavalin A (C) anchored poly(propyleneimine) (PPI) dendritic nanoconjugates were developed and evaluated for delivery of anti-cancer drug, paclitaxel (PTX) to the brain. MTT assay on U373MG human astrocytoma cells indicated IC50 values of 0.40, 0.65, 0.95, 2.00 and 3.50μM for PTX loaded SPPI, GPPI, CPPI, PPI formulations, and free PTX, respectively. The invivo pharmacokinetics and biodistribution studies in rats showed significantly higher accumulation of PTX in brain as compared to free PTX. The order of targeting potential of various ligands under investigation was found as sialic acid>glucosamine>concanavalin A. Thus, it can be concluded that sialic acid, glucosamine and Con A can be used as potential ligands to append PPI dendrimers for enhanced delivery of anticancer drugs to the brain for higher therapeutic outcome. PMID:27501037

  10. The Effect of Cationic Polyamidoamine Dendrimers on Physicochemical Characteristics of Hydrogels with Erythromycin

    PubMed Central

    Wróblewska, Magdalena; Winnicka, Katarzyna

    2015-01-01

    Polyamidoamine dendrimers (PAMAM) represent a new class of hyperbranched, monodisperse, three-dimensional polymers with unique properties, which make them very promising carriers of antimicrobial agents. The present study aimed to evaluate the influence of PAMAM-NH2 dendrimers generation two (G2) or three (G3) on physicochemical characteristics and structure of hydrogels with a model antibacterial lipophilic drug—erythromycin—commonly used in topical applications. From the obtained rheograms, it can be concluded that tested hydrogels were non-Newtonian thixotropic systems with shear-thinning behaviour. The dissolution tests revealed that erythromycin was definitely faster released from formulations containing PAMAM-NH2 in concentration and generation dependent manner. However, the addition of PAMAM-NH2 to hydrogels evoked only slight improvement of their antibacterial activity. It was also shown that the structure of hydrogels changed in the presence of PAMAM-NH2 becoming less compact, diversified and more porous. Designed hydrogels with PAMAM-NH2 G2 or G3 were stable stored up to three months at 40 ± 2 °C and 75% ± 5% RH. PMID:26343637

  11. Intracellular delivery of dendrimer triamcinolone acetonide conjugates into microglial and human retinal pigment epithelial cells.

    PubMed

    Kambhampati, Siva P; Mishra, Manoj K; Mastorakos, Panagiotis; Oh, Yumin; Lutty, Gerard A; Kannan, Rangaramanujam M

    2015-09-01

    Triamcinolone acetonide (TA) is a potent, intermediate-acting, steroid that has anti-inflammatory and anti-angiogenic activity. Intravitreal administration of TA has been used for diabetic macular edema, proliferative diabetic retinopathy and exudative age-related macular degeneration (AMD). However, the hydrophobicity, lack of solubility, and the side effects limit its effectiveness in the treatment of retinal diseases. In this study, we explore a PAMAM dendrimer-TA conjugate (D-TA) as a potential strategy to improve intracellular delivery and efficacy of TA to target cells. The conjugates were prepared with a high drug payload (∼ 21%) and were readily soluble in saline. Compared to free TA, D-TA demonstrated a significantly improved toxicity profile in two important target [microglial and human retinal pigment epithelium (RPE)] cells. The D-TA was ∼ 100-fold more effective than free TA in its anti-inflammatory activity (measured in microglia), and in suppressing VEGF production (in hypoxic RPE cells). Dendrimer-based delivery may improve the efficacy of TA towards both its key targets of inflammation and VEGF production, with significant clinical implications. PMID:25701805

  12. Structural characterization of lyotropic liquid crystals containing a dendrimer for solubilization and release of gallic acid.

    PubMed

    Bitan-Cherbakovsky, Liron; Aserin, Abraham; Garti, Nissim

    2013-12-01

    The role of 2nd generation polypropyleneimine (PPIG2) dendrimer in controlling the release of gallic acid (GA) as a model drug from lyotropic liquid crystal was explored. GA (0.2wt%) was solubilized in three types of mesophases: lamellar (Lα), cubic (space group of Ia3d, Q(G)), and reverse hexagonal (HII), composed of GMO and water (and d-α-tocopherol, or tricaprylin in the case of HII mesophases). Small angle X-ray scattering (SAXS) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) along with UV spectrophotometry were utilized to elucidate the structure modifications and release resulting from the cosolubilization of GA and PPIG2. Solubilization of PPIG2 into Lα and Q(G) phases caused transformation of both structures to HII. The diffusion of GA out of the mesophases was found to be dependent on water content and PPIG2 concentration. Rapid release from Lα+PPIG2 and Q(G)+PPIG2 mesophases was recorded. The release from both HII mixtures (with d-α-tocopherol and tricaprylin) was shown to be dependent on the type of oil. Release studies conducted for 72h showed that GA release can be modulated and sustained by the presence of PPIG2, supposedly due to the electrostatic interactions between the dendrimer and the drug molecule. PMID:23973908

  13. Thermodynamic properties of carbosilane dendrimers of the third and sixth generations with ethyleneoxide terminal groups

    NASA Astrophysics Data System (ADS)

    Smirnova, N. N.; Markin, A. V.; Letyanina, I. A.; Sologubov, S. S.; Novozhilova, N. A.; Tatarinova, E. A.; Muzafarov, A. M.

    2014-05-01

    The temperature dependences of the heat capacities of carbosilane dendrimers of the third and sixth generations with ethyleneoxide terminal groups are examined for the first time by means of precision adiabatic vacuum calorimetry at temperatures between 6.5 and 350 K. In this temperature range, physical transformations are observed and their standard thermodynamic characteristics are determined and discussed. The standard thermodynamic functions are calculated per nominal mole of a chosen unit using the obtained experimental data: C° p ( T), H°( T) - H°(0), S°( T) - S°(0), and G°( T) - H°(0) in the interval T → 0 to 350 K, and the standard entropies of formation at T = 298.15 K. The low-temperature ( T ≤ 50 K) heat capacity is analyzed using the Debye theory of specific heat and a multifractal model. The values of fractal dimension D are also determined, and conclusions on the investigated structures' topology are drawn. The corresponding thermodynamic properties of the studied dendrimers are compared as well.

  14. Single-Walled Carbon Nanotube-Polyamidoamine Dendrimer Hybrids for Heterogeneous Catalysis.

    PubMed

    Giacalone, Francesco; Campisciano, Vincenzo; Calabrese, Carla; La Parola, Valeria; Syrgiannis, Zois; Prato, Maurizio; Gruttadauria, Michelangelo

    2016-04-26

    We report the synthesis and catalytic properties of single-walled carbon nanotube-polyamidoamine dendrimers hybrids (SWCNT-PAMAM), prepared via a convergent strategy. The direct reaction of cystamine-based PAMAM dendrimers (generations 2.5 and 3.0) with pristine SWCNTs in refluxing toluene, followed by immobilization and reduction of [PdCl4](2-), led to the formation of highly dispersed small palladium nanoparticles homogeneously confined throughout the nanotube length. One of these functional materials proved to be an efficient catalyst in Suzuki and Heck reactions, able to promote the above processes down to 0.002 mol % showing a turnover number (TON) of 48 000 and a turnover frequency (TOF) of 566 000 h(-1). In addition, the hybrid material could be recovered and recycled for up to 6 times. No leaching of the metal has been detected during the Suzuki coupling. Additional experiments carried out on the spent catalyst permitted to suggest that a "release and catch" mechanism is operative in both reactions, although during Heck reaction small catalytically active soluble Pd species are also present. PMID:26974262

  15. Homogeneous alignment of liquid crystalline dendrimers confined in a slit-pore. A simulation study.

    PubMed

    Workineh, Zerihun G; Vanakaras, Alexandros G

    2016-03-23

    In this work we present results from isobaric-isothermal (NPT) Monte Carlo simulation studies of model liquid crystalline dendrimer (LCDr) systems confined in a slit-pore made of two parallel flat walls. The dendrimers are modelled as a collection of spherical and ellipsoidal particles corresponding to the junction points of the dendritic core and to the mesogenic units respectively. Assuming planar uniform (unidirectional) soft anchoring of the mesogenic units on the substrates we investigate the conformational and alignment properties of the LCDr system at different thermodynamic state points. Tractable coarse grained force fields have been used from our previous work. At low pressures the interior of the pore is almost empty, since almost all LCDrs are anchored to the substrates forming two-dimensional smectic-like structures with the mesogens aligned along the aligning direction of the substrates. As the pressure grows the LCDrs occupy the whole pore. However, even at low temperatures, the smectic organization does not transmit in the interior of the pore and is preserved for distances of 2-3 mesogenic diameters from the walls. For this reason, the global orientational order decreases with increasing pressure (density). In the vicinity (2-3 mesogenic diameters) of the pore walls, mesogenic units preserve the smectic structure whose layers are separated by layers of spherical beads. In this region individual LCDrs possess a rod like shape. PMID:26903080

  16. Thermodynamic stability and structural properties of cluster crystals formed by amphiphilic dendrimers

    NASA Astrophysics Data System (ADS)

    Lenz, Dominic A.; Mladek, Bianca M.; Likos, Christos N.; Blaak, Ronald

    2016-05-01

    We pursue the goal of finding real-world examples of macromolecular aggregates that form cluster crystals, which have been predicted on the basis of coarse-grained, ultrasoft pair potentials belonging to a particular mathematical class [B. M. Mladek et al., Phys. Rev. Lett. 46, 045701 (2006)]. For this purpose, we examine in detail the phase behavior and structural properties of model amphiphilic dendrimers of the second generation by means of monomer-resolved computer simulations. On augmenting the density of these systems, a fluid comprised of clusters that contain several overlapping and penetrating macromolecules is spontaneously formed. Upon further compression of the system, a transition to multi-occupancy crystals takes place, the thermodynamic stability of which is demonstrated by means of free-energy calculations, and where the FCC is preferred over the BCC-phase. Contrary to predictions for coarse-grained theoretical models in which the particles interact exclusively by effective pair potentials, the internal degrees of freedom of these molecules cause the lattice constant to be density-dependent. Furthermore, the mechanical stability of monodisperse BCC and FCC cluster crystals is restricted to a bounded region in the plane of cluster occupation number versus density. The structural properties of the dendrimers in the dense crystals, including their overall sizes and the distribution of monomers are also thoroughly analyzed.

  17. Synthesis, characterization, and manipulation of dendrimer-stabilized iron sulfide nanoparticles

    NASA Astrophysics Data System (ADS)

    Shi, Xiangyang; Sun, Kai; Balogh, Lajos P.; Baker, James R., Jr.

    2006-09-01

    FeS nanoparticles (NPs) were synthesized using ethylenediamine core poly(amidoamine) (PAMAM) dendrimers of generation 4 terminated with amino (G4·NH2), hydroxyl (G4·NGlyOH), and carboxyl (G4·SAH) groups, respectively, as stabilizers. These dendrimer-stabilized FeS NPs (FeS DSNPs) were characterized by ultraviolet-visible (UV-vis) spectrometry, zeta-potential measurements, and transmission electron microscopy (TEM). Deposition of FeS NPs onto mesoporous silica gel microparticles was attempted using two approaches: (A) direct coating of {FeS-G4·NH2} DSNPs onto silica particles; and (B) using G4·NH2-coated silica particles to incorporate Fe2+ ions for the subsequent formation of FeS NPs. Scanning electron microscopy (SEM) studies show that approach (B) was much more efficient in the incorporation of FeS NPs than approach (A). Such preparation and manipulation of FeS DSNPs provides a unique strategy for fabricating various reactive nanoplatforms for environmental remediation applications.

  18. Partially oxidized iridium clusters within dendrimers: size-controlled synthesis and selective hydrogenation of 2-nitrobenzaldehyde

    NASA Astrophysics Data System (ADS)

    Higaki, Tatsuya; Kitazawa, Hirokazu; Yamazoe, Seiji; Tsukuda, Tatsuya

    2016-06-01

    Iridium clusters nominally composed of 15, 30 or 60 atoms were size-selectively synthesized within OH-terminated poly(amidoamine) dendrimers of generation 6. Spectroscopic characterization revealed that the Ir clusters were partially oxidized. All the Ir clusters efficiently converted 2-nitrobenzaldehyde to anthranil and 2-aminobenzaldehyde under atmospheric hydrogen at room temperature in toluene via selective hydrogenation of the NO2 group. The selectivity toward 2-aminobenzaldehyde over anthranil was improved with the reduction of the cluster size. The improved selectivity is ascribed to more efficient reduction than intramolecular heterocyclization of a hydroxylamine intermediate on smaller clusters that have a higher Ir(0)-phase population on the surface.Iridium clusters nominally composed of 15, 30 or 60 atoms were size-selectively synthesized within OH-terminated poly(amidoamine) dendrimers of generation 6. Spectroscopic characterization revealed that the Ir clusters were partially oxidized. All the Ir clusters efficiently converted 2-nitrobenzaldehyde to anthranil and 2-aminobenzaldehyde under atmospheric hydrogen at room temperature in toluene via selective hydrogenation of the NO2 group. The selectivity toward 2-aminobenzaldehyde over anthranil was improved with the reduction of the cluster size. The improved selectivity is ascribed to more efficient reduction than intramolecular heterocyclization of a hydroxylamine intermediate on smaller clusters that have a higher Ir(0)-phase population on the surface. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr01460g

  19. Highly-sensitive liquid crystal biosensor based on DNA dendrimers-mediated optical reorientation.

    PubMed

    Tan, Hui; Li, Xia; Liao, Shuzhen; Yu, Ruqin; Wu, Zhaoyang

    2014-12-15

    A novel highly-sensitive liquid crystal (LC) biosensing approach based on target-triggering DNA dendrimers was developed for the detection of p53 mutation gene segment at the LC-aqueous interface. In this study, the mutant-type p53 gene segment was the target to trigger the formation of DNA dendrimers from hairpin DNA probes by hybridization chain reaction, and the latter as a 'signal enhancement element' further induced the LC reorientation from tilted to homeotropic alignment, resulting in a corresponding optical changes of LC biosensors from birefringent to honeycombed textures or dark framework. The distinct optical reorientational appearances can serve as a characteristic signal to distinguish target concentrations ranging from 0.08 nM to 8 nM. Moreover, these optical phenomena suggest that the LC reorientation is related to the electric-dipole coupling between the adsorbed DNA and LC molecules, the conformational constraints of DNA and the internal electric field induction upon hybridization. This label-free LC biosensing strategy can open up a new platform for the sensitive detection of specific DNA sequences and enrich the application scope of an LC biosensing technique. PMID:24984288

  20. An Alkane-Soluble Dendrimer as Electron-Transport Layer in Polymer Light-Emitting Diodes.

    PubMed

    Zhong, Zhiming; Zhao, Sen; Pei, Jian; Wang, Jian; Ying, Lei; Peng, Junbiao; Cao, Yong

    2016-08-10

    Polymer light-emitting diodes (PLEDs) have attracted broad interest due to their solution-processable properties. It is well-known that to achieve better performance, organic light-emitting diodes require multilayer device structures. However, it is difficult to realize multilayer device structures by solution processing for PLEDs. Because most semiconducting polymers have similar solubility in common organic solvents, such as toluene, xylene, chloroform, and chlorobenzene, the deposition of multilayers can cause layers to mix together and damage each layer. Herein, a novel semiorthogonal solubility relationship was developed and demonstrated. For the first time, an alkane-soluble dendrimer is utilized as the electron-transport layer (ETL) in PLEDs via a solution-based process. With the dendrimer ETL, the external quantum efficiency increases more than threefold. This improvement in the device performance is attributed to better exciton confinement, improved exciton energy transfer, and better charge carrier balance. The semiorthogonal solubility provided by alkane offers another process dimension in PLEDs. By combining them with water/alcohol-soluble polyelectrolytes, more exquisite multilayer devices can be fabricated to achieve high device performance, and new device structures can be designed and realized. PMID:27435357

  1. Dendrimer-triglycine-EGF nanoparticles for tumor imaging and targeted nucleic acid and drug delivery

    PubMed Central

    Yuan, Quan; Lee, Eunmee; Yeudall, W. Andrew; Yang, Hu

    2010-01-01

    We designed an epidermal growth factor (EGF)-containing polyamidoamine (PAMAM) Generation 4 dendrimer vector labeled with quantum dots for targeted imaging and nucleic acid delivery. 1H-NMR, SDS-PAGE, and western blotting were applied to characterize the synthesized G4.0-GGG-EGF nanoparticles. Targeting efficiency, cell viability, proliferation, and intracellular signal transduction were evaluated using HN12, NIH3T3, and NIH3T3/EGFR cells. We found that EGF-conjugated dendrimers did not stimulate growth of EGFR-expressing cells at the selected concentration. Consistent with this, minimal stimulation of post-receptor signaling pathways was observed. These nanoparticles can localize within cells that express the EGFR in a receptor-dependent manner, whereas uptake into cells lacking the receptor was low. A well characterized vimentin shRNA (shVIM) and siRNA YFP were used to test the delivery and transfection efficiency of the constructed targeted vector. Significant knockdown of expression was observed, indicating that this vector is useful for introduction of nucleic acids or drugs into cells by a receptor-targeted mechanism. PMID:20729136

  2. Association of nicotinic acid with a poly(amidoamine) dendrimer studied by molecular dynamics simulations.

    PubMed

    Caballero, Julio; Poblete, Horacio; Navarro, Cristell; Alzate-Morales, Jans H

    2013-02-01

    The interaction of poly(amidoamine)-G3 (PAMAM-G3) dendrimer with nicotinic acid (NA) was investigated by using molecular dynamics (MD) simulations. First, sample free energy profiles of NA crossing PAMAM-G3 at pH 6 and 3 were computed using the adaptive biasing force (ABF) method. We found that PAMAM-G3 provides a more appropriate environment for NA inclusion when internal tertiary amine groups are unprotonated (at pH 6). However, when internal tertiary amine groups are protonated (at pH 3), the PAMAM cavities are less hydrophobic; therefore the drug-dendrimer interactions become similar to drug-solvent interactions. Traditional MD simulations were also performed to investigate the structural stability of the PAMAM-NA complexes near the free energy minima at pH 6. We found that association of NA and PAMAM adopts a preferred binding mode around the surface of PAMAM, where hydrogen bond (HB) interactions with the amino and amide NH groups of the nearby monomers are established. These interactions are very stable whether additional van der Waals interactions between pyridine ring of NA and methylene groups of the more external monomers of PAMAM are established. PMID:23220284

  3. Intracellular delivery of dendrimer triamcinolone acetonide conjugates into microglial and human retinal pigment epithelial cells

    PubMed Central

    Kambhampati, Siva P.; Mishra, Manoj K.; Mastorakos, Panagiotis; Oh, Yumin; Lutty, Gerard A.; Kannan, Rangaramanujam M.

    2016-01-01

    Triamcinolone acetonide (TA) is a potent, intermediate-acting, steroid that has anti-inflammatory and anti-angiogenic activity. Intravitreal administration of TA has been used for diabetic macular edema, proliferative diabetic retinopathy and exudative age-related macular degeneration (AMD). However, the hydrophobicity, lack of solubility, and the side effects limit its effectiveness in the treatment of retinal diseases. In this study, we explore a PAMAM dendrimer-TA conjugate (D-TA) as a potential strategy to improve intracellular delivery and efficacy of TA to target cells. The conjugates were prepared with a high drug payload (~21%) and were readily soluble in saline. Compared to free TA, D-TA demonstrated a significantly improved toxicity profile in two important target [microglial and human retinal pigment epithelium (RPE)] cells. The D-TA was ~100-fold more effective than free TA in its anti-inflammatory activity (measured in microglia), and in suppressing VEGF production (in hypoxic RPE cells). Dendrimer-based delivery may improve the efficacy of TA towards both its key targets of inflammation and VEGF production, with significant clinical implications. PMID:25701805

  4. Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance

    PubMed Central

    Wei, Tuo; Chen, Chao; Liu, Juan; Liu, Cheng; Posocco, Paola; Liu, Xiaoxuan; Cheng, Qiang; Huo, Shuaidong; Liang, Zicai; Fermeglia, Maurizio; Liang, Xing-Jie; Rocchi, Palma; Peng, Ling

    2015-01-01

    Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy. PMID:25713374

  5. Efficacy of HIV antiviral polyanionic carbosilane dendrimer G2-S16 in the presence of semen

    PubMed Central

    Ceña-Diez, Rafael; García-Broncano, Pilar; de la Mata, Francisco Javier; Gómez, Rafael; Muñoz-Fernández, Mª Ángeles

    2016-01-01

    The development of a safe and effective microbicide to prevent the sexual transmission of human immunodeficiency virus (HIV)-1 is urgently needed. Unfortunately, the majority of microbicides, such as poly(L-lysine)-dendrimers, anionic polymers, or antiretrovirals, have proved inactive or even increased the risk of HIV infection in clinical trials, most probably due to the fact that these compounds failed to prevent semen-exposed HIV infection. We showed that G2-S16 dendrimer exerts anti-HIV-1 activity at an early stage of viral replication, blocking the gp120/CD4/CCR5 interaction and providing a barrier to infection for long periods, confirming its multifactorial and nonspecific ability. Previously, we demonstrated that topical administration of G2-S16 prevents HIV transmission in humanized BLT mice without irritation or vaginal lesions. Here, we demonstrated that G2-S16 is active against mock- and semen-exposed HIV-1 and could be a promising microbicide against HIV infection. PMID:27313457

  6. Efficacy of HIV antiviral polyanionic carbosilane dendrimer G2-S16 in the presence of semen.

    PubMed

    Ceña-Diez, Rafael; García-Broncano, Pilar; de la Mata, Francisco Javier; Gómez, Rafael; Muñoz-Fernández, M Ángeles

    2016-01-01

    The development of a safe and effective microbicide to prevent the sexual transmission of human immunodeficiency virus (HIV)-1 is urgently needed. Unfortunately, the majority of microbicides, such as poly(L-lysine)-dendrimers, anionic polymers, or antiretrovirals, have proved inactive or even increased the risk of HIV infection in clinical trials, most probably due to the fact that these compounds failed to prevent semen-exposed HIV infection. We showed that G2-S16 dendrimer exerts anti-HIV-1 activity at an early stage of viral replication, blocking the gp120/CD4/CCR5 interaction and providing a barrier to infection for long periods, confirming its multifactorial and nonspecific ability. Previously, we demonstrated that topical administration of G2-S16 prevents HIV transmission in humanized BLT mice without irritation or vaginal lesions. Here, we demonstrated that G2-S16 is active against mock- and semen-exposed HIV-1 and could be a promising microbicide against HIV infection. PMID:27313457

  7. Thermodynamic stability and structural properties of cluster crystals formed by amphiphilic dendrimers.

    PubMed

    Lenz, Dominic A; Mladek, Bianca M; Likos, Christos N; Blaak, Ronald

    2016-05-28

    We pursue the goal of finding real-world examples of macromolecular aggregates that form cluster crystals, which have been predicted on the basis of coarse-grained, ultrasoft pair potentials belonging to a particular mathematical class [B. M. Mladek et al., Phys. Rev. Lett. 46, 045701 (2006)]. For this purpose, we examine in detail the phase behavior and structural properties of model amphiphilic dendrimers of the second generation by means of monomer-resolved computer simulations. On augmenting the density of these systems, a fluid comprised of clusters that contain several overlapping and penetrating macromolecules is spontaneously formed. Upon further compression of the system, a transition to multi-occupancy crystals takes place, the thermodynamic stability of which is demonstrated by means of free-energy calculations, and where the FCC is preferred over the BCC-phase. Contrary to predictions for coarse-grained theoretical models in which the particles interact exclusively by effective pair potentials, the internal degrees of freedom of these molecules cause the lattice constant to be density-dependent. Furthermore, the mechanical stability of monodisperse BCC and FCC cluster crystals is restricted to a bounded region in the plane of cluster occupation number versus density. The structural properties of the dendrimers in the dense crystals, including their overall sizes and the distribution of monomers are also thoroughly analyzed. PMID:27250325

  8. Self-assembled films of dendrimers and metallophthalocyanines as FET-based glucose biosensors.

    PubMed

    Vieira, Nirton C S; Figueiredo, Alessandra; de Queiroz, Alvaro A A; Zucolotto, Valtencir; Guimarães, Francisco E G

    2011-01-01

    Separative extended gate field effect transistor (SEGFET) type devices have been used as an ion sensor or biosensor as an alternative to traditional ion sensitive field effect transistors (ISFETs) due to their robustness, ease of fabrication, low cost and possibility of FET isolation from the chemical environment. The layer-by-layer technique allows the combination of different materials with suitable properties for enzyme immobilization on simple platforms such as the extended gate of SEGFET devices enabling the fabrication of biosensors. Here, glucose biosensors based on dendrimers and metallophthalocyanines (MPcs) in the form of layer-by-layer (LbL) films, assembled on indium tin oxide (ITO) as separative extended gate material, has been produced. NH(3)(+) groups in the dendrimer allow electrostatic interactions or covalent bonds with the enzyme (glucose oxidase). Relevant parameters such as optimum pH, buffer concentration and presence of serum bovine albumin (BSA) in the immobilization process were analyzed. The relationship between the output voltage and glucose concentration shows that upon detection of a specific analyte, the sub-products of the enzymatic reaction change the pH locally, affecting the output signal of the FET transducer. In addition, dendritic layers offer a nanoporous environment, which may be permeable to H(+) ions, improving the sensibility as modified electrodes for glucose biosensing. PMID:22163704

  9. SAW arrays using dendrimers and pattern recognition to detect volatile organics

    SciTech Connect

    Ricco, A.J.; Osbourn, G.C.; Bartholomew, J.W.; Martinez, R.F.; Crooks, R.M.; Garcia, M.E.; Peez, R.; Spindler, R.; Kaiser, M.E.

    1998-08-01

    chemical sensor arrays eliminate the need to develop a high-selectivity material for every analyte. The application of pattern recognition to the simultaneous responses of different microsensors enables the identification and quantification of multiple analytes with a small array. Maximum materials diversity is the surest means to create an effective array for many analytes, but using a single material family simplifies coating development. Here the authors report the successful combination of an array of six dendrimer films with mass-sensitive SAW (surface acoustic wave) sensors to correctly identify 18 organic analytes over wide concentration ranges, with 99.5% accuracy. The set of materials for the array is selected and the results evaluated using Sandia`s Visual-Empirical Region of Influence (VERI) pattern recognition (PR) technique. The authors evaluated eight dendrimer films and one self-assembled monolayer (SAM) as potential SAW array coatings. The 18 organic analytes they examined were: cyclohexane, n-hexane, i-octane, kerosene, benzene, toluene, chlorobenzene, carbon tetrachloride, trichloroethylene, methanol, n-propanol, pinacolyl alcohol, acetone, methyl isobutyl ketone, dimethylmethylphosphate, diisopropylmethylphosphonate, tributylphosphate, and water.

  10. Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance.

    PubMed

    Wei, Tuo; Chen, Chao; Liu, Juan; Liu, Cheng; Posocco, Paola; Liu, Xiaoxuan; Cheng, Qiang; Huo, Shuaidong; Liang, Zicai; Fermeglia, Maurizio; Pricl, Sabrina; Liang, Xing-Jie; Rocchi, Palma; Peng, Ling

    2015-03-10

    Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy. PMID:25713374

  11. Facile formation of dendrimer-stabilized gold nanoparticles modified with diatrizoic acid for enhanced computed tomography imaging applications

    NASA Astrophysics Data System (ADS)

    Peng, Chen; Li, Kangan; Cao, Xueyan; Xiao, Tingting; Hou, Wenxiu; Zheng, Linfeng; Guo, Rui; Shen, Mingwu; Zhang, Guixiang; Shi, Xiangyang

    2012-10-01

    We report a facile approach to forming dendrimer-stabilized gold nanoparticles (Au DSNPs) through the use of amine-terminated fifth-generation poly(amidoamine) (PAMAM) dendrimers modified by diatrizoic acid (G5.NH2-DTA) as stabilizers for enhanced computed tomography (CT) imaging applications. In this study, by simply mixing G5.NH2-DTA dendrimers with gold salt in aqueous solution at room temperature, dendrimer-entrapped gold nanoparticles (Au DENPs) with a mean core size of 2.5 nm were able to be spontaneously formed. Followed by an acetylation reaction to neutralize the dendrimer remaining terminal amines, Au DSNPs with a mean size of 6 nm were formed. The formed DTA-containing [(Au0)50-G5.NHAc-DTA] DSNPs were characterized via different techniques. We show that the Au DSNPs are colloid stable in aqueous solution under different pH and temperature conditions. In vitro hemolytic assay, cytotoxicity assay, flow cytometry analysis, and cell morphology observation reveal that the formed Au DSNPs have good hemocompatibility and are non-cytotoxic at a concentration up to 3.0 μM. X-ray absorption coefficient measurements show that the DTA-containing Au DSNPs have enhanced attenuation intensity, much higher than that of [(Au0)50-G5.NHAc] DENPs without DTA or Omnipaque at the same molar concentration of the active element (Au or iodine). The formed DTA-containing Au DSNPs can be used for CT imaging of cancer cells in vitro as well as for blood pool CT imaging of mice in vivo with significantly improved signal enhancement. With the two radiodense elements of Au and iodine incorporated within one particle, the formed DTA-containing Au DSNPs may be applicable for CT imaging of various biological systems with enhanced X-ray attenuation property and detection sensitivity.We report a facile approach to forming dendrimer-stabilized gold nanoparticles (Au DSNPs) through the use of amine-terminated fifth-generation poly(amidoamine) (PAMAM) dendrimers modified by diatrizoic acid

  12. Dendrimer Brain Uptake and Targeted Therapy for Brain Injury in a Large Animal Model of Hypothermic Circulatory Arrest

    PubMed Central

    2015-01-01

    Treatment of brain injury following circulatory arrest is a challenging health issue with no viable therapeutic options. Based on studies in a clinically relevant large animal (canine) model of hypothermic circulatory arrest (HCA)-induced brain injury, neuroinflammation and excitotoxicity have been identified as key players in mediating the brain injury after HCA. Therapy with large doses of valproic acid (VPA) showed some neuroprotection but was associated with adverse side effects. For the first time in a large animal model, we explored whether systemically administered polyamidoamine (PAMAM) dendrimers could be effective in reaching target cells in the brain and deliver therapeutics. We showed that, upon systemic administration, hydroxyl-terminated PAMAM dendrimers are taken up in the brain of injured animals and selectively localize in the injured neurons and microglia in the brain. The biodistribution in other major organs was similar to that seen in small animal models. We studied systemic dendrimer–drug combination therapy with two clinically approved drugs, N-acetyl cysteine (NAC) (attenuating neuroinflammation) and valproic acid (attenuating excitotoxicity), building on positive outcomes in a rabbit model of perinatal brain injury. We prepared and characterized dendrimer-NAC (D-NAC) and dendrimer-VPA (D-VPA) conjugates in multigram quantities. A glutathione-sensitive linker to enable for fast intracellular release. In preliminary efficacy studies, combination therapy with D-NAC and D-VPA showed promise in this large animal model, producing 24 h neurological deficit score improvements comparable to high dose combination therapy with VPA and NAC, or free VPA, but at one-tenth the dose, while significantly reducing the adverse side effects. Since adverse side effects of drugs are exaggerated in HCA, the reduced side effects with dendrimer conjugates and suggestions of neuroprotection offer promise for these nanoscale drug delivery systems. PMID:24499315

  13. RGD peptide-modified dendrimer-entrapped gold nanoparticles enable highly efficient and specific gene delivery to stem cells.

    PubMed

    Kong, Lingdan; Alves, Carla S; Hou, Wenxiu; Qiu, Jieru; Möhwald, Helmuth; Tomás, Helena; Shi, Xiangyang

    2015-03-01

    We report the use of arginine-glycine-aspartic (Arg-Gly-Asp, RGD) peptide-modified dendrimer-entrapped gold nanoparticles (Au DENPs) for highly efficient and specific gene delivery to stem cells. In this study, generation 5 poly(amidoamine) dendrimers modified with RGD via a poly(ethylene glycol) (PEG) spacer and with PEG monomethyl ether were used as templates to entrap gold nanoparticles (AuNPs). The native and the RGD-modified PEGylated dendrimers and the respective well characterized Au DENPs were used as vectors to transfect human mesenchymal stem cells (hMSCs) with plasmid DNA (pDNA) carrying both the enhanced green fluorescent protein and the luciferase (pEGFPLuc) reporter genes, as well as pDNA encoding the human bone morphogenetic protein-2 (hBMP-2) gene. We show that all vectors are capable of transfecting the hMSCs with both pDNAs. Gene transfection using pEGFPLuc was demonstrated by quantitative Luc activity assay and qualitative evaluation by fluorescence microscopy. For the transfection with hBMP-2, the gene delivery efficiency was evaluated by monitoring the hBMP-2 concentration and the level of osteogenic differentiation of the hMSCs via alkaline phosphatase activity, osteocalcin secretion, calcium deposition, and von Kossa staining assays. Our results reveal that the stem cell gene delivery efficiency is largely dependent on the composition and the surface functionality of the dendrimer-based vectors. The coexistence of RGD and AuNPs rendered the designed dendrimeric vector with specific stem cell binding ability likely via binding of integrin receptor on the cell surface and improved three-dimensional conformation of dendrimers, which is beneficial for highly efficient and specific stem cell gene delivery applications. PMID:25658033

  14. Systemic and Intravitreal Delivery of Dendrimers to Activated Microglia/Macrophage in Ischemia/Reperfusion Mouse Retina

    PubMed Central

    Kambhampati, Siva P.; Clunies-Ross, Alexander J. M.; Bhutto, Imran; Mishra, Manoj K.; Edwards, Malia; McLeod, D. Scott; Kannan, Rangaramanujam M.; Lutty, Gerard

    2015-01-01

    Purpose Microglial activation and associated neuroinflammation play a key role in the pathogenesis of many diseases of the retina, including viral infection, diabetes, and retinal degeneration. Strategies to target activated microglia and macrophages and attenuate inflammation may be valuable in treating these diseases. We seek to develop dendrimer-based formulations that target retinal microglia and macrophages in a pathology-dependent manner, and deliver drugs, either intravenously or intravitreally. Methods Retinal uptake of cyanine dye (Cy5)-conjugated dendrimer (D-Cy5) was assessed in normal and ischemia/reperfusion (I/R) mouse eyes. Microglia/macrophage uptake of the dendrimer was assessed with immunofluorescence using rabbit Iba-1 antibody with Cy3-tagged secondary antibody (microglia/macrophage). Uptake in retina and other organs was quantified using fluorescence spectroscopy. Results Clearance of D-Cy5 from normal eyes was almost complete by 72 hours after intravitreal injection and 24 hours after intravenous delivery. In eyes with activated microglia after I/R injury, D-Cy5 was retained by activated microglia/macrophage (Iba1+ cells) up to 21 days after intravitreal and intravenous administration. In I/R eyes, the relative retention of intravitreal and intravenous D-Cy5 was comparable, if a 30-fold higher intravenous dose was used. Conclusions Intravitreal and systemic dendrimers target activated microglia and show qualitatively similar retinal biodistribution when administered by either route. Results provide proof-of-concept insights for developing dendrimer drug formulations as treatment options for retinal diseases associated with microglia or macrophage activation such as age-related macular degeneration, diabetic retinopathy, and retinal degenerations. PMID:26193917

  15. GPCR Ligand Dendrimer (GLiDe) Conjugates: Adenosine Receptor Interactions of a Series of Multivalent Xanthine Antagonists

    PubMed Central

    Kecskés, Angela; Tosh, Dilip K.; Wei, Qiang; Gao, Zhan-Guo; Jacobson, Kenneth A.

    2011-01-01

    Previously, G protein–coupled receptor (GPCR) agonists were tethered from polyamidoamine (PAMAM) dendrimers to provide high receptor affinity and selectivity. Here we prepared GPCR Ligand Dendrimer (GLiDe) conjugates from a potent adenosine receptor (AR) antagonist; such agents are of interest for treating Parkinson’s disease, asthma, and other conditions. Xanthine amine congener (XAC) was appended with an alkyne group on an extended C8 substituent for coupling by Cu(I)-catalyzed click chemistry to azide-derivatized G4 (fourth-generation) PAMAM dendrimers to form triazoles. These conjugates also contained triazole-linked PEG groups (8 or 22 moieties per 64 terminal positions) for increasing water-solubility and optionally prosthetic groups for spectroscopic characterization and affinity labeling. Human AR binding affinity increased progressively with the degree of xanthine substitution to reach Ki values in the nM range. The order of affinity of each conjugate was hA2AAR > hA3AR > hA1AR, while the corresponding monomer was ranked hA2AAR > hA1AR ≥ hA3AR. The antagonist activity of the most potent conjugate 14 (34 xanthines per dendrimer) was examined at the Gi-coupled A1AR. Conjugate 14 at 100 nM right-shifted the AR agonist concentration-response curve in a cyclic AMP functional assay in a parallel manner, but at 10 nM (lower than its Ki value) it significantly suppressed the maximal agonist effect in calcium mobilization. This is the first systematic probing of a potent AR antagonist tethered on a dendrimer and its activity as a function of variable loading. PMID:21539392

  16. Aptamer-Dendrimer Bioconjugates for Targeted Delivery of miR-34a Expressing Plasmid and Antitumor Effects in Non-Small Cell Lung Cancer Cells

    PubMed Central

    Guo, Caihong; Ren, Dunqiang; Zhao, Yandong; Xiao, Wei; Jiao, Wenjie

    2015-01-01

    Metastasis and drug resistance are major barriers for the treatment of non-small cell lung cancer (NSCLC). To explore new therapeutic options, we successfully encapsulated MicroRNA-34a (miR-34a), a potent endogenous tumor suppressor in NSCLC into S6 aptamer-conjugated dendrimer to form lung cancer-targeted gene delivery nanoparticles (PAM-Ap/pMiR-34a NPs). PAM-Ap/pMiR-34a NPs had a diameter of 100–200 nm and Zeta potential of ~30 mV at applied N/P ratio. The aptamer conjugation significantly improved cellular uptake as well as gene transfection efficiency of PAM-Ap/pMiR-34a NPs in cultured NSCLC cells. We showed that PAM-Ap/pMiR-34a NPs enhanced the regulation of targeted genes, BCL-2 and p53 in vitro. In addition, we revealed PAM-Ap/pMiR-34a NPs significantly inhibited cell growth, migration, invasion and induced apoptosis of lung cancer cells compared with non-targeted NPs. The method provided a novel therapeutic strategy for the experimental treatment of NSCLC. PMID:26406332

  17. Design of a new integrated chitosan-PAMAM dendrimer biosorbent for heavy metals removing and study of its adsorption kinetics and thermodynamics.

    PubMed

    Zarghami, Zabihullah; Akbari, Ahmad; Latifi, Ali Mohammad; Amani, Mohammad Ali

    2016-04-01

    In this research, different generations of PAMAM-grafted chitosan as integrated biosorbents were successfully synthesized via step by step divergent growth approach of dendrimer. The synthesized products were utilized as adsorbents for heavy metals (Pb(2+) in this study) removing from aqueous solution and their reactive Pb(2+) removal potential was evaluated. The results showed that as-synthesized products with higher generations of dendrimer, have more adsorption capacity compared to products with lower generations of dendrimer and sole chitosan. Adsorption capacity of as-prepared product with generation 3 of dendrimer is 18times more than sole chitosan. Thermodynamic and kinetic studies were performed for understanding equilibrium data of the uptake capacity and kinetic rate uptake, respectively. Thermodynamic and kinetic studies showed that Langmuir isotherm model and pseudo second order kinetic model are more compatible for describing equilibrium data of the uptake capacity and kinetic rate of the Pb(2+) uptake, respectively. PMID:26836608

  18. Preparation of unconventional dendrimers that contain rigid NH-triazine linkages and peripheral tert-butyl moieties for CO2 -selective adsorption.

    PubMed

    Lee, Cheng-Hua; Tsai, Meng-Rong; Chang, Yen-Tzu; Lai, Long-Li; Lu, Kuang-Lieh; Cheng, Kung-Lung

    2013-08-01

    Three unconventional dendrimers that contained rigid NH-triazine linkages and peripheral tert-butyl moieties were prepared by using a convergent approach and characterized by (1)H and (13)C NMR spectroscopy, mass spectrometry, and elemental analysis. Based on a thermogravimetric analysis study, these dendrimers were observed to display thermal stability at about 300 °C. The NH-triazine moiety, which possessed protonated and proton-free nitrogen sites (like the imidazole unit), displayed the capture of polarizable CO2 molecules through hydrogen-bond and/or dipole-quadrupole interactions. In addition, the adsorption of various amounts of CO2 and N2 at different pressures suggests that the dendritic pores, which arise from the stacking of the middle co-planar and rim protuberant dendrimers, Gn -N∼N-Gn (n=1-3), either swell or shrink at high pressure, thus indicating that these dendrimers may have a breathing ability. PMID:23794529

  19. Is the manifestation of the local dynamics in the spin-lattice NMR relaxation in dendrimers sensitive to excluded volume interactions?

    PubMed

    Shavykin, Oleg V; Neelov, Igor M; Darinskii, Anatolii A

    2016-09-21

    The effect of excluded volume (EV) interactions on the manifestation of the local dynamics in the spin-lattice NMR relaxation in dendrimers has been studied by using Brownian dynamics simulations. The study was motivated by the theory developed by Markelov et al., [J. Chem. Phys., 2014, 140, 244904] for a Gaussian dendrimer model without EV interactions. The theory connects the experimentally observed dependence of the spin-lattice relaxation rate 1/T(1)H on the location of NMR active groups with the restricted flexibility (semiflexibility) of dendrimers. Semiflexibility was introduced through the correlations between the orientations of different segments. However, these correlations exist even in flexible dendrimer models with EV interactions. We have simulated coarse-grained flexible and semiflexible dendrimer models with and without EV interactions. Every dendrimer segment consisted of two rigid bonds. Semiflexibility was introduced through a potential which restricts the fluctuations of angles between neighboring bonds but does not change orientational correlations in the EV model as compared to the flexible case. The frequency dependence of the reduced 1/T(1)H(ωH) for segments and bonds belonging to different dendrimer shells was calculated. It was shown that the main effect of EV interactions consists of a much stronger contribution of the overall dendrimer rotation to the dynamics of dendrimer segments as compared to phantom models. After the exclusion of this contribution the manifestation of internal dynamics in spin-lattice NMR relaxation appears to be practically insensitive to EV interactions. For the flexible models, the position ωmax of the peak of the modified 1/T(1)H(ωH) does not depend on the shell number. For semiflexible models, the maximum of 1/T(1)H(ωH) for internal segments or bonds shifts to lower frequencies as compared to outer ones. The dependence of ωmax on the number of dendrimer shells appears to be universal for segments and

  20. siRNA Delivery: Mastering Dendrimer Self-Assembly for Efficient siRNA Delivery: From Conceptual Design to In Vivo Efficient Gene Silencing (Small 27/2016).

    PubMed

    Chen, Chao; Posocco, Paola; Liu, Xiaoxuan; Cheng, Qiang; Laurini, Erik; Zhou, Jiehua; Liu, Cheng; Wang, Yang; Tang, Jingjie; Col, Valentina Dal; Yu, Tianzhu; Giorgio, Suzanne; Fermeglia, Maurizio; Qu, Fanqi; Liang, Zicai; Rossi, John J; Liu, Minghua; Rocchi, Palma; Pricl, Sabrina; Peng, Ling

    2016-07-01

    Supramolecular dendrimers created from small amphiphilic dendrons are able to mimic covalently constructed high-generation dendrimers for siRNA delivery, as presented by S. Pricl, L. Peng, and co-workers on page 3667. An optimal balance between the hydrophobic alkyl chain length and the hydrophilic dendritic portion is crucial for self-assembly of these amphiphilic dendrons into micellar nanostructures, and critically impacts the effectiveness of siRNA delivery and functional gene silencing. PMID:27412303

  1. The development of folate-PAMAM dendrimer conjugates for targeted delivery of anti-arthritic drugs and their pharmacokinetics and biodistribution in arthritic rats.

    PubMed

    Chandrasekar, Durairaj; Sistla, Ramakrishna; Ahmad, Farhan J; Khar, Roop K; Diwan, Prakash V

    2007-01-01

    The aim of this study was to synthesize folate-dendrimer conjugates as suitable vehicle for site specific delivery of anti-arthritic drug (indomethacin) to inflammatory regions and to determine its targeting efficiency, biodistribution in adjuvant induced arthritic rats. Folic acid was coupled to the surface amino groups of G4-PAMAM dendrimer (G4D) via a carbodiimide reaction and loaded with indomethacin. The conjugates were characterized by (1)H-NMR and IR spectroscopy. The drug content and percent encapsulation efficiency increased with increasing folate content for the dendrimer conjugates. The in vitro release rate was decreased for the folate conjugates when compared with unconjugated dendrimer (DNI). The plasma concentration profile showed a biphasic curve indicating rapid distribution followed by slow elimination. The AUC(0-infinity), half-life and residence time of indomethacin in inflamed paw was higher for folate-dendrimer conjugates. The time-averaged relative drug exposure (r(e)) of the drug in paw and overall drug targeting efficiency (T(e)) were higher for folate conjugate with 21 folate moieties (4.1 and 2.78, respectively) when compared with DNI (1.91 and 1.88, respectively). This study demonstrated the superiority of active targeting over dendrimer mediated passive targeting and also for the first time, folate-mediated targeting of an anti-arthritic drug to the inflammatory tissues. PMID:16996126

  2. Pharmacokinetics of Chiral Dendrimer-Triamine-Coordinated Gd-MRI Contrast Agents Evaluated by in Vivo MRI and Estimated by in Vitro QCM

    PubMed Central

    Miyake, Yuka; Ishikawa, Syungo; Kimura, Yu; Son, Aoi; Imai, Hirohiko; Matsuda, Tetsuya; Yamada, Hisatsugu; Toshimitsu, Akio; Kondo, Teruyuki

    2015-01-01

    Recently, we developed novel chiral dendrimer-triamine-coordinated Gd-MRI contrast agents (Gd-MRI CAs), which showed longitudinal relaxivity (r1) values about four times higher than that of clinically used Gd-DTPA (Magnevist®, Bayer). In our continuing study of pharmacokinetic differences derived from both the chirality and generation of Gd-MRI CAs, we found that the ability of chiral dendrimer Gd-MRI CAs to circulate within the body can be directly evaluated by in vitro MRI (7 T). In this study, the association constants (Ka) of chiral dendrimer Gd-MRI CAs to bovine serum albumin (BSA), measured and calculated with a quartz crystal microbalance (QCM) in vitro, were found to be an extremely easy means for evaluating the body-circulation ability of chiral dendrimer Gd-MRI CAs. The Ka values of S-isomeric dendrimer Gd-MRI CAs were generally greater than those of R-isomeric dendrimer Gd-MRI CAs, which is consistent with the results of our previous MRI study in vivo. PMID:26694418

  3. Formation of complexes between PAMAM-NH2 G4 dendrimer and L-α-tryptophan and L-α-tyrosine in water

    NASA Astrophysics Data System (ADS)

    Buczkowski, Adam; Urbaniak, Pawel; Belica, Sylwia; Sekowski, Szymon; Bryszewska, Maria; Palecz, Bartlomiej

    2014-07-01

    Interactions between electromagnetic radiation and the side substituents of aromatic amino acids are widely used in the biochemical studies on proteins and their interactions with ligand molecules. That is why the aim of our study was to characterize the formation of complexes between PAMAM-NH2 G4 dendrimer and L-α-tryptophan and L-α-tyrosine in water. The number of L-α-tryptophan and L-α-tyrosine molecules attached to the macromolecule of PAMAM-NH2 G4 dendrimer and the formation constants of the supramolecular complexes formed have been determined. The macromolecule of PAMAM-NH2 G4 can reversibly attach about 25 L-α-tryptophan molecules with equilibrium constant K equal to 130 ± 30 and 24 ± 6 L-α-tyrosine molecules. This characterization was deduced on the basis of the solubility measurements of the amino acids in aqueous dendrimer solutions, the 1H NMR and 2D-NOESY measurements of the dendrimer solutions with the amino acids, the equilibrium dialysis and the circular dichroism measurements of the dendrimer aqueous solutions with L-α-tryptophan. Our date confirmed the interactions of L-α-tryptophan and L-α-tyrosine with the dendrimer in aqueous solution and indicated a reversible character of the formed complexes.

  4. Interaction Mechanism of Nano-silicon Dioxide Modified by Poly(amidoamine) Dendrimers

    NASA Astrophysics Data System (ADS)

    Jin, Tao; Li, Xiao-yu

    2012-10-01

    To gain insight into the attachment of ≡Si+ (SC) ion (regarded as guest) to the lowest generation, NH2-terminated poly(amidoamine) (PAMAM) dendrimers (regarded as host) in the liquid phase, density functional theory is used to investigate the structures and energetics of the host-guest complex. The effect of solvent on the structures and energetics is also investigated. Various initial configurations of the ion bound to PAMAM are tested, and two stable conformers are found, i.e, types A (≡Si+ is bound to the amine site) and C (≡Si+ is bound to the amide site). Types A and C are the most stable due to the chemical bond formations of Si—N° (amine nitrogen atoms) and Si—O, respectively. The IR spectra for the lowest energy conformers are thoroughly analyzed and compared with the available experimental data.

  5. Supramolecular Assemblies of Poly(propyleneimine) Dendrimers Driven by Simple Monovalent Counterions

    NASA Astrophysics Data System (ADS)

    Eghtesadi, Seyed Ali; Haso, Fadi; Kashfipour, Marjan Alsadat; Lillard, Robert, , Dr.; Liu, Tianbo, , Dr.; Tianbo Liu's group Team, Dr.; Lillard's group Collaboration, Dr.

    Polyelectrolytes (PE) are fascinating class of polymers carrying dissociative ionic groups which give them unique properties in solutions and at charged surfaces. The properties of these polymers in solution are mainly depending on the fraction of dissociated ionic groups, the quality of solvent and salt concentration. Describing the solution properties of polyelectrolytes have always been an obstacle for polymer scientists due to their different behavior as a result of their dual character of being highly charged electrolytes and at macromolecular size. The question we tried to address was what happens to solution behavior of charged polyelectrolytes when they reach to the nano-scale size which can neither be considered as point charges nor colloids. Second generation of poly(propyleneimine) dendrimer in different solvent qualities, salt concentrations, pH and temperatures were studied using techniques such as LLS, TEM, AFM and zeta-potential, and dominant controlling factors over their self-assembly into hollow spherical ``Blackberry'' like nanoparticles was investigated.

  6. Unambiguous detection of nitrated explosive vapours by fluorescence quenching of dendrimer films

    PubMed Central

    Geng, Yan; Ali, Mohammad A.; Clulow, Andrew J.; Fan, Shengqiang; Burn, Paul L.; Gentle, Ian R.; Meredith, Paul; Shaw, Paul E.

    2015-01-01

    Unambiguous and selective standoff (non-contact) infield detection of nitro-containing explosives and taggants is an important goal but difficult to achieve with standard analytical techniques. Oxidative fluorescence quenching is emerging as a high sensitivity method for detecting such materials but is prone to false positives—everyday items such as perfumes elicit similar responses. Here we report thin films of light-emitting dendrimers that detect vapours of explosives and taggants selectively—fluorescence quenching is not observed for a range of common interferents. Using a combination of neutron reflectometry, quartz crystal microbalance and photophysical measurements we show that the origin of the selectivity is primarily electronic and not the diffusion kinetics of the analyte or its distribution in the film. The results are a major advance in the development of sensing materials for the standoff detection of nitro-based explosive vapours, and deliver significant insights into the physical processes that govern the sensing efficacy. PMID:26370931

  7. Non-adiabatic excited state molecular dynamics of phenylene ethynylene dendrimer using a multiconfigurational Ehrenfest approach.

    PubMed

    Fernandez-Alberti, Sebastian; Makhov, Dmitry V; Tretiak, Sergei; Shalashilin, Dmitrii V

    2016-04-21

    Photoinduced dynamics of electronic and vibrational unidirectional energy transfer between meta-linked building blocks in a phenylene ethynylene dendrimer is simulated using a multiconfigurational Ehrenfest in time-dependent diabatic basis (MCE-TDDB) method, a new variant of the MCE approach developed by us for dynamics involving multiple electronic states with numerous abrupt crossings. Excited-state energies, gradients and non-adiabatic coupling terms needed for dynamics simulation are calculated on-the-fly using the Collective Electron Oscillator (CEO) approach. A comparative analysis of our results obtained using MCE-TDDB, the conventional Ehrenfest method and the surface-hopping approach with and without decoherence corrections is presented. PMID:27004611

  8. Ruthenium(II) dendrimers containing carbazole-based chromophores as branches.

    PubMed

    McClenaghan, Nathan D; Passalacqua, Rosalba; Loiseau, Frédérique; Campagna, Sebastiano; Verheyde, Bert; Hameurlaine, Ahmed; Dehaen, Wim

    2003-05-01

    Three new luminescent and redox-active Ru(II) complexes containing novel dendritic polypyridine ligands have been synthesized, and their absorption spectra, luminescence properties (both at room temperature in fluid solution and at 77 K in rigid matrix), and redox behavior have been investigated. The dendritic ligands are made of 1,10-phenanthroline coordinating subunits and of carbazole groups as branching sites. The first and second generation species of this novel class of dendritic ligands (L1 and L2, respectively; see Figure 1 for their structural formulas) have been prepared and employed. The metal dendrimers investigated are [Ru(bpy)(2)(L1)](2+) (1; bpy = 2,2'-bipyridine), [Ru(bpy)(2)(L2)](2+) (2), and [Ru(L1)(3)](2+) (3; see Figure 2). For the sake of completeness and comparison purposes, also the absorption spectra, redox behavior, and luminescence properties of L1 and L2 have been studied, together with the properties of 3,6-di(tert-butyl)carbazole (L0) and [Ru(bpy)(2)(phen)](2+) (4, phen = 1,10-phenanthroline). The absorption spectra of the free dendritic ligands show features which can be assigned to the various subunits (i.e., carbazole and phenanthroline groups) and additional bands at lower energies (at lambda > 300 nm) which are assigned to carbazole-to-phenanthroline charge-transfer (CT) transitions. These latter bands are significantly red-shifted upon acid and/or zinc acetate addition. Both L1 and L2 exhibit relatively intense luminescence at room temperature in fluid solution (lifetimes in the nanosecond time scale, quantum yields of the order of 10(-2)-10(-1)) and at 77 K in rigid matrix (lifetimes in the millisecond time scale). Such a luminescence is assigned to CT states at room temperature and to phenanthroline-centered pi-pi triplet levels at 77 K. The room-temperature luminescence of L1 and L2 is totally quenched by acid or zinc acetate. The metal dendrimers exhibit the typical absorption and luminescence properties of Ru(II) polypyridine

  9. A polyphenylene dendrimer drug transporter with precisely positioned amphiphilic surface patches.

    PubMed

    Stangenberg, René; Wu, Yuzhou; Hedrich, Jana; Kurzbach, Dennis; Wehner, Daniel; Weidinger, Gilbert; Kuan, Seah Ling; Jansen, Malin Insa; Jelezko, Fedor; Luhmann, Heiko J; Hinderberger, Dariush; Weil, Tanja; Müllen, Klaus

    2015-02-18

    The design and synthesis of a polyphenylene dendrimer (PPD 3) with discrete binding sites for lipophilic guest molecules and characteristic surface patterns is presented. Its semi-rigidity in combination with a precise positioning of hydrophilic and hydrophobic groups at the periphery yields a refined architecture with lipophilic binding pockets that accommodate defined numbers of biologically relevant guest molecules such as fatty acids or the drug doxorubicin. The size, architecture, and surface textures allow to even penetrate brain endothelial cells that are a major component of the extremely tight blood-brain barrier. In addition, low to no toxicity is observed in in vivo studies using zebrafish embryos. The unique PPD scaffold allows the precise placement of functional groups in a given environment and offers a universal platform for designing drug transporters that closely mimic many features of proteins. PMID:25182694

  10. Nanoparticle-cored dendrimers: functional hybrid nanocomposites as a new platform for drug delivery systems

    NASA Astrophysics Data System (ADS)

    Brunetti, V.; Bouchet, L. M.; Strumia, M. C.

    2015-02-01

    Nanoparticle-cored dendrimers (NCDs) are now offering themselves as versatile carriers because of their colloidal stability, tunable membrane properties and ability to encapsulate or integrate a broad range of drugs and molecules. This kind of hybrid nanocomposite aims to combine the advantages of stimuli-responsive dendritic coatings, in order to regulate the drug release behaviour under different conditions and improve the biocompatibility and in vivo half-time circulation of the inorganic nanoparticles. Size, surface chemistry and shape are key nanocarrier properties to evaluate. Here, we have reviewed the most recent advances of NCDs in drug delivery systems, compared their behaviour with non-dendritic stabilized nanoparticles and highlighted their challenges and promising applications in the future.

  11. Difference in microchip electrophoretic mobility between partially and fully PEGylated poly(amidoamine) dendrimers.

    PubMed

    Park, Eun Ji; Na, Dong Hee

    2015-11-01

    The objective of this study was to investigate the difference in electrophoretic mobility between partially and fully poly(ethylene glycol)-conjugated poly(amidoamine) dendrimers (part-PEG-PAMAM and full-PEG-PAMAM, respectively) using a microchip capillary gel electrophoresis (MCGE). While MCGE allowed size-based separation of PEG-PAMAMs prepared with monomethoxy PEG-nitrophenyl carbonate, full-PEG-PAMAMs migrated slower than part-PEG-PAMAMs that were similar in size or larger. When the measured molecular weights obtained from MCGE analysis and the calculated molecular weights were plotted, each part-PEG-PAMAM and full-PEG-PAMAM showed correlation coefficients greater than 0.98. This study indicates that MCGE would be useful for characterizing PEG-PAMAMs with different PEGylation degrees. PMID:26253023

  12. Bimetallic dendrimer-encapsulated nanoparticles as catalysts: a review of the research advances.

    PubMed

    Peng, Xiaohong; Pan, Qinmin; Rempel, Garry L

    2008-08-01

    Bimetallic dendrimer-encapsulated nanoparticles (DENs) are important materials, because they have demonstrated improvement in performance compared to the monometallic DENs in many systems when they are used as catalysts. This tutorial review focuses on the recent research advances in bimetallic DENs with respect to their synthesis, characterization, and applications as catalysts. Bimetallic DENs can be made mainly via three routes: co-complexation, sequential loading, and partial displacement. The research in bimetallic DENs has been significantly promoted by the advancement of characterization instruments. The performances of bimetallic DENs as homogeneous and heterogeneous catalysts in organic synthesis have been compared with both monometallic DENs and their physical mixtures. It is concluded that the synergistic electronic effect in bimetallic nanoparticles enhances their catalytic activities. PMID:18648686

  13. Polymeric Carriers for Gene Delivery: Chitosan and Poly(amidoamine) Dendrimers

    PubMed Central

    Xu, Qingxing; Wang, Chi-Hwa; Pack, Daniel Wayne

    2012-01-01

    Gene therapy is a potential medical solution that promises new treatments and may hold the cure for many different types of diseases and disorders of the human race. However, gene therapy is still a growing medical field and the technology is still in its infancy. The main challenge for gene therapy is to find safe and effective vectors that are able to deliver genes to the specific cells and get them to express inside the cells. Due to safety concerns, synthetic delivery systems, rather than viral vectors, are preferred for gene delivery and significant efforts have been focused on the development of this field. However, we are faced with problems like low gene transfer efficiency, cytotoxicity and lack of cell-targeting capability for these synthetic delivery systems. Over the years, we have seen a variety of new and effective polymers which have been designed and synthesized specifically for gene delivery. Moreover, various strategies that aimed at enhancing their physicochemical properties, improving transfection efficiency, reducing cytotoxicity as well as incorporating functional groups that offer better targetability and higher cellular uptake are established. Here, we look at two potential polymeric carriers, chitosan and poly(amidoamine) dendrimers, which have been widely reported for gene delivery. For chitosan, the interest arises from their availability, excellent non-cytotoxicity profile, biodegradability and ease of modification. For poly(amidoamine) dendrimers, the interest arises from their ease of synthesis with controlled structure and size, minimal cytotoxicity, biodegradability and high transfection efficiencies. The latest developments on these polymers for gene delivery will be the main focus of this article. PMID:20618156

  14. Low generation polyamine dendrimers bearing flexible tetraethylene glycol as nanocarriers for plasmids and siRNA

    NASA Astrophysics Data System (ADS)

    Sharma, Rishi; Zhang, Issan; Shiao, Tze Chieh; Pavan, Giovanni M.; Maysinger, Dusica; Roy, René

    2016-02-01

    Low G1 generation polyamine dendrimers built around programmable, flexible, and short tetraethyleneglycol branches were readily prepared in a divergent manner using a combination of orthogonal AB3 or AB5 units and highly efficient chemical transformations based on Cu(i) catalyzed alkyne-azide cycloaddition (CUAAC) and thiol-ene click reactions. The constructs showed that the G1 polyamines with only twelve and eighteen amine surface groups can successfully deliver siRNA in human cells, with transfection efficiency comparable to that of Lipofectamine 2000®. Measurements of cell viability following transfection of plasmid DNA and siRNA showed that the dendritic polyamines are less cytotoxic than Lipofectamine 2000® and are thus preferable for biological applications.Low G1 generation polyamine dendrimers built around programmable, flexible, and short tetraethyleneglycol branches were readily prepared in a divergent manner using a combination of orthogonal AB3 or AB5 units and highly efficient chemical transformations based on Cu(i) catalyzed alkyne-azide cycloaddition (CUAAC) and thiol-ene click reactions. The constructs showed that the G1 polyamines with only twelve and eighteen amine surface groups can successfully deliver siRNA in human cells, with transfection efficiency comparable to that of Lipofectamine 2000®. Measurements of cell viability following transfection of plasmid DNA and siRNA showed that the dendritic polyamines are less cytotoxic than Lipofectamine 2000® and are thus preferable for biological applications. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06757j

  15. Dynamics of Energy Transfer in a Conjugated Dendrimer Driven by Ultrafast Localization of Excitations.

    PubMed

    Galindo, Johan F; Atas, Evrim; Altan, Aysun; Kuroda, Daniel G; Fernandez-Alberti, Sebastian; Tretiak, Sergei; Roitberg, Adrian E; Kleiman, Valeria D

    2015-09-16

    Solar energy conversion starts with the harvest of light, and its efficacy depends on the spatial transfer of the light energy to where it can be transduced into other forms of energy. Harnessing solar power as a clean energy source requires the continuous development of new synthetic materials that can harvest photon energy and transport it without significant losses. With chemically-controlled branched architectures, dendrimers are ideally suited for these initial steps, since they consist of arrays of chromophores with relative positioning and orientations to create energy gradients and to spatially focus excitation energies. The spatial localization of the energy delimits its efficacy and has been a point of intense research for synthetic light harvesters. We present the results of a combined theoretical experimental study elucidating ultrafast, unidirectional, electronic energy transfer on a complex molecule designed to spatially focus the initial excitation onto an energy sink. The study explores the complex interplay between atomic motions, excited-state populations, and localization/delocalization of excitations. Our findings show that the electronic energy-transfer mechanism involves the ultrafast collapse of the photoexcited wave function due to nonadiabatic electronic transitions. The localization of the wave function is driven by the efficient coupling to high-frequency vibrational modes leading to ultrafast excited-state dynamics and unidirectional efficient energy funneling. This work provides a long-awaited consistent experiment-theoretical description of excited-state dynamics in organic conjugated dendrimers with atomistic resolution, a phenomenon expected to universally appear in a variety of synthetic conjugated materials. PMID:26122872

  16. Polyamidoamine Dendrimer-Based Binders for High-Loading Lithium-Sulfur Battery Cathodes

    SciTech Connect

    Bhattacharya, Priyanka; Nandasiri, Manjula I.; Lv, Dongping; Schwarz, Ashleigh M.; Darsell, Jens T.; Henderson, Wesley A.; Tomalia, Donald A.; Liu, Jun; Zhang, Jiguang; Xiao, Jie

    2016-01-01

    Lithium-sulfur (Li-S) batteries are regarded as one of the most promising candidates for next generation energy storage systems because of their ultra high theoretical specific energy. To realize the practical application of Li-S batteries, however, a high S active material loading is essential (>70 wt% in the carbon-sulfur (C-S) composite cathode and >2 mg cm-2 in the electrode). A critical challenge to achieving this high capacity in practical electrodes is the dissolution of the longer lithium polysulfide reaction intermediates in the electrolyte (resulting in loss of active material from the cathode and contamination of the anode due to the polysulfide shuttle mechanism). The binder material used for the cathode is therefore crucial as this is a key determinant of the bonding interactions between the active material (S) and electronic conducting support (C), as well as the maintenance of intimate contact between the electrode materials and current collector. The battery performance can thus be directly correlated with the choice of binder, but this has received only minimal attention in the relevant Li-S battery published literature. Here, we investigated the application of polyamidoamine (PAMAM) dendrimers as functional binders in Li-S batteries—a class of materials which has been unexplored for electrode design. By using dendrimers, it is demonstrated that high S loadings (>4 mg cm-2) can be easily achieved using "standard" (not specifically tailored) materials and simple processing methods. An exceptional electrochemical cycling performance was obtained (as compared to cathodes with conventional linear polymeric binders such as carboxymethyl cellulose (CMC) and styrene-butadiene rubber (SBR)) with >100 cycles and 85-98% capacity retention, thus demonstrating the significant utility of this new binder architecture which exhibits critical physicochemical properties and flexible nanoscale design parameters (CNDP's).

  17. A Facile Strategy to Prepare Dendrimer-stabilized Gold Nanorods with Sub-10-nm Size for Efficient Photothermal Cancer Therapy

    PubMed Central

    Wang, Xinyu; Wang, Hanling; Wang, Yitong; Yu, Xiangtong; Zhang, Sanjun; Zhang, Qiang; Cheng, Yiyun

    2016-01-01

    Gold (Au) nanoparticles are promising photothermal agents with the potential of clinical translation. However, the safety concerns of Au photothermal agents including the potential toxic compositions such as silver and copper elements in their structures and the relative large size-caused retention and accumulation in the body post-treatment are still questionable. In this article, we successfully synthesized dendrimer-stabilized Au nanorods (DSAuNRs) with pure Au composition and a sub-10-nm size in length, which represented much higher photothermal effect compared with dendrimer-encapsulated Au nanoparticles due to their significantly enhanced absorption in the near-infrared region. Furthermore, glycidol-modified DSAuNRs exhibited the excellent biocompatibility and further showed the high photothermal efficiency of killing cancer cells in vitro and retarding tumor growth in vivo. The investigation depicted an optimal photothermal agent with the desirable size and safe composition. PMID:26956895

  18. The Structural Response of Polyelectrolyte Dendrimer toward the Molecular Protonation: The Inconsistence Revealed by SANS and NMR

    SciTech Connect

    Chen, Wei-Ren; Herwig, Kenneth W; Hong, Kunlun; Li, Xin; Liu, Emily; Liu, Yun; Porcar, L.; Shew, Chwen-Yang; Smith, Gregory Scott; Wu, Bin; Liu, Dazhi; Gao, Carrie Y

    2012-01-01

    Polyamidoamine (PAMAM) dendrimers and their charged state in deuterium oxide have been investigated with diffusion NMR and small angle neutron scattering (SANS) techniques. NMR measurement suggests that, upon increasing the molecular protonation by progressive acidification of solutions, significant variation of hydrodynamic radius, calculated by the Stokes-Einstein relation with given surface condition, is observed upon increasing the molecular protonation. However, comparative SANS experiment indicates little dependence of dendrimer global size, in terms of radius of gyration, on molecular protonation. This observed inconsistence indicates the necessity of incorporating the effect of molecular interface modification by dressed counterion, when dynamical measurements are used for determination the structural characteristics of ionic soft colloids even in a dilute enough suspension.

  19. Synthesis and steady-state photophysical properties of dye-labeled dendrimers having novel oligothiophene cores: A comparative study

    SciTech Connect

    Adronov, A.; Malenfant, P.R.L.; Frechet, J.M.J.

    2000-05-01

    Novel chromophore-labeled dendrimers with penta- and heptathiophene cores and coumarin-2 chromophores at their periphery have been shown to be very efficient light-harvesting systems. Excitation of the peripheral coumarin-2 chromophores results in energy transfer to the oligothiophene cores as a result of the large overlap between the donor emission spectrum and the acceptor absorption spectrum, as well as the large transition dipole moments of the oligothiophenes. Although these core dyes have low fluorescence quantum yields, their emission intensity is significantly enhanced by the ability of the large light-harvesting dendron to funnel absorbed energy to the core. Because of the large Stokes shift of the oligothiophenes, the emission spectrum of the dendrimers was red-shifted by 200 nm from the excitation wavelength. Additionally, it was found that oligothiophene orientation--end functionalization vs central functionalization--did not have a significant effect on energy-transfer efficiency.

  20. In vitro anti-Acanthamoeba synergistic effect of chlorhexidine and cationic carbosilane dendrimers against both trophozoite and cyst forms.

    PubMed

    Heredero-Bermejo, I; Sánchez-Nieves, J; Soliveri, J; Gómez, R; de la Mata, F J; Copa-Patiño, J L; Pérez-Serrano, J

    2016-07-25

    Acanthamoeba sp. are the causative agents of severe illnesses in humans such as Acanthamoeba keratitis (AK) and granulomatous amoebic encephalitis (GAE). Medical therapy is not yet well established. Treatments of AK last for several months and generate toxicity, resistances appear due to the cysts stage and recurrences can occur. In this study has been demonstrated that the combination of chlorhexidine digluconate (CLX) and carbosilane dendrimers containing ammonium or guanidine moieties has in vitro synergistic effect against Acanthamoeba polyphaga. This synergy provokes an important reduction in the minimal trophozoite amoebicidal concentration (MTAC) of CLX, which means a reduction of their toxic effects on human cells. Moreover, some CLX/dendrimer combinations show important activity against the cyst resistance stage. PMID:27173821

  1. An amplified electrochemical strategy using DNA-QDs dendrimer superstructure for the detection of thymine DNA glycosylase activity.

    PubMed

    Liu, Hongying; Lou, Youbing; Zhou, Fei; Zhu, Hao; Abdel-Halim, E S; Zhu, Jun-Jie

    2015-09-15

    A triple-signal amplification strategy was proposed for highly sensitive and selective detection of thymine DNA glycosylase (TDG) by coupling a dendrimer-like DNA label with the electrochemical method and quantum dots (QDs) tagging. The DNA-QDs dendrimer-like superstructure was designed by DNA hybridization and covalent assembling. Benefiting from outstanding performance of the amplification strategy, this assay showed high sensitivity, extraordinary stability, and easy operation. The limit of detection could reach 0.00003 U µL(-1) with a splendid specificity. The TDG content in different concentration of HeLa cell was also determined. This assay opens a new horizon for both qualitative and quantitative detection of TDG, holding great promise for potential application in cancer cell research and clinical diagnostics. PMID:25913445

  2. A Facile Strategy to Prepare Dendrimer-stabilized Gold Nanorods with Sub-10-nm Size for Efficient Photothermal Cancer Therapy

    NASA Astrophysics Data System (ADS)

    Wang, Xinyu; Wang, Hanling; Wang, Yitong; Yu, Xiangtong; Zhang, Sanjun; Zhang, Qiang; Cheng, Yiyun

    2016-03-01

    Gold (Au) nanoparticles are promising photothermal agents with the potential of clinical translation. However, the safety concerns of Au photothermal agents including the potential toxic compositions such as silver and copper elements in their structures and the relative large size-caused retention and accumulation in the body post-treatment are still questionable. In this article, we successfully synthesized dendrimer-stabilized Au nanorods (DSAuNRs) with pure Au composition and a sub-10-nm size in length, which represented much higher photothermal effect compared with dendrimer-encapsulated Au nanoparticles due to their significantly enhanced absorption in the near-infrared region. Furthermore, glycidol-modified DSAuNRs exhibited the excellent biocompatibility and further showed the high photothermal efficiency of killing cancer cells in vitro and retarding tumor growth in vivo. The investigation depicted an optimal photothermal agent with the desirable size and safe composition.

  3. Self-assembly of amphiphilic Janus dendrimers into uniform onion-like dendrimersomes with predictable size and number of bilayers

    PubMed Central

    Zhang, Shaodong; Sun, Hao-Jan; Hughes, Andrew D.; Moussodia, Ralph-Olivier; Bertin, Annabelle; Chen, Yingchao; Pochan, Darrin J.; Heiney, Paul A.; Klein, Michael L.; Percec, Virgil

    2014-01-01

    A constitutional isomeric library synthesized by a modular approach has been used to discover six amphiphilic Janus dendrimer primary structures, which self-assemble into uniform onion-like vesicles with predictable dimensions and number of internal bilayers. These vesicles, denoted onion-like dendrimersomes, are assembled by simple injection of a solution of Janus dendrimer in a water-miscible solvent into water or buffer. These dendrimersomes provide mimics of double-bilayer and multibilayer biological membranes with dimensions and number of bilayers predicted by the Janus compound concentration in water. The simple injection method of preparation is accessible without any special equipment, generating uniform vesicles, and thus provides a promising tool for fundamental studies as well as technological applications in nanomedicine and other fields. PMID:24927561

  4. Photoinduced Synthesis of Dual-Emissive Tetraphenylethene-Based Dendrimers with Tunable Aggregates and Solution States Emissions.

    PubMed

    Abd-El-Aziz, Alaa S; Agatemor, Christian; Etkin, Nola; Wagner, Brian

    2016-08-01

    Photoactive materials are actively researched, piloting breakthroughs that have enriched fundamental understanding of science, and have led to real applications. Tetraphenylethene, a photoactive molecule that is of interest from fundamental and applied perspectives, features photochemical properties that are not exploited in the design of photoactive, dual-emissive materials. Here, tetraphenylethene-based, dual-emissive dendrimers are constructed via a synthetic approach that involves a photochemical reaction that exploits the photochemistry of tetraphenylethene. These dendrimers are emissive in solution and in the aggregate state with tunable dual emissions at 368 and 469 nm. The photochemical reaction also tunes the size of the aggregates, increasing the size after UV irradiation. The reported synthetic strategy is a direct and facile approach to accessing dual-emissive macromolecules, especially tetraphenylethene-based systems for real applications. PMID:27226397

  5. A Facile Strategy to Prepare Dendrimer-stabilized Gold Nanorods with Sub-10-nm Size for Efficient Photothermal Cancer Therapy.

    PubMed

    Wang, Xinyu; Wang, Hanling; Wang, Yitong; Yu, Xiangtong; Zhang, Sanjun; Zhang, Qiang; Cheng, Yiyun

    2016-01-01

    Gold (Au) nanoparticles are promising photothermal agents with the potential of clinical translation. However, the safety concerns of Au photothermal agents including the potential toxic compositions such as silver and copper elements in their structures and the relative large size-caused retention and accumulation in the body post-treatment are still questionable. In this article, we successfully synthesized dendrimer-stabilized Au nanorods (DSAuNRs) with pure Au composition and a sub-10-nm size in length, which represented much higher photothermal effect compared with dendrimer-encapsulated Au nanoparticles due to their significantly enhanced absorption in the near-infrared region. Furthermore, glycidol-modified DSAuNRs exhibited the excellent biocompatibility and further showed the high photothermal efficiency of killing cancer cells in vitro and retarding tumor growth in vivo. The investigation depicted an optimal photothermal agent with the desirable size and safe composition. PMID:26956895

  6. Gd3+-DTPA-Meglumine-Anionic Linear Globular Dendrimer G1: Novel Nanosized Low Toxic Tumor Molecular MR Imaging Agent

    PubMed Central

    Darvish Mohamadi, Tahmineh; Ghalandarlaki, Negar; Mehravi, Bita; Shafiee Ardestani, Mehdi; Yaghmaei, Parichehr

    2013-01-01

    Despite the great efforts in the areas of early diagnosis and treatment of cancer, this disease continues to grow and is still a global killer. Cancer treatment efficiency is relatively high in the early stages of the disease. Therefore, early diagnosis is a key factor in cancer treatment. Among the various diagnostic methods, molecular imaging is one of the fastest and safest ones. Because of its unique characteristics, magnetic resonance imaging has a special position in most researches. To increase the contrast of MR images, many pharmaceuticals have been known and used so far. Gadopentetate (with commercial name Magnevist) is the first magnetic resonance imaging contrast media that has been approved by the US Food and Drug Administration. In this study, gadopentetate was first synthesized and then attached to a tree-like polymer called dendrimer which is formed by polyethylene glycol core and surrounding citric acid groups. Stability studies of the drug were carried out to ensure proper synthesis. Then, the uptake of the drug into liver hepatocellular cell line and the drug cytotoxicity were evaluated. Finally, in vitro and in vivo MR imaging were performed with the new synthetic drug. Based on the findings of this research, connecting gadopentetate to dendrimer surface produces a stronger, safer, and more efficient contrast media. Gd(III)-diethylenetriamine pentaacetate-meglumine-dendrimer drug has the ability to enter cells and does not produce significant cytotoxicity. It also increases the relaxivity of tissue and enhances the MR images contrast. The obtained results confirm the hypothesis that the binding of gadopentetate to citric acid dendrimer produces a new, biodegradable, stable, and strong version of the old contrast media. PMID:23533819

  7. The effect of dendrimer generations on the structure of Q(G) LLC mesophase and drug release.

    PubMed

    Bitan-Cherbakovsky, Liron; Aserin, Abraham; Garti, Nissim

    2014-10-01

    In this paper the cosolubilization of 2nd, 3rd, and 4th generations of polypropyleneimine (PPI: PPI-G2, -G3, and -G4) dendrimers with sodium diclofenac (Na-DFC) into reverse gyroid cubic (Q(G)) liquid crystals is reported. Structural properties and interactions of PPI dendrimers with and without the drug were studied using small-angle X-ray scattering, attenuated total reflected Fourier transform infrared (ATR-FTIR) spectroscopy, and differential scanning calorimetry (DSC) measurements. Incorporation of PPI-G2 (without Na-DFC) into Q(G) mesophase led to a decrease of 78Å in the lattice parameter. Solubilization of higher PPI generations, G3 and G4, led to increases in the lattice parameter to 57Å and 64Å, respectively. At 25wt%, each of the dendrimers caused a phase transition Q(G)→reverse hexagonal (HII). According to ATR-FTIR and DSC, the large lattice parameter values of G3 and G4 (relative to G2) embedment were assigned to their interactions with the carboxyl groups of GMO at the interface in comparison to the strong interaction of PPI-G2 with the water. Cosolubilization of Na-DFC with PPI-G2 revealed enlargement of the lattice parameter (of the new HII mesophase), while in the case of G3 and G4 systems no significant influence was seen with Na-DFC. The release of Na-DFC from Q(G) and HII systems was followed by UV-vis spectroscopy and revealed generation-dependence on drug release. As dendrimer generation increased, the cumulative drug release decreased. PMID:25016542

  8. Ex vivo culturing of stromal cells with dexamethasone-loaded carboxymethylchitosan/poly(amidoamine) dendrimer nanoparticles promotes ectopic bone formation.

    PubMed

    Oliveira, J M; Kotobuki, N; Tadokoro, M; Hirose, M; Mano, J F; Reis, R L; Ohgushi, H

    2010-05-01

    Recently, our group has proposed a combinatorial strategy in tissue engineering principles employing carboxymethylchitosan/poly(amidoamine) dendrimer nanoparticles (CMCht/PAMAM) towards the intracellular release and regimented supply of dexamethasone (Dex) aimed at controlling stem cell osteogenic differentiation in the absence of typical osteogenic inducers, in vivo. In this work, we have investigated if the Dex-loaded CMCht/PAMAM dendrimer nanoparticles could play a crucial role in the regulation of osteogenesis, in vivo. Macroporous hydroxyapatite (HA) scaffolds were seeded with rat bone marrow stromal cells (RBMSCs), whose cells were expanded in MEM medium supplemented with 0.01 mg ml(-1) Dex-loaded CMCht/PAMAM dendrimer nanoparticles and implanted subcutaneously on the back of rats for 2 and 4 weeks. HA porous ceramics without RBMSCs and RBMSCs/HA scaffold constructs seeded with cells expanded in the presence and absence of 10(-8) M Dex were used as controls. The effect of initial cell number seeded in the HA scaffolds on the bone-forming ability of the constructs was also investigated. Qualitative and quantitative new bone formation was evaluated in a non-destructive manner using micro-computed tomography analyses of the explants. Haematoxylin and Eosin stained implant sections were also used for the histomorphometrical analysis. Toluidine blue staining was carried out to investigate the synthesis of proteoglycan extracellular matrix. In addition, alkaline phosphatase and osteocalcin levels in the explants were also quantified, since these markers denote osteogenic differentiation. At 4 weeks post-implantation results have shown that the novel Dex-loaded carboxymethylchitosan/poly(amidoamine) dendrimer nanoparticles may be beneficial as an intracellular nanocarrier, supplying Dex in a regimented manner and promoting superior ectopic de novo bone formation. PMID:20152952

  9. Vibrational spectra study of fluorescent dendrimers built from the cyclotriphosphazene core with terminal dansyl and carbamate groups

    NASA Astrophysics Data System (ADS)

    Furer, V. L.; Vandyukova, I. I.; Vandyukov, A. E.; Fuchs, S.; Majoral, J. P.; Caminade, A. M.; Kovalenko, V. I.

    2011-08-01

    The FTIR and FT Raman spectra of the "Janus"-type dendrimers, possessing five carbamate groups on one side and five fluorescent dansyl derivatives on the other side, with amide G1 and hydrazone G2 central linkages were studied. These surface-block dendrimers are obtained by the coupling of two different dendrons. The FTIR and FT-Raman spectra of the zero generation dendrons, built from the hexafunctional cyclotriphosphazene core, with five dansyl terminal groups and one carbamate G0 v and one oxybenzaldehyde function G0v have been recorded. The structural optimization and normal mode analysis were performed for dendron G0v on the basis of the density functional theory (DFT). The calculated geometrical parameters and harmonic vibrational frequencies are predicted in a good agreement with the experimental data. It was found that dendron molecule G0v has a concave lens structure with planar -O-C6H4-CHdbnd O fragments and slightly non-planar cyclotriphosphazene core. The experimental IR and Raman spectra of dendron G0v were interpreted by means of potential energy distributions. Relying on DFT calculations a complete vibrational assignment is proposed. The strong band 1597 cm -1 show marked changes of the optical density in dependence of substituents in the aromatic ring. The frequencies of ν(N-H) bands in the IR spectra reveal the presence of the different types of H-bonds in the dendrimers.

  10. Micro- and nanofabrication of robust reactive arrays based on the covalent coupling of dendrimers to activated monolayers.

    PubMed

    Degenhart, Geerten H; Dordi, Barbara; Schönherr, Holger; Vancso, G Julius

    2004-07-20

    We report on methods to fabricate robust micro- and nanopatterned platforms, comprising high functional group densities and quasi three-dimensional structures, for possible applications in biochip array technologies. For this purpose, amine-terminated poly(amidoamine) (PAMAM) dendrimers were immobilized via amide linkage formation on 11,11'-dithiobis(N-hydroxysuccinimidylundecanoate) (NHS-C10) self-assembled monolayers (SAMs) on gold surfaces. The coupling reaction and the resulting assemblies were characterized by grazing incidence reflection Fourier transform infrared spectroscopy, contact angle measurements, X-ray photoelectron spectroscopy (XPS), and atomic force microscopy; the obtained surface coverage values were successfully fitted with a Langmuir isotherm. The fraction of unreacted peripheral primary amine groups of the surface-immobilized PAMAM dendrimers was 28% as determined by XPS analysis of trifluoroacetic anhydride-labeled assemblies. Patterning of the PAMAM dendrimers on NHS-C10 SAMs on the micrometer and sub-100-nm scale was achieved by microcontact printing and dip pen nanolithography. The resulting patterns are characterized by their high degree of order and stability of the transferred molecules due to covalent attachment. PMID:15248705

  11. Mastering Dendrimer Self-Assembly for Efficient siRNA Delivery: From Conceptual Design to In Vivo Efficient Gene Silencing.

    PubMed

    Chen, Chao; Posocco, Paola; Liu, Xiaoxuan; Cheng, Qiang; Laurini, Erik; Zhou, Jiehua; Liu, Cheng; Wang, Yang; Tang, Jingjie; Col, Valentina Dal; Yu, Tianzhu; Giorgio, Suzanne; Fermeglia, Maurizio; Qu, Fanqi; Liang, Zicai; Rossi, John J; Liu, Minghua; Rocchi, Palma; Pricl, Sabrina; Peng, Ling

    2016-07-01

    Self-assembly is a fundamental concept and a powerful approach in molecular science. However, creating functional materials with the desired properties through self-assembly remains challenging. In this work, through a combination of experimental and computational approaches, the self-assembly of small amphiphilic dendrons into nanosized supramolecular dendrimer micelles with a degree of structural definition similar to traditional covalent high-generation dendrimers is reported. It is demonstrated that, with the optimal balance of hydrophobicity and hydrophilicity, one of the self-assembled nanomicellar systems, totally devoid of toxic side effects, is able to deliver small interfering RNA and achieve effective gene silencing both in cells - including the highly refractory human hematopoietic CD34(+) stem cells - and in vivo, thus paving the way for future biomedical implementation. This work presents a case study of the concept of generating functional supramolecular dendrimers via self-assembly. The ability of carefully designed and gauged building blocks to assemble into supramolecular structures opens new perspectives on the design of self-assembling nanosystems for complex and functional applications. PMID:27244195

  12. Functionalization of a Triazine Dendrimer Presenting Four Maleimides on the Periphery and a DOTA Group at the Core.

    PubMed

    Lee, Changsuk; Ji, Kun; Simanek, Eric E

    2016-01-01

    A readily and rapidly accessible triazine dendrimer was manipulated in four steps with 23% overall yield to give a construct displaying four maleimide groups and DOTA. The maleimide groups of the dendrimer are sensitive to hydrolysis under basic conditions. The addition of up to four molecules of water can be observed via mass spectrometry and HPLC. The evolution in the alkene region of the ¹H-NMR--the transformation of the maleimide singlet to the appearance of two doublets--is consistent with imide hydrolysis and not the Michael addition. The hydrolysis events that proceeded over hours are sufficiently slower than the desired thiol addition reactions that occur in minutes. The addition of thiols to maleimides can be accomplished in a variety of solvents. The thiols examined derived from cysteine and include the protected amino acid, a protected dipeptide, and native oligopeptides containing either 9 or 18 amino acids. The addition reactions were monitored with HPLC and mass spectrometry in most cases. Complete substitution was observed for small molecule reactants. The model peptides containing nine or eighteen amino acids provided a mixture of products averaging between 3 and 4 substitutions/dendrimer. The functionalization of the chelate group with gadolinium was also accomplished easily. PMID:26978338

  13. Molecular modeling and in vivo imaging can identify successful flexible triazine dendrimer-based siRNA delivery systems

    PubMed Central

    Merkel, Olivia M.; Zheng, Mengyao; Mintzer, Meredith A.; Pavan, Giovanni M.; Librizzi, Damiano; Maly, Marek; Höffken, Helmut; Danani, Andrea; Simanek, Eric E.; Kissel, Thomas

    2011-01-01

    This study aimed to identify suitable siRNA delivery systems based on flexible generation 2–4 triazine dendrimers by correlating physico-chemical and biological in vitro and in vivo properties of the complexes with thermodynamic parameters calculated using molecular modeling. The siRNA binding properties of the dendrimers and PEI 25 kDa were simulated, binding and stability were measured in SYBR Gold assays, and hydrodynamic diameters, zeta potentials, and cytotoxicity were quantified. These parameters were compared with cellular uptake of the complexes and their ability to mediate RNAi. Radiolabeled complexes were administered intravenously, and pharmacokinetic profiles and biodistribution of these polyplexes were assessed both invasively and non-invasively. All flexible triazine dendrimers formed thermodynamically more stable complexes than PEI. While PEI and the generation 4 dendrimer interacted more superficially with siRNA, generation 2 and 3 virtually coalesced with siRNA, forming a tightly intertwined structure. These dendriplexes were therefore more efficiently charge-neutralized than PEI complexes, reducing agglomeration. This behavior was confirmed by results of hydrodynamic diameters (72.0 nm – 153.5 nm) and zeta potentials (4.9 mV – 21.8 mV in 10 mM HEPES) of the dendriplexes in comparison to PEI complexes (312.8 nm – 480.0 nm and 13.7 mV 17.4 mV in 10 mM HEPES). All dendrimers, even generation 3 and 4, were less toxic than PEI. All dendriplexes were efficiently endocytosed and showed significant and specific luciferase knockdown in HeLa/Luc cells. Scintillation counting confirmed that the generation 2 triazine complexes showed more than twofold prolonged circulation times as a result of their good thermodynamic stability. Conversely, generation 3 complexes dissociated in vivo, and generation 4 complexes were captured by the reticulo-endothelial system due to their increased surface charge. Molecular modeling proves very valuable for

  14. Polyamidoamine (PAMAM) Dendrimer Conjugates of Clickable Agonists of the A3 Adenosine Receptor and Coactivation of the P2Y14 Receptor by a Tethered Nucleotide

    SciTech Connect

    Tosh, Dilip, K.; Yoo, Lena S.; Chinn, Moshe; Hong, Kunlun; Kilbey, II, S Michael; Barrett, Matthew O.; Fricks, Ingrid P.; Harden, T. Kendall; Jacobson, Kenneth A.

    2010-01-01

    We previously synthesized a series of potent and selective A{sub 3} adenosine receptor (AR) agonists (North-methanocarba nucleoside 5{prime}-uronamides) containing dialkyne groups on extended adenine C2 substituents. We coupled the distal alkyne of a 2-octadiynyl nucleoside by Cu(I)-catalyzed 'click' chemistry to azide-derivatized G4 (fourth-generation) PAMAM dendrimers to form triazoles. A{sub 3}AR activation was preserved in these multivalent conjugates, which bound with apparent Ki of 0.1-0.3 nM. They were substituted with nucleoside moieties, solely or in combination with water-solubilizing carboxylic acid groups derived from hexynoic acid. A comparison with various amide-linked dendrimers showed that triazole-linked conjugates displayed selectivity and enhanced A{sub 3}AR affinity. We prepared a PAMAM dendrimer containing equiproportioned peripheral azido and amino groups for conjugation of multiple ligands. A bifunctional conjugate activated both A{sub 3} and P2Y{sub 14} receptors (via amide-linked uridine-5{prime}-diphosphoglucuronic acid), with selectivity in comparison to other ARs and P2Y receptors. This is the first example of targeting two different GPCRs with the same dendrimer conjugate, which is intended for activation of heteromeric GPCR aggregates. Synergistic effects of activating multiple GPCRs with a single dendrimer conjugate might be useful in disease treatment.

  15. Hyaluronic acid-conjugated polyamidoamine dendrimers for targeted delivery of 3,4-difluorobenzylidene curcumin to CD44 overexpressing pancreatic cancer cells.

    PubMed

    Kesharwani, Prashant; Xie, Lingxiao; Banerjee, Sanjeev; Mao, Guangzhao; Padhye, Subhash; Sarkar, Fazlul H; Iyer, Arun K

    2015-12-01

    The current study was aimed to develop a targeted dendrimer formulation of 3, 4-difluorobenzylidene curcumin (CDF) and evaluate its potential in CD44 targeted therapy for pancreatic cancer. Using amine terminated fourth generation poly(amidoamine) (PAMAM) dendrimer nanocarrier and hyaluronic acid (HA) as a targeting ligand, we engineered a CD44-targeted PAMAM dendrimer (HA-PAMAM) formulation of CDF. The resulting dendrimer nanosystem (HA-PAMAM-CDF) had a particle size and surface charge of 9.3 ± 1.5 nm and -7.02 ± 9.53 mV, respectively. When CD44 receptor overexpressing MiaPaCa-2 and AsPC-1 human pancreatic cancer cells were treated with HA-PAMAM-CDF, a dose-dependent cytotoxicity was observed. Furthermore, blocking the CD44 receptors present on the MiaPaCa-2 cells using free excess soluble HA prior to treatment with HA-PAMAM-CDF nano-formulation resulted in 1.71 fold increase in the IC50 value compared to non-targeted formulation (PAMAM-CDF), confirming target specificity of HA-PAMAM-CDF. Additionally, HA-PAMAM-CDF formulation when compared to PAMAM-CDF, displayed higher cellular uptake in MiaPaCa-2 cancer cell lines as shown by fluorescence studies. In summary, the novel CD44 targeted dendrimer based nanocarriers appear to be proficient in mediating site-specific delivery of CDF via CD44 receptors, with an improved therapeutic margin and safety. PMID:26440757

  16. Study of the interactions of PAMAM G3-NH2 and G3-OH dendrimers with 5-fluorouracil in aqueous solutions.

    PubMed

    Buczkowski, Adam; Waliszewski, Dariusz; Urbaniak, Pawel; Palecz, Bartlomiej

    2016-05-30

    The results of spectroscopic measurements (increase in solubility, equilibrium dialysis, (1)H NMR titration) and calorimetric measurements (isothermal titration ITC) indicate spontaneous (ΔG<0) bonding of 5-fluorouracil by both cationic PAMAM G3-NH2 dendrimer and hydroxyl PAMAM G3-OH dendrimer in aqueous solutions. PAMAM G3-NH2 dendrimer bonds about n= 25±8 drug molecules. Some of them n1= 5±1 are bonded by terminal amine groups with equilibrium constant K1= 3890±930, while the remaining ones n2= 24 ±3 are bonded by amide groups with equilibrium constant K2= 110±30. Hydroxyl PAMAM G3-OH dendrimer bonds n=6.0±1.6 molecules of 5-fluorouracil through tertiary amine groups with equilibrium constant K= 65±10. The parameters of bonding 5-fluorouracil by PAMAM G3-NH2 and G3-OH dendrimer were compared with those of bonding this drug by the macromolecules of PAMAM of generations G4-NH2, G5-NH2 and G5-OH. PMID:27039147

  17. Mono(pyridine-N-oxide) DOTA analog and its G1/G4-PAMAM dendrimer conjugates labeled with 177Lu: radiolabeling and biodistribution studies.

    PubMed

    Laznickova, A; Biricova, V; Laznicek, M; Hermann, P

    2014-02-01

    (177)Lu radiolabeling of the first (G1-) or fourth (G4-) generation polyaminoamide (PAMAM) dendrimer conjugates with DOTA-like bifunctional chelator with one methylenepyridine-N-oxide pendant arm (DO3A-py(NO-C)) stability of the radiolabeled species and their pharmacokinetic characteristics were evaluated in preclinical experiments. The results showed that the G1- and G4-dendrimer conjugates, modified in average with 7.5 or 57 DO3A-py(NO-C) chelating units, respectively, can also be labeled with (177)Lu with a high specific activity and radiochemical purity even at 37 °C. The radiolabeled species were stable for at least 24h. Distribution profile of G1-dendrimer conjugate in organs and tissues of rats was more favorable than that of G4 one. On the other hand, the later dendrimer conjugate bears a substantially higher number of metal chelators per molecule enabling binding of a considerably larger number of radiometals. Our results indicate that an employment of dendrimer-chelate conjugates with bound radiometals might represent a prospective way for radiolabeling of biologically active target-specific macromolecules to obtain markedly high specific activity. PMID:24333746

  18. Supramolecular disassembly of facially amphiphilic dendrimer assemblies in response to physical, chemical, and biological stimuli.

    PubMed

    Raghupathi, Krishna R; Guo, Jing; Munkhbat, Oyuntuya; Rangadurai, Poornima; Thayumanavan, S

    2014-07-15

    CONSPECTUS: Supramolecular assemblies formed from spontaneous self-assembly of amphiphilic macromolecules are explored as biomimetic architectures and for applications in areas such as sensing, drug delivery, and diagnostics. Macromolecular assemblies are usually preferred, compared with their simpler small molecule counterparts, due to their low critical aggregate concentrations (CAC) and high thermodynamic stability. This Account focuses on the structural and functional aspects of assemblies formed from dendrimers, specifically facially amphiphilic dendrons that form micelle or inverse micelle type supramolecular assemblies depending on the nature of the solvent medium. The micelle type assemblies formed from facially amphiphilic dendrons sequester hydrophobic guest molecules in their interiors. The stability of these assemblies is dependent on the relative compatibility of the hydrophilic and hydrophobic functionalities with water, often referred to as hydrophilic-lipophilic balance (HLB). Disruption of the HLB, using an external stimulus, could lead to disassembly of the aggregates, which can then be utilized to cause an actuation event, such as guest molecule release. Studying these possibilities has led to (i) a robust and general strategy for stimulus-induced disassembly and molecular release and (ii) the introduction of a new approach to protein-responsive supramolecular disassembly. The latter strategy provides a particularly novel avenue for impacting biomedical applications. Most of the stimuli-sensitive supramolecular assemblies have been designed to be responsive to factors such pH, temperature, and redox conditions. The reason for this interest stems from the fact that certain disease microenvironments have aberrations in these factors. However, these variations are the secondary imbalances in biology. Imbalances in protein activity are the primary reasons for most, if not all, human pathology. There have been no robust strategies in stimulus

  19. Dendrimer-templated Pd nanoparticles and Pd nanoparticles synthesized by reverse microemulsions as efficient nanocatalysts for the Heck reaction: A comparative study.

    PubMed

    Noh, Ji-Hyang; Meijboom, Reinout

    2014-02-01

    Palladium nanoparticles (NPs) were prepared using a dendrimer-templated method using G4, G5 and G6 PAMAM-OH dendrimers as well as a reverse microemulsion method using the water/dioctyl sulfosuccinate sodium salt (aerosol-OT, AOT) surfactant/isooctane system with water to surfactant ratios (ω0) of 5, 10 and 13. These 6 catalysts were characterized by UV-Vis spectroscopy, TEM, EDX, and XRD. TEM micrographs showed that the average sizes of 2.74-3.32nm with narrower size distribution were achieved by using dendrimer-templated synthetic methods, whereas the reverse microemulsion method resulted in broad size distribution with an average size of 3.87-5.06nm. The influence of various reaction parameters such as base, catalyst dosing, alkene, aryl halide and temperature on the Heck C-C coupling reaction was evaluated. The activation parameters were derived from the reaction rate of each catalyst obtained at various temperatures. A correlation of catalytic activity, enthalpy of activation and particle size is discussed. Particle size changes of each catalyst were investigated after the catalytic reaction. Overall results indicated that dendrimer-templated Pd NP catalysts showed superior activity as compared to the Pd NPs synthesized by reverse microemulsions, with the dendrimer-templated G5-OH(Pd80) showing the best activity. These catalysts were also reusable for 3 cycles, retaining high yield and showing excellent yields under mild conditions. Therefore, the dendrimer-templated Pd NPs are efficient catalyst systems for the ligand-free Heck C-C coupling reaction. PMID:24267330

  20. Microbial fuel cell cathode with dendrimer encapsulated Pt nanoparticles as catalyst

    NASA Astrophysics Data System (ADS)

    Yang, Xiaoling; Lu, Jindan; Zhu, Yihua; Shen, Jianhua; Zhang, Zhen; Zhang, Jianmei; Chen, Cheng; Li, Chunzhong

    In this paper, we investigated the use of polyamidoamine (PAMAM) dendrimer-encapsulated platinum nanoparticles (Pt-DENs) as a promising type of cathode catalyst for air-cathode single chamber microbial fuel cells (SCMFCs). The Pt-DENs, prepared via template synthesis method, have uniform diameter distribution with size range of 3-5 nm. The Pt-DENs then loaded on to a carbon substrate. For comparison, we also electrodeposited Pt on carbon substrate. The calculation shows that the loading amount of Pt-DENs on carbon substrate is about 0.1 mg cm -2, which is three times lower than that of the electrodeposited Pt (0.3 mg cm -2). By measuring batch experiments, the results show that Pt-DENs in air-cathode SCMFCs have a power density of 630 ± 5 mW m -2 and a current density of 5200 ± 10 mA m -2 (based on the projected anodic surface area), which is significantly better than electrodeposited Pt cathodes (power density: 275 ± 5 mW m -2 and current density: 2050 ± 10 mA m -2). Additionally, Pt-DENs-based cathodes resulted in a higher power production with 129.1% as compared to cathode with electrodeposited Pt. This finding suggests that Pt-DENs in MFC cathodes is a better catalyst and has a lower loading amount than electrodeposited Pt, and may serve as a novel and alternative catalyst to previously used noble metals in MFC applications.

  1. Detection of TNT using a sensitive two-photon organic dendrimer for remote sensing

    NASA Astrophysics Data System (ADS)

    Narayanan, Aditya; Varnavski, Oleg; Mongin, Oliver; Majoral, Jean-Pierre; Blanchard-Desce, Mireille; Goodson, Theodore, III

    2008-03-01

    There is currently a need for superior stand-off detection schemes for protection against explosive weapons of mass destruction. Fluorescence detection at small distances from the target has proven to be attractive. A novel unexplored route in fluorescence chemical sensing that utilizes the exceptional spectroscopic capabilities of nonlinear optical methods is two-photon excited fluorescence. This approach utilizes infra-red light for excitation of remote sensors. Infra-red light suffers less scattering in porous materials which is beneficial for vapor sensing and has greater depth of penetration through the atmosphere, and there are fewer concerns regarding eye safety in remote detection schemes. We demonstrate this method using a novel dendritic system which possesses both excellent fluorescence sensitivity to the presence of TNT with infra-red pulses of light and high two-photon absorption (TPA) response. This illustrates the use of TPA for potential stand-off detection of energetic materials in the infra-red spectral regions in a highly two-photon responsive dendrimer.

  2. Screening of efficient siRNA carriers in a library of surface-engineered dendrimers.

    PubMed

    Liu, Hongmei; Chang, Hong; Lv, Jia; Jiang, Cong; Li, Zhenxi; Wang, Fei; Wang, Hui; Wang, Mingming; Liu, Chongyi; Wang, Xinyu; Shao, Naimin; He, Bingwei; Shen, Wanwan; Zhang, Qiang; Cheng, Yiyun

    2016-01-01

    Polymers are widely used as non-viral carriers for siRNA delivery, but concern has also arisen in their limited efficacy and inherent toxicity. Whilst many of previous efforts have been documented towards improving the performance of polymers via chemical modifications, the structure-activity relationships (SAR) of these ligand-modified polymers are not well understood. To address this issue, we systemically prepared a library of surface-engineered dendrimers (>300) as the screening pool to discover efficient siRNA carriers. The modified ligands include alkyls and fluoroalkyls, amino acids, benzene derivatives and heterocyclic compounds. Gene silencing results showed that the lead material shows excellent efficacy even in hard-to-transfect cells such as mesenchymal stem cells. The SAR studies revealed that ligands containing appropriate hydrophobicity, or ligands with both hydrophobic and functional atoms/groups are essential for polymers to achive efficient knockdown efficacy. A second-generation library designed based on the above principles further confirms the proposed design criteria. The results enable the future rational design of potent siRNA carriers. PMID:27121799

  3. Optimized Mn-doped iron oxide nanoparticles entrapped in dendrimer for dual contrasting role in MRI.

    PubMed

    Haribabu, Viswanathan; Farook, Abubacker Sulaiman; Goswami, Nirmalya; Murugesan, Ramachandran; Girigoswami, Agnishwar

    2016-05-01

    Magnetic resonance imaging has acquired importance as a major tool for diagnosis and staging of cancers in humans. Injection of certain imaging agents have proved to improve contrast between normal and cancer cells on magnetic resonance imaging (MRI). Using the principles of MR contrast imaging, we have designed a dual mode (T1 and T2) contrast agent based on folic acid functionalized manganese ferrite nanoparticles (MNP) entrapped in 3G polyamidoamide (PAMAM) dendrimers. The ratio of Mn:Fe was tuned to achieve optimal performance. This multifunctional nanocarrier system was developed for targeting cancer cells to produce both T1 and T2 contrast which in turn helps in better diagnosis and staging of cancer. FTIR spectroscopy, X-Ray diffraction, atomic absorption spectroscopy, UV-Visible spectroscopy, and dynamic light scattering measurements were employed to characterize the multifunctional system at different stages of engineering. The ratio of relaxivities r2 /r1 is 4.6 at 1.5 T for the MNP prepared with 0.5 molar ratio of Mn/Fe based on MR images obtained from phantom and tumor bearing mouse. The value of r2 /r1 shows that the 0.5 molar ratio of Mn/Fe can be used to prepare MNP for the production of dual mode contrast in MR imaging. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 817-824, 2016. PMID:26460478

  4. Self-Assembly and Molecular Dynamics of Peptide-Functionalized Polyphenylene Dendrimers

    SciTech Connect

    Mondeshki,M.; Milhov, G.; Graf, R.; Spiess, H.; Mullen, K.; Papadopoulos, P.; Gitsas, A.; Floudas, G.

    2006-01-01

    The self-assembly mechanism and the associated molecular dynamics are studied for a series of poly-L-lysine-functionalized polyphenylene dendrimer melts as a function of the core size (generation), functionality, and polypeptide length using X-rays, solid-state NMR, calorimetry, and dielectric spectroscopy. A striking dependence of the polyphenylene self-assembly on the poly-L-lysine length is shown. In addition, the type ({alpha}helix/{beta}-sheet) of peptide secondary structure is controlled by the packing restrictions imposed by the polyphenylene core. We show that constrained poly-L-lysines can adopt different secondary structures from their linear analogues. The dynamic investigation revealed significant mobility associated solely with the polypeptide through three processes: a glass transition, a slower process associated with the relaxation of {alpha}-helical segments, and a glassy mode whose origin could be resolved by site-specific solid-state NMR techniques. Solid-state NMR studies further indicated a mobility gradient in going from the rigid peptide backbone to the side chains.

  5. Plasmid pORF-hTRAIL targeting to glioma using transferrin-modified polyamidoamine dendrimer

    PubMed Central

    Gao, Song; Li, Jianfeng; Jiang, Chen; Hong, Bo; Hao, Bing

    2016-01-01

    A gene drug delivery system for glioma therapy based on transferrin (Tf)-modified polyamidoamine dendrimer (PAMAM) was prepared. Gene drug, tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL)-encoding plasmid open reading frame (pORF-hTRAIL, Trail), was condensed by Tf-modified PAMAM to form nanoparticles (NPs). PAMAM-PEG-Tf/DNA NPs showed higher cellular uptake, in vitro gene expression, and cytotoxicity than PAMAM-PEG/DNA NPs in C6 cells. The in vivo targeting efficacy of NPs was visualized by ex vivo fluorescence imaging. Tf-modified NPs showed obvious glioma-targeting trend. Plasmid encoding green fluorescence protein (GFP) was also condensed by modified or unmodified PAMAM to evaluate the in vivo gene expression level. The PAMAM-PEG-Tf/plasmid encoding enhanced green fluorescence protein (pEGFP) NPs exhibited higher GFP expression level than PAMAM-PEG/pEGFP NPs. TUNEL assay revealed that Tf-modified NPs could induce much more tumor apoptosis. The median survival time of PAMAM-PEG-Tf/Trail-treated rats (28.5 days) was longer than that of rats treated with PAMAM-PEG/Trail (25.5 days), temozolomide (24.5 days), PAMAM-PEG-Tf/pEGFP (19 days), or saline (17 days). The therapeutic effect was further confirmed by magnetic resonance imaging. This study demonstrated that targeting gene delivery system had potential application for the treatment of glioma. PMID:26719669

  6. Effect of mass transfer on the oxygen reduction reaction catalyzed by platinum dendrimer encapsulated nanoparticles