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Sample records for peptide-derivatized dendrimers inhibit

  1. Peptide-Derivatized SB105-A10 Dendrimer Inhibits the Infectivity of R5 and X4 HIV-1 Strains in Primary PBMCs and Cervicovaginal Histocultures

    PubMed Central

    Bon, Isabella; Lembo, David; Rusnati, Marco; Clò, Alberto; Morini, Silvia; Miserocchi, Anna; Bugatti, Antonella; Grigolon, Sonia; Musumeci, Giuseppina; Landolfo, Santo; Re, Maria Carla; Gibellini, Davide

    2013-01-01

    Peptide dendrimers are a class of molecules that exhibit a large array of biological effects including antiviral activity. In this report, we analyzed the antiviral activity of the peptide-derivatized SB105-A10 dendrimer, which is a tetra-branched dendrimer synthetized on a lysine core, in activated peripheral blood mononuclear cells (PBMCs) that were challenged with reference and wild-type human immunodeficiency virus type 1 (HIV-1) strains. SB105-A10 inhibited infections by HIV-1 X4 and R5 strains, interfering with the early phases of the viral replication cycle. SB105-A10 targets heparan sulfate proteoglycans (HSPGs) and, importantly, the surface plasmon resonance (SPR) assay revealed that SB105-A10 strongly binds gp41 and gp120, most likely preventing HIV-1 attachment/entry through multiple mechanisms. Interestingly, the antiviral activity of SB105-A10 was also detectable in an organ-like structure of human cervicovaginal tissue, in which SB105-A10 inhibited the HIV-1ada R5 strain infection without altering the tissue viability. These results demonstrated the strong antiviral activity of SB105-A10 and suggest a potential microbicide use of this dendrimer to prevent the heterosexual transmission of HIV-1. PMID:24116111

  2. Peptide-derivatized albumins that inhibit fibrin polymerization.

    PubMed

    Watson, Joseph W; Doolittle, Russell F

    2011-11-15

    Synthetic peptides patterned on sequences that appear during thrombin proteolysis of fibrinogen are known to influence fibrin formation in very different ways. A-Knob sequences (GPR-) inhibit polymerization, but B-knob sequences (GHR-) can actually enhance the process. We now report that when such peptides are attached to albumin carriers, both knob conjugates inhibit fibrin formation. In contrast, the 2-aminoethylthiol-albumin conjugate control enhances the polymerization to the same degree as albumin. The peptide AHRPam, which is known to bind exclusively to the βC holes of fibrinogen/fibrin, nullifies the inhibitory effects of the GHRPYGGGCam-albumin conjugate on fibrin polymerization, indicating that the inhibition was exclusively due to interactions with βC holes. AHRPam was much less effective in countering inhibition by the GPRPGGGGCam-albumin conjugate, suggesting that the observed effects with this conjugate involve mainly the γC holes of fibrin/fibrinogen. This study demonstrates that peptides modeled on fibrin polymerization knobs tethered to albumin retain their capacity to interact with fibrinogen/fibrin and may prove useful as inhibitors of clotting in vivo.

  3. Dendrimers

    NASA Astrophysics Data System (ADS)

    Bryant, L. Henry; Bulte, Jeff W. M.

    Dendrimers have received an enormous amount of attention in the last ten years and several recent review articles have appeared in the literature that address their potential applications [1-3]. Stoddart et al [1] have stated that: "We are now approaching a time when the study of dendriniers bec omes inextricably linked with many other fields, leaving the comprehensive reviewer of the subject a near-impossible task to fulfil". On that note, this review provides a brief introduction to the chemical principles of dendrimers by highlighting main synthetic strategies and methods for characterisation. p]Dendrimers containing heteroatoms will not be reviewed per se since these have recently been reviewed [4]. The major thrust of this review is the potential applications of dendrimers in such areas as boron neutron capture therapy, as contrast agents in magnetic resonance imaging, as vaccines, as cellular transfection agents and as bioconjugate dendrimers, i.e., in-vitro immunoassays for antigens. The outline used in this review proved to be effective in classifying most published papers about dendrimers, but it must be kept in mind that some articles not only transcended two different classifications, such as synthesis and characterisation, but several classifications such as synthesis, characterisation and at least one potential application covered in this review.

  4. 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

  5. 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

  6. Potential inhibition of HIV-1 encapsidation by oligoribonucleotide–dendrimer nanoparticle complexes

    PubMed Central

    Parboosing, Raveen; Chonco, Louis; de la Mata, Francisco Javier; Govender, Thavendran; Maguire, Glenn EM; Kruger, Hendrik G

    2017-01-01

    Background Encapsidation, the process during which the genomic RNA of HIV is packaged into viral particles, is an attractive target for antiviral therapy. This study explores a novel nanotechnology-based strategy to inhibit HIV encapsidation by an RNA decoy mechanism. The design of the 16-mer oligoribonucleotide (RNA) decoy is based on the sequence of stem loop 3 (SL3) of the HIV packaging signal (Ψ). Recognition of the packaging signal is essential to the encapsidation process. It is theorized that the decoy RNA, by mimicking the packaging signal, will disrupt HIV packaging if efficiently delivered into lymphocytes by complexation with a carbosilane dendrimer. The aim of the study is to measure the uptake, toxicity, and antiviral activity of the dendrimer–RNA nanocomplex. Materials and methods A dendriplex was formed between cationic carbosilane dendrimers and the RNA decoy. Uptake of the fluorescein-labeled RNA into MT4 lymphocytes was determined by flow cytometry and confocal microscopy. The cytoprotective effect (50% effective concentration [EC50]) and the effect on HIV replication were determined in vitro by the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and viral load measurements, respectively. Results Flow cytometry and confocal imaging demonstrated efficient transfection of lymphocytes. The dendriplex containing the Ψ decoy showed some activity (EC50 =3.20 µM, selectivity index =8.4). However, there was no significant suppression of HIV viral load. Conclusion Oligoribonucleotide decoys containing SL3 of the packaging sequence are efficiently delivered into lymphocytes by carbosilane dendrimers where they exhibit a modest cytoprotective effect against HIV infection. PMID:28115849

  7. RGD peptide-modified multifunctional dendrimer platform for drug encapsulation and targeted inhibition of cancer cells.

    PubMed

    He, Xuedan; Alves, Carla S; Oliveira, Nilsa; Rodrigues, João; Zhu, Jingyi; Bányai, István; Tomás, Helena; Shi, Xiangyang

    2015-01-01

    Development of multifunctional nanoscale drug-delivery systems for targeted cancer therapy still remains a great challenge. Here, we report the synthesis of cyclic arginine-glycine-aspartic acid (RGD) peptide-conjugated generation 5 (G5) poly(amidoamine) dendrimers for anticancer drug encapsulation and targeted therapy of cancer cells overexpressing αvβ3 integrins. In this study, amine-terminated G5 dendrimers were used as a platform to be sequentially modified with fluorescein isothiocyanate (FI) via a thiourea linkage and RGD peptide via a polyethylene glycol (PEG) spacer, followed by acetylation of the remaining dendrimer terminal amines. The developed multifunctional dendrimer platform (G5.NHAc-FI-PEG-RGD) was then used to encapsulate an anticancer drug doxorubicin (DOX). We show that approximately six DOX molecules are able to be encapsulated within each dendrimer platform. The formed complexes are water-soluble, stable, and able to release DOX in a sustained manner. One- and two-dimensional NMR techniques were applied to investigate the interaction between dendrimers and DOX, and the impact of the environmental pH on the release rate of DOX from the dendrimer/DOX complexes was also explored. Furthermore, cell biological studies demonstrate that the encapsulation of DOX within the G5.NHAc-FI-PEG-RGD dendrimers does not compromise the anticancer activity of DOX and that the therapeutic efficacy of the dendrimer/DOX complexes is solely related to the encapsulated DOX drug. Importantly, thanks to the role played by RGD-mediated targeting, the developed dendrimer/drug complexes are able to specifically target αvβ3 integrin-overexpressing cancer cells and display specific therapeutic efficacy to the target cells. The developed RGD peptide-targeted multifunctional dendrimers may thus be used as a versatile platform for targeted therapy of different types of αvβ3 integrin-overexpressing cancer cells.

  8. Dendrimers incorporating benzenesulfonamide moieties strongly inhibit carbonic anhydrase isoforms I-XIV.

    PubMed

    Carta, Fabrizio; Osman, Sameh M; Vullo, Daniela; AlOthman, Zeid; Supuran, Claudiu T

    2015-06-21

    As extension of our previous study herein we report a comprehensive investigation of poly(amidoamine) (PAMAM) dendrimers as modulators of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I-XIV. Interestingly inhibitory activity was observed for the non-functionalized dendrimers against the hCA I, VII, IX, XII and XIV isoforms, whereas activation properties were reported only for the cytosolic abundant hCA II. Highly efficient inhibitory action against many isoforms having medicinal chemistry applications, such as hCA II, V, VII, IX, XII and XIV, was observed for the PAMAM functionalized counterparts bearing 4, 8, 16 and 32 benzenesulfonamide moieties. Possible applications of dendrimer-CA inhibitors as therapeutic/diagnostic agents are envisaged.

  9. 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 Central

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

    2016-01-01

    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

  10. 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.

    PubMed

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

    2015-03-07

    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.

  11. 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

  12. Tryptophan dendrimers that inhibit HIV replication, prevent virus entry and bind to the HIV envelope glycoproteins gp120 and gp41.

    PubMed

    Rivero-Buceta, Eva; Doyagüez, Elisa G; Colomer, Ignacio; Quesada, Ernesto; Mathys, Leen; Noppen, Sam; Liekens, Sandra; Camarasa, María-José; Pérez-Pérez, María-Jesús; Balzarini, Jan; San-Félix, Ana

    2015-12-01

    Dendrimers containing from 9 to 18 tryptophan residues at the peryphery have been efficiently synthesized and tested against HIV replication. These compounds inhibit an early step of the replicative cycle of HIV, presumably virus entry into its target cell. Our data suggest that HIV inhibition can be achieved by the preferred interaction of the compounds herein described with glycoproteins gp120 and gp41 of the HIV envelope preventing interaction between HIV and the (co)receptors present on the host cells. The results obtained so far indicate that 9 tryptophan residues on the periphery are sufficient for efficient gp120/gp41 binding and anti-HIV activity.

  13. Inhibition of Bacterial Growth and Intramniotic Infection in a Guinea Pig Model of Chorioamnionitis Using PAMAM Dendrimers

    PubMed Central

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

    2010-01-01

    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 µg of generation-4 neutral dendrimer (G4-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 post treatment showed absence of E. coli growth in the cultures plated with it. The cytokine level [tumor necrosis factor (TNFα) and interleukin (IL-6 and IL-1β)] in placenta of the G4-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 G4-PAMAM-NH2 shows superior antibacterial activity, it was found to be cytotoxic to human cervical epithelial cell line above 10µg / mL, while the G4-PAMAM-OH was non cytotoxic upto 1mg / mL concentration. Cell integrity, outer (OM) and inner (IM) membrane permeabilization assays showed that G4-PAMAM-OH dendrimer efficiently changed the OM permeability, while G4-PAMAM-NH2 and G3.5-PAMAM-COOH damaged both OM and IM causing the bacterial lysis. The possible antibacterial mechanism are; G4-PAMAM-NH2 acts as polycation binding to the polyanionic lipopolysaccharide in E. coli, the G4-PAMAM-OH forms hydrogen bonds with the hydrophilic O-antigens in E. coli membrane and the G3.5-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 G4-PAMAM-OH dendrimer acts as an antibacterial agent. PMID:20580797

  14. 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.

  15. SRL-Coated PAMAM Dendrimer Nano-Carrier for Targeted Gene Delivery to the Glioma Cells and Competitive Inhibition by Lactoferrin

    PubMed Central

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

    2016-01-01

    Glioma, as a primary tumor of central nervous system, is the main cause of death in patients with brain cancer. Therefore, development of an efficient strategy for treatment of glioma is worthy. The aim of the current study was to develop a SRL peptide-coated dendrimer as a novel dual gene delivery system for targeting the LRP receptor, an up-regulated gene in both BBB and glioma cells. To perform this investigation, our newly developed nanocarrier (PAMAM-PEG-SRL) was used for gene delivery to C6 glioma cell lines. DNA (GFP) was loaded in these functionalized nanoparticles and their cellular uptake/distribution and gene transfection efficacy was evaluated by fluorescence and confocal microscopy. In vitro studies showed that SRL-modified nanoparticles have good transfection efficacy. Results revealed improved gene transfection efficiency of newly-synthesized delivery system. We also found that lactoferrin, as a LRP ligand, reduced the gene transfection efficacy of the delivery system due to its higher affinity compared to SRL peptides (Competitive inhibition). The present results suggest that the synthesized delivery system has the potential to be used as an alternative targeted drug delivery system for brain tumors. PMID:28243262

  16. The influence of PAMAM dendrimers surface groups on their interaction with porcine pepsin.

    PubMed

    Ciolkowski, Michal; Rozanek, Monika; Bryszewska, Maria; Klajnert, Barbara

    2013-10-01

    In this study the ability of three polyamidoamine (PAMAM) dendrimers with different surface charge (positive, neutral and negative) to interact with a negatively charged protein (porcine pepsin) was examined. It was shown that the dendrimer with a positively charged surface (G4 PAMAM-NH2), as well as the dendrimer with a neutral surface (G4 PAMAM-OH), were able to inhibit enzymatic activity of pepsin. It was also found that these dendrimers act as mixed partially non-competitive pepsin inhibitors. The negatively charged dendrimer (G3.5 PAMAM-COOH) was not able to inhibit the enzymatic activity of pepsin, probably due to the electrostatic repulsion between this dendrimer and the protein. No correlation between changes in enzymatic activity of pepsin and alterations in CD spectrum of the protein was observed. It indicates that the interactions between dendrimers and porcine pepsin are complex, multidirectional and not dependent only on disturbances of the secondary structure.

  17. 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.

  18. Antiviral properties against HIV of water soluble copper carbosilane dendrimers and their EPR characterization.

    PubMed

    Galan, M; Sanchez-Rodriguez, J; Cangiotti, M; Garcia-Gallego, S; Jimenez, J L; Gomez, R; Ottaviani, M F; Munoz-Fernandez, M A; de la Mata, F J

    2012-01-01

    We describe here the use of anionic carbosilane dendrimers to obtain new copper complexes. UV-Vis and a computer aided analysis of the EPR spectra provided information about the coordination modes of copper depending on the nature of the dendrimer and about the geometry and structure of the complexes in solution. Some of these metallo-dendrimers have been tested "in vitro" as antiviral compounds in the inhibition of HIV infection in pre and post-infection treatment.

  19. Light harvesting dendrimers.

    PubMed

    Nantalaksakul, Arpornrat; Reddy, D Raghunath; Bardeen, Christopher J; Thayumanavan, S

    2006-01-01

    Tree-like dendrimers with decreasing number of chromophores from periphery to core is an attractive candidate for light-harvesting applications. Numerous dendritic designs with different kinds of light-collecting chromophores at periphery and an energy-sink at the core have been demonstrated with high energy transfer efficiency. These building blocks are now being developed for several applications such as light-emitting diodes, frequency converters and other photonic devices. This review outlines the efforts that are based on both conjugated and non-conjugated dendrimers.

  20. Self-interrupted synthesis of sterically hindered aliphatic polyamide dendrimers.

    PubMed

    Jishkariani, Davit; MacDermaid, Christopher M; Timsina, Yam N; Grama, Silvia; Gillani, Syeda S; Divar, Masoumeh; Yadavalli, Srujana S; Moussodia, Ralph-Olivier; Leowanawat, Pawaret; Berrios Camacho, Angely M; Walter, Ricardo; Goulian, Mark; Klein, Michael L; Percec, Virgil

    2017-03-21

    2,2-Bis(azidomethyl)propionic acid was prepared in four steps and 85% yield from the commercially available 2,2-bis(hydroxymethyl)propionic acid and used as the starting building block for the divergent, convergent, and double-stage convergent-divergent iterative methods for the synthesis of dendrimers and dendrons containing ethylenediamine (EDA), piperazine (PPZ), and methyl 2,2-bis(aminomethyl)propionate (COOMe) cores. These cores have the same multiplicity but different conformations. A diversity of synthetic methods were used for the synthesis of dendrimers and dendrons. Regardless of the method used, a self-interruption of the synthesis was observed at generation 4 for the dendrimer with an EDA core and at generation 5 for the one with a PPZ core, whereas for the COOMe core, self-interruption was observed at generation 6 dendron, which is equivalent to generation 5 dendrimer. Molecular modeling and molecular-dynamics simulations demonstrated that the observed self-interruption is determined by the backfolding of the azide groups at the periphery of the dendrimer. The latter conformation inhibits completely the heterogeneous hydrogenation of the azide groups catalyzed by 10% Pd/carbon as well as homogeneous hydrogenation by the Staudinger method. These self-terminated polyamide dendrimers are enzymatically and hydrolytically stable and also exhibit antimicrobial activity. Thus, these nanoscale constructs open avenues for biomedical applications.

  1. 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.

  2. Lactose-Functionalized Dendrimers Arbitrate the Interaction of Galectin-3/MUC1 Mediated Cancer Cellular Aggregation

    PubMed Central

    Michel, Anna K.; Nangia-Makker, Pratima; Raz, Avraham

    2015-01-01

    By using lactose-functionalized poly(amidoamine) dendrimers as a tunable multivalent platform, we studied cancer cell aggregation in three different cell lines (A549, DU-145, and HT-1080) with galectin-3. We found that small lactose-functionalized G(2)-dendrimer 1 inhibited galectin-3-induced aggregation of the cancer cells. In contrast, dendrimer 4 (a larger, generation 6 dendrimer with 100 carbohydrate end groups) caused cancer cells to aggregate through a galectin-3 pathway. This study indicates that inhibition of cellular aggregation occurred because 1 provided competitive binding sites for galectin-3 (compared to its putative cancer cell ligand, TF-antigen on MUC1). Dendrimer 4, in contrast, provided an excess of ligands for galectin-3 binding; this caused crosslinking and aggregation of cells to be increased. PMID:25138772

  3. Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth

    PubMed Central

    Al-Jamal, Khuloud T.; Al-Jamal, Wafa’ T.; Akerman, Simon; Podesta, Jennifer E.; Yilmazer, Açelya; Turton, John A.; Bianco, Alberto; Vargesson, Neil; Kanthou, Chryso; Florence, Alexander T.; Tozer, Gillian M.; Kostarelos, Kostas

    2010-01-01

    This study describes the previously unreported intrinsic capacity of poly-L-lysine (PLL) sixth generation (G6) dendrimer molecules to exhibit systemic antiangiogenic activity that could lead to solid tumor growth arrest. The PLL-dendrimer-inhibited tubule formation of SVEC4-10 murine endothelial cells and neovascularization in the chick embryo chick chorioallantoic membrane (CAM) assay. Intravenous administration of the PLL-dendrimer molecules into C57BL/6 mice inhibited vascularisation in Matrigel plugs implanted subcutaneously. Antiangiogenic activity was further evidenced using intravital microscopy of tumors grown within dorsal skinfold window chambers. Reduced vascularization of P22 rat sarcoma implanted in the dorsal window chamber of SCID mice was observed following tail vein administration (i.v.) of the PLL dendrimers. Also, the in vivo toxicological profile of the PLL-dendrimer molecules was shown to be safe at the dose regime studied. The antiangiogenic activity of the PLL dendrimer was further shown to be associated with significant suppression of B16F10 solid tumor volume and delayed tumor growth. Enhanced apoptosis/necrosis within tumors of PLL-dendrimer-treated animals only and reduction in the number of CD31 positive cells were observed in comparison to protamine treatment. This study suggests that PLL-dendrimer molecules can exhibit a systemic antiangiogenic activity that may be used for therapy of solid tumors, and in combination with their capacity to carry other therapeutic or diagnostic agents may potentially offer capabilities for the design of theranostic systems. PMID:20150514

  4. Dendrimer-protein interactions versus dendrimer-based nanomedicine.

    PubMed

    Shcharbin, Dzmitry; Shcharbina, Natallia; Dzmitruk, Volha; Pedziwiatr-Werbicka, Elzbieta; Ionov, Maksim; Mignani, Serge; de la Mata, F Javier; Gómez, Rafael; Muñoz-Fernández, Maria Angeles; Majoral, Jean-Pierre; Bryszewska, Maria

    2017-04-01

    Dendrimers are hyperbranched polymers belonging to the huge class of nanomedical devices. Their wide application in biology and medicine requires understanding of the fundamental mechanisms of their interactions with biological systems. Summarizing, electrostatic force plays the predominant role in dendrimer-protein interactions, especially with charged dendrimers. Other kinds of interactions have been proven, such as H-bonding, van der Waals forces, and even hydrophobic interactions. These interactions depend on the characteristics of both participants: flexibility and surface charge of a dendrimer, rigidity of protein structure and the localization of charged amino acids at its surface. pH and ionic strength of solutions can significantly modulate interactions. Ligands and cofactors attached to a protein can also change dendrimer-protein interactions. Binding of dendrimers to a protein can change its secondary structure, conformation, intramolecular mobility and functional activity. However, this strongly depends on rigidity versus flexibility of a protein's structure. In addition, the potential applications of dendrimers to nanomedicine are reviwed related to dendrimer-protein interactions.

  5. 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.

  6. 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

  7. 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

  8. Cationic PAMAM dendrimers as pore-blocking binary toxin inhibitors.

    PubMed

    Förstner, Philip; Bayer, Fabienne; Kalu, Nnanya; Felsen, Susanne; Förtsch, Christina; Aloufi, Abrar; Ng, David Y W; Weil, Tanja; Nestorovich, Ekaterina M; Barth, Holger

    2014-07-14

    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.

  9. Dendrimers: synthesis, applications, and properties

    NASA Astrophysics Data System (ADS)

    Abbasi, Elham; Aval, Sedigheh Fekri; Akbarzadeh, Abolfazl; Milani, Morteza; Nasrabadi, Hamid Tayefi; Joo, Sang Woo; Hanifehpour, Younes; Nejati-Koshki, Kazem; Pashaei-Asl, Roghiyeh

    2014-05-01

    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.

  10. Dendrimers as drug delivery vehicles: non-covalent interactions of bioactive compounds with dendrimers

    PubMed Central

    Crampton, Hannah L; Simanek, Eric E

    2009-01-01

    This mini review highlights issues associated with the use of dendrimers as drug delivery vehicles. The review introduces dendrimers and summarizes findings on their use in vivo and in vitro. Specifically, this review is limited to examples wherein the drug is non-covalently associated with the dendrimer. Examples wherein the drug is covalently attached to the dendrimer are not discussed. PMID:19960104

  11. 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

  12. 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.

  13. 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

    2013-11-06

    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.

  14. Fluorous Mixture Synthesis of Asymmetric Dendrimers

    PubMed Central

    Jiang, Zhong-Xing; Yu, Yihua Bruce

    2010-01-01

    A divergent fluorous mixture synthesis (FMS) of asymmetric fluorinated dendrimers has been developed. Four generations of fluorinated dendrimers with the same fluorinated moiety were prepared with high efficiency, yield and purity. Comparison of the physicochemical properties of these dendrimers provided valuable information for their application and future optimization. This strategy has not only provided a practical method for the synthesis and purification of dendrimers, but also established the possibility of utilizing the same fluorinated moiety for FMS. PMID:20170088

  15. Phosphorus-Based Dendrimer ABP Treats Neuroinflammation by Promoting IL-10-Producing CD4(+) T Cells.

    PubMed

    Hayder, Myriam; Varilh, Marjorie; Turrin, Cédric-Olivier; Saoudi, Abdelhadi; Caminade, Anne-Marie; Poupot, Rémy; Liblau, Roland S

    2015-11-09

    Dendrimers are polyfunctional nano-objects of perfectly defined structure that can provide innovative alternatives for the treatment of chronic inflammatory diseases, including multiple sclerosis (MS). To investigate the efficiency of a recently described amino-bis(methylene phosphonate)-capped ABP dendrimer as a potential drug candidate for MS, we used the classical mouse model of MOG35-55-induced experimental autoimmune encephalomyelitis (EAE). Our study provides evidence that the ABP dendrimer prevents the development of EAE and inhibits the progression of established disease with a comparable therapeutic benefit as the approved treatment Fingolimod. We also show that the ABP dendrimer redirects the pathogenic myelin-specific CD4(+) T cell response toward IL-10 production.

  16. 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.

  17. In Situ-Forming Polyamidoamine Dendrimer Hydrogels with Tunable Properties Prepared via Aza-Michael Addition Reaction.

    PubMed

    Wang, Juan; He, Hongliang; Cooper, Remy C; Yang, Hu

    2017-03-29

    In this work, we describe synthesis and characterization of novel in situ-forming polyamidoamine (PAMAM) dendrimer hydrogels (DHs) with tunable properties prepared via highly efficient aza-Michael addition reaction. PAMAM dendrimer G5 was chosen as the underlying core and functionalized with various degrees of acetylation using acetic anhydride. The nucleophilic amines on the dendrimer surface reacted with α, β-unsaturated ester in acrylate groups of polyethylene glycol diacrylate (PEG-DA, Mn = 575 g/mol) via aza-Michael addition reaction to form dendrimer hydrogels without the use of any catalyst. The solidification time, rheological behavior, network structure, swelling, and degradation properties of the hydrogel were tuned by adjusting the dendrimer surface acetylation degree and dendrimer concentration. The DHs were shown to be highly cytocompatible and support cell adhesion and proliferation. We also prepared an injectable dendrimer hydrogel formulation to deliver the anticancer drug 5-fluorouracil (5-FU) and demonstrated that the injectable formulation efficiently inhibited tumor growth following intratumoral injection. Taken together, this new class of dendrimer hydrogel prepared by aza-Michael addition reaction can serve as a safe tunable platform for drug delivery and tissue engineering.

  18. The specific contribution of phosphorus in dendrimer chemistry.

    PubMed

    Majoral, Jean-Pierre; Caminade, Anne-Marie; Maraval, Valérie

    2002-12-21

    Besides properties commonly found for all types of dendrimers, phosphorus-containing dendrimers possess some specific properties seldom or never found for other types of dendrimers. Emphasis will be put on these specificities.

  19. Nanomedicine for prion disease treatment: new insights into the role of dendrimers.

    PubMed

    McCarthy, James M; Appelhans, Dietmar; Tatzelt, Jörg; Rogers, Mark S

    2013-01-01

    Despite their devastating impact, no effective therapeutic yet exists for prion diseases at the symptomatic stage in humans or animals. Progress is hampered by the difficulty in identifying compounds that affect PrP (Sc) and the necessity of any potential therapeutic to gain access to the CNS. Synthetic polymers known as dendrimers are a particularly promising candidate in this area. Studies with cell culture models of prion disease and prion infected brain homogenate have demonstrated that numerous species of dendrimers eliminate PrP (Sc) in a dose and time dependent fashion and specific glycodendrimers are capable of crossing the CNS. However, despite their potential a number of important questions remained unanswered such as what makes an effective dendrimer and how dendrimers eliminate prions intracellularly. In a number of recent studies we have tackled these questions and revealed for the first time that a specific dendrimer can inhibit the intracellular conversion of PrP (C) to PrP (Sc) and that a high density of surface reactive groups is a necessity for dendrimers in vitro anti-prion activity. Understanding how a therapeutic works is a vital component in maximising its activity and these studies therefore represent a significant development in the race to find effective treatments for prion diseases.

  20. [Study on the interaction of cobalt (II) polyamidomine dendrimer with DNA by spectrometry techniques].

    PubMed

    Li, Jin-Huan; Ai, Shi-Yun; Shi, Wei-Jie; Yin, Huan-Shun; Du, Hong-Xia

    2009-03-01

    Cobalt (II) polyamidomine dendrimer was prepared by the reaction of cobalt chloride, glyoxal and polyamidomine dendrimer of 5.0 generation. The interaction of cobalt (II) polyamidomine dendrimer complex with herring sperm (hsDNA) was carried out using methylene blue (MB) as the probe molecule by absorption and fluorescence spectroscopy and synchronous fluorescence spectroscopy. The results showed that the intensity of absorption peaks and fluorescence peaks increased when the complex interacted with hsDNA. The effect of sodium chloride showed that sodium ion can significantly constrain the interaction of cobalt(II) polyamidomine dendrimer with hsDNA. The curves indicated the competitive inhibition of MB binding to hsDNA in the presence of cobalt (II) polyamidomine dendrimer complexes, also MB could insert into interior of cobalt (II) polyamidomine dendrimer complexes. The results suggested that the complex mainly interacted with negatively charged phosphate moieties on hsDNA through electrostatic attraction and stacked on the surface of double stranded hsDNA, which may reduce the binding affinity of MB to hsDNA in the surrounding site. It was indicated that sodium ion might neutralize the negatively charged phosphate backbone of hsDNA, and then weaken the electrostatic attraction between complexes and hsDNA.

  1. Precise localization of metal nanoparticles in dendrimer nanosnakes or inner periphery and consequences in catalysis

    NASA Astrophysics Data System (ADS)

    Liu, Xiang; Gregurec, Danijela; Irigoyen, Joseba; Martinez, Angel; Moya, Sergio; Ciganda, Roberto; Hermange, Philippe; Ruiz, Jaime; Astruc, Didier

    2016-10-01

    Understanding the relationship between the location of nanoparticles (NPs) in an organic matrix and their catalytic performances is essential for catalyst design. Here we show that catalytic activities of Au, Ag and CuNPs stabilized by dendrimers using coordination to intradendritic triazoles, galvanic replacement or stabilization outside dendrimers strongly depends on their location. AgNPs are found at the inner click dendrimer periphery, whereas CuNPs and AuNPs are encapsulated in click dendrimer nanosnakes. AuNPs and AgNPs formed by galvanic replacement are larger than precursors and only partly encapsulated. AuNPs are all the better 4-nitrophenol reduction catalysts as they are less sterically inhibited by the dendrimer interior, whereas on the contrary CuNPs are all the better alkyne azide cycloaddition catalysts as they are better protected from aerobic oxidation inside dendrimers. This work highlights the role of the location in macromolecules on the catalytic efficiency of metal nanoparticles and rationalizes optimization in catalyst engineering.

  2. Precise localization of metal nanoparticles in dendrimer nanosnakes or inner periphery and consequences in catalysis

    PubMed Central

    Liu, Xiang; Gregurec, Danijela; Irigoyen, Joseba; Martinez, Angel; Moya, Sergio; Ciganda, Roberto; Hermange, Philippe; Ruiz, Jaime; Astruc, Didier

    2016-01-01

    Understanding the relationship between the location of nanoparticles (NPs) in an organic matrix and their catalytic performances is essential for catalyst design. Here we show that catalytic activities of Au, Ag and CuNPs stabilized by dendrimers using coordination to intradendritic triazoles, galvanic replacement or stabilization outside dendrimers strongly depends on their location. AgNPs are found at the inner click dendrimer periphery, whereas CuNPs and AuNPs are encapsulated in click dendrimer nanosnakes. AuNPs and AgNPs formed by galvanic replacement are larger than precursors and only partly encapsulated. AuNPs are all the better 4-nitrophenol reduction catalysts as they are less sterically inhibited by the dendrimer interior, whereas on the contrary CuNPs are all the better alkyne azide cycloaddition catalysts as they are better protected from aerobic oxidation inside dendrimers. This work highlights the role of the location in macromolecules on the catalytic efficiency of metal nanoparticles and rationalizes optimization in catalyst engineering. PMID:27759006

  3. Poly(amidoamine) dendrimers show carbonic anhydrase inhibitory activity against α-, β-, γ- and η-class enzymes.

    PubMed

    Carta, Fabrizio; Osman, Sameh M; Vullo, Daniela; AlOthman, Zeid; Del Prete, Sonia; Capasso, Clemente; Supuran, Claudiu T

    2015-11-01

    Four generations of poly(amidoamine) (PAMAM) dendrimers incorporating benzenesulfonamide moieties were investigated as inhibitors of carbonic anhydrases (CAs, EC 4.2.1.1) belonging to the α-, β-, γ- and η-classes which are present in pathogenic bacteria, fungi or protozoa. The following bacterial, fungal and protozoan organisms were included in the study: Vibrio cholerae, Trypanosoma cruzi, Leishmania donovani chagasi, Porphyromonas gingivalis, Cryptococcus neoformans, Candida glabrata, and Plasmodium falciparum. The eight pathozymes present in these organisms were efficiently inhibited by the four generations PAMAM-sulfonamide dendrimers, but multivalency effects were highly variable among the different enzyme classes. The Vibrio enzyme VchCA was best inhibited by the G3 dendrimer incorporating 32 sulfamoyl moieties. The Trypanosoma enzyme TcCA on the other hand was best inhibited by the first generation dendrimer G0 (with 4 sulfamoyl groups), whereas for other enzymes the optimal inhibitory power was observed for the G1 or G2 dendrimers, with 8 and 16 sulfonamide functionalities. This study thus proves that the multivalency may be highly relevant for enzyme inhibition for some but not all CAs from pathogenic organisms. On the other hand, some dendrimers investigated here showed a better inhibitory power compared to acetazolamide for enzymes from widespread pathogens, such as the η-CA from Plasmodium falciparum. Overall, the main conclusion is that this class of molecules may lead to important developments in the field of anti-infective CA inhibitors.

  4. Labeling Cells with Silver/Dendrimer Nanocomposites

    DTIC Science & Technology

    2005-01-01

    labeling. A PAMAME5.NH 2 dendrimer was used as a template to prepare first a silver -dendrimer complex in an aqueous solution at biologic pH=7.4...electron microscope operating at 200 kV. Samples were prepared by mounting a drop of aqueous solutions of nanoparticles on carbon-coated copper grids...UNCLASSIFIED Defense Technical Information Center Compilation Part Notice ADP019741 TITLE: Labeling Cells with Silver /Dendrimer Nanocomposites

  5. Controlling Androgen receptor nuclear localization by dendrimer conjugates

    NASA Astrophysics Data System (ADS)

    Wang, Haoyu

    Androgen Receptor (AR) antagonists, such as bicalutamide and flutamide have been used widely in the treatment of prostate cancer. Although initial treatment is effective, prostate cancer cells often acquire antiandrogen resistance with prolonged treatment. AR over-expression and AR mutations contribute to the development of antiandrogen resistant cancer. Second generation antiandrogens such as enzalutamide are more effective and show reduced AR nuclear localization. In this study, derivatives of PAN52, a small molecule antiandrogen previously developed in our lab, were conjugated to the surface of generation 4 and generation 6 PAMAM dendrimers to obtain antiandrogen PAMAM dendrimer conjugates (APDC). APDCs readily enter cells and associate with AR in the cytoplasm. Due to their large size and positive charge, they can not enter the nucleus, thus retaining AR in the cytoplasm. In addition, APDCs are effective in decreasing AR mediated transcription and cell proliferation. APDC is the first AR antagonists that inhibit DHT-induced nuclear localization of AR. By inhibiting AR nuclear localization, APDC represents a new class of antiandrogens that offer an alternative approach to addressing antiandrogen-resistant prostate cancer. Lysine post-translational modification of AR Nuclear Localization Sequence (NLS) has great impact on AR cellular localization. It is of interest to understand which modifications modulate AR translocation into the nucleus. In this study, we prepared dendrimer-based acetyltransferase mimetic (DATM), DATM is able to catalytically acetylate AR in CWR22Rv1 cells, which will be a useful tool for studying AR modification effect on AR cellular localization. Derivatives of DATM, which transfer other chemical groups to AR, can be prepared similarly, and with more dendrimer based AR modification tools prepared in future, we will be able to understand and control AR cellular localization through AR modification.

  6. Design considerations for PAMAM dendrimer therapeutics.

    PubMed

    Goonewardena, Sascha N; Kratz, Jeremy D; Zong, Hong; Desai, Ankur M; Tang, Shengzhuang; Emery, Sarah; Baker, James R; Huang, Baohua

    2013-05-15

    We have previously shown that methotrexate (MTX) conjugated to a cancer-specific poly amido amine (PAMAM) dendrimer has a higher therapeutic index than MTX alone. Unfortunately, these therapeutics have been difficult to advance because of the complicated syntheses and an incomplete understanding of the dendrimer properties. We wished to address these obstacles by using copper-free click chemistry to functionalize the dendrimer scaffolds and to exploring the effects of two dendrimer properties (the targeting ligand and drug linkage) on cytotoxicity. We conjugated either ester or amide-linker modified MTX to dendrimer scaffolds with or without folic acid (FA). Because of multivalency, the FA and MTX functionalized dendrimers had similar capacities to target the folate receptor on cancer cells. Additionally, we found that the ester- and amide-linker modified MTX compounds had similar cytotoxicity but the dendrimer-ester MTX conjugates were much more cytotoxic than the dendrimer-amide MTX conjugates. These results clarify the impact of these properties on therapeutic efficacy and will allow us to design more effective polymer therapeutics.

  7. Cucurbituril and Cyclodextrin Complexes of Dendrimers

    NASA Astrophysics Data System (ADS)

    Wang, Wei; Kaifer, Angel E.

    This chapter reviews the growing body of data on the binding interactions between dendrimers and two types of well-established molecular hosts: cyclodextrins and cucurbit[n]urils. Dendrimers are highly branched macromolecules to which functional groups can be attached in spatially defined locations. The attachment of guest functional groups to dendrimers allows the investigation of their binding interactions with freely diffusing hosts/receptors. The effect of dendrimer size on the thermodynamics of these host-guest reactions varies widely depending on factors described here. In optimum cases, it is possible to use these binding interactions to exert redox control on dendrimer self-assembly and even control the size of the resulting assemblies.

  8. 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.

  9. 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

  10. Dendrimer building toolkit: model building and characterization of various dendrimer architectures.

    PubMed

    Maingi, Vishal; Jain, Vaibhav; Bharatam, Prasad V; Maiti, Prabal K

    2012-09-30

    We have developed a graphical user interface based dendrimer builder toolkit (DBT) which can be used to generate the dendrimer configuration of desired generation for various dendrimer architectures. The validation of structures generated by this tool was carried out by studying the structural properties of two well known classes of dendrimers: ethylenediamine cored poly(amidoamine) (PAMAM) dendrimer, diaminobutyl cored poly(propylene imine) (PPI) dendrimer. Using full atomistic molecular dynamics (MD) simulation we have calculated the radius of gyration, shape tensor and monomer density distribution for PAMAM and PPI dendrimer at neutral and high pH. A good agreement between the available simulation and experimental (small angle X-ray and neutron scattering; SAXS, SANS) results and calculated radius of gyration was observed. With this validation we have used DBT to build another new class of nitrogen cored poly(propyl ether imine) dendrimer and study it's structural features using all atomistic MD simulation. DBT is a versatile tool and can be easily used to generate other dendrimer structures with different chemistry and topology. The use of general amber force field to describe the intra-molecular interactions allows us to integrate this tool easily with the widely used molecular dynamics software AMBER. This makes our tool a very useful utility which can help to facilitate the study of dendrimer interaction with nucleic acids, protein and lipid bilayer for various biological applications.

  11. 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

  12. Polyamidoamine dendrimers surface-engineered with biomimetic phosphorylcholine as potential drug delivery carriers.

    PubMed

    Jia, Lan; Xu, Jian-Ping; Wang, Hai; Ji, Jian

    2011-05-01

    Biomimetic acryloyloxyethyl phosphorylcholine (APC) was used to react with generation 5 poly(amido amine) (PAMAM) dendrimers (G5) via the Michael addition reaction between primary amino group of PAMAM dendrimers and acrylic functional group of APC. FTIR and (1)H NMR confirmed the success of surface modification of G5. The primary amino and phosphorylcholine (PC) group numbers of the surface engineered PAMAM dendrimers (G5-PC) were calculated to be 56 and 50 via (1)H NMR and potentiometric titration. Cell viability and cell morphology studies indicated that biomimetic phosphorylcholine surface engineering successfully lowered the cytotoxicity of G5 PAMAM dendrimers. The hydrophobic interior of G5-PC was used to incorporate anti-cancer drug Adriamycin (ADR) and the G5-PC showed sustained releasing behavior for ADR. Cell morphology and viability tests indicated that the drug-loaded G5-PC conjugate could effectively enter the cancer cells and inhibit the growth of cancer cells. Biomimetic phosphorylcholine surface engineered PAMAM dendrimers with lowered cytotoxicity and high cellular penetrating ability showed great potential for the biomedical applications as nanocarrier system.

  13. 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.

  14. Analysis of polyamidoamine dendrimers by isoelectric focusing.

    PubMed

    Upadhaya, Samik K; Swanson, Douglas R; Tomalia, Donald A; Sharma, Ajit

    2014-01-01

    Polyamidoamine dendrimers have been studied extensively for their potential applications in nanomedicine. Their uses as imaging, drug, and nucleic acid delivery agents are nearing clinical trials. As such, characterization of polyamidoamine dendrimers and their nano-devices is of immense importance for monitoring the efficiency of their synthesis, purity, and quality control of manufactured products as well as their in vivo behavior. We report here the analysis of polyamidoamine dendrimers possessing various cores and surface groups with a simple and inexpensive isoelectric focusing method. The isoelectric points of the dendrimers were readily determined from a calibration plot generated by running proteins with known pI values. The isoelectric points for various surface-modified polyamidoamine dendrimers ranged from 4 to 9. Polyamidoamine dendrimers possessing terminal hydroxyl groups gave a pI > 7, while those with terminal carboxyl groups exhibit a pI < 7. Generation number and cores of the dendrimers did not significantly affect their isoelectric points. Isoelectric focusing thus offers another important tool for characterizing these nanomolecules.

  15. Conductive dendrimers obtained by click chemistry

    NASA Astrophysics Data System (ADS)

    Lewis, Donald G.; Krasnova, Larissa B.; Skinner, Philip J.; Fokin, Valery V.

    2010-08-01

    First generation dendrimers having a high level of size/shape/symmetry homogeneity were fabricated using a synthetic scheme that employs highly quantitative copper-catalyzed azide-alkyne cycloaddition (CuAAC) reactions in combination with a molecular architecture that favors homogeneity. An "outside-in" or convergent synthetic approach was employed wherein dendrons having Sierpinski triangular fractal architectures were coupled to core structures having D2h or D3h point group symmetries to form the desired dendrimers. The individual dendrons consisted of branched-backbone conductive polymers having benzene branch points and 1,2,3-triazole linkages with uninterrupted π-electron cloud overlap throughout. Each dendron was then coupled to a benzene core structure having acetylene substituents by means of a CuAAC reaction so as to extend the uninterrupted π-conjugation from the dendron to the core structure for imparting conductivity throughout the entire dendrimer. The resulting dendrimers maintained the point group symmetry of their core structure, with the core structure serving to electronically couple the dendrons to one another by extension of their uninterrupted π-electron systems. Synthesis of these first generation dendrimers provides a proof of principle for the synthesis of higher generation conductive dendrimers. Since the nanophotonic properties of conductive dendrimers may be dependent, at least in some instances, upon their size, shape, and symmetry, enhancements with respect to their homogeneity may unmask new nanophotonic properties.

  16. Dendrimers as Nanovectors for Nucleic Acid Delivery

    NASA Astrophysics Data System (ADS)

    Liu, Xiaoxuan; Wang, Qi; Peng, Ling

    2013-09-01

    Nucleic acid based gene therapy holds great promise in the treatment of various diseases. However, the success of both DNA- and siRNAbased gene therapies depends critically on safe and efficient nucleic acid delivery systems. Owing to their well-defined structure and multivalent cooperativity, dendrimers have attracted particular attention as ideal nanocarriers for nucleic acid delivery. The present chapter highlights the current status of dendrimers as non-viral nanovectors for both DNA and siRNA delivery, focusing on the different dendrimers investigated for their delivery efficiency with respect to structural alterations in the view to developing safe and efficient nanovectors for gene therapy application.

  17. Type III-B rotaxane dendrimers.

    PubMed

    Ho, Watson K-W; Lee, Siu-Fung; Wong, Chi-Hin; Zhu, Xiao-Ming; Kwan, Chak-Shing; Chak, Chun-Pong; Mendes, Paula M; Cheng, Christopher H K; Leung, Ken Cham-Fai

    2013-11-28

    Type III-B first generation [3]rotaxane and second generation [4]rotaxane dendrimers have been synthesized via (1) a modified copper-catalyzed alkyne-azide cycloaddition (CuAAC), (2) Glaser-Hay's acetylenic oxidative homo-coupling, and (3) amide formation. The dendron does not reveal obvious cytotoxicities in L929 fibroblast cells. The rotaxane dendrimers can capture ammonia and are switchable both in solution and on surfaces.

  18. 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.

  19. Protective effects and mechanisms of G5 PAMAM dendrimers against acute pancreatitis induced by caerulein in mice.

    PubMed

    Tang, Yin; Han, Yingchun; Liu, Lu; Shen, Wenwen; Zhang, Huayu; Wang, Yunan; Cui, Xin; Wang, Yuhui; Liu, George; Qi, Rong

    2015-01-12

    In this study, generation 5 (G5) polyamidoamine (PAMAM) dendrimers with two different surface groups, G4.5-COOH and G5-OH, were investigated for their protective effects on pancreas injury in a caerulein-induced acute pancreatitis (AP) mouse model. Both dendrimers significantly decreased pathological changes in the pancreas and reduced the inflammatory infiltration of macrophages in pancreatic tissues. In addition, the expression of pro-inflammatory cytokines was significantly inhibited by the two dendrimers, not only in pancreatic tissues from AP mice but also in vitro in mouse peritoneal macrophages with LPS-induced inflammation. G4.5-COOH, which had better in vivo protective effects for AP than G5-OH, led to a significant reduction in the total number of plasma white blood cells (WBCs) and monocytes in AP mice, and its anti-inflammatory mechanism was related to inhibition of the nuclear translocation of NF-κB in macrophages.

  20. Dendrimers--revolutionary drugs for infectious diseases.

    PubMed

    Lazniewska, Joanna; Milowska, Katarzyna; Gabryelak, Teresa

    2012-01-01

    Over recent years innovative nanomolecules in a form of dendrimers have been gaining increasing interest. These compounds can be designed and modified in many ways giving a molecule which meets required expectations. For this reason dendrimers are the object of intensive studies in many fields of nanoscience including one of the most thriving--biomedicine. Numerous studies provide evidence that some dendrimers exhibit activities against many species/strains of viruses, bacteria, fungi, and prions. These types of dendritic nanostructures which are distinguished by antipathogenic properties and low cytotoxicity to eukaryotic cells may be potentially applied in medicine as novel drugs for various infectious diseases, especially those which are persistent, marked by high mortality rate, or untreatable. Dendrimers can exert their effect via different mechanisms of action, which are, in most cases, related to multivalency of the nanomolecule. The application of dendrimers is likely to be a breakthrough in prevention and treatment of infectious diseases which still beset humanity and may significantly improve the quality of people's life.

  1. A novel dendrimer based on poly (L-glutamic acid) derivatives as an efficient and biocompatible gene delivery vector

    NASA Astrophysics Data System (ADS)

    Zeng, Xin; Pan, Shirong; Li, Jie; Wang, Chi; Wen, Yuting; Wu, Hongmei; Wang, Cuifeng; Wu, Chuanbin; Feng, Min

    2011-09-01

    Non-viral gene delivery systems based on cationic polymers have faced limitations related to their relative low gene transfer efficiency, cytotoxicity and system instability in vivo. In this paper, a flexible and pompon-like dendrimer composed of poly (amidoamine) (PAMAM) G4.0 as the inner core and poly (L-glutamic acid) grafted low-molecular-weight polyethylenimine (PLGE) as the surrounding multiple arms was synthesized (MGI dendrimer). The novel MGI dendrimer was designed to combine the merits of size-controlled PAMAM G4.0 and the low toxicity and flexible chains of PLGE. In phosphate-buffered saline dispersions the well-defined DNA/MGI complex above a N/P ratio of 30 showed good stability with particle sizes of approximately 200 nm and a comparatively low polydispersity index. However, the particle size of the DNA/25 kDa polyethylenimine (DNA/PEI 25K) complex was larger than 700 nm under the same salt conditions. The shielding of the compact amino groups at the periphery of flexible PAMAM and biocompatible PLGE chains in MGI resulted in a dramatic decrease of the cytotoxicity compared to native PAMAM G4.0 dendrimer. The in vitro transfection efficiency of DNA/MGI dendrimer complex was higher than that of PAMAM G4.0 dendrimer. Importantly, in serum-containing medium, DNA/MGI complexes at their optimal N/P ratio maintained the same high levels of transfection efficiency as in serum-free medium, while the transfection efficiency of native PAMAM G4.0, PEI 25K and Lipofectamine 2000 were sharply decreased. In vivo gene delivery of pVEGF165/MGI complex into balloon-injured rabbit carotid arteries resulted in significant inhibition of restenosis by increasing VEGF165 expression in local vessels. Therefore, the pompon-like MGI dendrimer may be a promising vector candidate for efficient gene delivery in vivo.

  2. Viologen-phosphorus dendrimers exhibit minor toxicity against a murine neuroblastoma cell line.

    PubMed

    Lazniewska, Joanna; Milowska, Katarzyna; Katir, Nadia; El Kadib, Abdelkim; Bryszewska, Maria; Majoral, Jean-Pierre; Gabryelak, Teresa

    2013-09-01

    Dendrimers containing viologen (derivatives of 4,4'-bipyridyl) units in their structure have been demonstrated to exhibit antiviral activity against human immunodeficiency virus (HIV-1). It has also recently been revealed that novel dendrimers with both viologen units and phosphorus groups in their structure show different antimicrobial, cytotoxic and hemotoxic properties, and have the ability to influence the activity of cholinesterases and to inhibit α-synuclein fibrillation. Since the influence of viologen-phosphorus structures on basic cellular processes had not been investigated, we examined the impact of such macromolecules on the murine neuroblastoma cell line (N2a). We selected three water-soluble viologen-phosphorus (VPD) dendrimers, which differ in their core structure, number of viologen units and number and type of surface groups, and analyzed several aspects of the cellular response. These included cell viability, generation of reactive oxygen species (ROS), alterations in mitochondrial activity, morphological modifications, and the induction of apoptosis and necrosis. The MTT assay results suggest that all of the tested dendrimers are only slightly cytotoxic. Although some changes in ROS formation and mitochondrial function were detected, the three compounds did not induce apoptosis or necrosis. In light of these results, we can assume that the tested VPD are relatively safe for mouse neuroblastoma cells. Although more research on their safety is needed, VPD seem to be promising nanoparticles for further biomedical investigation.

  3. 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.

  4. Tetrahedron DNA dendrimers and their encapsulation of gold nanoparticles.

    PubMed

    Zhou, Tao; Wang, Yijie; Dong, Yuanchen; Chen, Chun; Liu, Dongsheng; Yang, Zhongqiang

    2014-08-15

    DNA dendrimers have achieved increasing attention recently. Previously reported DNA dendrimers used Y-DNA as monomers. Tetrahedron DNA is a rigid tetrahedral cage made of DNA. Herein, we use tetrahedron DNA as monomers to prepare tetrahedron DNA dendrimers. The prepared tetrahedron DNA dendrimers have larger size compared with those made of Y-DNA. In addition, thanks to the central cavity of tetrahedron DNA monomers, some nanoscale structures (e.g., gold nanoparticles) can be encapsulated within tetrahedron DNA monomers. Tetrahedron DNA encapsulated with gold nanoparticles can be further assembled into dendrimers, guiding gold nanoparticles into clusters.

  5. Targeted nanosystems: Advances in targeted dendrimers for cancer therapy

    PubMed Central

    Yang, Hu

    2015-01-01

    Dendrimers possess discrete highly compact nanostructures constituted of successive branched layers. Soon after the inception of dendrimers, recognition of their tunable structures and biologically favorable properties provoked a great enthusiasm in delving deeply into the utility of dendrimers for biomedical and pharmaceutical applications. One of the most important nanotechnology applications is the development of nanomedicines for targeted cancer therapies. Tremendous success in targeted therapies has been achieved with the use of dendrimer-based nanomedicines. This article provides a concise review on latest advances in the utility of dendrimers in immunotherapies and hormone therapies. PMID:26706410

  6. Pharmaceutical and biomedical potential of surface engineered dendrimers.

    PubMed

    Satija, Jitendra; Gupta, Umesh; Jain, Narendra Kumar

    2007-01-01

    Dendrimers are hyperbranched, globular, monodisperse, nanometric polymeric architecture, having definite molecular weight, shape, and size (which make these an inimitable and optimum carrier molecule in pharmaceutical field). Dendritic architecture is having immense potential over the other carrier systems, particularly in the field of drug delivery because of their unique properties, such as structural uniformity, high purity, efficient membrane transport, high drug pay load, targeting potential, and good colloidal, biological, and shelf stability. Despite their enormous applicability in different areas, the inherent cytotoxicity, reticuloendothelial system (RES) uptake, drug leakage, immunogenicity, and hemolytic toxicity restricted their use in clinical applications, which is primarily associated with cationic charge present on the periphery due to amine groups. To overcome this toxic nature of dendrimers, some new types of nontoxic, biocompatible, and biodegradable dendrimers have been developed (e.g., polyester dendrimer, citric acid dendrimer, arginine dendrimer, carbohydrate dendrimers, etc.). The surface engineering of parent dendrimers is graceful and convenient strategy, which not only shields the positive charge to make this carrier more biomimetic but also improves the physicochemical and biological behavior of parent dendrimers. Thus, surface modification chemistry of parent dendrimers holds promise in pharmaceutical applications (such as solubilization, improved drug encapsulation, enhanced gene transfection, sustained and controlled drug release, intracellular targeting) and in the diagnostic field. Development of multifunctional dendrimer holds greater promise toward the biomedical applications because a number of targeting ligands determine specificity in the same manner as another type of group would secure stability in biological milieu and prolonged circulation, whereas others facilitate their transport through cell membranes. Therefore, as a

  7. 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.

  8. 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

  9. 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

  10. Generation 3 PAMAM dendrimer TAMRA conjugates containing precise dye/dendrimer ratios

    PubMed Central

    Manono, Janet; Dougherty, Casey A.; Jones, Kirsten; DeMuth, Joshua; Holl, Mark M. Banaszak; DiMaggio, Stassi

    2015-01-01

    The synthesis, isolation, and characterization of generation 3 poly(amidoamine) (G3 PAMAM) dendrimer containing precise ratios of 5-carboxytetramethylrhodamine succinimidyl ester (TAMRA) dye (n = 1–3) per polymer particle are reported. Stochastic conjugation of TAMRA dye to the dendrimer was followed by separation into precise dye-polymer ratios using rp-HPLC. The isolated materials were characterized by rp-UPLC, MALDI-TOF-MS, and 1H NMR spectroscopy, UV–vis, and fluorescence spectroscopies. PMID:26549978

  11. Bidentate iminodiacetate modified dendrimer for bone imaging.

    PubMed

    Pes, Lara; Kim, Young; Tung, Ching-Hsuan

    2017-03-01

    A new dendrimer probe was designed for bone imaging. Bidentate iminodiacetate groups were introduced to the probe to obtain strong bind to bones. The assembled dendrimeric probe, with four iminodiacetate moieties and a fluorescent tag, displayed good selectivity to hydroxyapatite, calcium oxalate and calcium phosphate salts. In mice, the probe offered vivid skeletal details after intravenous delivery.

  12. 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.

  13. Smart AS1411-aptamer conjugated pegylated PAMAM dendrimer for the superior delivery of camptothecin to colon adenocarcinoma in vitro and in vivo.

    PubMed

    Alibolandi, Mona; Taghdisi, Seyed Mohammad; Ramezani, Pouria; Hosseini Shamili, Fazileh; Farzad, Sara Amel; Abnous, Khalil; Ramezani, Mohammad

    2017-03-15

    In the current study camptothecin-loaded pegylated PAMAM dendrimer were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against colorectal cancer cells which over expresses nucleolin receptors. The morphological properties and size dispersity of the prepared nanoparticles were evaluated using transmission electron microscope (TEM) and DLS. The drug-loading content and encapsulation efficiency were obtained 8.1% and 93.67% respectively. The in vitro release of camptothecin from the formulation was provided the sustained release of encapsulated camptothecin during 4days. Comparative in vitro cytotoxicity experiments demonstrated that the targeted camptothecin loaded-pegylated dendrimers had higher antiproliferation activity, towards nucleolin-positive HT29 and C26 colorectal cancer cells than nucleolin-negative CHO cell line. Fluorscence microscopy and flow cytometry also confirmed the enhanced cellular uptake of AS1411 targeted pegylated-dendrimer. In vivo study in C26 tumor-bearing BALB/C mice revealed that the AS1411-functionalized camptothecin loaded pegylated dendrimers improved antitumor activity and survival rate of the encapsulated camptothecin. Conjugation of AS1411 aptamer to the camptothecin loaded-pegylated dendrimer surface provides site-specific delivery of camptothecin, inhibit C26 tumor growth in vivo and significantly decrease systemic toxicity. These results suggested that the new nucleolin-targeted pegylated PAMAM dendrimer as a delivery system for camptothecin have the potential for the treatment of nucleolin-overexpressed colorectal cancer.

  14. Structure-activity relationship studies on a Trp dendrimer with dual activities against HIV and enterovirus A71. Modifications on the amino acid.

    PubMed

    Martínez-Gualda, Belén; Sun, Liang; Rivero-Buceta, Eva; Flores, Aida; Quesada, Ernesto; Balzarini, Jan; Noppen, Sam; Liekens, Sandra; Schols, Dominique; Neyts, Johan; Leyssen, Pieter; Mirabelli, Carmen; Camarasa, María-José; San-Félix, Ana

    2017-03-01

    We have recently described a new class of dendrimers with tryptophan (Trp) on the surface that show dual antiviral activities against HIV and EV71 enterovirus. The prototype compound of this family is a pentaerythritol derivative with 12 Trps on the periphery. Here we complete the structure-activity relationship studies of this family to identify key features that might be significant for the antiviral activity. With this aim, novel dendrimers containing different amino acids (aromatic and non-aromatic), tryptamine (a "decarboxylated" analogue of Trp) and N-methyl Trp on the periphery have been prepared. Dendrimer with N-Methyl Trp was the most active against HIV-1 and HIV-2 while dendrimer with tyrosine was endowed with the most potent antiviral activity against EV71. This tyrosine dendrimer proved to inhibit a large panel of EV71 clinical isolates (belonging to different clusters) in the low nanomolar/high picomolar range. In addition, a new synthetic procedure (convergent approach) has been developed for the synthesis of the prototype and some other dendrimers. This convergent approach proved more efficient (higher yields, easier purification) than the divergent approach previously reported.

  15. Transport and Biodistribution of Dendrimers Across Human Fetal Membranes: Implications for Intravaginal Administration of Dendrimers

    PubMed Central

    Menjoge, Anupa R.; Navath, Raghavendra S.; Asad, Abbas; Kannan, Sujatha; Kim, Chong Jai; Romero, Roberto; Kannan, Rangaramanujam M.

    2010-01-01

    Dendrimers are emerging as promising topical antimicrobial agents, and as targeted nanoscale drug delivery vehicles. Topical intravaginal antimicrobial agents are prescribed to treat the ascending genital infections in pregnant women. The fetal membranes separate the extra-amniotic space and fetus. The purpose of the study is to determine if the dendrimers can be selectively used for local intravaginal application to pregnant women without crossing the membranes into the fetus. In the present study, the transport and permeability of PAMAM (poly(amidoamine)) dendrimers, across human fetal membrane (using a side-by-side diffusion chamber), and its biodistribution (using immunofluorescence) are evaluated ex-vivo. Transport across human fetal membranes (from the maternal side) was evaluated using Fluorescein (FITC), an established transplacental marker (positive control, size~ 400 Da) and fluorophore-tagged G4-PAMAM dendrimers (~ 16 kDa). The fluorophore-tagged G4-PAMAM dendrimers were synthesized and characterized using 1H NMR, MALDI TOF-MS and HPLC analysis. Transfer was measured across the intact fetal membrane (chorioamnion), and the separated chorion and amnion layers. Over a five hour period, the dendrimer transport across all the three membranes was less than < 3 %, whereas the transport of FITC was relatively fast with as much as 49% transport across the amnion. The permeability of FITC (7.9 × 10-7 cm2/s) through the chorioamnion was 7-fold higher than that of the dendrimer (5.8 × 10-8 cm2/s). The biodistribution showed that the dendrimers were largely present in interstitial spaces in the decidual stromal cells and the chorionic trophoblast cells (in 2.5 to 4 h) and surprisingly, to a smaller extent internalized in nuclei of trophoblast cells and nuclei and cytoplasm of stromal cells. Passive diffusion and paracellular transport appear to be the major route for dendrimer transport. The overall findings further suggest that entry of drugs conjugated to

  16. Hyperbranched polymer films and dendrimers: Their chemistry and applications

    NASA Astrophysics Data System (ADS)

    Zhao, Mingqi

    The research in this dissertation examines the chemistry and applications of dendritic polymers; specifically, hyperbranched polymer thin films and dendrimers. We examined hyperbranched, fluorinated and unfluorinated poly(acrylic acid) (PAA) films on gold substrates, poly(amidoamine) (PAMAM) dendrimer monolayers and dendrimer-alkanethiol mixed monolayers on gold substrates, PAMAM dendrimer/poly(anhydride) and poly(iminopropane-1,3-diyl) (Cascade) dendrimer/poly(anhydride) multilayer films on silicon, gold, and aluminum substrates, PAMAM dendrimer/metal-ion composites, and PAMAM dendrimer-encapsulated metal nanoclusters in solution and on electrode surfaces. Hyperbranched PAA films have pH-dependent blocking abilities: at low pH PAA films effectively passivate Au electrodes while at high pH they are open and permeable. Fluorinated PAA films are far less permeable at any pH. Dendrimers ranging from generation 4 to 8 (G4--G8) can form highly stable and nearly close-packed monolayers and mixed monolayers with hexadecanethiol (C16SH) on surfaces. Moreover, dendrimers embedded within C16SH can act as gates of molecular dimension that control intradendrimer mass transfer of ions. Dendrimer/poly(anhydride) multilayers on surfaces were synthesized and their permeability was investigated. These composite membranes exhibit fully reversible, pH-switchable permselectivity for both cationic and anionic probe molecules because of their pH-dependent electrostatic properties. After heating, such films become highly blocking over the pH range studied due to thermally induced interdendrimer imidization, and other reactions. Finally, we show that PAMAM dendrimers can act first as templates for the preparation of transition-metal nanoclusters, and subsequently as stabilizers. Dendrimers quantitatively complex many transition-metal ions, including Cu 2+, Pt2+, Pd2+, Ru3+, and Ni2+, within their interiors. Chemical reduction of such nanocomposites results in formation of dendrimer

  17. 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.

  18. 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.

  19. Synthesis of giant rigid pi-conjugated dendrimers.

    PubMed

    Jiang, Yang; Lu, Yi-Xuan; Cui, Yu-Xin; Zhou, Qi-Feng; Ma, Yuguo; Pei, Jian

    2007-10-25

    A novel family of giant pi-conjugated dendrimers (G0, G1, and G2) solely constructed by 5,5,10,10,15,15-hexahexyltruxene units has been developed in a convergent manner through a Suzuki cross-coupling reaction. The overall yields to such large rigid conjugated dendrimers are quite satisfying. The structures and purity of these nanosize rigid dendrimers are verified by 1H and 13C NMR, MALDI-TOF MS, and elemental analysis.

  20. Nanosilver based anionic linear globular dendrimer with a special significant antiretroviral activity.

    PubMed

    Ardestani, Mehdi Shafiee; Fordoei, Alireza Salehi; Abdoli, Asghar; Ahangari Cohan, Reza; Bahramali, Golnaz; Sadat, Seyed Mehdi; Siadat, Seyed Davar; Moloudian, Hamid; Nassiri Koopaei, Nasser; Bolhasani, Azam; Rahimi, Pooneh; Hekmat, Soheila; Davari, Mehdi; Aghasadeghi, Mohammad Reza

    2015-05-01

    HIV is commonly caused to a very complicated disease which has not any recognized vaccine, so designing and development of novel antiretroviral agents with specific application of nanomedicine is a globally interested research subject worldwide. In the current study, a novel structure of silver complexes with anionic linear globular dendrimer was synthesized, characterized and then assessed against HIV replication pathway in vitro as well. The results showed a very good yield of synthesis (up to 70%) for the nano-complex as well as a very potent significant (P < 0.05) antiretroviral activity with non-severe toxic effects in comparison with the Nevirapine as standard drug in positive control group. According to the present data, silver anionic linear globular dendrimers complex may have a promising future to inhibit replication of HIV viruse in clinical practice.

  1. Novel Aldehyde-Terminated Dendrimers; Synthesis and Cytotoxicity Assay

    PubMed Central

    Hamidi, Aliasghar; Sharifi, Simin; Davaran, Soodabeh; Ghasemi, Saeed; Omidi, Yadollah; Rashidi, Mohammad-Reza

    2012-01-01

    Introduction Polyamidoamine (PAMAM) dendrimers are a unique family of dendritic polymers with numerous pharmaceutical and biomedical applications. One major problem with these polymers is their cytotoxicity. The purpose of this study was to synthesize novel dendrimers with aldehyde terminal groups and compare their cytotoxicity with that of dendri¬mers containing amine-terminated groups. Methods G1(first generation) and G2 (second generation) dendrimers with amine-terminated groups were synthesized by divergent method and then the amine-terminated groups were converted to the aldehyde groups using surface modification of the functional group inversion (FGI) method. The cytotoxicity of the novel G1 and G2 polyamidoaldehyde (PAMAL) dendrimers together with that of G1 and G2 PAMAM-NH2 dendrimers was investigated by MTT assay using MCF-7 cell line. Results The results showed that cytotoxicity of dendrimers with aldehyde-terminated groups is much lower than that of G1 and G2 PAMAM-NH2 dendri¬mers. Conclusion Dendrimers with aldehyde-terminated groups could be used as novel and convenient carriers for drug delivery with low cytotoxic effect compared with the amine-terminated dendrimers. The results revealed that the same generations of the dendri¬mers with aldehyde-terminated groups are far less toxic than the corresponding amine-terminated dendrimers. PMID:23678447

  2. Cell uptake mechanisms of PAMAM G4-FITC dendrimer in human myometrial cells

    NASA Astrophysics Data System (ADS)

    Oddone, Natalia; Zambrana, Ana I.; Tassano, Marcos; Porcal, Williams; Cabral, Pablo; Benech, Juan C.

    2013-07-01

    The high incidence and severity of diseases which involve smooth muscle dysfunction dictates the need of continued search for novel therapeutic strategies to treat these conditions. Dendrimers are branched macromolecules with multiple end-groups that can be functionalized for applications which include drug delivery. There is no data regarding the cellular uptake mechanisms used by dendrimers in smooth muscle human myometrial cells (HMC). Polyamidoamine G4 dendrimers were conjugated with fluorescein isothiocyanate (FITC) and the resulting conjugate (G4-FITC) was characterized using high-performance liquid chromatography, nuclear magnetic resonance, and atomic force microscopy. G4-FITC showed to have no significant effect on the primary culture HMC viability up to 48 h. HMC incubated with G4-FITC were analyzed by laser confocal microscopy. Peri-nuclear fluorescence distribution was observed at 5 h of incubation or more (24, 36, and 48 h). At 24 h, G4-FITC partially co-localized with lysotracker. Uptake of G4-FITC by HMC was slightly inhibited by filipin (8.0 ± 3.9 %) and significantly inhibited by chlorpromazine (63.5 ± 3.7 %). In non-electroporated HMC, G4-FITC was never observed inside the cell nucleus. Interestingly, we detected G4-FITC inside the nuclear domain of some electroporated cells. Thus, electroporation changed intracellular G4-FITC localization. Isolated nuclei of HMC incubated with G4-FITC showed fluorescence signal inside the nuclear domain. The results suggest that in HMC, G4-FITC is taken up by clathrin-mediated endocytosis with endosomal and lysosomal localization at 24 h. The combination of electroporation and dendrimers could be an interesting technology to electrotransfer drugs into smooth muscle cells cytosol and nuclei.

  3. 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.

  4. Biogenic and Synthetic Polyamines Bind Cationic Dendrimers

    PubMed Central

    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 Kspm-mPEG-G3 = 7.6×104 M−1, Kspm-mPEG-PAMAM-G4 = 4.6×104 M−1, Kspm-PAMAM-G4 = 6.6×104 M−1, Kspmd-mPEG-G3 = 1.0×105 M−1, Kspmd-mPEG-PAMAM-G4 = 5.5×104 M−1, Kspmd-PAMAM-G4 = 9.2×104 M−1, KBE-333-mPEG-G3 = 4.2×104 M−1, KBe-333-mPEG-PAMAM-G4 = 3.2×104 M−1, KBE-333-PAMAM-G4 = 3.6×104 M−1, KBE-3333-mPEG-G3 = 2.2×104 M−1, KBe-3333-mPEG-PAMAM-G4 = 2.4×104 M−1, KBE-3333-PAMAM-G4 = 2.3×104 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. PMID:22558341

  5. Impact of Dendrimer Terminal Group Chemistry on Blockage of the Anthrax Toxin Channel: A Single Molecule Study

    PubMed Central

    Yamini, Goli; Kalu, Nnanya; Nestorovich, Ekaterina M.

    2016-01-01

    Nearly all the cationic molecules tested so far have been shown to reversibly block K+ current through the cation-selective PA63 channels of anthrax toxin in a wide nM–mM range of effective concentrations. A significant increase in channel-blocking activity of the cationic compounds was achieved when multiple copies of positively charged ligands were covalently linked to multivalent scaffolds, such as cyclodextrins and dendrimers. Even though multivalent binding can be strong when the individual bonds are relatively weak, for drug discovery purposes we often strive to design multivalent compounds with high individual functional group affinity toward the respective binding site on a multivalent target. Keeping this requirement in mind, here we perform a single-channel/single-molecule study to investigate kinetic parameters of anthrax toxin PA63 channel blockage by second-generation (G2) poly(amido amine) (PAMAM) dendrimers functionalized with different surface ligands, including G2-NH2, G2-OH, G2-succinamate, and G2-COONa. We found that the previously reported difference in IC50 values of the G2-OH/PA63 and G2-NH2/PA63 binding was determined by both on- and off-rates of the reversible dendrimer/channel binding reaction. In 1 M KCl, we observed a decrease of about three folds in kon and a decrease of only about ten times in tres with G2-OH compared to G2-NH2. At the same time for both blockers, kon and tres increased dramatically with transmembrane voltage increase. PAMAM dendrimers functionalized with negatively charged succinamate, but not carboxyl surface groups, still had some residual activity in inhibiting the anthrax toxin channels. At 100 mV, the on-rate of the G2-succinamate binding was comparable with that of G2-OH but showed weaker voltage dependence when compared to G2-OH and G2-NH2. The residence time of G2-succinamate in the channel exhibited opposite voltage dependence compared to G2-OH and G2-NH2, increasing with the cis-negative voltage increase

  6. Programmable Self-Assembly of DNA-Dendrimer and DNA-Fullerene Nanostructures

    DTIC Science & Technology

    2004-10-01

    OF PHOTO-REACTIVE PSORALEN -CONTAINING DENDRIMERS .........................................33 4.4. DNA-DENDRIMERS AND DNA-DENDRON CONJUGATES ON... Psoralen -Containing Dendrimers We report the synthesis and characterization of photo-reactive psoralen -containing dendrimers in order to develop...a novel labeling method for the detection of DNA. Psoralens are unique in their ability to detect hybridized DNA: planar psoralen molecules

  7. Bioapplications of poly(amidoamine) (PAMAM) dendrimers in nanomedicine

    NASA Astrophysics Data System (ADS)

    Taghavi Pourianazar, Negar; Mutlu, Pelin; Gunduz, Ufuk

    2014-04-01

    Poly(amidoamine) (PAMAM) dendrimers are a novel class of spherical, well-designed branching polymers with interior cavities and abundant terminal groups on the surface which can form stable complexes with drugs, plasmid DNA, oligonucleotides, and antibodies. Amine-terminated PAMAM dendrimers are able to solubilize different families of hydrophobic drugs, but the cationic charges on dendrimer surface may disturb the cell membrane. Therefore, surface modification by PEGylation, acetylation, glycosylation, and amino acid functionalization is a convenient strategy to neutralize the peripheral amine groups and improve dendrimer biocompatibility. Anticancer agents can be either encapsulated in or conjugated to dendrimer and be delivered to the tumor via enhanced permeability and retention (EPR) effect of the nanoparticle and/or with the help of a targeting moiety such as antibody, peptides, vitamins, and hormones. Biodegradability, non-toxicity, non-immunogenicity, and multifunctionality of PAMAM dendrimer are the key factors which facilitate steady increase of its application in drug delivery, gene transfection, tumor therapy, and diagnostics applications with precision and selectivity. This review deals with the major topics of PAMAM dendrimers including structure, synthesis, toxicity, surface modification, and also possible new applications of these spherical polymers in biomedical fields as dendrimer-based nanomedicine.

  8. 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.

  9. Dendrimer-Functionalized Laponite Nanodisks as a Platform for Anticancer Drug Delivery

    PubMed Central

    Mustafa, Rania; Luo, Yu; Wu, Yilun; Guo, Rui; Shi, Xiangyang

    2015-01-01

    In this study, we synthesized dendrimer-functionalized laponite (LAP) nanodisks for loading and delivery of anticancer drug doxorubicin (DOX). Firstly, LAP was modified with silane coupling agents and succinic anhydride to render abundant carboxyl groups on the surface of LAP. Then, poly(amidoamine) (PAMAM) dendrimer of generation 2 (G2) were conjugated to form LM-G2 nanodisks. Anticancer drug DOX was then loaded on the LM-G2 with an impressively high drug loading efficiency of 98.4% and could be released in a pH-sensitive and sustained manner. Moreover, cell viability assay results indicate that LM-G2/DOX complexes could more effectively inhibit the proliferation of KB cells (a human epithelial carcinoma cell line) than free DOX at the same drug concentration. Flow cytometry analysis and confocal laser scanning microscope demonstrated that LM-G2/DOX could be uptaken by KB cells more effectively than free DOX. Considering the exceptional high drug loading efficiency and the abundant dendrimer amine groups on the surface that can be further modified, the developed LM-G2 nanodisks may hold a great promise to be used as a novel platform for anticancer drug delivery.

  10. Modification of regenerated cellulose membrane based on thiol dendrimer.

    PubMed

    Vázquez, M Isabel; Algarra, Manuel; Benavente, Juana

    2015-10-20

    This work describes the modification of a highly swollen commercial regenerated cellulose (RC) membrane with a dendritic molecule (thiol DAB dendrimer of generation 3) by the dip coating method, and its possible use in electrochemical systems with saline solutions fluxes. Moreover, cellulosic membrane modification with dendrimer covered-CdSe quantum dot was also performed, since it allows dendrimer assortment by fluorescence. Changes in electrical, mechanical and diffusive membrane parameters were determined by impedance spectroscopy, elasticity curves and diffusional permeability measurements. The results indicate a reduction in the free volume of the RC chains in the original membrane associated with the thiol dendrimer inclusion, which reduces diffusive permeability. This demonstrates the possibility of using the thiol dendrimer-modified membrane in low/medium concentration level (0.001M/0.01M) devices with NaCl and PbCl2 solutions.

  11. Synthesis and Spectral Studies of CdTe-Dendrimer Conjugates

    NASA Astrophysics Data System (ADS)

    Ghosh, Srabanti; Saha, Abhijit

    2009-08-01

    In order to couple high cellular uptake and target specificity of dendrimer molecule with excellent optical properties of semiconductor nanoparticles, the interaction of cysteine-capped CdTe quantum dots with dendrimer was investigated through spectroscopic techniques. NH2-terminated dendrimer molecule quenched the photoluminescence of CdTe quantum dots. The binding constants and binding capacity were calculated, and the nature of binding was found to be noncovalent. Significant decrease in luminescence intensity of CdTe quantum dots owing to noncovalent binding with dendrimer limits further utilization of these nanoassemblies. Hence, an attempt is made, for the first time, to synthesize stable, highly luminescent, covalently linked CdTe-Dendrimer conjugate in aqueous medium using glutaric dialdehyde (G) linker. Conjugate has been characterized through Fourier transform infrared spectroscopy and transmission electron microscopy. In this strategy, photoluminescence quantum efficiency of CdTe quantum dots with narrow emission bandwidths remained unaffected after formation of the conjugate.

  12. Dendrimer nanoarchitectures for cancer diagnosis and anticancer drug delivery.

    PubMed

    Sharma, Ashok Kumar; Gothwal, Avinash; Kesharwani, Prashant; Alsaab, Hashem; Iyer, Arun K; Gupta, Umesh

    2017-02-01

    Dendrimers are novel nanoarchitectures with unique properties including a globular 3D shape, a monodispersed unimicellar nature and a nanometric size range. The availability of multiple peripheral functional groups and tunable surface engineering enable the facile modification of the dendrimer surface with different therapeutic drugs, diagnostic agents and targeting ligands. Drug encapsulation, and solubilizing and passive targeting also equally contribute to the therapeutic use of dendrimers. In this review, we highlight recent advances in the delivery of anticancer drugs using dendrimers, as well as other biomedical and diagnostic applications. Taken together, the immense potential and utility of dendrimers are envisaged to have a significant positive impact on the growing arena of drug delivery and targeting.

  13. 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

  14. 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.

  15. Antibacterial activity and cytotoxicity of PEGylated poly(amidoamine) dendrimers.

    PubMed

    Lopez, Analette I; Reins, Rose Y; McDermott, Alison M; Trautner, Barbara W; Cai, Chengzhi

    2009-10-01

    We have investigated the antibacterial activity and cytotoxicity of a series of amino-terminated poly(amidoamine) (PAMAM) dendrimers modified with poly(ethylene glycol) (PEG) groups. The antibacterial activity of the PAMAM dendrimers and their derivatives against the common ocular pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, was evaluated by their minimum inhibitory concentrations (MICs). For the unmodified third and fifth generation (G3 and G5) amino-terminated dendrimers, the MICs against both P. aeruginosa and S. aureus were in the range of 6.3-12.5 microg mL(-1), comparable to that of the antimicrobial peptide LL-37 (1.3-12.5 microg mL(-1)) and within the wide range of 0.047-128 microg mL(-1) for the fluoroquinolone antibiotics. PEGylation of the dendrimers decreased their antibacterial activities, especially for the Gram-positive bacteria (S. aureus). The reduction in potency is likely due to the decrease in the number of protonated amino groups and shielding of the positive charges by the PEG chains, thus decreasing the electrostatic interactions of the dendrimers with the negatively-charged bacterial surface. Interestingly, localization of a greater number of amino groups on G5 vs. G3 dendrimers did not improve the potency. Significantly, even a low degree of PEGylation, e.g. 6% with EG(11) on G3 dendrimer, greatly reduced the cytotoxicity towards human corneal epithelial cells while maintaining a high potency against P. aeruginosa. The cytotoxicity of the PEGylated dendrimers to host cells is much lower than that reported for antimicrobial peptides. Furthermore, the MICs of these dendrimers against P. aeruginosa are more than two orders of magnitude lower than other antimicrobial polymers reported to date. These results motivate further exploration of the potential of cationic dendrimers as a new class of antimicrobial agents that may be less likely to induce bacterial resistance than standard antibiotics.

  16. Dendrimer assisted dispersion of carbon nanotubes: a molecular dynamics study.

    PubMed

    Pramanik, Debabrata; Maiti, Prabal K

    2016-10-19

    Various unique physical, chemical, mechanical and electronic properties of carbon nanotubes (CNTs) make them very useful materials for diverse potential application in many fields. Experimentally synthesized CNTs are generally found in bundle geometry with a mixture of different chiralities and present a unique challenge to separate them. In this paper we have proposed the PAMAM dendrimer to be an ideal candidate for this separation. To estimate the efficiency of the dendrimer for the dispersion of CNTs from the bundle geometry, we have calculated potential of mean forces (PMF). Our PMF study of two dendrimer-wrapped CNTs shows lesser binding affinity compared to the two bare CNTs. PMF study shows that the binding affinity decreases for non-protonated dendrimer, and for the protonated case the interaction is fully repulsive in nature. For both the non-protonated as well as protonated cases, the PMF increases gradually with increasing dendrimer generations from 2 to 4 compared to the bare PMF. We have performed PMF calculations with (6,5) and (6,6) chirality to study the chirality dependence of PMF. Our study shows that the PMFs between two (6,5) and two (6,6) CNTs respectively are ∼-29 kcal mol(-1) and ∼-27 kcal mol(-1). Calculated PMF for protonated dendrimer-wrapped chiral CNTs is more compared to the protonated dendrimer-wrapped armchair CNTs for all the generations studied. However, for non-protonated dendrimer-wrapped CNTs, such chirality dependence is not very prominent. Our study suggests that the dispersion efficiency of the protonated dendrimer is more compared to the non-protonated dendrimer and can be used as an effective dispersing agent for the dispersion of CNTs from the bundle geometry.

  17. Modular Integration of Upconverting Nanocrystal-Dendrimer Composites for Folate Receptor-Specific NIR Imaging and Light-Triggered Drug Release.

    PubMed

    Wong, Pamela T; Chen, Dexin; Tang, Shengzhuang; Yanik, Sean; Payne, Michael; Mukherjee, Jhindan; Coulter, Alexa; Tang, Kenny; Tao, Ke; Sun, Kang; Baker, James R; Choi, Seok Ki

    2015-12-02

    Upconversion nanocrystals (UCNs) display near-infrared (NIR)-responsive photoluminescent properties for NIR imaging and drug delivery. The development of effective strategies for UCN integration with other complementary nanostructures for targeting and drug conjugation is highly desirable. This study reports on a core/shell-based theranostic system designed by UCN integration with a folate (FA)-conjugated dendrimer for tumor targeting and with photocaged doxorubicin as a cytotoxic agent. Two types of UCNs (NaYF4:Yb/Er (or Yb/Tm); diameter = ≈50 to 54 nm) are described, each displaying distinct emission properties upon NIR (980 nm) excitation. The UCNs are surface modified through covalent attachment of photocaged doxorubicin (ONB-Dox) and a multivalent FA-conjugated polyamidoamine (PAMAM) dendrimer G5(FA)6 to prepare UCN@(ONB-Dox)(G5FA). Surface plasmon resonance experiments performed with G5(FA)6 dendrimer alone show nanomolar binding avidity (KD = 5.9 × 10(-9) M) to the folate binding protein. This dendrimer binding corresponds with selective binding and uptake of UCN@(ONB-Dox)(G5FA) by FAR-positive KB carcinoma cells in vitro. Furthermore, UCN@(ONB-Dox)(G5FA) treatment of FAR(+) KB cells inhibits cell growth in a light dependent manner. These results validate the utility of modularly integrated UCN-dendrimer nanocomposites for cell type specific NIR imaging and light-controlled drug release, thus serving as a new theranostic system.

  18. Nanoscale effects in dendrimer-mediated targeting of neuroinflammation

    PubMed Central

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

    2017-01-01

    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

  19. Dendrimer mediated transfer of engineered chromosomes.

    PubMed

    Katona, Robert L

    2011-01-01

    Gene therapy encounters important problems such as insertional mutagenesis caused by the integration of viral vectors. These problems could be circumvented by the use of mammalian artificial chromosomes (MACs) that are unique and high capacity gene delivery tools. MACs were delivered into various target cell lines including stem cells by microcell-mediated chromosome transfer (MMCT), microinjection, and cationic lipid and dendrimer mediated transfers. MACs were also cleansed to more than 95% purity before transfer with an expensive technology. We present here a method by which MACs can be delivered into murine embryonic stem (ES) cells with a nonexpensive, less tedious, but still efficient way.

  20. Nonlinear mechanics of thermoreversibly associating dendrimer glasses

    NASA Astrophysics Data System (ADS)

    Srikanth, Arvind; Hoy, Robert S.; Rinderspacher, Berend C.; Andzelm, Jan W.

    2013-10-01

    We model the mechanics of associating trivalent dendrimer network glasses with a focus on their energy dissipation properties. Various combinations of sticky bond (SB) strength and kinetics are employed. The toughness (work to fracture) of these systems displays a surprising deformation-protocol dependence; different association parameters optimize different properties. In particular, “strong, slow” SBs optimize strength, while “weak, fast” SBs optimize ductility via self-healing during deformation. We relate these observations to breaking, reformation, and partner switching of SBs during deformation. These studies point the way to creating associating-polymer network glasses with tailorable mechanical properties.

  1. Novel chlorambucil-conjugated anionic linear-globular PEG-based second-generation dendrimer: in vitro/in vivo improved anticancer activity.

    PubMed

    Assadi, Artin; Najafabadi, Vahideh Sharifi; Shandiz, Seyed Ataollah Sadat; Boroujeni, Azadah Shayeq; Ashrafi, Sepehr; Vaziri, Ali Zaman; Ghoreishi, Seyedeh Masoumeh; Aghasadeghi, Mohammad Reza; Ebrahimi, Seyed Esmaeil Sadat; Pirali-Hamedani, Morteza; Ardestani, Mehdi Shafiee

    2016-01-01

    Evaluating the efficacy of anticancer drugs is an evolving and research-oriented issue. The objective of this study was to reduce the insolubility of chlorambucil (CBL) in water and improve the anticancer activity of CBL in vitro and in vivo through the conjugation of CBL with anionic linear-globular dendrimer (second generation, G2). In the current study, the anticancer activity among three groups that include CBL, CBL-G2 dendrimer, and control was measured in vitro and in vivo. In vitro studies showed that G2 anionic linear-globular polyethylene-glycol-based dendrimer, which conjugated to the CBL exterior through an ester linkage, was able to significantly improve the treatment efficacy over clinical CBL alone with respect to proliferation assay, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide; half maximal inhibitory concentration (IC50) was calculated to be 141 µg/mL for CBL alone and 27.7 µg/mL for CBL-G2 dendrimer; P<0.05. In addition, CBL-G2 dendrimer conjugate forestalled the growth of MCF-7 cancerous cells in addition to enhancing the number of apoptotic and necrotic cells as demonstrated by an annexin V-fluorescein isothiocyanate assay. CBL-G2 dendrimer conjugate was able to checkmate antiapoptotic Bcl-2 expression and Bcl-2/Bax ratio in a large scale compared with the control group and CBL alone (P<0.005). In vivo studies showed that tumor treatment by CBL-G2 dendrimer conjugate outstrips the efficacy of treatment compared with CBL alone. The evaluation was based on reduction in tumor volume and tumor growth inhibition of murine 4T1 mammary tumor cells. Tumor volume of 140%±8% was measured in the treatment with CBL-G2 dendrimer, whereas 152%±13.5% was calculated in the treatment with free CBL (P<0.05). However, there were no significant differences in histological assay among the three groups. In conclusion, tumor growth suppression potential of CBL-G2 dendrimer, which was assessed in both in vitro and in vivo experiments

  2. Novel chlorambucil-conjugated anionic linear-globular PEG-based second-generation dendrimer: in vitro/in vivo improved anticancer activity

    PubMed Central

    Assadi, Artin; Najafabadi, Vahideh Sharifi; Shandiz, Seyed Ataollah Sadat; Boroujeni, Azadah Shayeq; Ashrafi, Sepehr; Vaziri, Ali Zaman; Ghoreishi, Seyedeh Masoumeh; Aghasadeghi, Mohammad Reza; Ebrahimi, Seyed Esmaeil Sadat; Pirali-Hamedani, Morteza; Ardestani, Mehdi Shafiee

    2016-01-01

    Evaluating the efficacy of anticancer drugs is an evolving and research-oriented issue. The objective of this study was to reduce the insolubility of chlorambucil (CBL) in water and improve the anticancer activity of CBL in vitro and in vivo through the conjugation of CBL with anionic linear-globular dendrimer (second generation, G2). In the current study, the anticancer activity among three groups that include CBL, CBL–G2 dendrimer, and control was measured in vitro and in vivo. In vitro studies showed that G2 anionic linear-globular polyethylene-glycol-based dendrimer, which conjugated to the CBL exterior through an ester linkage, was able to significantly improve the treatment efficacy over clinical CBL alone with respect to proliferation assay, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide; half maximal inhibitory concentration (IC50) was calculated to be 141 µg/mL for CBL alone and 27.7 µg/mL for CBL–G2 dendrimer; P<0.05. In addition, CBL–G2 dendrimer conjugate forestalled the growth of MCF-7 cancerous cells in addition to enhancing the number of apoptotic and necrotic cells as demonstrated by an annexin V-fluorescein isothiocyanate assay. CBL–G2 dendrimer conjugate was able to checkmate antiapoptotic Bcl-2 expression and Bcl-2/Bax ratio in a large scale compared with the control group and CBL alone (P<0.005). In vivo studies showed that tumor treatment by CBL–G2 dendrimer conjugate outstrips the efficacy of treatment compared with CBL alone. The evaluation was based on reduction in tumor volume and tumor growth inhibition of murine 4T1 mammary tumor cells. Tumor volume of 140%±8% was measured in the treatment with CBL–G2 dendrimer, whereas 152%±13.5% was calculated in the treatment with free CBL (P<0.05). However, there were no significant differences in histological assay among the three groups. In conclusion, tumor growth suppression potential of CBL–G2 dendrimer, which was assessed in both in vitro and in vivo

  3. Continuous-time quantum walks on multilayer dendrimer networks

    NASA Astrophysics Data System (ADS)

    Galiceanu, Mircea; Strunz, Walter T.

    2016-08-01

    We consider continuous-time quantum walks (CTQWs) on multilayer dendrimer networks (MDs) and their application to quantum transport. A detailed study of properties of CTQWs is presented and transport efficiency is determined in terms of the exact and average return probabilities. The latter depends only on the eigenvalues of the connectivity matrix, which even for very large structures allows a complete analytical solution for this particular choice of network. In the case of MDs we observe an interplay between strong localization effects, due to the dendrimer topology, and good efficiency from the linear segments. We show that quantum transport is enhanced by interconnecting more layers of dendrimers.

  4. Selective peptide binding using facially amphiphilic dendrimers.

    PubMed

    Gomez-Escudero, Andrea; Azagarsamy, Malar A; Theddu, Naresh; Vachet, Richard W; Thayumanavan, S

    2008-08-20

    Amphiphilic dendrimers, which contain both hydrophobic and hydrophilic groups in every repeat unit, exhibit environment-dependent assemblies both in hydrophilic solvent, water, and in lipophilic solvent, toluene. Upon investigating the status of these assemblies in a mixture of immiscible solvents, these dendrimers were found to be kinetically trapped in the solvent in which they are initially assembled. This property has been exploited to selectively extract peptides from aqueous solution into an organic phase, where the peptides bind to the interior functionalities of the dendritic inverse micelles. While the corresponding small molecule surfactant does not exhibit any selective binding toward peptides, all dendrons (G1-G3) are capable of this selective binding. We show that the inverse micelle-type assembly itself is crucial for the binding event and that the assembly formed by the G1 dendron has a greater capability for binding compared to the G2 or G3 dendrons. We have also shown that the average apparent pKa of the carboxylic acid functionalities varies with generation, and this could be the reason for the observed differences in binding capacity.

  5. 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

  6. Thermodynamic properties of a liquid crystal carbosilane dendrimer

    NASA Astrophysics Data System (ADS)

    Samosudova, Ya. S.; Markin, A. V.; Smirnova, N. N.; Ogurtsov, T. G.; Boiko, N. I.; Shibaev, V. P.

    2016-11-01

    The temperature dependence of the heat capacity of a first-generation liquid crystal carbosilane dendrimer with methoxyphenyl benzoate end groups is studied for the first time in the region of 6-370 K by means of precision adiabatic vacuum calorimetry. Physical transformations are observed in this interval of temperatures, and their standard thermodynamic characteristics are determined and discussed. Standard thermodynamic functions C p ° ( T), H°( T) - H°(0), S°( T) - S°(0), and G°( T) - H°(0) are calculated from the obtained experimental data for the region of T → 0 to 370 K. The standard entropy of formation of the dendrimer in the partially crystalline state at T = 298.15 K is calculated, and the standard entropy of the hypothetic reaction of its synthesis at this temperature is estimated. The thermodynamic properties of the studied dendrimer are compared to those of second- and fourth-generation liquid crystal carbosilane dendrimers with the same end groups studied earlier.

  7. Optimization of carboxylate-terminated poly(amidoamine) dendrimer-mediated cisplatin formulation.

    PubMed

    Kulhari, Hitesh; Pooja, Deep; Singh, Mayank K; Chauhan, Abhay S

    2015-02-01

    Abstract Cisplatin is mainly used in the treatment of ovarian, head and neck and testicular cancer. Poor solubility and non-specific interactions causes hurdles in the development of successful cisplatin formulation. There were few reports on poly(amidoamine) (PAMAM) dendrimer-cisplatin complexes for anticancer treatment. But the earlier research was mainly focused on therapeutic effect of PAMAM dendrimer-cisplatin complex, with less attention paid on the formulation development of these complexes. Objective of the present study is to optimize and validate the carboxylate-terminated, EDA core PAMAM dendrimer-based cisplatin formulation with respect to various variables such as dendrimer core, generation, drug entrapment, purification, yield, reproducibility, stability, storage and in-vitro release. Dendrimer-cisplatin complex was prepared by an efficient method which significantly increases the % platinum (Pt) content along with the product yield. Dendrimers showed reproducible (∼27%) platinum loading by weight. Variation in core and generations does not produce significant change in the % Pt content. Percentage Pt content of dendrimeric formulation increases with increase in drug/dendrimer mole ratio. Formulation with low drug/dendrimer mole ratio showed delayed release compared to the higher drug/dendrimer mole ratio; these dendrimer formulations are stable in room temperature. In vitro release profiles of the stored dendrimer-cisplatin samples showed comparatively slow release of cisplatin, which may be due to formation of strong bond between cisplatin and dendrimer. This study will contribute to create a fine print for the formulation development of PAMAM dendrimer-cisplatin complexes.

  8. Applications of dendrimers for brain delivery and cancer therapy.

    PubMed

    Somani, Sukrut; Dufès, Christine

    2014-10-01

    Dendrimers are emerging as potential nonviral vectors for the efficient delivery of drugs and nucleic acids to the brain and cancer cells. These polymers are highly branched, 3D macromolecules with modifiable surface functionalities and available internal cavities that make them attractive as delivery systems for drug and gene delivery applications. This article highlights the recent therapeutic advances resulting from the use of dendrimers for brain targeting and cancer treatment.

  9. 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

  10. Multivalent dendrimer vectors with DNA intercalation motifs for gene delivery.

    PubMed

    Wong, Pamela T; Tang, Kenny; Coulter, Alexa; Tang, Shengzhuang; Baker, James R; Choi, Seok Ki

    2014-11-10

    Poly(amido amine) (PAMAM) dendrimers constitute an important class of nonviral, cationic vectors in gene delivery. Here we report on a new concept for dendrimer vector design based on the incorporation of dual binding motifs: DNA intercalation, and receptor recognition for targeted delivery. We prepared a series of dendrimer conjugates derived from a fifth generation (G5) PAMAM dendrimer, each conjugated with multiple folate (FA) or riboflavin (RF) ligands for cell receptor targeting, and with 3,8-diamino-6-phenylphenanthridinium ("DAPP")-derived ligands for anchoring a DNA payload. Polyplexes of each dendrimer with calf thymus dsDNA were made and characterized by surface plasmon resonance (SPR) spectroscopy, dynamic light scattering (DLS) and zeta potential measurement. These studies provided evidence supporting polyplex formation based on the observation of tight DNA-dendrimer adhesion, and changes in particle size and surface charge upon coincubation. Further SPR studies to investigate the adhesion of the polyplex to a model surface immobilized with folate binding protein (FBP), demonstrated that the DNA payload has only a minimal effect on the receptor binding activity of the polyplex: KD = 0.22 nM for G5(FA)(DAPP) versus 0.98 nM for its polyplex. Finally, we performed in vitro transfection assays to determine the efficiency of conjugate mediated delivery of a luciferase-encoding plasmid into the KB cancer cell line and showed that RF-conjugated dendrimers were 1 to 2 orders of magnitude more effective in enhancing luciferase gene transfection than a plasmid only control. In summary, this study serves as a proof of concept for DNA-ligand intercalation as a motif in the design of multivalent dendrimer vectors for targeted gene delivery.

  11. Conformational Analysis of Triazine Dendrimers: Using NMR Spectroscopy To Probe the Choreography of a Dendrimer's Dance.

    PubMed

    Moreno, Karlos X; Simanek, Eric E

    2008-06-24

    One-dimensional (1D) and two-dimensional (2D) NMR studies are used to probe the conformation of a melamine dendrimer bearing unique NMR signals from the core to the periphery. Four conceptual anchors for dendrimer conformation emerge from these experiments. First, changes in isomer populations observed by (1)H NMR reveal the onset of globular structure. Second, NOE complexity emerges with globular structure: variable temperature NOESY studies show that the peripheral groups, BOC-protected aliphatic amines, fold back into the globular core of the macromolecule at 75 degrees C in DMSO-d(6). Third, variable temperature coefficients measured for NH protons suggest that solvent is largely excluded from the interior of the dendrimer: the carbamate NH groups of the periphery are most sensitive to temperature while the NHs nearest the core show little temperature dependence. Conformation is influenced by solvent choice: backfolding is observed in DMSO-d(6), but not in either CDCl(3) or CD(3)OD. Finally, relaxation studies show that peripheral groups are more dynamic than groups at the core. These anchors consolidate observations made by many groups on disparate systems within a common architecture.

  12. 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

  13. Carbosilane dendrimers bearing globotriaoses: syntheses of globotrioasyl derivative and introduction into carbosilane dendrimers.

    PubMed

    Matsuoka, Koji; Terabatake, Mikiko; Umino, Atsushi; Esumi, Yasuaki; Hatano, Ken; Terunuma, Daiyo; Kuzuhara, Hiroyoshi

    2006-08-01

    As an application of a one-pot reaction involving Birch reduction and subsequent S(N)2 reaction in liquid ammonia, synthetic assembly of trisaccharidic moieties of globotriaosyl ceramide onto carbosilane dendrimers was accomplished using tris(3-bromopropyl)phenylsilane and tris[tris(3-bromopropyl)silylpropyl]phenylsilane as the core scaffolds. The common globotriaosyl derivative having benzylsulfide functionality at the terminal of the aglycon was efficiently prepared from d-galactose and d-lactose as starting materials. The glycosyl donor derived from galactose and the glycosyl acceptor derived from lactose were condensed in the presence of silver triflate as the best promoter to provide corresponding trisaccharide with newly formed alpha-1-4 linkages in 90% yield. Fully benzylated protection of the trisaccharide was deprotected under the Birch reduction condition followed by acetylation to give an acetate in which alkene was converted into benzyl sulfide by radical addition of alpha-toluenethiol in high yields. On the other hand, carbosilane dendrimers were prepared from appropriate chlorosilanes as starting materials by a combination of hydrosylation followed by alkenylation. The terminal C=C double bonds of the carbosilanes were converted into corresponding alcohols by means of the usual hydroboration reaction, and the alcohols underwent further chemical manipulation to give carbosilane dendrimers with peripheral bromine atoms.

  14. Design and Evaluation of Tumor-Specific Dendrimer Epigenetic Therapeutics.

    PubMed

    Zong, Hong; Shah, Dhavan; Selwa, Katherine; Tsuchida, Ryan E; Rattan, Rahul; Mohan, Jay; Stein, Adam B; Otis, James B; Goonewardena, Sascha N

    2015-06-01

    Histone deacetylase inhibitors (HDACi) are promising therapeutics for cancer. HDACi alter the epigenetic state of tumors and provide a unique approach to treat cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off-target effects have limited their use. To overcome some of the challenges of traditional HDACi, we sought to use a tumor-specific dendrimer scaffold to deliver HDACi directly to cancer cells. Here we report the design and evaluation of tumor-specific dendrimer-HDACi conjugates. The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer. Using a cancer cell model, we demonstrate the functionality of the tumor-specific dendrimer-HDACi conjugates. Furthermore, we demonstrate that unlike traditional HDACi, dendrimer-HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges. We anticipate that this new class of cell-specific epigenetic therapeutics will have tremendous potential in the treatment of cancer.

  15. The interaction mechanism between lipopeptide (daptomycin) and polyamidoamine (PAMAM) dendrimers.

    PubMed

    Chanvorachote, Boontarika; Qiu, Jiang; Muangsiri, Walaisiri; Nimmannit, Ubonthip; Kirsch, Lee E

    2015-04-01

    The interaction mechanism of lipopeptide antibiotic daptomycin and polyamidoamine (PAMAM) dendrimers was studied using fluorescence spectroscopy. The fluorescence changes observed are associated with daptomycin-dendrimer interactions. The binding isotherms were constructed by plotting the fluorescence difference at 460 nm from kynurenine (Kyn-13) of daptomycin in the presence and absence of dendrimer. A one-site and two-site binding model were quantitatively generated to estimate binding capacity and affinity constants from the isotherms. The shape of the binding isotherm and the dependence of the estimated capacity constants on dendrimer sizes and solvent pH values provide meaningful insight into the mechanism of interactions. A one-site binding model adequately describes the binding isotherm obtained under a variety of experimental conditions with dendrimers of various sizes in the optimal binding pH region 3.5 to 4.5. Comparing the pH-dependent binding capacity with the ionization profiles of daptomycin and dendrimer, the ionized aspartic acid residue (Asp-9) of daptomycin primarily interact with PAMAM cationic surface amine.

  16. Factors affecting interactions between sulphonate-terminated dendrimers and proteins: A three case study.

    PubMed

    González-García, Estefanía; Maly, Marek; de la Mata, Francisco Javier; Gómez, Rafael; Marina, María Luisa; García, María Concepción

    2017-01-01

    This work proposes a deep study on the interactions between sulphonate-terminated carbosilane dendrimers and proteins. Three different proteins with different molecular weights and isoelectric points were employed and different pHs, dendrimer concentrations and generations were tested. Variations in fluorescence intensity and emission wavelength were used as protein-dendrimer interaction probes. Interaction between dendrimers and proteins greatly depended on the protein itself and pH. Other important issues were the dendrimer concentration and generation. Protein-dendrimer interactions were favored under acidic working conditions when proteins were positively charged. Moreover, in general, high dendrimer generations promoted these interactions. Modeling of protein-dendrimer interactions allowed to understand the different behaviors observed for every protein.

  17. Fluorescence quenching mechanism of a polyphenylene polyelectrolyte with other macromolecules: cytochrome c and dendrimers.

    PubMed

    Liu, Min; Kaur, Palwinder; Waldeck, D H; Xue, Cuihua; Liu, Haiying

    2005-03-01

    This study investigates the fluorescence quenching of a polyphenyl based polyelectrolyte by positively charged macromolecules (proteins and dendrimers). This work shows that the fluorescence quenching of the dendrimer materials does not involve energy transfer or electron transfer but is correlated to the overall charge on the dendrimer and its size. The quenching is hypothesized to result from conformational changes that occur upon binding the polyelectrolyte to the protein or dendrimer. This mechanism is qualitatively different from that invoked for small-molecule analytes.

  18. 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.

  19. 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…

  20. Influence of peptide dendrimers and sonophoresis on the transdermal delivery of ketoprofen.

    PubMed

    Manikkath, Jyothsna; Hegde, Aswathi R; Kalthur, Guruprasad; Parekh, Harendra S; Mutalik, Srinivas

    2017-02-02

    The aim of this study was to determine the individual and combined effects of peptide dendrimers and low frequency ultrasound on the transdermal permeation of ketoprofen. Arginine terminated peptide dendrimers of varying charges (4(+), 8(+) and 16(+), named as A4. A8 and A16 respectively) were synthesized and characterized. Ketoprofen was subjected to passive, peptide dendrimer-assisted and sonophoretic permeation studies (with and without dendrimer application) across Swiss albino mouse skin, both in vitro and in vivo. The studies revealed that the synthesized peptide dendrimers considerably increased the transdermal permeation of ketoprofen and displayed enhancement ratios of up to 3.25 (with A16 dendrimer), compared to passive diffusion of drug alone in vitro. Moreover, the combination of peptide dendrimer treatment and ultrasound application worked in synergy and gave enhancement ratios of up to 1369.15 (with ketoprofen-A16 dendrimer complex). In vivo studies demonstrated that dendrimer and ultrasound-assisted permeation of drug achieved much higher plasma concentration of drug, compared to passive diffusion. Comparison of transdermal and oral absorption studies revealed that transdermal administration of ketoprofen with A8 dendrimer showed comparable absorption and plasma drug levels with oral route. The excised mouse skin after in vivo permeation study with dendrimers and ultrasound did not show major toxic reactions. This study demonstrates that arginine terminated peptide dendrimers combined with sonophoresis can effectively improve the transdermal permeation of ketoprofen.

  1. Interaction of nucleic acids with carbon nanotubes and dendrimers.

    PubMed

    Nandy, Bidisha; Santosh, Mogurampelly; Maiti, Prabal K

    2012-07-01

    Nucleic acid interaction with nanoscale objects like carbon nanotubes (CNTs) and dendrimers is of fundamental interest because of their potential application in CNT separation, gene therapy and antisense therapy. Combining nucleic acids with CNTs and dendrimers also opens the door towards controllable self-assembly to generate various supra-molecular and nano-structures with desired morphologies. The interaction between these nanoscale objects also serve as a model system for studying DNA compaction, which is a fundamental process in chromatin organization. By using fully atomistic simulations, here we report various aspects of the interactions and binding modes of DNA and small interfering RNA (siRNA) with CNTs, graphene and dendrimers. Our results give a microscopic picture and mechanism of the adsorption of single- and double-strand DNA (ssDNA and dsDNA) on CNT and graphene. The nucleic acid-CNT interaction is dominated by the dispersive van der Waals (vdW) interaction. In contrast, the complexation of DNA (both ssDNA and dsDNA) and siRNA with various generations of poly-amido-amine (PAMAM) dendrimers is governed by electrostatic interactions. Our results reveal that both the DNA and siRNA form stable complex with the PAMAM dendrimer at a physiological pH when the dendrimer is positively charged due to the protonation of the primary amines. The size and binding energy of the complex increase with increase in dendrimer generation. We also give a summary of the current status in these fields and discuss future prospects.

  2. Dendrimers Bind Antioxidant Polyphenols and cisPlatin Drug

    PubMed Central

    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 NH2 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 102 M−1 to 103 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

  3. Comparative toxicological assessment of PAMAM and thiophosphoryl dendrimers using embryonic zebrafish

    PubMed Central

    Pryor, Joseph B; Harper, Bryan J; Harper, Stacey L

    2014-01-01

    Dendrimers are well-defined, polymeric nanomaterials currently being investigated for biomedical applications such as medical imaging, gene therapy, and tissue targeted therapy. Initially, higher generation (size) dendrimers were of interest because of their drug carrying capacity. However, increased generation was associated with increased toxicity. The majority of studies exploring dendrimer toxicity have focused on a small range of materials using cell culture methods, with few studies investigating the toxicity across a wide range of materials in vivo. The objective of the present study was to investigate the role of surface charge and generation in dendrimer toxicity using embryonic zebrafish (Danio rerio) as a model vertebrate. Due to the generational and charge effects observed at the cellular level, higher generation cationic dendrimers were hypothesized to be more toxic than lower generation anionic or neutral dendrimers with the same core composition. Polyamidoamine (PAMAM) dendrimers elicited significant morbidity and mortality as generation was decreased. No significant adverse effects were observed from the suite of thiophosphoryl dendrimers studied. Exposure to ≥50 ppm cationic PAMAM dendrimers G3-amine, G4-amine, G5-amine, and G6-amine caused 100% mortality by 24 hours post-fertilization. Cationic PAMAM G6-amine at 250 ppm was found to be statistically more toxic than both neutral PAMAM G6-amidoethanol and anionic PAMAM G6-succinamic acid at the same concentration. The toxicity observed within the suite of varying dendrimers provides evidence that surface charge may be the best indicator of dendrimer toxicity. Dendrimer class and generation are other potential contributors to the toxicity of dendrimers. Further studies are required to better understand the relative role each plays in driving the toxicity of dendrimers. To the best of our knowledge, this is the first in vivo study to address such a broad range of dendrimers. PMID:24790436

  4. 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

    2015-11-02

    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.

  5. 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.

  6. 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

  7. Mechanism of PAMAM Dendrimers Internalization in Hippocampal Neurons.

    PubMed

    Vidal, Felipe; Vásquez, Pilar; Díaz, Carola; Nova, Daniela; Alderete, Joel; Guzmán, Leonardo

    2016-10-03

    Polyamidoamine (PAMAM) dendrimers are hyperbranched macromolecules which have been described as one of the most promising drug nanocarrier systems. A key process to understand is their cellular internalization mechanism because of its direct influence on their intracellular distribution, association with organelles, entry kinetics, and cargo release. Despite that internalization mechanisms of dendrimers have been studied in different cell types, in the case of neurons they are not completely described. Considering the relevance of central nervous system (CNS) diseases and neuropharmacology, the aim of this report is to describe the molecular internalization mechanism of different PAMAM-based dendrimer systems in hippocampal neurons. Four dendrimers based on fourth generation PAMAM with different surface properties were studied: unmodified G4, with a positively charged surface; PP50, with a substitution of the 50% of amino surface groups with polyethylene glycol neutral groups; PAc, with a substitution of the 30% of amino surface groups with acrylate anionic groups; and PFO, decorated with folic acid groups in a 25% of total terminal groups. Confocal images show that both G4 and PFO are able to enter the neurons, but not PP50 and PAc. Colocalization study with specific endocytosis markers and specific endocytosis inhibitor assay demonstrate that clathrin-mediated endocytosis would be the main internalization mechanism for G4, whereas clathrin- and caveolae-mediated endocytosis would be implicated in PFO internalization. These results show the existence of different internalization mechanisms for PAMAM dendrimers in neurons and the possibility to control their internalization properties with specific chemical modifications.

  8. 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

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

    PubMed

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

    2015-11-14

    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.

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

    PubMed

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

    2015-05-20

    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.

  11. The use of nanoscaffolds and dendrimers in tissue engineering.

    PubMed

    Gorain, Bapi; Tekade, Muktika; Kesharwani, Prashant; Iyer, Arun K; Kalia, Kiran; Tekade, Rakesh Kumar

    2017-02-20

    To avoid tissue rejection during organ transplantation, research has focused on the use of tissue engineering to regenerate required tissues or organs for patients. The biomedical applications of hyperbranched, multivalent, structurally uniform, biocompatible dendrimers in tissue engineering include the mimicking of natural extracellular matrices (ECMs) in the 3D microenvironment. Dendrimers are unimolecular architects that can incorporate a variety of biological and/or chemical substances in a 3D architecture to actively support the scaffold microenvironment during cell growth. Here, we review the use of dendritic delivery systems in tissue engineering. We discuss the available literature, highlighting the 3D architecture and preparation of these nanoscaffolds, and also review challenges to, and advances in, the use dendrimers in tissue engineering. Advances in the manufacturing of dendritic nanoparticles and scaffold architectures have resulted in the successful incorporation of dendritic scaffolds in tissue engineering.

  12. Inhibition of phosphoinositol 3 kinase contributes to nanoparticle-mediated exaggeration of endotoxin-induced leukocyte procoagulant activity

    PubMed Central

    Ilinskaya, Anna N; Man, Sonny; Patri, Anil K; Clogston, Jeffrey D; Crist, Rachael M; Cachau, Raul E; McNeil, Scott E; Dobrovolskaia, Marina A

    2014-01-01

    Aim Disseminated intravascular coagulation is an increasing concern for certain types of engineered nanomaterials. Recent studies have shed some light on the nanoparticle physicochemical properties contributing to this toxicity; however, the mechanisms are poorly understood. Leukocyte procoagulant activity (PCA) is a key factor contributing to the initiation of this toxicity. We have previously reported on the exaggeration of endotoxin-induced PCA by cationic dendrimers. Herein, we report an effort to discern the mechanism. Materials & methods Poly(amidoamine) dendrimers with various sizes and surface functionalities were studied in vitro by the recalcification test, flow cytometry and other relevant assays. Results & conclusion Cationic dendrimers exaggerated endotoxin-induced PCA, but their anionic or neutral counterparts did not; the cationic charge prompts this phenomenon, but different cationic surface chemistries do not influence it. Cationic dendrimers and endotoxin differentially affect the PCA complex. The inhibition of phosphoinositol 3 kinase by dendrimers contributes to the exaggeration of the endotoxin-induced PCA. PMID:24279459

  13. Behavior of PPI-G2 Dendrimer in a Microemulsion.

    PubMed

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

    2017-03-16

    Dendrimer nanostructures are of eminent interest in biomedical applications because of their uniform and well-defined molecular size and shape, and their ability to cross cell membranes and reduce the risk of premature clearance from the human body. Dendrimers perform as gene and drug carriers and have also shown significant therapeutic properties for treating cancer and neurodegenerative diseases. A complex drug delivery system, based on a dendrimer solubilized in the aqueous core of a water-in-oil (W/O) microemulsion (ME) along with the drug may combine the advantages of both dendrimers and MEs to provide better control of drug release. We propose a new microemulsion composed of drug-permitted surfactants and dendrimer that can be used as a potential controlled drug delivery nanosystem. The influence of second generation poly(propyleneimine) (PPI-G2) dendrimer; solubilized in (W/O) ME with a capacity of up to 25 wt% PPI-G2 at various pHs; and their interactions with the surfactant phosphatidylcholine (PC), cosurfactant (butanol), and water was studied. SAXS and EPR measurements indicated that increasing PPI-G2 concentration reduces droplet curvature and increases droplet size thus increasing macro-(SAXS) and micro-(EPR) order degree. Furthermore, SD-NMR and ATR-FTIR show stronger interactions between PPI-G2 and water molecules at the expense of PC and butanol headgroups hydration, which increases microviscosity (EPR). PPI-G2's effect is somewhat opposite to the increasing water phase effect, thus reducing the amount of free water (DSC) and slowing the mobility of all ME components (SD-NMR).

  14. Temperature echoes revisited to probe the vibrational behavior of dendrimers

    NASA Astrophysics Data System (ADS)

    Paulo, Pedro M. R.

    2010-03-01

    Temperature quench echoes were induced in molecular dynamics simulations of dendrimers. This phenomenon was used to probe the vibrational behavior of these molecules by comparing simulation results with harmonic model predictions. The echo depth for short time intervals between temperature quenches is well described by the harmonic approximation and the fluctuations observed are related to the vibrational density of states. The echo depth for long time intervals decays progressively revealing dephasing due to anharmonic interactions. The density of states was calculated from the temperature fluctuations after the first quench and high-frequency modes were assigned by comparison with vibrational spectra of similar dendrimers.

  15. Temperature echoes revisited to probe the vibrational behavior of dendrimers.

    PubMed

    Paulo, Pedro M R

    2010-03-21

    Temperature quench echoes were induced in molecular dynamics simulations of dendrimers. This phenomenon was used to probe the vibrational behavior of these molecules by comparing simulation results with harmonic model predictions. The echo depth for short time intervals between temperature quenches is well described by the harmonic approximation and the fluctuations observed are related to the vibrational density of states. The echo depth for long time intervals decays progressively revealing dephasing due to anharmonic interactions. The density of states was calculated from the temperature fluctuations after the first quench and high-frequency modes were assigned by comparison with vibrational spectra of similar dendrimers.

  16. Electrochemiluminescent (ECL) [Ru(bpy)3](2+)/PAMAM dendrimer reactions: coreactant effect and 5-fluorouracil/dendrimer complex formation.

    PubMed

    Jimenez-Ruiz, Aila; Grueso, Elia; Perez-Tejeda, Pilar; Muriel-Delgado, Fernando; Torres-Marquez, Concepcion

    2016-10-01

    Electrogenerated chemiluminescence (ECL) reactions between tris(2,2'-bipyridine)ruthenium(II) and PAMAM dendrimers of the full (G1.0) and half (G1.5) generations were carried out in an aqueous medium at pH 6.1 and 10.0. In the absence of 5-fluoro-1H,3H-pyrimidine-2,4-dione (5-fluorouracil, 5-Fu) (coreactant effect study), the ECL efficiency trends as a function of [G1.0] and [G1.5] at pH 6.1 and 10.0 revealed that PAMAM dendrimers are about 100 (G1.5, pH 6.1), 60 (G1.5, pH 10.0), 26 (G1.0, pH 10.0) and 13 (G1.0, pH 6.1) times more efficient as ECL coreactants than oxalate anion is. Moreover, ECL reactions were done in the presence of several solutions of 5-Fu at a fixed concentration of the G1.0 and G1.5 dendrimers at pH 6.1 and 10.0 (binding study). The ECL efficiency trends as a function of [5-Fu] highlighted a dendrimer/5-Fu binding. Therefore, one of the most remarkable and novel findings of this work is the potential of PAMAM dendrimers to be used as both sensors and biosensors in an aqueous medium in the presence of a suitable sensitizer. Redox potentials of the [Ru(bpy)3](3+/2+) couple were also determined in the absence and presence of 5-Fu at both pHs. In the absence of 5-Fu the positive or negative shift of redox potentials showed the influence of the repulsive or attractive electrostatic long-range and short-range interactions between the charged dendrimer surface and the oxidized and reduced forms of the couple. In the presence of 5-Fu the trends of redox potentials highlighted the existence of a charged dendrimer/5-Fu species. Graphical Abstract ECL emission for the [Ru(bpy)3](2+)/ G1.0 dendrimer reaction in the presence of the 5-Fu at pH 6.1.

  17. Fluorophore:dendrimer ratio impacts cellular uptake and intracellular fluorescence lifetime.

    PubMed

    Dougherty, Casey A; Vaidyanathan, Sriram; Orr, Bradford G; Banaszak Holl, Mark M

    2015-02-18

    G5-NH2-TAMRAn (n = 1-4, 5+, and 1.5(avg)) were prepared with n = 1-4 as a precise dye:dendrimer ratio, 5+ as a mixture of dendrimers with 5 or more dye per dendrimer, and 1.5(avg) as a Poisson distribution of dye:dendrimer ratios with a mean of 1.5 dye per dendrimer. The absorption intensity increased sublinearly with n whereas the fluorescence emission and lifetime decreased with an increasing number of dyes per dendrimer. Flow cytometry was employed to quantify uptake into HEK293A cells. Dendrimers with 2-4 dyes were found to have greater uptake than dendrimer with a single dye. Fluorescence lifetime imaging microscopy (FLIM) showed that the different dye:dendrimer ratio alone was sufficient to change the fluorescence lifetime of the material observed inside cells. We also observed that the lifetime of G5-NH2-TAMRA5+ increased when present in the cell as compared to solution. However, cells treated with G5-NH2-TAMRA1.5(avg) did not exhibit the high lifetime components present in G5-NH2-TAMRA1 and G5-NH2-TAMRA5+. In general, the effects of the dye:dendrimer ratio on fluorescence lifetime were of similar magnitude to environmentally induced lifetime shifts.

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

    NASA Astrophysics Data System (ADS)

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

    2016-02-01

    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.

  19. Characterization of Pt@Cu core@shell dendrimer-encapsulated nanoparticles synthesized by Cu underpotential deposition.

    PubMed

    Carino, Emily V; Crooks, Richard M

    2011-04-05

    Dendrimer-encapsulated nanoparticles (DENs) containing averages of 55, 147, and 225 Pt atoms immobilized on glassy carbon electrodes served as the electroactive surface for the underpotential deposition (UPD) of a Cu monolayer. This results in formation of core@shell (Pt@Cu) DENs. Evidence for this conclusion comes from cyclic voltammetry, which shows that the Pt core DENs catalyze the hydrogen evolution reaction before Cu UPD, but that after Cu UPD this reaction is inhibited. Results obtained by in situ electrochemical X-ray absorption spectroscopy (XAS) confirm this finding.

  20. 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

  1. Enzyme-responsive peptide dendrimer-gemcitabine conjugate as a controlled-release drug delivery vehicle with enhanced antitumor efficacy.

    PubMed

    Zhang, Chengyuan; Pan, Dayi; Li, Jin; Hu, Jiani; Bains, Ashika; Guys, Nicholas; Zhu, Hongyan; Li, Xiaohui; Luo, Kui; Gong, Qiyong; Guc, Zhongwei

    2017-03-01

    Stimuli-responsive peptide dendrimer-drug conjugates have presented significant potential for cancer therapy. To develop an effective nanoscale chemotherapeutic prodrug, we developed a novel enzyme-responsive PEGylated lysine peptide dendrimer-gemcitabine conjugate (Dendrimer-GEM) based nanoparticle via the highly efficient click reaction. Owing to the glycylphenylalanylleucylglycine tetra-peptide (GFLG) as an enzyme-cleavable linker to conjugate gemcitabine (GEM), the prepared nanoparticles were able to release drug significantly faster in the tumor cellular environments, which specifically contains secreted Cathepsin B, quantifiably more than 80% GEM was released with Cathepsin B compared to the condition without Cathepsin B at 24h. This nanoparticle demonstrated enhanced antitumor efficacy in a 4T1 murine breast cancer model without obvious systemic toxicity, resulting in significantly suppressed relative tumor volumes (86.17 ± 38.27%) and a 2-fold higher value of tumor growth inhibition (~90%) than GEM∙HCl treatment. These results suggest that the PEGylated peptide dendrimer-gemcitabine conjugate can be an effective antitumor agent for breast cancer therapy. Statement of significance We found that the functionalized dendrimer based nanoscale drug delivery vehicles exhibited enhanced therapeutic indexes and reduced toxicity as compared to the free drug gemcitabine. Compared with current nanoparticles, such as dendritic anticancer drug delivery systems, the new design was capable of self-assembling into nanoscale particles with sizes of about 80-110 nm, which is suitable as antitumor drug delivery vehicle due to the potential longer intravascular half-life and higher accumulation in tumor tissue via EPR effect. Owing to the optimized architecture, the system was given the enzyme-responsive drug release feature, and showed excellent antitumor activity on the 4T1 breast tumor model due to the evidences from tumor growth curves, immunohistochemical analysis and

  2. FTIR spectroscopy and DFT studies of carbosilane dendrimers.

    PubMed

    Furer, V L; Vandukova, I I; Tatarinova, E A; Muzafarov, A M; Kovalenko, V I

    2008-08-01

    The FTIR spectra of G(3), G(4), and G(9) generations of polybutylcarbosilane dendrimers have been recorded and analyzed. The structural optimization and normal mode analysis were performed for G(1) generation on the basis of density functional theory (DFT). This calculation gave vibrational frequencies and infrared intensities for the t,t- and g,-g-conformers of the butyl terminal groups, attached to the same silicon atom. The g,-g-conformer is 5.83 kcal/mol less stable compared to t,t-conformer. Relying on DFT calculations a complete vibrational assignment is proposed for different parts of the studied dendrimers. The dependence of band full width at half height in the IR spectra on generation number is established. The IR spectra of carbosilane dendrimers at higher temperatures at the ambient air and isolated from atmosphere air were studied. At temperature 180 degrees C all studied carbosilane dendrimers are stable when contact with atmosphere is absent, in the air they oxidize and thus CO and SiO groups appear.

  3. Complexing Methylene Blue with Phosphorus Dendrimers to Increase Photodynamic Activity.

    PubMed

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

    2017-02-23

    The efficiency of photodynamic therapy is limited mainly due to low selectivity, unfavorable biodistribution of photosensitizers, and long-lasting skin sensitivity to light. However, drug delivery systems based on nanoparticles may overcome the limitations mentioned above. Among others, dendrimers are particularly attractive as carriers, because of their globular architecture and high loading capacity. The goal of the study was to check whether an anionic phosphorus dendrimer is suitable as a carrier of a photosensitizer-methylene blue (MB). As a biological model, basal cell carcinoma cell lines were used. We checked the influence of the MB complexation on its singlet oxygen production ability using a commercial fluorescence probe. Next, cellular uptake, phototoxicity, reactive oxygen species (ROS) generation, and cell death were investigated. The MB-anionic dendrimer complex (MB-1an) was found to generate less singlet oxygen; however, the complex showed higher cellular uptake and phototoxicity against basal cell carcinoma cell lines, which was accompanied with enhanced ROS production. Owing to the obtained results, we conclude that the photodynamic activity of MB complexed with an anionic dendrimer is higher than free MB against basal cell carcinoma cell lines.

  4. Click hybridization of immune cells and polyamidoamine dendrimers.

    PubMed

    Xu, Leyuan; Zolotarskaya, Olga Yu; Yeudall, W Andrew; Yang, Hu

    2014-09-01

    Immobilizing highly branched polyamidoamine (PAMAM) dendrimers to the cell surface represents an innovative method of enhancing cell surface loading capacity to deliver therapeutic and imaging agents. In this work, hybridized immune cells, that is, macrophage RAW264.7 (RAW), with PAMAM dendrimer G4.0 (DEN) on the basis of bioorthogonal chemistry are clicked. Efficient and selective cell surface immobilization of dendrimers is confirmed by confocal microscopy. Viability and motility of RAW-DEN hybrids remain the same as untreated RAW cells according to WST-1 assay and wound closure assay. Furthermore, Western blot analysis reveals that there are no significant alterations in the expression levels of signaling molecules AKT, p38, and NFκB (p65) and their corresponding activated (phosphorylated) forms in RAW cells treated with azido sugar and dendrimer, indicating that the hybridization process neither induced cell stress response nor altered normal signaling pathways. Taken together, this work shows the feasibility of applying bioorthogonal chemistry to create cell-nanoparticle hybrids and demonstrates the noninvasiveness of this cell surface engineering approach.

  5. 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…

  6. Dendrimers and methods of preparing same through proportionate branching

    DOEpatents

    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.

  7. Low-Bandgap Thiophene Dendrimers for Improved Light Harvesting

    SciTech Connect

    Rupert, B. L.; Mitchell, W. J.; Ferguson, A. J.; Kose, M. E.; Rance, W. L.; Rumbles, G.; Ginley, D. S.; Shaheen, S. E.; Kopidakis, N.

    2009-01-01

    This article follows our previous work on the synthesis and characterization of pi-conjugated dendrimers for use in organic solar cells. Here we discuss five new thiophene-based dendrimers that were synthesized in order to study the relationship between their chemical structures and electronic properties. Three of these dendrimers incorporate acetylene spacers, included to relieve steric strain, between the thiophene arms and phenyl cores used in previous studies. Only a small effect on the electronic properties is observed upon inclusion of the acetylene spacer in the three-arm dendrimer, 3G1-2S-Ac. In contrast, a decrease in the bandgap is observed for the four-arm dendrimer, 4G1-2S-Ac, due to a reduction of interactions between the arms in the more sterically congested 1,2,4,5-arrangement around the phenyl core, resulting in delocalization of the exciton through the phenyl core. Incorporation of electron-withdrawing cyano groups on the phenyl core of the three-arm dendrimer, 3G1-2S-CN, resulted in a very large ({approx}0.5 eV) decrease in the bandgap, due to stabilization of the lowest unoccupied molecular orbital, and the low energy absorption band in this material is attributed to a transition with significant intramolecular charge-transfer character. The electronic properties of three- and four-arm dendrimers with electron-donating dibutylaniline moieties attached to the end of the thiophene dendron, 3G1-2S-N and 4G1-2S-N respectively, are almost identical, indicating that they are dominated by the arms, with no through-core communication allowed, even for the para-linked arms of 4G1-2S-N. However, there is a significant increase in the molar absorptivity of these materials, concomitant with significant broadening of the absorption spectrum, which is an important attribute in light-harvesting applications.

  8. 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

  9. 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.

  10. 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

  11. Interaction of single-walled carbon nanotubes with poly(propyl ether imine) dendrimers

    SciTech Connect

    Jayamurugan, G.; Rajesh, Y. B. R. D.; Jayaraman, N.; Vasu, K. S.; Kumar, S.; Sood, A. K.; Vasumathi, V.; Maiti, P. K.

    2011-03-14

    We study the complexation of nontoxic, native poly(propyl ether imine) dendrimers with single-walled carbon nanotubes (SWNTs). The interaction was monitored by measuring the quenching of inherent fluorescence of the dendrimer. The dendrimer-nanotube binding also resulted in the increased electrical resistance of the hole doped SWNT, due to charge-transfer interaction between dendrimer and nanotube. This charge-transfer interaction was further corroborated by observing a shift in frequency of the tangential Raman modes of SWNT. We also report the effect of acidic and neutral pH conditions on the binding affinities. Experimental studies were supplemented by all atom molecular dynamics simulations to provide a microscopic picture of the dendrimer-nanotube complex. The complexation was achieved through charge transfer and hydrophobic interactions, aided by multitude of oxygen, nitrogen, and n-propyl moieties of the dendrimer.

  12. Structural characterization of poly(amino)ester dendrimers and related impurities by electrospray tandem mass spectrometry.

    PubMed

    Tintaru, Aura; Monnier, Valérie; Bouillon, Camille; Giordanengo, Rémi; Quéléver, Gilles; Peng, Ling; Charles, Laurence

    2010-08-15

    An acid-terminated poly(amino)ester dendrimer was studied by electrospray ionization tandem mass spectrometry to establish its fragmentation pathways, with the aim of using them to investigate the structure of any defective molecules generated during the dendrimer synthesis. This poly(amino)ester dendrimer could be ionized in both polarities but the most structurally relevant dissociation pathways were found from the deprotonated molecule in negative ion mode. The dissociation pattern of this dendrimer is fully described and supported by accurate mass measurements. The main dissociation reactions of the negatively charged polyacidic dendrimer were shown to consist of (i) the release of carbon dioxide and ethene within a branch, which proceeds as many times as intact neutral branches are available; and (ii) the elimination of an entire dendrimer arm. Monitoring the occurrence of these reactions together with any deviation from these two main routes allowed six major dendritic impurities to be structurally characterized.

  13. Interaction of single-walled carbon nanotubes with poly(propyl ether imine) dendrimers

    NASA Astrophysics Data System (ADS)

    Jayamurugan, G.; Vasu, K. S.; Rajesh, Y. B. R. D.; Kumar, S.; Vasumathi, V.; Maiti, P. K.; Sood, A. K.; Jayaraman, N.

    2011-03-01

    We study the complexation of nontoxic, native poly(propyl ether imine) dendrimers with single-walled carbon nanotubes (SWNTs). The interaction was monitored by measuring the quenching of inherent fluorescence of the dendrimer. The dendrimer-nanotube binding also resulted in the increased electrical resistance of the hole doped SWNT, due to charge-transfer interaction between dendrimer and nanotube. This charge-transfer interaction was further corroborated by observing a shift in frequency of the tangential Raman modes of SWNT. We also report the effect of acidic and neutral pH conditions on the binding affinities. Experimental studies were supplemented by all atom molecular dynamics simulations to provide a microscopic picture of the dendrimer-nanotube complex. The complexation was achieved through charge transfer and hydrophobic interactions, aided by multitude of oxygen, nitrogen, and n-propyl moieties of the dendrimer.

  14. Exploiting dendrimer multivalency to combat emerging and re-emerging infectious diseases

    PubMed Central

    Mintzer, Meredith A.; Dane, Eric L.; O’Toole, George A.; Grinstaff, Mark W.

    2013-01-01

    The emergence and re-emergence of bacterial strains that are resistant to current antibiotics reveals the clinical need for new agents that possess broad-spectrum antibacterial activity. Furthermore, bacteriophobic coatings that repel bacteria are important for medical devices, as the lifetime, reliability, and performance of implant devices are hindered by bacterial adhesion and infection. Dendrimers, a specific class of monodisperse macromolecules, have recently shown potential to function as both antibacterial agents as well as antimicrobial surface coatings. This review discusses the limitations with currently used antibacterial agents and describes how various classes of dendrimers, including glycodendrimers, cationic dendrimers, anionic dendrimers, and peptide dendrimers, have the potential to improve upon or replace certain antibiotics. Furthermore, the unexplored areas in this field of research will be mentioned to present opportunities for additional studies regarding the use of dendrimers as antimicrobial agents. PMID:22126461

  15. Diffusion of Alexa Fluor 488-conjugated dendrimers in rat aortic tissue.

    PubMed

    Cho, Brenda S; Roelofs, Karen J; Majoros, Istvan J; Baker, James R; Stanley, James C; Henke, Peter K; Upchurch, Gilbert R

    2006-11-01

    In this study, the distribution of labeled dendrimers in native and aneurysmal rat aortic tissue was examined. Adult male rats underwent infrarenal aorta perfusion with generation 5 (G5) acetylated Alexa Fluor 488-conjugated dendrimers for varying lengths of time. In a second set of experiments, rats underwent aortic elastase perfusion followed by aortic dendrimer perfusion 7 days later. Aortic diameters were measured prior to and postelastase perfusion, and again on the day of harvest. Aortas were harvested 0, 12, or 24 h postperfusion, fixed, and mounted. Native aortas were harvested and viewed as negative controls. Aortic cross-sections were viewed and imaged using confocal microscopy. Dendrimers were quantified (counts/high-powered field). Results were evaluated by repeated measures ANOVA and Student's t-test. We found that in native aortas, dendrimers penetrated the aortic wall in all groups. For all perfusion times, fewer dendrimers were present as time between dendrimer perfusion and aortic harvest increased. Longer perfusion times resulted in increased diffusion of dendrimers throughout the aortic wall. By 24 h, the majority of the dendrimers were through the wall. Dendrimers in aneurysmal aortas, on day 0 postdendrimer perfusion, diffused farther into the aortic wall than controls. In conclusion, this study documents labeled dendrimers delivered intra-arterially to native rat aortas in vivo, and the temporal diffusion of these molecules within the aortic wall. Increasing perfusion time and length of time prior to harvest resulted in continued dendrimer diffusion into the aortic wall. These preliminary data provide a novel mechanism whereby local inhibitory therapy may be delivered locally to aortic tissue.

  16. Synthesis, photophysical studies and ¹O₂ generation of carboxylate-terminated zinc phthalocyanine dendrimers.

    PubMed

    Setaro, Francesca; Ruiz-González, Rubén; Nonell, Santi; Hahn, Uwe; Torres, Tomás

    2014-07-01

    Highly water-soluble dendrimers have been prepared consisting of a central zinc phthalocyanine moiety and dendritic wedges with terminal carboxylate groups. The biggest polyelectrolyte comprises 32 negative charges at the dendrimer surface. The photophysical studies reveal a strong correlation between the degree of dendritic environment, the extent of aggregation, and the ability to generate singlet oxygen in aqueous media. Compared to dendrimers having an axial derivatization the functionalization on the outer rim also significantly improves the phthalocyanine's ability to photosensitize singlet oxygen.

  17. TRANSEPITHELIAL TRANSPORT AND TOXICITY OF PAMAM DENDRIMERS: IMPLICATIONS FOR ORAL DRUG DELIVERY

    PubMed Central

    Sadekar, S.; Ghandehari, H.

    2011-01-01

    This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer – drug conjugates, as a function of physicochemical properties will further need to be assessed. PMID:21983078

  18. Multiscale modeling of dendrimers and their interactions with bilayers and polyelectrolytes.

    PubMed

    Lee, Hwankyu; Larson, Ronald G

    2009-01-19

    Recent advances in molecular dynamics simulation methodologies and computational power have allowed accurate predictions of dendrimer size, shape, and interactions with bilayers and polyelectrolytes with modest computational effort. Atomistic and coarse-grained (CG) models show strong interactions of cationic dendrimers with lipid bilayers. The CG simulations with explicit lipid and water capture bilayer penetration and pore formation, showing that pore formation is enhanced at high dendrimer concentration, but suppressed at low temperature and high salt concentration, in agreement with experiments. Cationic linear polymers have also been simulated, but do not perforate membranes, evidently because by deforming into a pancake, the charges on a linear polymer achieve intimate contact with a single bilayer leaflet. The relatively rigid dendrimers, on the other hand, penetrate the bilayer, because only by interacting with both leaflets can they achieve a similar degree of contact between charged groups. Also, a "dendrimer-filled vesicle" structure for the dendrimer-membrane interaction is predicted by mesoscale thermodynamic simulations, in agreement with a picture derived from experimental observations. In simulations of complexes of dendrimer and polyelectrolyte, anionic linear chains wrap around the cationic dendrimer and penetrate inside it. Overall, these new results indicate that simulations can now provide predictions in excellent agreement with experimental observations, and provide atomic-scale insights into dendrimer structure and dynamics.

  19. Dendrimer-based magnetic iron oxide nanoparticles: their synthesis and biomedical applications.

    PubMed

    Sun, Wenjie; Mignani, Serge; Shen, Mingwu; Shi, Xiangyang

    2016-12-01

    Magnetic iron oxide nanoparticles (MIO NPs) bearing different appropriate surface modifications can be prepared using diverse physical and chemical methods. As an ideal macromolecule, dendrimers have attracted considerable attention because of their unique properties, including their three 3D architecture, monodispersity, highly branched macromolecular characteristics, and tunable terminal functionalities. These properties make dendrimers a powerful nanoplatform for the creation of functional organic and/or inorganic hybrid NPs, in particular dendrimer-based MIO NPs. Here, we report on recent advances in the preparation of dendrimer-based MIO NPs for different biomedical applications, such as magnetic resonance (MR) imaging, drug and gene delivery, and protein immobilization.

  20. Poly(amidoamine) (PAMAM) dendrimers: from biomimicry to drug delivery and biomedical applications.

    PubMed

    Esfand, R; Tomalia, D A.

    2001-04-01

    Poly(amidoamine) (PAMAM) dendrimers are the first complete dendrimer family to be synthesized, characterized and commercialized. Based on this extensive activity, they are recognized as a unique new class of synthetic nanostructures. Dendrimers allow the precise control of size, shape and placement of functional groups that is desirable for many life science applications. From this perspective, this review focuses on crucial properties of biomimetic dendrimers that will broaden the potential for their use as macromolecular vectors in novel drug delivery and biomedical applications.

  1. Quaternized and Thiazole-Functionalized Free Radical-Generating Organometallic Dendrimers as Antimicrobial Platform against Multidrug-Resistant Microorganisms.

    PubMed

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

    2017-03-31

    New macromolecules such as dendrimers are increasingly needed to drive breakthroughs in diverse areas, for example, healthcare. Here, the authors report hybrid antimicrobial dendrimers synthesized by functionalizing organometallic dendrimers with quaternary ammonium groups or 2-mercaptobenzothiazole. The functionalization tunes the glass transition temperature and antimicrobial activities of the dendrimers. Electron paramagnetic resonance spectroscopy reveals that the dendrimers form free radicals, which have significant implications for catalysis and biology. In vitro antimicrobial assays indicate that the dendrimers are potent antimicrobial agents with activity against multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium as well as other microorganisms. The functionalization increases the activity, especially in the quaternary ammonium group-functionalized dendrimers. Importantly, the activities are selective because human epidermal keratinocytes cells and BJ fibroblast cells exposed to the dendrimers are viable after 24 h.

  2. Highly Efficient and Safe Delivery of VEGF siRNA by Bioreducible Fluorinated Peptide Dendrimers for Cancer Therapy.

    PubMed

    Cai, Xiaojun; Zhu, Haofang; Zhang, Yanmei; Gu, Zhongwei

    2017-03-22

    RNA interference (RNAi) has a great promise in treating various acquired and hereditary diseases. However, it remains highly desirable to develop new delivery system to circumvent complex extra- and intracellular barriers for successful clinical translation. Here, we report on a versatile polymeric vector, bioreducible fluorinated peptide dendrimers (BFPD), for efficient and safe small interfering RNA (siRNA) delivery. In virtue of skillfully integrating all of the unique advantages of reversible cross-linking, fluorination, and peptide dendrimers, this novel vector can surmount almost all extra- and intracellular barriers associated with local siRNA delivery through highly improved physiological stability and serum resistance, significantly increased intratumoral enrichment, cellular internalization, successful facilitation of endosomal escape, and cytosolic siRNA release. BFPD polyplexes, carrying small interfering vascular endothelial growth factor (siVEGF), demonstrated excellent VEGF silencing efficacy (∼65%) and a strong capability for inhibiting HeLa cell proliferation. More importantly, these polyplexes showed superior performance in long-term enrichment in the tumor sites and had a high level of tumor growth inhibition. Furthermore, these polyplexes not only exhibited excellent in vivo antitumor efficacy but also demonstrated superior biocompatibility, compared with LPF2000, both in vivo and in vitro. These findings indicate that BFPD is an efficient and safe siRNA delivery system and has remarkable potential for RNAi-based cancer treatment.

  3. 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

  4. In Silico Characterization of the Binding Affinity of Dendrimers to Penicillin-Binding Proteins (PBPs): Can PBPs be Potential Targets for Antibacterial Dendrimers?

    PubMed

    Ahmed, Shaimaa; Vepuri, Suresh B; Ramesh, Muthusamy; Kalhapure, Rahul; Suleman, Nadia; Govender, Thirumala

    2016-04-01

    We have shown that novel silver salts of poly (propyl ether) imine (PETIM) dendron and dendrimers developed in our group exhibit preferential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule, explore the mechanism of binding with biological targets, and explain their preferential antibacterial activity. The current article reports the conformational landscape as well as mechanism of binding of generation 1 PETIM dendron and dendrimers to penicillin-binding proteins (PBPs) in order to understand the antibacterial activity profiles of their silver salts. Molecular dynamics at different simulation protocols and conformational analysis were performed to elaborate on the conformational features of the studied dendrimers, as well as to create the initial structure for further binding studies. The results showed that for all compounds, there were no significant conformational changes due to variation in simulation conditions. Molecular docking calculations were performed to investigate the binding theme between the studied dendrimers and PBPs. Interestingly, in significant accordance with the experimental data, dendron and dendrimer with aliphatic cores were found to show higher activity against S. aureus than the dendrimer with an aromatic core. The latter showed higher activity against MRSA. The findings from this computational and molecular modeling report together with the experimental results serve as a road map toward designing more potent antibacterial dendrimers against resistant bacterial strains.

  5. 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.

  6. Sodium sensing in neurons with a dendrimer-based nanoprobe.

    PubMed

    Lamy, Christophe M; Sallin, Olivier; Loussert, Céline; Chatton, Jean-Yves

    2012-02-28

    Ion imaging is a powerful methodology to assess fundamental biological processes in live cells. The limited efficiency of some ion-sensing probes and their fast leakage from cells are important restrictions to this approach. In this study, we present a novel strategy based on the use of dendrimer nanoparticles to obtain better intracellular retention of fluorescent probes and perform prolonged fluorescence imaging of intracellular ion dynamics. A new sodium-sensitive nanoprobe was generated by encapsulating a sodium dye in a PAMAM dendrimer nanocontainer. This nanoprobe is very stable and has high sodium sensitivity and selectivity. When loaded in neurons in live brain tissue, it homogenously fills the entire cell volume, including small processes, and stays for long durations, with no detectable alterations of cell functional properties. We demonstrate the suitability of this new sodium nanosensor for monitoring physiological sodium responses such as those occurring during neuronal activity.

  7. Photoinduced electron transfer between benzyloxy dendrimer phthalocyanine and benzoquinone

    NASA Astrophysics Data System (ADS)

    Zhang, Tiantian; Ma, Dongdong; Pan, Sujuan; Wu, Shijun; Jiang, Yufeng; Zeng, Di; Yang, Hongqin; Peng, Yiru

    2016-10-01

    Photo-induced electron transfer (PET) is an important and fundamental process in natural photosynthesis. To mimic such interesting PET process, a suitable donor and acceptor couple were properly chosen. Dendrimer phthalocyanines and their derivatives have emerged as promising materials for artificial photosynthesis systems. In this paper, the electron transfer between the light harvest dendrimer phthalocyanine (donor) and the 1,4-benzoquinone (acceptor) was studied by UV/Vis and fluorescence spectroscopic methods. It was found that fluorescence of phthalocyanine was quenched by benzoquinone (BQ) via excited state electron transfer, from the phthalocyanine to the BQ upon excitation at 610 nm. The Stern-Volmer constant (KSV) of electron transfer was calculated. Our study suggests that this dendritic phthalocyanine is an effective new electron donor and transmission complex and could be used as a potential artificial photosynthesis system.

  8. Enhanced Bioactivity of Internally Functionalized Cationic Dendrimers with PEG Cores

    DTIC Science & Technology

    2012-11-09

    purchased from Laysan Bio. 2,2′-Azobis(2- methylpropionitrile) (98%), cysteamine hydrochloride (98%) and 2,2- dimethoxy-2-phenylacetophenone (99%) were... cysteamine hydrochloride (1.7 g, 15 mmol), and DMPA (38 mg, 0.15 mmol) were dissolved in MeOH (5 mL). The mixture was purged with argon for 10 min and...68.3, 58.6, 58.4, 55.0, 54.7, 45.8, 35.0, 31.5, 30.1. Dendrimer 4-armPEG-G4. Dendrimer 4-armPEG-G3 (100 mg, 6.4 μmol), cysteamine hydrochloride (930 mg

  9. Hydrogels for osteochondral repair based on photocrosslinkable carbamate dendrimers.

    PubMed

    Degoricija, Lovorka; Bansal, Prashant N; Söntjens, Serge H M; Joshi, Neel S; Takahashi, Masaya; Snyder, Brian; Grinstaff, Mark W

    2008-10-01

    First generation, photocrosslinkable dendrimers consisting of natural metabolites (i.e., succinic acid, glycerol, and beta-alanine) and nonimmunogenic poly(ethylene glycol) (PEG) were synthesized divergently in high yields using ester and carbamate forming reactions. Aqueous solutions of these dendrimers were photocrosslinked with an eosin-based photoinitiator to afford hydrogels. The hydrogels displayed a range of mechanical properties based on their structure, generation size, and concentration in solution. All of the hydrogels showed minimal swelling characteristics. The dendrimer solutions were then photocrosslinked in situ in an ex vivo rabbit osteochondral defect (3 mm diameter and 10 mm depth), and the resulting hydrogels were subjected to physiologically relevant dynamic loads. Magnetic resonance imaging (MRI) showed the hydrogels to be fixated in the defect site after the repetitive loading regimen. The ([G1]-PGLBA-MA) 2-PEG hydrogel was chosen for the 6 month pilot in vivo rabbit study because this hydrogel scaffold could be prepared at low polymer weight (10 wt %) and possessed the largest compressive modulus of the 10% formulations, a low swelling ratio, and contained carbamate linkages, which are more hydrolytically stable than the ester linkages. The hydrogel-treated osteochondral defects showed good attachment in the defect site and histological analysis showed the presence of collagen II and glycosaminoglycans (GAGs) in the treated defects. By contrast, the contralateral unfilled defects showed poor healing and negligible GAG or collagen II production. Good mechanical properties, low swelling, good attachment to the defect site, and positive in vivo results illustrate the potential of these dendrimer-based hydrogels as scaffolds for osteochondral defect repair.

  10. 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

  11. Dendrimer-Silver Complexes and Nanocomposites as Antimicrobial Agents

    DTIC Science & Technology

    2001-01-01

    especially important in the topical antibacterial treatment of burn wounds, where transient bacteremia is commonly cited.1 Silver sulfonamides, par...In this test, dendrimer- silver compounds were examined for diffusible antimicrobial activity by placing a 10 µL sample of each solution onto a 6 mm...compound, it does not have visible absorption over 300 nm wavelength. Absorption at longer wavelength is caused by the silver nanoparticles . Spec

  12. Isolation and Characterization of Precise Dye/Dendrimer Ratios

    PubMed Central

    Dougherty, Casey A.; Furgal, Joseph C.; van Dongen, Mallory A.; Goodson, Theodore; Banaszak Holl, Mark M.; Manono, Janet; DiMaggio, Stassi

    2014-01-01

    Fluorescent dyes are commonly conjugated to nanomaterials for imaging applications using stochastic synthesis conditions that result in a Poisson distribution of dye/particle ratios and therefore a broad range of photophysical and biodistribution properties. We report the isolation and characterization of generation 5 poly(amidoamine) (G5 PAMAM) dendrimer samples containing 1, 2, 3, and 4 fluorescein (FC) or 6-carboxytetramethylrhodamine succinimidyl ester (TAMRA) dyes per polymer particle. For the fluorescein case, this was achieved by stochastically functionalizing dendrimer with a cyclooctyne `click' ligand, separation into sample containing precisely defined `click' ligand/particle ratios using reverse-phase high performance liquid chromatography (rp-HPLC), followed by reaction with excess azide-functionalized fluorescein dye. For the TAMRA samples, stochastically functionalized dendrimer was directly separated into precise dye/particle ratios using rp-HPLC. These materials were characterized using 1H and 19F NMR, rp-HPLC, UV-Vis and fluorescence spectroscopy, lifetime measurements, and MALDI. PMID:24604830

  13. Biodegradable polydisulfide dendrimer nanoclusters as MRI contrast agents.

    PubMed

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

    2012-11-27

    Gadolinium-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 premetalated 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.

  14. Partially PEGylated PAMAM dendrimers as solubility enhancers of Silybin.

    PubMed

    Diaz, Carola; Guzmán, José L; Jiménez, Verónica A; Alderete, Joel B

    2017-04-03

    PEGylated PAMAM-G4 dendrimers with substitution percentages of 50% and intermediate size PEG chains (0.55 and 2.0 kDa) were synthesized and evaluated as solubility enhancers and potential supramolecular carriers for the poorly soluble drug Silybin (SIL). Aqueous solubility profiles revealed that the PEGylated system with 2.0 kDa chains induced a five-fold solubility increase for SIL and the largest drug-loading capacity within the systems under study with an average complex stoichiometry of 71:1 according to the Higuchi-Connors formulation for multiple binding sites. The supramolecular interaction between SIL and PEGylated PAMAM-G4 dendrimers was confirmed by 2D-NOESY experiments, which evidenced the simultaneous complexation of the drug in both PAMAM-G4 branches and outermost PEG chains. In vitro release studies showed that 2.0 kDa PEG chains induced a more extended release time compared to 0.5 kDa PEG chains. This result was attributed to the enhancement of PEG-assistance to SIL complexation in systems with longer PEG chains, which are able to self-penetrate into dendrimer cavities and cooperate in the stabilization of SIL complexes, thus delaying the release of SIL from the supramolecular host. These results are valuable for the future design and development of novel PAMAM-based systems for SIL complexation and delivery.

  15. Structural analysis of binding functionality of folic acid-PEG dendrimers against folate receptor.

    PubMed

    Sampogna-Mireles, Diana; Araya-Durán, Ingrid D; Márquez-Miranda, Valeria; Valencia-Gallegos, Jesús A; González-Nilo, Fernando D

    2017-03-01

    Dendrimers functionalized with folic acid (FA) are drug delivery systems that can selectively target cancer cells with folate receptors (FR-α) overexpression. Incorporation of polyethylene glycol (PEG) can enhance dendrimers solubility and pharmacokinetics, but ligand-receptor binding must not be affected. In this work we characterized, at atomic level, the binding functionality of conventional site-specific dendrimers conjugated with FA with PEG 750 or PEG 3350 as a linker. After Molecular Dynamics simulation, we observed that both PEG's did not interfere over ligand-receptor binding functionality. Although binding kinetics could be notably affected, the folate fragment from both dendrimers remained exposed to the solvent before approaching selectively to FR-α. PEG 3350 provided better solubility and protection from enzymatic degradation to the dendrimer than PEG 750. Also, FA-PEG3350 dendrimer showed a slightly better interaction with FR-α than FA-PEG750 dendrimer. Therefore, theoretical evidence supports that both dendrimers are suitable as drug delivery systems for cancer therapies.

  16. Orientational mobility and relaxation spectra of dendrimers: Theory and computer simulation.

    PubMed

    Markelov, Denis A; Lyulin, Sergey V; Gotlib, Yuli Y; Lyulin, Alexey V; Matveev, Vladimir V; Lahderanta, Erkki; Darinskii, Anatolij A

    2009-01-28

    The developed theory of the orientational mobility of individual segments of a perfectly branched dendrimer is used to calculate the relaxation spectrum of a dendrimer. Frequency dependences of NMR relaxation 1/T(1) and of the nuclear Overhauser effect have been theoretically calculated from the Brownian dynamics simulation data. The dendrimer segmental orientational mobility is governed by three main relaxation processes: (i) the rotation of the dendrimer as a whole, (ii) the rotation of the dendrimer's branch originated from a given segment, and (iii) the local reorientation of the segment. The internal orientational mobility of an individual dendrimer segment depends only on the topological distance between this segment and the terminal shell of the dendrimer. Characteristic relaxation times of all processes and their contributions to the segmental mobility have been calculated. The influence of the number of generations and the number of the generation shell on the relaxation times has been studied. The correlation between the characteristic times and the calculated relaxation spectrum of the dendrimer has been established.

  17. 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

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

    PubMed

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

    2015-01-14

    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.

  19. 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.

  20. 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.

  1. Dendrimer-based organic/inorganic hybrid nanoparticles in biomedical applications

    NASA Astrophysics Data System (ADS)

    Shen, Mingwu; Shi, Xiangyang

    2010-09-01

    This review reports some recent advances on the synthesis, self-assembly, and biofunctionalization of various dendrimer-based organic/inorganic hybrid nanoparticles (NPs) for various biomedical applications, including but not limited to protein immobilization, gene delivery, and molecular diagnosis. In particular, targeted molecular imaging of cancer using dendrimer-based organic/inorganic hybrid NPs will be introduced in detail.

  2. 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

  3. 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.

  4. Dendrimer nanofluids in the concentrated regime: from polymer melts to soft spheres.

    PubMed

    Pilkington, Georgia A; Pedersen, Jan S; Briscoe, Wuge H

    2015-03-24

    Understanding dendrimer structures and their interactions in concentrated solutions is important to a wide range of applications, such as drug delivery and lubrication. However, controversy has persisted concerning whether, when confined to proximity, dendrimers would entangle as observed for polymer systems, or act as deformable spheres. Furthermore, how such behavior may be related to their size-dependent molecular architecture remains unclear. Using small-angle X-ray scattering (SAXS), the intermolecular interactions and structures in aqueous nanofluids containing three generations of carboxyl-terminated poly(amidoamine) (PAMAM) dendrimers (G0.5, Rg = 9.3 Å; G3.5, Rg = 22.6 Å; G5.5, Rg = 39.9 Å, where Rg is the radius of gyration) over a mass fraction range 0.005 ≤ x ≤ 0.316 have been studied. In the highly concentrated regime (x ≥ 0.157), we observe that the solution properties depend on the dendrimer generation. Our results suggest that the smaller G0.5 dendrimers form a highly entangled polymer melt, while the larger dendrimers, G3.5 and G5.5, form densely packed and ordered structures, in which the individual dendrimers exhibit some degree of mutual overlap or deformation. Our results demonstrate the tunability of interdendrimer interactions via their molecular architecture, which in turn may be harnessed to control and tailor the physical properties of dendrimer nanofluids.

  5. Spectrophotometric titration of bimetallic metal cation binding in polyamido(amine) dendrimer templates.

    PubMed

    Marvin, Katherine A; Johnson, Justin A; Rodenbusch, Stacia E; Gong, Lucy; Vanden Bout, David A; Stevenson, Keith J

    2012-06-05

    Spectrophotometric titration and a binding isotherm were used to accurately assess the loading capacity of generation four polyamido(amine) (PAMAM) dendrimer templates with terminal alcohol groups (G4-OH). Preparation of bimetallic G4-OH dendrimer-encapsulated metal nanoclusters (DENs) necessitates knowledge of the precise metal-ion binding capacity. The binding of metal ions such as Pt(2+) and Pd(2+) has proven difficult to assess via UV-vis spectroscopy because the absorbance shifts associated with metal-ion binding within the dendrimer template are masked by the absorbance of the PAMAM dendrimer itself. In contrast, the binding of Cu(2+) to G4-OH PAMAM dendrimer results in a strong, distinct absorption band at 300 nm, making UV-vis spectrophotometric titration with copper straightforward. Here we use copper binding as a means to assess the number of binding sites remaining within the PAMAM G4-OH dendrimer after the complexation of a specified molar excess of Pd(2+) or Pt(2+). In addition, we use a binding isotherm to mathematically estimate the loading capacity of the dendrimer in each case. The loading capacities for M(2+) in the G4-OH dendrimer were found to be ∼16 for copper alone, ∼21 for copper combined with palladium, and ∼25 for copper combined with platinum.

  6. Atomic level insights into realistic molecular models of dendrimer-drug complexes through MD simulations

    NASA Astrophysics Data System (ADS)

    Jain, Vaibhav; Maiti, Prabal K.; Bharatam, Prasad V.

    2016-09-01

    Computational studies performed on dendrimer-drug complexes usually consider 1:1 stoichiometry, which is far from reality, since in experiments more number of drug molecules get encapsulated inside a dendrimer. In the present study, molecular dynamic (MD) simulations were implemented to characterize the more realistic molecular models of dendrimer-drug complexes (1:n stoichiometry) in order to understand the effect of high drug loading on the structural properties and also to unveil the atomistic level details. For this purpose, possible inclusion complexes of model drug Nateglinide (Ntg) (antidiabetic, belongs to Biopharmaceutics Classification System class II) with amine- and acetyl-terminated G4 poly(amidoamine) (G4 PAMAM(NH2) and G4 PAMAM(Ac)) dendrimers at neutral and low pH conditions are explored in this work. MD simulation analysis on dendrimer-drug complexes revealed that the drug encapsulation efficiency of G4 PAMAM(NH2) and G4 PAMAM(Ac) dendrimers at neutral pH was 6 and 5, respectively, while at low pH it was 12 and 13, respectively. Center-of-mass distance analysis showed that most of the drug molecules are located in the interior hydrophobic pockets of G4 PAMAM(NH2) at both the pH; while in the case of G4 PAMAM(Ac), most of them are distributed near to the surface at neutral pH and in the interior hydrophobic pockets at low pH. Structural properties such as radius of gyration, shape, radial density distribution, and solvent accessible surface area of dendrimer-drug complexes were also assessed and compared with that of the drug unloaded dendrimers. Further, binding energy calculations using molecular mechanics Poisson-Boltzmann surface area approach revealed that the location of drug molecules in the dendrimer is not the decisive factor for the higher and lower binding affinity of the complex, but the charged state of dendrimer and drug, intermolecular interactions, pH-induced conformational changes, and surface groups of dendrimer do play an

  7. Polymerization of a divalent/tetravalent metal-storing atom-mimicking dendrimer

    PubMed Central

    Albrecht, Ken; Hirabayashi, Yuki; Otake, Masaya; Mendori, Shin; Tobari, Yuta; Azuma, Yasuo; Majima, Yutaka; Yamamoto, Kimihisa

    2016-01-01

    The phenylazomethine dendrimer (DPA) has a layer-by-layer electron density gradient that is an analog of the Bohr atom (atom mimicry). In combination with electron pair mimicry, the polymerization of this atom-mimicking dendrimer was achieved. The valency of the mimicked atom was controlled by changing the chemical structure of the dendrimer. By mimicking a divalent atom, a one-dimensional (1D) polymer was obtained, and by using a planar tetravalent atom mimic, a 2D polymer was obtained. These poly(dendrimer) polymers could store Lewis acids (SnCl2) in their unoccupied orbitals, thus indicating that these poly(dendrimer) polymers consist of a series of nanocontainers. PMID:27957538

  8. Quasi-elastic light scattering of platinum dendrimer-encapsulated nanoparticles.

    PubMed

    Wales, Christina H; Berger, Jacob; Blass, Samuel; Crooks, Richard M; Asherie, Neer

    2011-04-05

    Platinum dendrimer-encapsulated nanoparticles (DENs) containing an average 147 atoms were prepared within sixth-generation, hydroxyl-terminated poly(amidoamine) dendrimers (G6-OH). The hydrodynamic radii (R(h)) of the dendrimer/nanoparticle composites (DNCs) were determined by quasi-elastic light scattering (QLS) at high (pH ∼10) and neutral pH for various salt concentrations and identities. At high pH, the size of the DNC (R(h) ∼4 nm) is close to that of the empty dendrimer. At neutral pH, the size of the DNC approximately doubles (R(h) ∼8 nm) whereas that of the empty dendrimer remains unchanged. Changes in ionic strength also alter the size of the DNCs. The increase in size of the DNC is likely due to electrostatic interactions involving the metal nanoparticle.

  9. 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

    2015-11-09

    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.

  10. Small-angle x-ray scattering study of polymer structure: Carbosilane dendrimers in hexane solution

    NASA Astrophysics Data System (ADS)

    Shtykova, E. V.; Feigin, L. A.; Volkov, V. V.; Malakhova, Yu. N.; Streltsov, D. R.; Buzin, A. I.; Chvalun, S. N.; Katarzhanova, E. Yu.; Ignatieva, G. M.; Muzafarov, A. M.

    2016-09-01

    The three-dimensional organization of monodisperse hyper-branched macromolecules of regular structure—carbosilane dendrimers of zero, third, and sixth generations—has been studied by small-angle X-ray scattering (SAXS) in solution. The use of modern methods of SAXS data interpretation, including ab initio modeling, has made it possible to determine the internal architecture of the dendrimers in dependence of the generation number and the number of cyclosiloxane end groups (forming the shell of dendritic macromolecules) and show dendrimers to be spherical. The structural results give grounds to consider carbosilane dendrimers promising objects for forming crystals with subsequent structural analysis and determining their structure with high resolution, as well as for designing new materials to be used in various dendrimer-based technological applications.

  11. 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.

  12. Poly(Propylene Imine) Dendrimers and Amoxicillin as Dual-Action Antibacterial Agents.

    PubMed

    Wrońska, Natalia; Felczak, Aleksandra; Zawadzka, Katarzyna; Poszepczyńska, Martyna; Różalska, Sylwia; Bryszewska, Maria; Appelhans, Dietmar; Lisowska, Katarzyna

    2015-10-23

    Besides acting as antimicrobial compounds, dendrimers can be considered as agents that improve the therapeutic effectiveness of existing antibiotics. In this work we present a new approach to using amoxicillin (AMX) against reference strains of common Gram-negative pathogens, alone and in combination with poly(propylene imine) (PPI) dendrimers, or derivatives thereof, in which 100% of the available hydrogen atoms are substituted with maltose (PPI 100%malG3). The concentrations of dendrimers used remained in the range non-toxic to eukaryotic cells. The results indicate that PPI dendrimers significantly enhance the antibacterial effect of amoxicillin alone, allowing antibiotic doses to be reduced. It is important to reduce doses of amoxicillin because its widespread use in medicine could lead to the development of bacterial resistance and environmental pollution. This is the first report on the combined antibacterial activity of PPI surface-modified maltose dendrimers and amoxicillin.

  13. Polymerization of a divalent/tetravalent metal-storing atom-mimicking dendrimer.

    PubMed

    Albrecht, Ken; Hirabayashi, Yuki; Otake, Masaya; Mendori, Shin; Tobari, Yuta; Azuma, Yasuo; Majima, Yutaka; Yamamoto, Kimihisa

    2016-12-01

    The phenylazomethine dendrimer (DPA) has a layer-by-layer electron density gradient that is an analog of the Bohr atom (atom mimicry). In combination with electron pair mimicry, the polymerization of this atom-mimicking dendrimer was achieved. The valency of the mimicked atom was controlled by changing the chemical structure of the dendrimer. By mimicking a divalent atom, a one-dimensional (1D) polymer was obtained, and by using a planar tetravalent atom mimic, a 2D polymer was obtained. These poly(dendrimer) polymers could store Lewis acids (SnCl2) in their unoccupied orbitals, thus indicating that these poly(dendrimer) polymers consist of a series of nanocontainers.

  14. 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.

  15. Methotrexate-conjugated PEGylated dendrimers show differential patterns of deposition and activity in tumor-burdened lymph nodes after intravenous and subcutaneous administration in rats.

    PubMed

    Kaminskas, Lisa M; McLeod, Victoria M; Ascher, David B; Ryan, Gemma M; Jones, Seth; Haynes, John M; Trevaskis, Natalie L; Chan, Linda J; Sloan, Erica K; Finnin, Benjamin A; Williamson, Mark; Velkov, Tony; Williams, Elizabeth D; Kelly, Brian D; Owen, David J; Porter, Christopher J H

    2015-02-02

    The current study sought to explore whether the subcutaneous administration of lymph targeted dendrimers, conjugated with a model chemotherapeutic (methotrexate, MTX), was able to enhance anticancer activity against lymph node metastases. The lymphatic pharmacokinetics and antitumor activity of PEGylated polylysine dendrimers conjugated to MTX [D-MTX(OH)] via a tumor-labile hexapeptide linker was examined in rats and compared to a similar system where MTX was α-carboxyl O-tert-butylated [D-MTX(OtBu)]. The latter has previously been shown to exhibit longer plasma circulation times. D-MTX(OtBu) was well absorbed from the subcutaneous injection site via the lymph, and 3 to 4%/g of the dose was retained by sentinel lymph nodes. In contrast, D-MTX(OH) showed limited absorption from the subcutaneous injection site, but absorption was almost exclusively via the lymph. The retention of D-MTX(OH) by sentinel lymph nodes was also significantly elevated (approximately 30% dose/g). MTX alone was not absorbed into the lymph. All dendrimers displayed lower lymph node targeting after intravenous administration. Despite significant differences in the lymph node retention of D-MTX(OH) and D-MTX(OtBu) after subcutaneous and intravenous administration, the growth of lymph node metastases was similarly inhibited. In contrast, the administration of MTX alone did not significantly reduce lymph node tumor growth. Subcutaneous administration of drug-conjugated dendrimers therefore provides an opportunity to improve drug deposition in downstream tumor-burdened lymph nodes. In this case, however, increased lymph node biodistribution did not correlate well with antitumor activity, possibly suggesting constrained drug release at the site of action.

  16. Targeted and pH-responsive delivery of doxorubicin to cancer cells using multifunctional dendrimer-modified multi-walled carbon nanotubes.

    PubMed

    Wen, Shihui; Liu, Hui; Cai, Hongdong; Shen, Mingwu; Shi, Xiangyang

    2013-09-01

    We report the use of multifunctional dendrimer-modified multi-walled carbon nanotubes (MWCNTs) for targeted and pH-responsive delivery of doxorubicin (DOX) into cancer cells. In this study, amine-terminated generation 5 poly(amidoamine) (PAMAM) dendrimers modified with fluorescein isothiocyanate (FI) and folic acid (FA) were covalently linked to acid-treated MWCNTs, followed by acetylation of the remaining dendrimer terminal amines to neutralize the positive surface potential. The formed multifunctional MWCNTs (MWCNT/G5.NHAc-FI-FA) were characterized via different techniques. Then, the MWCNT/G5.NHAc-FI-FA was used to load DOX for targeted and pH-responsive delivery to cancer cells overexpressing high-affinity folic acid receptors (FAR). We showed that the MWCNT/G5.NHAc-FI-FA enabled a high drug payload and encapsulation efficiency both up to 97.8% and the formed DOX/MWCNT/G5.NHAc-FI-FA complexes displayed a pH-responsive release property with fast DOX release under acidic environment and slow release at physiological pH conditions. Importantly, the DOX/MWCNT/G5.NHAc-FI-FA complexes displayed effective therapeutic efficacy, similar to that of free DOX, and were able to target to cancer cells overexpressing high-affinity FAR and effectively inhibit the growth of the cancer cells. The synthesized multifunctional dendrimer-modified MWCNTs may be used as a targeted and pH-responsive delivery system for targeting therapy of different types of cancer cells.

  17. Enhanced Photoelectrochemical Method for Sensitive Detection of Protein Kinase A Activity Using TiO2/g-C3N4, PAMAM Dendrimer, and Alkaline Phosphatase.

    PubMed

    Li, Xue; Zhu, Lusheng; Zhou, Yunlei; Yin, Huanshun; Ai, Shiyun

    2017-02-21

    A novel photoelectrochemical (PEC) assay is developed for sensitive detection of protein kinase A (PKA) activity based on PKA-catalyzed phosphorylation reaction in solution and signal amplification strategy triggered by PAMAM dendrimer and alkaline phosphatase (ALP). In this strategy, it is noteworthy at this point that PKA phosphorylation was achieved in solution instead of on the surface of the electrode, which has advantages of the good contact in reactants and simple experimental procedure. For immobilizing the phosphorylated peptide (P-peptide) on electrode surface, graphite-like carbon nitride (g-C3N4) and titanium dioxide (TiO2) complex is synthesized and characterized, which plays a significant role for TiO2 conjugating phosphate groups and g-C3N4 providing PEC signal. Subsequently, PAMAM dendrimer and ALP can be captured on P-peptide and TiO2/g-C3N4 modified ITO electrode via interaction between the -COOH groups on the surface of PAMAM dendrimer and the -NH2 groups of peptide and ALP, which can lead to the increase of ALP amount on the modified electrode surface assisted with the PAMAM dendrimer. As a result, the amount of ALP catalyzes of L-ascorbic acid 2-phosphate trisodium salt (AAP) to produce electron donor of ascorbic acid (AA), resulting in an increased photocurrent. The proposed detection assay displays high selectivity and low detection limit of 0.048 U/mL (S/N = 3) for PKA activity. This biosensor can also be applied for the evaluation of PKA inhibition and PKA activity assay in cell samples. Therefore, the fabricated PEC biosensor is potentionally well in PKA activity detection and inhibitor screening.

  18. The Role of Ganglioside GM1 in Cellular Internalization Mechanisms of Poly(amidoamine) Dendrimers

    PubMed Central

    Hong, Seungpyo; Rattan, Rahul; Majoros, István J.; Mullen, Douglas G.; Peters, Jennifer L.; Shi, Xiangyang; Bielinska, Anna U.; Blanco, Luz; Orr, Bradford G.; Baker, James R.; Holl, Mark M. Banaszak

    2015-01-01

    Generation 7 (G7) poly(amidoamine) (PAMAM) dendrimers with amine, acetamide, and carboxylate end groups were prepared to investigate polymer/cell membrane interactions in vitro. G7 PAMAM dendrimers were used in this study because higher generation of dendrimers are more effective in permeabilization of cell plasma membranes and in the formation of nanoscale holes in supported lipid bilayers than smaller, lower generation dendrimers. Dendrimer-based conjugates were characterized by 1H NMR, UV/Vis spectroscopy, GPC, HPLC, and CE. Positively charged amine-terminated G7 dendrimers (G7-NH2) were observed to internalize into KB, Rat2 and C6 cells at a 200 nM concentration. By way of contrast, neither negatively charged G7 carboxylate-terminated dendrimers (G7-COOH) nor neutral acetamide-terminated G7 dendrimers (G7-Ac) associated with the cell plasma membrane or internalized under similar conditions. A series of in vitro experiments employing endocytic markers cholera toxin subunit B (CTB), transferrin, and GM1-pyrene were performed to further investigate mechanisms of dendrimer internalization into cells. G7-NH2 dendrimers co-localized with CTB, however, experiments with C6 cells indicated that internalization of G7-NH2 was not ganglioside GM1 dependent. The G7/CTB co-localization was thus ascribed to an artifact of direct interaction between the two species. The presence of GM1 in the membrane also had no effect upon XTT assays of cell viability or lactate dehydrogenase (LDH) assays of membrane permeability. PMID:19583240

  19. Poly-(amidoamine) dendrimers with a precisely core positioned sulforhodamine B molecule for comparative biological tracing and profiling.

    PubMed

    Wu, Lin-Ping; Ficker, Mario; Mejlsøe, Søren L; Hall, Arnaldur; Paolucci, Valentina; Christensen, Jørn B; Trohopoulos, Panagiotis N; Moghimi, Seyed M

    2017-01-28

    We report on a simple robust procedure for synthesis of generation-4 poly-(amidoamine) (PAMAM) dendrimers with a precisely core positioned single sulforhodamine B molecule. The labelled dendrimers exhibited high fluorescent quantum yields where the absorbance and fluorescence spectrum of the fluorophore was not affected by pH and temperature. Since the stoichiometry of the fluorophore to the dendrimer is 1:1, we were able to directly compare uptake kinetics, the mode of uptake, trafficking and safety of dendrimers of different end-terminal functionality (carboxylated vs. pyrrolidonated) by two phenotypically different human endothelial cell types (the human brain capillary endothelial cell line hCMEC/D3 and human umbilical vein endothelial cells), and without interference of the fluorophore in uptake processes. The results demonstrate comparable uptake kinetics and a predominantly clathrin-mediated endocytotic mechanism, irrespective of dendrimer end-terminal functionality, where the majority of dendrimers are directed to the endo-lysosomal compartments in both cell types. A minor fraction of dendrimers, however, localize to endoplasmic reticulum and the Golgi apparatus, presumably through the recycling endosomes. In contrast to amino-terminated PAMAM dendrimers, we confirm safety of carboxylic acid- and pyrrolidone-terminated PAMAM dendrimers through determination of cell membrane integrity and comprehensive respiratory profiling (measurements of mitochondrial oxidative phosphorylation and determination of its coupling efficiency). Our dendrimer core-labelling approach could provide a new conceptual basis for improved understanding of dendrimer performance within biological settings.

  20. The adsorption-desorption transition of double-stranded DNA interacting with an oppositely charged dendrimer induced by multivalent anions.

    PubMed

    Jiang, Yangwei; Zhang, Dong; Zhang, Yaoyang; Deng, Zhenyu; Zhang, Linxi

    2014-05-28

    The adsorption-desorption transition of DNA in DNA-dendrimer solutions is observed when high-valence anions, such as hexavalent anions, are added to the DNA-dendrimer solutions. In the DNA-dendrimer solutions with low-valence anions, dendrimers bind tightly with the V-shaped double-stranded DNA. When high-valence anions, such as pentavalent or hexavalent anions, are added to the DNA-dendrimer solutions, the double-stranded DNA chains can be stretched straightly and the dendrimers are released from the double-stranded DNA chains. In fact, adding high-valence anions to the solutions can change the charge spatial distribution in the DNA-dendrimer solutions, and weaken the electrostatic interactions between the positively charged dendrimers and the oppositely charged DNA chains. Adsorption-desorption transition of DNA is induced by the overcharging of dendrimers. This investigation is capable of helping us understand how to control effectively the release of DNA in gene/drug delivery because an effective gene delivery for dendrimers includes non-covalent DNA-dendrimer binding and the effective release of DNA in gene therapy.

  1. The adsorption-desorption transition of double-stranded DNA interacting with an oppositely charged dendrimer induced by multivalent anions

    NASA Astrophysics Data System (ADS)

    Jiang, Yangwei; Zhang, Dong; Zhang, Yaoyang; Deng, Zhenyu; Zhang, Linxi

    2014-05-01

    The adsorption-desorption transition of DNA in DNA-dendrimer solutions is observed when high-valence anions, such as hexavalent anions, are added to the DNA-dendrimer solutions. In the DNA-dendrimer solutions with low-valence anions, dendrimers bind tightly with the V-shaped double-stranded DNA. When high-valence anions, such as pentavalent or hexavalent anions, are added to the DNA-dendrimer solutions, the double-stranded DNA chains can be stretched straightly and the dendrimers are released from the double-stranded DNA chains. In fact, adding high-valence anions to the solutions can change the charge spatial distribution in the DNA-dendrimer solutions, and weaken the electrostatic interactions between the positively charged dendrimers and the oppositely charged DNA chains. Adsorption-desorption transition of DNA is induced by the overcharging of dendrimers. This investigation is capable of helping us understand how to control effectively the release of DNA in gene/drug delivery because an effective gene delivery for dendrimers includes non-covalent DNA-dendrimer binding and the effective release of DNA in gene therapy.

  2. 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.

  3. Enzyme-Sensitive and Amphiphilic PEGylated Dendrimer-Paclitaxel Prodrug-Based Nanoparticles for Enhanced Stability and Anticancer Efficacy.

    PubMed

    Li, Ning; Cai, Hao; Jiang, Lei; Hu, Jiani; Bains, Ashika; Hu, Jesse; Gong, Qiyong; Luo, Kui; Gu, Zhongwei

    2017-03-01

    In this study, we prepared a smart polymeric vehicle for the hydrophobic drug paclitaxel (PTX) that allowed a maximum steady-state circulation and a fast intracellular release in tumors. PTX was linked to the Janus PEGylated (PEG = poly(ethylene glycol)) peptide dendrimer via an enzyme-sensitive linker glycylphenylalanylleucylglycine tetrapeptide by efficient click reaction, resulting in Janus dendritic prodrug with 20.9% PTX content. The prodrug self-assembled into nanoscale particles with appropriate nanosizes, compact morphology, and negative surface charge. In addition to high stability during circulation, as demonstrated by protein adsorption assays and drug release studies in the cancer's intracellular environment, the nanoparticles were able to quickly release the drug intact in its original molecular structure, as verified via high-performance liquid chromatography and mass spectrometry analyses. Compared to free PTX, the enzyme-responsive feature of nanoparticles promoted higher cytotoxicity against 4T1 cancer cells and much lower cytotoxicity against normal cells. The nanoparticles accumulated in the tumor and were retained for an extended period of time, as confirmed by fluorescence imaging. Therefore, these nanoparticles exhibited significantly enhanced antitumor efficiency in the 4T1 breast cancer model as indicated by the observed inhibition of angiogenesis and proliferation as well as induction of apoptosis. Moreover, the nanoparticles reduced the occurrence of side effects, particularly dose-limited toxicities, as monitored by body weight and hematological features. Hence, our Janus PEGylated dendrimer-PTX prodrug-based nanoparticles may potentially serve as nanoscale vehicles for breast cancer therapy.

  4. Polyvalent Folate-Dendrimer-Coated Iron Oxide Theranostic Nanoparticles for Simultaneous Magnetic Resonance Imaging and Precise Cancer Cell Targeting.

    PubMed

    Luong, Duy; Sau, Samaresh; Kesharwani, Prashant; Iyer, Arun K

    2017-03-09

    The low therapeutic index of conventional chemotherapy and poor prognosis of patients diagnosed with metastatic cancers are prompting clinicians to adopt newer strategies to simultaneously detect cancer lesions at an early stage and to precisely deliver anticancer drugs to tumor sites. In this study, we employed a novel strategy to engineer a polyvalent theranostic nanocarrier consisting of superparamagnetic iron oxide nanoparticle core (SPIONs) decorated with folic acid-polyamidoamine dendrimers surface (FA-PAMAM). In addition, a highly potent hydrophobic anticancer agent 3,4-difluorobenzylidene-curcumin (CDF) was coloaded in the FA-PAMAM dendrimer to increase its solubility and assess its therapeutic potentials. The resulting targeted nanoparticles (SPIONs@FA-PAMAM-CDF) exhibited high MR contrast. When tested on folate receptor overexpressing ovarian (SKOV3) and cervical (HeLa) cancer cells, the CDF loaded targeted nanoformulations showed higher accumulation with a better anticancer activity as compared to the nontargeted counterparts, possibly due to multivalent folate receptor binding interaction with cells overexpressing the target. The results were corroborated by observation of a larger population of cells undergoing apoptosis due to upregulation of tumor suppressor phosphatase and tensis homologue (PTEN), caspase 3, and inhibition of NF-κB in groups treated with the targeted formulations, which further confirmed the ability of the multivalent theranostic nanoparticles for simultaneous imaging and therapy of cancers.

  5. Synthesis of silica-PAMAM dendrimer nanoparticles as promising carriers in Neuro blastoma cells.

    PubMed

    Yesil-Celiktas, Ozlem; Pala, Cansu; Cetin-Uyanikgil, E Oyku; Sevimli-Gur, Canan

    2017-02-15

    Mesoporous silica carriers are emerging as therapeutic drug delivery systems. The objective of this study was to develop a formulation for synthesizing silica-PAMAM dendrimer hybrid nanoparticles with sol-gel technique. Subsequently, black carrot anthocyanins were encapsulated and investigated for their capability in terms of inhibiting the proliferative effects of neuroblastoma (Neuro 2A). In this context, particle size distributions were ascertained followed by thermal analysis (DSC), scanning electron microscopy and encapsulation efficiency. Subsequently, in vitro release kinetics was determined along with cytotoxicity of empty and anthocyanin doped hybrid nanoparticles. The lowest particle size was 134.8 nm with a zeta potential of +19.78 mV which enhanced electrostatic interaction with the cell membrane in the cytotoxicity analyses. As the anthocyanin content was totally released at the end of 6 days, the cytotoxicity was observed for 134 h, reaching an inhibition of 87.9%. On the other hand, Neuro 2A cells incubated with empty nanoparticles exhibited a high proliferation indicating that hybrid nanoparticles were not toxic to the cells and the inhibitory effect was associated with the anthocyanins.

  6. 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.

  7. Interaction of a patterned amphiphilic polyphenylene dendrimer with a lipid monolayer: electrostatic interactions dominate.

    PubMed

    Okuno, Masanari; Mezger, Markus; Stangenberg, René; Baumgarten, Martin; Müllen, Klaus; Bonn, Mischa; Backus, Ellen H G

    2015-02-17

    Dendrimeric macromolecules with defined shape and size are promising candidates for delivering drug or DNA molecules into cells. In this work we study the influence of an amphiphilic polyphenylene dendrimer on a model cell membrane consisting of a condensed 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid monolayer. A small surface pressure decrease is observed when the dendrimer solution is injected into the aqueous phase below the monolayer. X-ray reflectivity measurements show that the surface monolayer remains intact. The molecular-scale picture is obtained with sum-frequency generation spectroscopy. With this technique, we observe that the tails of the surfactant molecules become less ordered upon interaction with the amphiphilic polyphenylene dendrimer. In contrast, the water molecules below the DPPC layer become more ordered. Our observations suggest that electrostatic interactions between the negative charge of the dendrimer and the positively charged part of the DPPC headgroup keep the dendrimer located below the headgroup. No evidence of dendrimer insertion into the membrane has been observed. Apparently before entering the cell membrane the dendrimer can stick at the hydrophilic part of the lipids.

  8. Dendrimers in Nanoscale Confinement: The Interplay between Conformational Change and Nanopore Entrance.

    PubMed

    Ficici, Emel; Andricioaei, Ioan; Howorka, Stefan

    2015-07-08

    Hyperbranched dendrimers are nanocarriers for drugs, imaging agents, and catalysts. Their nanoscale confinement is of fundamental interest and occurs when dendrimers with bioactive payload block or pass biological nanochannels or when catalysts are entrapped in inorganic nanoporous support scaffolds. The molecular process of confinement and its effect on dendrimer conformations are, however, poorly understood. Here, we use single-molecule nanopore measurements and molecular dynamics simulations to establish an atomically detailed model of pore dendrimer interactions. We discover and explain that electrophoretic migration of polycationic PAMAM dendrimers into confined space is not dictated by the diameter of the branched molecules but by their size and generation-dependent compressibility. Differences in structural flexibility also rationalize the apparent anomaly that the experimental nanopore current read-out depends in nonlinear fashion on dendrimer size. Nanoscale confinement is inferred to reduce the protonation of the polycationic structures. Our model can likely be expanded to other dendrimers and be applied to improve the analysis of biophysical experiments, rationally design functional materials such as nanoporous filtration devices or nanoscale drug carriers that effectively pass biological pores.

  9. Development of TREN dendrimers over mesoporous SBA-15 for CO 2 adsorption

    NASA Astrophysics Data System (ADS)

    Bhagiyalakshmi, Margandan; Park, Sang Do; Cha, Wang Seog; Jang, Hyun Tae

    2010-09-01

    Mesoporous SBA-15 was synthesized using rice husk ash (RHA) as the silica source and their defective Si-OH groups were grafted with tris(2-aminoethyl) amine (TREN) dendrimers generation through step-wise growth technique. The X-ray diffraction (XRD) and nitrogen adsorption/desorption results of parent SBA-15 obtained from RHA, suggests its resemblance with SBA-15 synthesized using conventional silica sources. Furthermore, the nitrogen adsorption/desorption results of SBA-15/TREN dendrimer generations (G1-G3) illustrates the growth of dendrimer inside the mesopores of SBA-15 and their CO 2 adsorption capacity was determined at 25 °C. The maximum CO 2 adsorption capacity of 5-6 and 7-8 wt% over second and third dendrimer generation was observed which is discernibly higher than the reported melamine and PAMAM dendrimers. The experimental CO 2 adsorption capacity was found to be less than theoretically calculated CO 2 adsorption capacity due to inter and intra molecular amidation as result of steric hindrance during the dendrimer growth. These SBA-15/TREN dendrimer generations also exhibit thermal stability up to 350 °C and CO 2 adsorption capacity remains unaltered upon seven consecutive runs.

  10. Cholesterol-conjugated supramolecular assemblies of low generations polyamidoamine dendrimers for enhanced EGFP plasmid DNA transfection

    NASA Astrophysics Data System (ADS)

    Golkar, Nasim; Samani, Soliman Mohammadi; Tamaddon, Ali Mohammad

    2016-05-01

    Aimed to prepare an enhanced gene delivery system with low cytotoxicity and high transfection efficiency, various cholesterol-conjugated derivates of low generation polyamidoamine (PAMAM) dendrimers were prepared. The conjugates were characterized by TNBS assay, FTIR, and 1H-NMR spectroscopy. Self-assembly of the dendrimer conjugates (G1-Chol, G2-Chol, and G3-Chol) was investigated by pyrene assay. Following formation of the complexes between enhanced green fluorescence protein plasmid and the dendrimer conjugates at various N (primary amine)/P (phosphate) mole ratios, plasmid condensation, biologic stability, cytotoxicity, and protein expression were investigated. The conjugates self-assembled into micellar dispersions with the critical micelle concentration values (<50 µg/ml) depending on the dendrimer generation and cholesterol/amine mole ratio. Cholesterol conjugation resulted in higher resistance of the condensed plasmid DNA in a competition assay with heparin sulfate. Also, the transfection efficiency was determined higher for the cholesterol conjugates than unmodified dendrimers in HepG2 cells, showing the highest for G2-Chol at 40 % degree of cholesterol modification (G2-Chol40 %) among various dendrimer generations. Interestingly, such conjugate showed a complete protection of plasmid against serum nucleases. Our results confirmed that the cholesterol conjugation to PAMAM dendrimers of low generations bearing little cytotoxicity improves their several physicochemical and biological characteristics required for an enhanced delivery of plasmid DNA into cells.

  11. 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.

  12. Structure-function relationship of PAMAM dendrimers as robust oil dispersants.

    PubMed

    Geitner, Nicholas K; Wang, Bo; Andorfer, Rachel E; Ladner, David A; Ke, Pu Chun; Ding, Feng

    2014-11-04

    PAMAM dendrimers have recently been investigated as efficient and biocompatible oil dispersants utilizing their encapsulation capacity; however, their high cationic charge density has been shown to be cytotoxic. It is therefore imperative to mitigate cationic charge-induced toxicity and understand the effects of such changes. Presented here is a synergistic experimental and computational approach to examine the effects of varying terminal surface charge on the capacity of dendrimers to disperse model liner, polycyclic aromatic, and hybrid hydrocarbons. Uncharged dendrimers collapse by forming intramolecular hydrogen bonds, which reduce the hosting capability. On the other hand, changing the surface charges from positive to negative greatly shifts the pKa of tertiary amines of the PAMAM dendrimer interior. As a result, the negatively charged dendrimers have a significant percentage of tertiary amines protonated, ∼30%. This unexpected change in the interior protonation state causes electrostatic interactions with the anionic terminal groups, leading to contraction and a marked decrease in hydrocarbon hosting capacity. The present work highlights the robust nature of dendrimer oil dispersion and also illuminates potentially unintended or unanticipated effects of varying dendrimer surface chemistry on their encapsulation or hosting efficacy, which is important for their environmental, industrial, and biomedical applications.

  13. Shape-persistent and adaptive multivalency: rigid transgeden (TGD) and flexible PAMAM dendrimers for heparin binding.

    PubMed

    Bromfield, Stephen M; Posocco, Paola; Fermeglia, Maurizio; Tolosa, Juan; Herreros-López, Ana; Pricl, Sabrina; Rodríguez-López, Julián; Smith, David K

    2014-07-28

    This study investigates transgeden (TGD) dendrimers (polyamidoamine (PAMAM)-type dendrimers modified with rigid polyphenylenevinylene (PPV) cores) and compares their heparin-binding ability with commercially available PAMAM dendrimers. Although the peripheral ligands are near-identical between the two dendrimer families, their heparin binding is very different. At low generation (G1), TGD outperforms PAMAM, but at higher generation (G2 and G3), the PAMAMs are better. Heparin binding also depends strongly on the dendrimer/heparin ratio. We explain these effects using multiscale modelling. TGD dendrimers exhibit "shape-persistent multivalency"; the rigidity means that small clusters of surface amines are locally well optimised for target binding, but it prevents the overall nanoscale structure from rearranging to maximise its contacts with a single heparin chain. Conversely, PAMAM dendrimers exhibit "adaptive multivalency"; the flexibility means individual surface ligands are not so well optimised locally to bind heparin chains, but the nanostructure can adapt more easily and maximise its binding contacts. As such, this study exemplifies important new paradigms in multivalent biomolecular recognition.

  14. Evaluation of electrostatic binding of PAMAM dendrimers and charged phthalocyanines by fluorescence correlation spectroscopy.

    PubMed

    Garcia-Fernandez, Emilio; Paulo, Pedro M R; Costa, Sílvia M B

    2015-02-14

    We have assessed host-guest interactions between PAMAM dendrimers and charged phthalocyanine probes by Fluorescence Correlation Spectroscopy (FCS). Our results show strong binding in water at low ionic strength with an affinity that decreases from KB ∼ 10(9) to 10(8) M(-1) upon decreasing the phthalocyanine charge of z = -4, -2 and -1. The binding affinity also decreases significantly upon salt addition leading to KB values of ca. 10(5)-10(6) M(-1). The changes of binding affinity probed by varying the phthalocyanine charge, and by changing the ionic strength or pH conditions, allowed us to evaluate the electrostatic contribution (Kel) in dendrimer-phthalocyanine interactions. In particular, this approach afforded values of electrostatic potential for PAMAM dendrimers in water at low ionic strength and at dendrimer concentrations in the nanomolar range. The electrostatic potential of PAMAM generations 4 and 7 are around 50 mV in close agreement with theoretical estimates using the Poisson-Boltzmann cell model. Interestingly, the nonelectrostatic binding is significant and contributes even more than electrostatic binding to dendrimer-phthalocyanine interactions. The nonelectrostatic binding contributes to an affinity of KB above 10(5) M(-1), as measured under conditions of low dendrimer charge and high ionic strength, which makes these dendrimers promising hosts as drug carriers.

  15. 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

  16. Maltose modified poly(propylene imine) dendrimers as potential carriers of nucleoside analog 5'-triphosphates.

    PubMed

    Szulc, Aleksandra; Signorelli, Marco; Schiraldi, Alberto; Appelhans, Dietmar; Voit, Brigitte; Bryszewska, Maria; Klajnert-Maculewicz, Barbara; Fessas, Dimitrios

    2015-11-30

    Poly(propylene imine) (PPI) dendrimers contained surface maltose modification are proposed as drug carriers for nucleoside analog (NA) 5'-triphosphates. The aim of this study was to investigate the interactions between PPI dendrimers of 3rd (G3) or 4th (G4) generation and cytidine-5'-triphosphate (CTP) by Isothermal Titration Calorimetry method. CTP was used as a model molecule of pyrimidine nucleoside analog-cytarabine (ara-CTP) commonly used in leukemia treatment. Complexes of PPI dendrimers with NAs may help to overcome severe limitations of NAs associated with their low solubility and stability or resistance in cancer cells. In the present work, we evaluated stoichiometry and a mechanism of forming complexes between dendrimers and the nucleotide. Moreover, we examined the efficiency of complex formation in relation to dendrimer generations, a type of dendrimer modification with maltose residues and a type of solvent. It was observed that PPI dendrimers create complexes with CTP with high efficiency that makes them promising candidates for a drug delivery system.

  17. Thermodynamic studies on PNA and PNA/DNA dendrimer formation.

    PubMed

    Moccia, Maria; Musumeci, Domenica; Valente, Margherita; Roviello, Giovanni N; Sapio, Roberto; Pedone, Carlo; Bucci, Enrico M

    2007-01-01

    In this work we report a kinetic and thermodynamic study relative to the formation of gel systems based on PNA and PNA/DNA dendrimers, useful for drug delivery or diagnostic applications. We realized two kinds of systems: a PNA-based monomolecular system formed by an autoassembling PNA tridendron (A) and a PNA/DNA bimolecular system based on a PNA tridendron with a mixed sequence and a DNA crosslinker (B). Both systems have the ability to form a three-dimensional network by means of specific W-C base pairing.

  18. "Lego" chemistry for the straightforward synthesis of dendrimers.

    PubMed

    Maraval, Valérie; Pyzowski, Jaroslaw; Caminade, Anne-Marie; Majoral, Jean-Pierre

    2003-07-25

    A new straightforward method of synthesis of dendrimers, using two branched monomers (CA(2) and DB(2)), is described. Each generation is obtained in a single quantitative step, with only N(2) or H(2)O as byproducts; generation 4 is obtained in only four steps. The end groups are alternatively phosphines and hydrazines; their versatile reactivity is illustrated by the reaction of generation 4 with a branched CD(5) monomer, which increases the number of end groups in a single step from 48 to 250.

  19. Enhancement of muramyldipeptide (MDP) immunostimulatory activity by controlled multimerization on dendrimers.

    PubMed

    Sorensen, Nanna S; Boas, Ulrik; Heegaard, Peter M H

    2011-11-10

    Peptidoglycan is a widespread bacterial PAMP molecule and a powerful initiator of innate immune responses. It consists of repeating units of MDP, which as a monomer is only weakly immunostimulatory. Here, MDP-coupled dendrimers were prepared and investigated for stimulation of pig blood mononuclear cells. Compared to monomeric MDP, MDP-dendrimers induced a markedly enhanced production of IL-12 p40, IL-1β and IL-6 and completely down-regulated surface expression of B7 and MHC class II. These results suggest a possible novel strategy based on controlled multimerization of minimal PAMP motifs on dendrimers for preparing molecularly defined immunostimulators with predictable bioactivities.

  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.

  1. Poly(amido)amine (PAMAM) dendrimer-cisplatin complexes for chemotherapy of cisplatin-resistant ovarian cancer cells

    NASA Astrophysics Data System (ADS)

    Yellepeddi, Venkata Kashyap; Vangara, Kiran Kumar; Palakurthi, Srinath

    2013-09-01

    Dendrimer-cisplatin complexes were prepared using PAMAM dendrimers with terminal -NH2 and -COOH groups as well as biotin-conjugated dendrimers. Preformulation parameters of dendrimer-cisplatin complexes were studied using differential scanning calorimetry (DSC) and inductively coupled plasma-mass spectrometry (ICP-MS). Cytotoxicity and mechanism of cytotoxicity of dendrimer-cisplatin complexes was investigated in OVCAR-3, SKOV, A2780 and cisplatin-resistant CP70 human ovarian cancer cell lines. The loading of cisplatin in dendrimers was 11 % (w/w). PAMAM G4 dendrimers with amine surface groups (biotinylated and native) have shown 2.5- to 3.0-fold reduction in IC50 values in ovarian cancer cells when compared with carboxylate surface dendrimers ( p < 0.05). A correlation was observed among cytotoxicity of the complexes, cellular uptake, and platinum-DNA adduct formation. Treatment with dendrimer-cisplatin complexes resulted in a 7.0-fold increase ( p < 0.05) in expression of apoptotic genes ( Bcl2, Bax, p53) and 13.2- to 27.1-fold increase ( p < 0.05) in the activity of caspases 3, 8, and 9 in vitro. Results suggest that PAMAM dendrimers can be used as potential carrier for cisplatin chemotherapy of ovarian cancer.

  2. Energetic and conformational aspects of dendrimer overcharging by linear polyelectrolytes.

    PubMed

    Lyulin, Sergey V; Darinskii, Anatolij A; Lyulin, Alexey V

    2008-10-01

    Extensive Brownian dynamics simulations of conformational changes accompanying the overcharging of a dendrimer by an oppositely charged long linear polyelectrolyte (LPE) have been carried out. The simulated results have been compared with the predictions of the Nguen and Shklovskii correlation theory [Physica A 293, 324 (2001)] for impenetrable charged spherical macroion. Dendrimer overcharging is caused by the spatial correlations between the "excess" of the LPE charges adsorbed onto its surface. The simulated LPE-length dependence of the corresponding "correlation" energy is in agreement with the theoretical predictions. Maximum of the LPE adsorption occurs at some critical LPE length N{ch};{c} , and the first order phase transition from completely coiled conformation to the conformation with released tails takes place. The phase transition is accompanied by the drastic increase in the relative fluctuations of the polyelectrolyte size. Upon increasing the linear-chain length above N{ch};{c} , the one-long-tail conformation becomes energetically preferable; the exchange time between the long-tail conformation and the short-tail conformation is very large.

  3. PEO Hydrogels Prepared by End-linking with PAMAM Dendrimers

    NASA Astrophysics Data System (ADS)

    Unal, Burcu; Hedden, Ronald C.

    2006-03-01

    End-linking is a preferred synthetic technique for preparing polymer networks and gels for fundamental structure/property studies. End-functionalized telechelic linear polymers are joined to a multifunctional crosslinker to form a network in which the molar mass of the polymer chains between chemical crosslink points is known. Although end-linked elastomers prepared in bulk have been well-studied over the preceding decade, much remains to be learned about how the presence of a good solvent affects the equilibrium swelling and modulus of end-linked gels. We prepared well-defined hydrogels in a good solvent (water) by linking epoxide end-functionalized, linear poly(ethylene oxide) (PEO) to the amine endgroups of poly(amidoamine) (PAMAM) dendrimers of generations 0, 2, and 4. Dendrimers can serve as well-defined macromolecular crosslink junctions because they can have nearly monodisperse numbers of reactive endgroups. We have characterized how reaction conditions such as junction functionality, polymer concentration at preparation, ratio of crosslinker endgroups to precursor endgroups, and precursor molar mass affect gelation and equilibrium swelling. We will discuss the somewhat surprising observation of ``superabsorbent'' behavior in selected PAMAM- PEO gels.

  4. Click chemistry with polymers, dendrimers, and hydrogels for drug delivery.

    PubMed

    Lallana, Enrique; Fernandez-Trillo, Francisco; Sousa-Herves, Ana; Riguera, Ricardo; Fernandez-Megia, Eduardo

    2012-04-01

    During the last decades, great efforts have been devoted to design polymers for reducing the toxicity, increasing the absorption, and improving the release profile of drugs. Advantage has been also taken from the inherent multivalency of polymers and dendrimers for the incorporation of diverse functional molecules of interest in targeting and diagnosis. In addition, polymeric hydrogels with the ability to encapsulate drugs and cells have been developed for drug delivery and tissue engineering applications. In the long road to this successful story, pharmaceutical sciences have been accompanied by parallel advances in synthetic methodologies allowing the preparation of precise polymeric materials with enhanced properties. In this context, the introduction of the click concept by Sharpless and coworkers in 2001 focusing the attention on modularity and orthogonality has greatly benefited polymer synthesis, an area where reaction efficiency and product purity are significantly challenged. The purpose of this Expert Review is to discuss the impact of click chemistry in the preparation and functionalization of polymers, dendrimers, and hydrogels of interest in drug delivery.

  5. 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.

  6. 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

  7. Comparative study of microtubule inhibitors--estramustine and natural podophyllotoxin conjugated PAMAM dendrimer on glioma cell proliferation.

    PubMed

    Sk, Ugir Hossain; Dixit, Deobrat; Sen, Ellora

    2013-10-01

    The synthetic estramustine (EM) and natural podophyllotoxin (PODO) anti-mitotic agents that inhibit tubulin polymerization are known anticancer agents. As low bioavailability limits their anticancer properties, we investigated whether conjugation with PAMAM dendrimer (D) could enhance the activity of D-EM and D-PODO by altering their release pattern. Release kinetics indicated synthesized conjugates to be stable against hydrolytic cleavage and showed sustained release characteristics. However, release of D-EM was slow compared to D-PODO conjugate. Antitumor effect of these conjugates on glioma cells revealed (i) increased cell death and cell cycle arrest (ii) decreased migration and (iii) increased tubulin depolymerization as compared to free drug. Importantly, the effects of natural PODO conjugate on glioma cell survival and migration is more pronounced than D-EM.

  8. 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

  9. 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

    2015-09-08

    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.

  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.

  11. Encapsulating fluorescein using adipic acid self-assembly on the surface of PPI-3 dendrimer.

    PubMed

    Chai, Minghui; Holley, Aaron K; Kruskamp, Michael

    2007-01-14

    A water-soluble self-assembly has been formed by associating adipic acid molecules onto the surface of the third generation poly(propyleneimine) dendrimer and this system has been used to encapsulate fluorescein.

  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.

  14. 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

  15. Dendrimers as vectors for genetic material delivery to the nervous system.

    PubMed

    Pérez-Martínez, F C; Ocaña, A V; Pérez-Carrión, M D; Ceña, V

    2012-01-01

    Transfection of genetic material into primary neuronal cultures remains a challenge because of the intrinsic difficulty in transfecting this type of cell. This review covers the recent developments in the use of dendrimers for siRNA and DNA transfection in both neuronal and glial cells. Crossing the blood brain barrier crossing represents a challenge for the effective use of dendrimer-mediated delivery of therapeutic agents to the central nervous system. We will discuss the effectiveness, both in vitro and in vivo, of various dendrimers in delivering genetic material to neural tissue and its ability to cross the blood-brain barrier. In addition, the use of dendrimers as a potential new therapy in the treatment of glioblastoma will be presented.

  16. 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

  17. Unusual concentration-dependent microscopic dynamics of dendrimers in aqueous solution

    NASA Astrophysics Data System (ADS)

    Wong, Kaikin; Wu, Chin Ming; Lam, Hak Fai; Chathoth, Suresh M.

    2016-05-01

    Dendrimers are novel three-dimensional, hyperbranched globular nanopolymeric macromolecules. The nanoscopic size, narrow polydispersity index, excellent control over molecular structure, availability of multiple functional groups at the periphery, and cavities in the interior made them very attractive candidate for drug delivery. In this communication, we have studied the microscopic dynamics of tetra-acid and pentaerythritol glycidyl ether dendrimers dissolved in aqueous solution with different concentrations. The effects of concentration and temperature to their long-range diffusion process are investigated by dynamic light scattering. Experimental results show a huge variation in the translational diffusion coefficient for the two dendrimers samples. Besides, the dependence of diffusion coefficients on concentration is unusually different in these dendrimer samples. Although the diffusion process follows Arrhenius relation with the temperature in both systems, the activation energy for the diffusion process has a distinct concentration dependence.

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

    PubMed

    Riechers, Shawn; 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.

  19. Solubility enhancement of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) using polypolypropylene oxide core PAMAM dendrimers.

    PubMed

    Koç, Fatma Ebru; Senel, Mehmet

    2013-07-15

    The aim of the present study was to evaluate the aqueous solubility enhancement properties of polypropylene oxide cored PAMAM (PPO@PAMAM) dendrimers. The solubility of NSAIDs (Ketoprofen, Ibuprofen and Diflunisal) was investigated in the presence of PPO@PAMAM dendrimers at room temperature in buffer solution. The effects of dendrimer concentration, generation and core size on the solubility of NSAIDs have been investigated. The experimental results showed that the solubility of the NSAIDs was approximately proportional to dendrimer concentration and generation. In addition, the effect of core size on the solubility of NSAIDs in constant generation and concentration of PPO@PAMAM dendrimer was Ketoprofen>Diflunisal>Ibuprofen. Under optimized conditions, PPO@PAMAM dendrimers are highly effective solubility enhancer for NSAIDs due to its new polypropylene oxide core.

  20. 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

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

    PubMed

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

    2009-12-07

    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.

  2. Conjugated oligothienyl dendrimers based on a pyrazino[2,3-g]quinoxaline core.

    PubMed

    Mastalerz, Michael; Fischer, Viktor; Ma, Chang-Qi; Janssen, René A J; Bäuerle, Peter

    2009-10-15

    The synthesis of a new series of conjugated dendrimers based on an electron-accepting core is introduced. The compounds showed broad absorption bands over 300-700 nm and have reduced HOMO-LUMO gaps of 1.7-1.9 eV. Incorporation of these compounds in bulk heterojunction solar cells as electron-donating material along with PC61BM as electron acceptor gave power conversion efficiencies of up to 1.3% for the second-generation dendrimer.

  3. Surface Modification of Poly(amidoamine) (PAMAM) Dendrimer as Antimicrobial Agents.

    PubMed

    Charles, Shakira; Vasanthan, Nadarajah; Kwon, Dong; Sekosan, Gabriela; Ghosh, Subhas

    2012-12-05

    Poly(amidoamine) (PAMAM) (G3) dendrimer was modified into quaternary ammonium salts using tertiary amines with different chain lengths: dimethyldodecyl amine, dimethylhexyl amine, and dimethylbutyl amine using an efficient synthetic route. The antimicrobial activity of these dendrimer ammonium salts against Staphylococcus and E-coli bacteria was examined using the disc diffusion method. It was found that quaternary ammonium salt prepared with the dimethyldodecyl amine exhibits antimicrobial efficacy against Staphalococus and E.coli bacteria.

  4. 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

  5. Encapsulation and Residency of a Hydrophobic Dye within the Water-Filled Interior of a PAMAM Dendrimer Molecule.

    PubMed

    Koley, Somnath; Ghosh, Subhadip

    2017-03-02

    Tightly confined water within a small droplet behaves differently from bulk water. This notion is obtained on the basis of several reports showing unusual behaviors of water droplet residing at the core of a reverse micelle. In this study, we have shown a well-known hydrophobic dye, coumarin 153 (C153), which prefers to reside at the water-rich region inside the dendrimer molecule. Optical density (OD) measurement at the absorption peak of C153 shows that it is almost insoluble in bulk water but highly soluble in aqueous dendrimer solution. The OD of C153 increases several times in the latter case as compared to that in the former. We found the most interesting observation when we compared the data from fluorescence correlation spectroscopy (FCS) with the fluorescence anisotropy decay of C153 in aqueous dendrimer solution. The FCS measurement reveals a much slower translational diffusion time (τD) of C153 attached to a dendrimer molecule as compared to that of free C153 in bulk water in the absence of dendrimer. The slower τD in the former case is commensurate with the size of the dendrimer molecule. This is possible only when C153 is encapsulated by the dendrimer molecule. In contrast to the FCS study, the fluorescence anisotropy decay of C153 in water remains largely invariant after addition of the dendrimer. This can happen if a bulk-water-like environment at the C153 surroundings is preserved within the C153-dendrimer complex. This supports our institutive expectation that C153 resides within the water-rich peripheral cavities of the dendrimer molecule. A more expected binding of C153 to the hydrophobic core of dendrimer may not be possible here because of an inadequate size of the dendrimer core.

  6. Enhancing the performance of nanofiltration membranes by modifying the active layer with aramide dendrimers.

    PubMed

    de Jubera, Ana M Saenz; Gao, Yuan; Moore, Jeffrey S; Cahill, David G; Mariñas, Benito J

    2012-09-04

    The fully aromatic polyamide active layer of a commercial nanofiltration membrane was modified with three generations (G1, G2, and G3) of aramide dendrimers, all with oligoethylene glycol chains on their peripheries. Permeation experiments revealed that the rejection of Rhodamine WT, used as a surrogate for organic contaminants, improved 1-2 orders of magnitude for membranes modified with G2 and G3 dendrimers at loadings of 0.7-3.5 μg/cm(2) (dendrimer layer thicknesses of ~1-6 nm) compared to the performance of unmodified membranes. In contrast, the corresponding water permeability of dendrimer-modified membranes decreased by only ~30%. Although an enhancement in the rejection of H(3)AsO(3), NaCl, and BaCl(2) was also observed for dendritic membranes, the effect was less pronounced than that for rhodamine WT. Characterization of membranes modified with 3.5 μg/cm(2) dendrimers G2 and G3 by Rutherford backscattering spectrometry with the aid of heavy ion probes (Ag(+) and Ba(2+)) revealed that accessibility of the larger Ba(2+) probe to carboxylate groups on the active layer decreased for the membranes modified with dendrimers.

  7. Prolonged blood circulation and enhanced tumor accumulation of folate-targeted dendrimer-polymer hybrid nanoparticles.

    PubMed

    Sunoqrot, Suhair; Bugno, Jason; Lantvit, Daniel; Burdette, Joanna E; Hong, Seungpyo

    2014-10-10

    Nanoparticle (NP)-based drug delivery platforms have received a great deal of attention over the past two decades for their potential in targeted cancer therapies. Despite the promises, passive targeting approaches utilizing relatively larger NPs (typically 50-200nm in diameter) allow for passive tumor accumulation, but hinder efficient intratumoral penetration. Conversely, smaller, actively targeted NPs (<20nm in diameter) penetrate well into the tumor mass, but are limited by their rapid systemic elimination. To overcome these limitations, we have designed a multi-scale hybrid NP platform that loads smaller poly(amidoamine) (PAMAM) dendrimers (~5nm in diameter) into larger poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PLA) NPs (~70nm). A biodistribution study in healthy mice revealed that the hybrid NPs circulated longer than free dendrimers and were mostly cleared by macrophages in the liver and spleen, similar to the in vivo behavior of PEG-PLA NPs. When injected intravenously into the BALB/c athymic nude mice bearing folate receptor (FR)-overexpressing KB xenograft, the targeted hybrid NPs encapsulating folate (FA)-targeted dendrimers achieved longer plasma circulation than free dendrimers and higher tumor concentrations than both free dendrimers and the empty PEG-PLA NPs. These results suggest that the hybrid NPs successfully combine the in vivo advantages of dendrimers and polymeric NPs, demonstrating their potential as a new, modular platform for drug delivery.

  8. Cationic Phosphorus Dendrimer Enhances Photodynamic Activity of Rose Bengal against Basal Cell Carcinoma Cell Lines.

    PubMed

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

    2017-04-06

    In the last couple of decades, photodynamic therapy emerged as a useful tool in the treatment of basal cell carcinoma. However, it still meets limitations due to unfavorable properties of photosensitizers such as poor solubility or lack of selectivity. Dendrimers, polymers widely studied in biomedical field, may play a role as photosensitizer carriers and improve the efficacy of photodynamic treatment. Here, we describe the evaluation of an electrostatic complex of cationic phosphorus dendrimer and rose bengal in such aspects as singlet oxygen production, cellular uptake, and phototoxicity against three basal cell carcinoma cell lines. Rose bengal-cationic dendrimer complex in molar ratio 5:1 was compared to free rose bengal. Obtained results showed that the singlet oxygen production in aqueous medium was significantly higher for the complex than for free rose bengal. The cellular uptake of the complex was 2-7-fold higher compared to a free photosensitizer. Importantly, rose bengal, rose bengal-dendrimer complex, and dendrimer itself showed no dark toxicity against all three cell lines. Moreover, we observed that phototoxicity of the complex was remarkably enhanced presumably due to high cellular uptake. On the basis of the obtained results, we conclude that rose bengal-cationic dendrimer complex has a potential in photodynamic treatment of basal cell carcinoma.

  9. 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

  10. 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

  11. Covalent-bonded immobilization of lipase on poly(phenylene sulfide) dendrimers and their hydrolysis ability.

    PubMed

    Yemul, Omprakash; Imae, Toyoko

    2005-01-01

    Covalent-bonded immobilization of lipase from burkholderia cepacia onto two poly(phenylene sulfide) (PPS) dendrimers with different generations (two and three) was achieved using carbodiimide as a coupling reagent. The hydrolysis activity of olive oil to fatty acid was studied on enzyme-immobilized PPS dendrimers. Enzyme activity was proportional to the enzyme loading, and highest recovered activity was obtained at the medium enzyme loading for both G2 and G3 dendrimers. The immobilization improved the optimum pH and caused the temperature range to widen. Immobilization of enzyme has enhanced the thermal stability of enzyme activity in comparison with free enzyme. The immobilized enzyme as a biocatalyst for batch hydrolysis of olive oil retained 80 approximately 90% activity even after 20 times of recycling. This retention of activity after recycle is very valuable and powerful in enzyme technology. The present noteworthy and vital availability on enzyme reaction of the covalently bonded immobilized lipase on dendrimer came from the structure of dendrimer with a large number of functional terminal groups, which are easily available for immobilization of many lipases at the situation keeping reactive enzymes on the surface of dendrimer.

  12. Optimization and in vitro toxicity evaluation of G4 PAMAM dendrimer-risperidone complexes.

    PubMed

    Prieto, María Jimena; Temprana, Carlos Facundo; del Río Zabala, Nahuel Eduardo; Marotta, Cristian Hernán; Alonso, Silvia del Valle

    2011-03-01

    Risperidone is an approved antipsychotic drug belonging to the chemical class of benzisoxazole. This drug has low solubility in aqueous medium and poor bioavailability due to extensive first-pass metabolism and high protein binding (>90%). As new strategies to improve treatments efficiency are needed, we have studied cationic G4 PAMAM dendrimers' performance to act as efficient nanocarriers for this therapeutic drug. In this respect, we explored dendrimer-risperidone complexation dependence on solvent, temperature, pH and salt concentration, as well as in vitro cytotoxicity measured on L929 cell line and human red blood cells. The best dendrimer-risperidone incorporation was achieved when a mixture of 70:30 and 90:10 v/v chloroform:methanol was used, obtaining 17 and 32 risperidone molecules per dendrimer, respectively. No cytotoxicity on L929 cells was found when dendrimer concentration was below 3 × 10(-2) μM and risperidone concentration below 5.1 μM. Also, no significant hemolysis or morphological changes were observed on human red blood cells. Finally, attempting to obtain an efficient drug delivery system for risperidone, incorporation in G4 PAMAM dendrimers was optimized, improving drug solubility with low cytotoxicity.

  13. Monolayers of poly(amido amine) dendrimers on mica - In situ streaming potential measurements.

    PubMed

    Michna, Aneta; Adamczyk, Zbigniew; Sofińska, Kamila; Matusik, Katarzyna

    2017-01-01

    The deposition of poly(amido amine) dendrimers on mica at various pHs was studied by the atomic force microscopy (AFM) and in situ streaming potential measurements. Bulk characteristics of dendrimers were acquired by using the dynamic light scattering (DLS) and the laser Doppler velocimetry (LDV). The hydrodynamic radius derived from DLS measurements was 5.2nm for the ionic strength of 10(-2)M and pH range 4-10. The electrophoretic mobility, the zeta potential and the number of electrokinetic charges per molecule were derived as a function of pH from the LDV measurements. It was revealed that the dendrimers are positively charged for pH up to 10. This promoted their deposition on negatively charged mica substrate whose kinetics was quantitatively evaluated by direct AFM imaging and streaming potential measurements interpreted in terms of the electrokinetic model. The desorption kinetics of dendrimers under flowing conditions from monolayers of various coverage was also studied. It was revealed that dendrimer deposition was partially reversible for pH above 5.8. The acid-base properties of the dendrimer monolayers deposited on mica were characterized.

  14. Principal physicochemical methods used to characterize dendrimer molecule complexes used as genetic therapy agents, nanovaccines or drug carriers.

    PubMed

    Alberto, Rodríguez Fonseca Rolando; Joao, Rodrigues; de Los Angeles, Muñoz-Fernández María; Alberto, Martínez Muñoz; Jonathan, Fragoso Vázquez Manuel; José, Correa Basurto

    2017-02-20

    Nanomedicine is the application of nanotechnology to medicine. This field is related to the study of nanodevices and nanomaterials applied to various medical uses, such as in improving the pharmacological properties of different molecules. Dendrimers are synthetic nanoparticles whose physicochemical properties vary according to their chemical structure. These molecules have been extensively investigated as drug nanocarriers to improve drug solubility and as sustained-release systems. New therapies such as gene therapy and the development of nanovaccines can be improved by the use of dendrimers. The biophysical and physicochemical characterization of nucleic acid/peptide-dendrimer complexes is crucial to identify their functional properties prior to biological evaluation. In that sense, it is necessary to first identify whether the peptide-dendrimer or nucleic acid-dendrimer complexes can be formed and whether the complex can dissociate under the appropriate conditions at the target cells. In addition, biophysical and physicochemical characterization is required to determine how long the complexes remain stable, what proportion of peptide or nucleic acid is required to form the complex or saturate the dendrimer, and the size of the complex formed. In this review, we present the latest information on characterization systems for dendrimer-nucleic acid, dendrimer-peptide and dendrimer-drug complexes with several biotechnological and pharmacological applications.

  15. Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model.

    PubMed

    Zhang, Fan; Trent Magruder, J; Lin, Yi-An; Crawford, Todd C; Grimm, Joshua C; Sciortino, Christopher M; Wilson, Mary Ann; Blue, Mary E; Kannan, Sujatha; Johnston, Michael V; Baumgartner, William A; Kannan, Rangaramanujam M

    2017-03-10

    Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the injured brain, and deliver therapeutics in small and large animal models. We investigated the effect of dendrimer size on brain uptake and explored the pharmacokinetics in a clinically-relevant canine model of HCA-induced brain injury. Generation 6 (G6, ~6.7nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, ~4.3nm), which were undetectable in the brain by 48h after final administration. High levels of G6 dendrimers were found in cerebrospinal fluid (CSF) of injured animals with a CSF/serum ratio of ~20% at peak, a ratio higher than that of many neurologic pharmacotherapies already in clinical use. Brain penetration (measured by drug CSF/serum level) of G6 dendrimers correlated with the severity of neuroinflammation observed. G6 dendrimers also showed decreased renal clearance rate, slightly increased liver and spleen uptake compared to G4 dendrimers. These results, in a large animal model, may offer insights into the potential clinical translation of dendrimers.

  16. Mechanistic Studies of Viral Entry: An Overview of Dendrimer-Based Microbicides As Entry Inhibitors Against Both HIV and HSV-2 Overlapped Infections.

    PubMed

    Sepúlveda-Crespo, Daniel; Ceña-Díez, Rafael; Jiménez, José Luis; Ángeles Muñoz-Fernández, Ma

    2017-01-01

    This review provides an overview of the development of different dendrimers, mainly polyanionic, against human immunodeficiency virus (HIV) and genital herpes (HSV-2) as topical microbicides targeting the viral entry process. Vaginal topical microbicides to prevent sexually transmitted infections such as HIV and HSV-2 are urgently needed. To inhibit HIV/HSV-2 entry processes, new preventive targets have been established to maximize the current therapies against wild-type and drug-resistant viruses. The entry of HIV/HSV-2 into target cells is a multistep process that triggers a cascade of molecular interactions between viral envelope proteins and cell surface receptors. Polyanionic dendrimers are highly branched nanocompounds with potent activity against HIV/HSV-2. Inhibitors of each entry step have been identified with regard to generations and surface groups, and possible roles for these agents in anti-HIV/HSV-2 therapies have also been discussed. Four potential binding sites for impeding HIV infection (HSPG, DC-SIGN, GSL, and CD4/gp120 inhibitors) and HSV-2 infection (HS, gB, gD, and gH/gL inhibitors) exist according to their mechanisms of action and structures. This review clarifies that inhibition of HIV/HSV-2 entry continues to be a promising target for drug development because nanotechnology can transform the field of HIV/HSV-2 prevention by improving the efficacy of the currently available antiviral treatments.

  17. Controlled doping by self-assembled dendrimer-like macromolecules

    PubMed Central

    Wu, Haigang; Guan, Bin; Sun, Yingri; Zhu, Yiping; Dan, Yaping

    2017-01-01

    Doping via self-assembled macromolecules might offer a solution for developing single atom electronics by precisely placing individual dopants at arbitrary location to meet the requirement for circuit design. Here we synthesize dendrimer-like polyglycerol macromolecules with each carrying one phosphorus atom in the core. The macromolecules are immobilized by the coupling reagent onto silicon surfaces that are pre-modified with a monolayer of undecylenic acid. Nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) are employed to characterize the synthesized macromolecules and the modified silicon surfaces, respectively. After rapid thermal annealing, the phosphorus atoms carried by the macromolecules diffuse into the silicon substrate, forming dopants at a concentration of 1017 cm−3. Low-temperature Hall effect measurements reveal that the ionization process is rather complicated. Unlike the widely reported simple ionization of phosphorus dopants, nitrogen and carbon are also involved in the electronic activities in the monolayer doped silicon. PMID:28145485

  18. Controlled doping by self-assembled dendrimer-like macromolecules

    NASA Astrophysics Data System (ADS)

    Wu, Haigang; Guan, Bin; Sun, Yingri; Zhu, Yiping; Dan, Yaping

    2017-02-01

    Doping via self-assembled macromolecules might offer a solution for developing single atom electronics by precisely placing individual dopants at arbitrary location to meet the requirement for circuit design. Here we synthesize dendrimer-like polyglycerol macromolecules with each carrying one phosphorus atom in the core. The macromolecules are immobilized by the coupling reagent onto silicon surfaces that are pre-modified with a monolayer of undecylenic acid. Nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) are employed to characterize the synthesized macromolecules and the modified silicon surfaces, respectively. After rapid thermal annealing, the phosphorus atoms carried by the macromolecules diffuse into the silicon substrate, forming dopants at a concentration of 1017 cm‑3. Low-temperature Hall effect measurements reveal that the ionization process is rather complicated. Unlike the widely reported simple ionization of phosphorus dopants, nitrogen and carbon are also involved in the electronic activities in the monolayer doped silicon.

  19. Dendrimer light-harvesting: intramolecular electrodynamics and mechanisms.

    PubMed

    Andrews, David L; Bradshaw, David S; Jenkins, Robert D; Rodríguez, Justo

    2009-12-07

    In the development of highly efficient materials for harvesting solar energy, there is an increasing focus on purpose-built dendrimers and allied multi-chromophore systems. A proliferation of antenna chromophores is not the only factor determining the sought light-harvesting efficiency; the internal geometry and photophysics of these molecules are also crucially important. In particular, the mechanisms by means of which radiant energy is ultimately trapped depends on an intricate interplay of electronic, structural, energetic and symmetry properties. To better understand these processes a sound theoretical representation of the intramolecular electrodynamics is required. A suitable formalism, based on quantum electrodynamics, readily delivers physical insights into the necessary excitation channelling processes, and it affords a rigorous basis for modelling the intramolecular flow of energy.

  20. Controlled doping by self-assembled dendrimer-like macromolecules.

    PubMed

    Wu, Haigang; Guan, Bin; Sun, Yingri; Zhu, Yiping; Dan, Yaping

    2017-02-01

    Doping via self-assembled macromolecules might offer a solution for developing single atom electronics by precisely placing individual dopants at arbitrary location to meet the requirement for circuit design. Here we synthesize dendrimer-like polyglycerol macromolecules with each carrying one phosphorus atom in the core. The macromolecules are immobilized by the coupling reagent onto silicon surfaces that are pre-modified with a monolayer of undecylenic acid. Nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) are employed to characterize the synthesized macromolecules and the modified silicon surfaces, respectively. After rapid thermal annealing, the phosphorus atoms carried by the macromolecules diffuse into the silicon substrate, forming dopants at a concentration of 10(17) cm(-3). Low-temperature Hall effect measurements reveal that the ionization process is rather complicated. Unlike the widely reported simple ionization of phosphorus dopants, nitrogen and carbon are also involved in the electronic activities in the monolayer doped silicon.

  1. 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

  2. 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

  3. 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

  4. Dendrimer Probes for Enhanced Photostability and Localization in Fluorescence Imaging

    PubMed Central

    Kim, Younghoon; Kim, Sung Hoon; Tanyeri, Melikhan; Katzenellenbogen, John A.; Schroeder, Charles M.

    2013-01-01

    Recent advances in fluorescence microscopy have enabled high-resolution imaging and tracking of single proteins and biomolecules in cells. To achieve high spatial resolutions in the nanometer range, bright and photostable fluorescent probes are critically required. From this view, there is a strong need for development of advanced fluorescent probes with molecular-scale dimensions for fluorescence imaging. Polymer-based dendrimer nanoconjugates hold strong potential to serve as versatile fluorescent probes due to an intrinsic capacity for tailored spectral properties such as brightness and emission wavelength. In this work, we report a new, to our knowledge, class of molecular probes based on dye-conjugated dendrimers for fluorescence imaging and single-molecule fluorescence microscopy. We engineered fluorescent dendritic nanoprobes (FDNs) to contain multiple organic dyes and reactive groups for target-specific biomolecule labeling. The photophysical properties of dye-conjugated FDNs (Cy5-FDNs and Cy3-FDNs) were characterized using single-molecule fluorescence microscopy, which revealed greatly enhanced photostability, increased probe brightness, and improved localization precision in high-resolution fluorescence imaging compared to single organic dyes. As proof-of-principle demonstration, Cy5-FDNs were used to assay single-molecule nucleic acid hybridization and for immunofluorescence imaging of microtubules in cytoskeletal networks. In addition, Cy5-FDNs were used as reporter probes in a single-molecule protein pull-down assay to characterize antibody binding and target protein capture. In all cases, the photophysical properties of FDNs resulted in enhanced fluorescence imaging via improved brightness and/or photostability. PMID:23561533

  5. 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

  6. Polyamidoamine dendrimers as novel potential absorption enhancers for improving the small intestinal absorption of poorly absorbable drugs in rats.

    PubMed

    Lin, Yulian; Fujimori, Takeo; Kawaguchi, Naoko; Tsujimoto, Yuiko; Nishimi, Mariko; Dong, Zhengqi; Katsumi, Hidemasa; Sakane, Toshiyasu; Yamamoto, Akira

    2011-01-05

    Effects of polyamidoamine (PAMAM) dendrimers on the intestinal absorption of poorly absorbable drugs were examined by an in situ closed loop method in rats. 5(6)-Carboxyfluorescein (CF), fluorescein isothiocyanate-dextrans (FDs) with various molecular weights, calcitonin and insulin were used as model drugs of poorly absorbable drugs. The absorption of CF, FD4 and calcitonin from the rat small intestine was significantly enhanced in the presence of PAMAM dendrimers. The absorption-enhancing effects of PAMAM dendrimers for improving the small intestinal absorption of CF were concentration and generation dependent and a maximal absorption-enhancing effect was observed in the presence of 0.5% (w/v) G2 PAMAM dendrimer. However, G2 PAMAM dendrimer had almost no absorption-enhancing effect on the small intestinal absorption of macromolecular drugs including FD10 and insulin. Overall, the absorption-enhancing effects of G2 PAMAM dendrimer in the small intestine decreased as the molecular weights of drug increased. However, G2 PAMAM dendrimer did not enhance the intestinal absorption of these drugs with different molecular weights in the large intestine. Furthermore, we evaluated the intestinal membrane damage with or without G2 PAMAM dendrimer. G2 PAMAM dendrimer (0.5% (w/v)) significantly increased the activities of lactate dehydrogenase (LDH) and the amounts of protein released from the intestinal membranes, but the activities and amounts of these toxic markers were less than those in the presence of 3% Triton X-100 used as a positive control. Moreover, G2 PAMAM dendrimer at concentrations of 0.05% (w/v) and 0.1% (w/v) did not increase the activities and amounts of these toxic markers. These findings suggested that PAMAM dendrimers at lower concentrations might be potential and safe absorption enhancers for improving absorption of poorly absorbable drugs from the small intestine.

  7. Anticancer copper(II) phosphorus dendrimers are potent proapoptotic Bax activators.

    PubMed

    Mignani, Serge; El Brahmi, Nabil; Eloy, Laure; Poupon, Joel; Nicolas, Valérie; Steinmetz, Anke; El Kazzouli, Said; Bousmina, Mosto M; Blanchard-Desce, Mireille; Caminade, Anne-Marie; Majoral, Jean-Pierre; Cresteil, Thierry

    2017-03-21

    A multivalent phosphorus dendrimer 1G3 and its corresponding Cu-complex, 1G3-Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 Å thickness and 49 Å diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G3 moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non-complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G3-Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway.

  8. 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

  9. Hyperbranched-dendrimer architectural copolymer gene delivery using hyperbranched PEI conjugated to poly(propyleneimine) dendrimers: synthesis, characterization, and evaluation of transfection efficiency

    NASA Astrophysics Data System (ADS)

    Alavi, Seyyed Jamal; Gholami, Leila; Askarian, Saeedeh; Darroudi, Majid; Massoudi, Abdolhossein; Rezaee, Mehdi; Kazemi Oskuee, Reza

    2017-02-01

    The applications of dendrimer-based vectors seem to be promising in non-viral gene delivery because of their potential for addressing the problems with viral vectors. In this study, generation 3 poly(propyleneimine) (G3-PPI) dendrimers with 1, 4-diaminobutane as a core initiator was synthesized using a divergent growth approach. To increase the hydrophobicity and reduce toxicity, 10% of primary amines of G3-PPI dendrimers were replaced with bromoalkylcarboxylates with different chain lengths (6-bromohexanoic and 10-bromodecanoic). Then, to retain the overall buffering capacity and enhance transfection, the alkylcarboxylate-PPIs were conjugated to 10 kDa branched polyethylenimine (PEI). The results showed that the modified PPI was able to form complexes with the diameter of less than 60 nm with net-positive surface charge around 20 mV. No significant toxicity was observed in modified PPIs; however, the hexanoate conjugated PPI-PEI (PPI-HEX-10% PEI) and the decanoate conjugated PPI-PEI (PPI-DEC-10%-PEI) showed the best transfection efficiency in murine neuroblastoma (Neuro-2a) cell line, even PPI-HEX-10%-PEI showed transfection efficiency equal to standard PEI 25 kDa with reduced toxicity. This study suggested a new series of hyperbranched (PEI)-dendrimer (PPI) architectural copolymers as non-viral gene delivery vectors with high transfection efficiency and low toxicity.

  10. Dendrimer-based targeted intravitreal therapy for sustained attenuation of neuroinflammation in retinal degeneration.

    PubMed

    Iezzi, Raymond; Guru, Bharath R; Glybina, Inna V; Mishra, Manoj K; Kennedy, Alexander; Kannan, Rangaramanujam M

    2012-01-01

    Retinal neuroinflammation, mediated by activated microglia, plays a key role in the pathogenesis of photoreceptor and retinal pigment epithelial cell loss in age-related macular degeneration and retinitis pigmentosa. Targeted drug therapy for attenuation of neuroinflammation in the retina was explored using hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices. We show that, upon intravitreal administration, PAMAM dendrimers selectively localize within activated outer retinal microglia in two rat models of retinal degeneration, but not in the retina of healthy controls. This pathology-dependent biodistribution was exploited for drug delivery, by covalently conjugating fluocinolone acetonide to the dendrimer. The conjugate released the drug in a sustained manner over 90 days. In vivo efficacy was assessed using the Royal College of Surgeons (RCS) rat retinal degeneration model over a four-week period when peak retinal degeneration occurs. One intravitreal injection of 1 μg of FA conjugated to 7 μg of the dendrimer was able to arrest retinal degeneration, preserve photoreceptor outer nuclear cell counts, and attenuate activated microglia, for an entire month. These studies suggest that PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia, and can deliver drugs inside these cells for a sustained period for the treatment of retinal neuroinflammation.

  11. Aggregation-controlled excimer emission from anthracene-containing polyamidoamine dendrimers.

    PubMed

    Lekha, P K; Prasad, Edamana

    2010-03-22

    Lower generations of polyamidoamine (PAMAM) dendrimers were peripherally modified with anthracene moieties, and excimer emission from anthracene chromophores was investigated in an acetonitrile-water mixture at acidic and basic pH values. Results from fluorescence spectroscopic experiments suggest that 1) the propensity of anthracene-modified PAMAM dendrimers to aggregate in acetonitrile is substantial in the presence of 15-20 vol % of water, and 2) aggregate formation in anthracene-modified PAMAM dendrimers leads to unique morphologies in the ground state, where the anthracene units are pre-arranged to form stable excimers upon photoexcitation. Three types of anthracene excimers are generated in the system, with face-to-face, angular, and T-shaped geometry. The formation of different types of anthracene excimers was confirmed by steady-state and time-resolved fluorescence spectroscopic experiments. Experimental results further suggest that it is feasible to alter the type of excimer formed by anthracene units attached to the PAMAM dendrimers through altering the propensity for ground-state aggregation. Most excitingly, increased pi conjugation in the molecular framework of anthracene-substituted PAMAM dendrimers leads to intense and exclusive excimer emission from anthracene at room temperature.

  12. Facile and Efficient Synthesis of Carbosiloxane Dendrimers via Orthogonal Click Chemistry Between Thiol and Ene.

    PubMed

    Zhang, Zhida; Feng, Shengyu; Zhang, Jie

    2016-02-01

    A combination of a thiol-Michael addition reaction and a free radical mediated thiol-ene reaction is employed as a facile and efficient approach to carbosiloxane dendrimer synthesis. For the first time, carbosiloxane dendrimers are constructed rapidly by an orthogonal click strategy without protection/deprotection procedures. The chemoselectivity of these two thiol-ene click reactions leads to a design of a new monomer containing both electron-deficient carbon-carbon double bonds and unconjugated carbon-carbon double bonds. Siloxane bonds are introduced as the linker between these two kinds of carbon-carbon double bonds. Starting from a bifunctional thiol core, the dendrimers are constructed by iterative thiol-ene click reactions under different but both mild reaction conditions. After simple purification steps the fifth dendrimer with 54 peripheral functional groups is obtained with an excellent overall yield in a single day. Furthermore, a strong blue glow is observed when the dendrimer is excited by a UV lamp.

  13. Modulation of biogenic amines content by poly(propylene imine) dendrimers in rats.

    PubMed

    Ciepluch, Karol; Ziemba, Barbara; Janaszewska, Anna; Appelhans, Dietmar; Klajnert, Barbara; Bryszewska, Maria; Fogel, Wiesława Agnieszka

    2012-09-01

    Biogenic amines and polyamines participate in all vital organism functions, their levels being important function determinants. Studies were performed to check whether repeated administration of poly(propylene imine) (PPI) dendrimers, synthetic macromolecules with diaminobutane core, and peripheral primary amine groups, may influence the endogenous level of amines, as represented by the two of them: spermidine, a natural derivative of diaminobutane, and histamine. The experiment was carried out on Wistar rats. Fourth generation PPI dendrimer, as well as maltotriose-modified fourth generation PPI dendrimers with (a) cationic open sugar shell and (b) neutral dense sugar shell that possess a higher biocompatibility, was used. Applying the combination of column chromatography on Cellex P and spectrofluorimetric assays of o-phthaldialdehyde, the final amine condensation products were employed to analyze tissue spermidine and histamine outside the central nervous system. Furthermore, radioenzymatic assay was used to measure histamine levels in the brain. The obtained results indicate that in some tissues, the endogenous concentrations of histamine and spermidine may be affected by dendrimers depending on their dose and type of dendrimers.

  14. 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.

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

    PubMed

    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/cm(2) cumulative drug permeated through the skin, while the DF-dendrimer gel without sonophoresis treatment (run 14) showed 257.3 µg/cm(2) 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/cm(2). It was concluded that dendrimer-coupled sonophoresis-mediated transdermal drug delivery system has the potential to enhance the permeation of DF through the skin.

  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. 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.

  18. Synthesis of metal-carbonyl-dendrimer-antibody immunoconjugates: towards a new format for carbonyl metallo immunoassay.

    PubMed

    Fischer-Durand, Nathalie; Salmain, Michèle; Rudolf, Bogna; Vessières, Anne; Zakrzewski, Janusz; Jaouen, Gérard

    2004-04-02

    We report the preparation of metal-carbonyl-dendrimer-antibody conjugates. These metal-carbonyl-multilabeled antibodies are designed to be used in a new solid-phase-format carbonyl metallo immunoassay (CMIA). A fourth-generation polyamidoamine dendrimer was labeled with 10-25 (eta5-cyclopentadienyl)iron dicarbonyl (eta1-N-succinimidyl) entities. An antibody was chemically modified at its carbohydrate chains by a site-directed process used to preserve the antigen-antibody binding site. The antibody was then coupled with the dendrimer labeled with 10 metal carbonyl groups. An average of 1.4 labeled dendrimers were grafted per antibody molecule. These metal-carbonyl-dendrimer-antibody conjugates were used as new universal detection reagents that recognize their specific antigens. The antigens were spotted onto nitrocellulose membranes and detected by using the conjugates in combination with Fourier transform infrared spectroscopy. A detection level in the range 5-200 pmol per membrane was achieved. This approach opens the way to a new CMIA format.

  19. 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

  20. Multichromophoric polyphenylene dendrimers: toward brilliant light emitters with an increased number of fluorophores.

    PubMed

    Oesterling, Ingo; Müllen, Klaus

    2007-04-18

    Two routes for the introduction of highly fluorescent peryleneimide chromophores into the scaffolding of polyphenylene dendrimers via iterative Diels-Alder cycloadditions are presented. The key intermediates for the divergent dendrimer buildup were two cyclopentadienone branching units carrying two peryleneimides and two masked terminal alkynes. The difference between the two reagents is the mode of incorporation of the chromophores. In the first case, the chromophores were attached to the alpha-position of the tetraphenylcyclopentadienones. In the second case, peryleneimides are used as a "spacer" in the beta-position of the cyclopentadienones giving rise to dendrimers with extended molecular diameters (up to 12 nm) and 24 chromophores within their scaffold. Absorption and emission characteristics of the new multichromophoric nanoparticles were investigated and compared to those of the parent dyes. Additionally, an asymmetrically substituted first-generation dendrimer with six perylene diimide chromophores and one ester functionality is reported. The ester serves as a potential anchor group, and this nanoemitter paves the way to a multichromophoric fluorescence label. All dendrimers have good solubility in common organic solvents, high fluorescence quantum yields, and defined distances between the chromophores, making them attractive candidates for single-molecule spectroscopy.

  1. Role of PAMAM-OH dendrimers against the fibrillation pathway of biomolecules.

    PubMed

    Sekar, Gajalakshmi; Florance, Ida; Sivakumar, A; Mukherjee, Amitava; Chandrasekaran, Natarajan

    2016-12-01

    The binding behavior of nanoparticle with proteins determines its biocompatibility. This study reports the interaction of ten different biomolecules (proteins-BSA, HSA, haemoglobin, gamma globulin, transferrin and enzymes-hog and bacillus amylase, lysozyme from chicken and human and laccases from Tramates versicolor) with a surface group hydroxylated Poly AMido AMide dendrimer (PAMAM) of generation 5. The study has utilized various spectroscopic methods like UV-vis spectroscopy, Fluorescence emission, Synchronous, 3-D spectroscopy and Circular Dichroism to detect the binding induced structural changes in biomolecules that occur upon interaction with mounting concentration of the dendrimers. Aggregation of proteins results in the formation of amyloid fibrils causing several human diseases. In this study, fibrillar samples of all ten biomolecules formed in the absence and the presence of dendrimers were investigated with Congo Red absorbance and ThT Assay to detect fibril formation, Trp Emission and 3-D scan to evaluate the effect of fibrillation on aromatic environment of biomolecules, and CD spectroscopy to measure the conformational changes in a quantitative manner. These assays have generated useful information on the role of dendrimers in amyloid fibril formation of biomolecules. The outcomes of the study remain valuable in evaluating the biological safety of PAMAM-OH dendrimers for their biomedical application in vivo.

  2. 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.

  3. 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

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

    PubMed

    Márquez-Miranda, Valeria; Camarada, María Belén; 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.

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. Thermal stability of second generation carbosilane dendrimers with peripheral ammonia groups

    NASA Astrophysics Data System (ADS)

    Popescu, Maria-Cristina; Gómez, Rafael; de la Mata, Fco Javier; Rasines, Beatriz; Simionescu, Bogdan C.

    2013-10-01

    Thermal analysis has a wide range of applications in pharmaceutical industry, in designing new molecules, control of raw materials, stability, compatibility studies, and development of new formulations. This paper evaluates the thermodynamic properties of two second generation G2 carbosilane dendrimers with peripheral ammonia groups by differential scanning calorimetry and TG/FTIR coupled techniques. The physical transformations have been detected and their thermodynamic characteristics have been estimated and analyzed. Both dendrimers are stable up to 150 °C, have the Tg at 75 and 59 °C and melting temperatures at 113 and 128 °C, respectively. The decomposition process proved to be very complex and takes place in three steps in nitrogen atmosphere and four steps in air, for both types of dendrimers. IR spectroscopic analysis was used to observe the evolution of the gaseous products versus temperature.

  10. Dendrimers and Dendrons as Versatile Building Blocks for the Fabrication of Functional Hydrogels.

    PubMed

    Kaga, Sadik; Arslan, Mehmet; Sanyal, Rana; Sanyal, Amitav

    2016-04-15

    Hydrogels have emerged as a versatile class of polymeric materials with a wide range of applications in biomedical sciences. The judicious choice of hydrogel precursors allows one to introduce the necessary attributes to these materials that dictate their performance towards intended applications. Traditionally, hydrogels were fabricated using either polymerization of monomers or through crosslinking of polymers. In recent years, dendrimers and dendrons have been employed as well-defined building blocks in these materials. The multivalent and multifunctional nature of dendritic constructs offers advantages in either formulation or the physical and chemical properties of the obtained hydrogels. This review highlights various approaches utilized for the fabrication of hydrogels using well-defined dendrimers, dendrons and their polymeric conjugates. Examples from recent literature are chosen to illustrate the wide variety of hydrogels that have been designed using dendrimer- and dendron-based building blocks for applications, such as sensing, drug delivery and tissue engineering.

  11. 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

  12. 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.

  13. Facile synthesis of polyester dendrimers from sequential click coupling of asymmetrical monomers.

    PubMed

    Ma, Xinpeng; Tang, Jianbin; Shen, Youqing; Fan, Maohong; Tang, Huadong; Radosz, Maciej

    2009-10-21

    Polyester dendrimers are attractive for in vivo delivery of bioactive molecules due to their biodegradability, but their synthesis generally requires multistep reactions with intensive purifications. A highly efficient approach to the synthesis of dendrimers by simply "sticking" generation by generation together is achieved by combining kinetic or mechanistic chemoselectivity with click reactions between the monomers. In each generation, the targeted molecules are the major reaction product as detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The only separation needed is to remove the little unreacted monomer by simple precipitation or washing. This simple clicklike process without complicated purification is particularly suitable for the synthesis of custom-made polyester dendrimers.

  14. NMR relaxation of the orientation of single segments in semiflexible dendrimers

    SciTech Connect

    Markelov, Denis A. Gotlib, Yuli Ya.; Dolgushev, Maxim; Blumen, Alexander

    2014-06-28

    We study the orientational properties of labeled segments in semiflexible dendrimers making use of the viscoelastic approach of Dolgushev and Blumen [J. Chem. Phys. 131, 044905 (2009)]. We focus on the segmental orientational autocorrelation functions (ACFs), which are fundamental for the frequency-dependent spin-lattice relaxation times T{sub 1}(ω). We show that semiflexibility leads to an increase of the contribution of large-scale motions to the ACF. This fact influences the position of the maxima of the [1/T{sub 1}]-functions. Thus, going from outer to inner segments, the maxima shift to lower frequencies. Remarkably, this feature is not obtained in the classical bead-spring model of flexible dendrimers, although many experiments on dendrimers manifest such a behavior.

  15. 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.

  16. 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

  17. 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

    2015-07-14

    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.

  18. 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

  19. Use of polyamidoamine dendrimers to engineer BDNF-producing human mesenchymal stem cells.

    PubMed

    Shakhbazau, Antos; Shcharbin, Dzmitry; Seviaryn, Ihar; Goncharova, Natalya; Kosmacheva, Svetlana; Potapnev, Mihail; Gabara, Barbara; Ionov, Maxim; Bryszewska, Maria

    2010-04-01

    We report the use of polyamidoamine (PAMAM-NH(2)) dendrimers along with other non-viral vehicles for the in vitro transfection of human bone marrow mesenchymal stem cells (hMSCs) and for engineering MSCs to secrete brain-derived neurotrophic factor (BDNF). Different generations of cationic polyamidoamine dendrimers (generations 3-6) were tested on HEK 293T cells. hMSCs were then transfected with PAMAM-NH(2) G4 dendrimers and Lipofectamine 2000, which elicited the expression of GFP reporter in around 6 and 20% of the cells, respectively. Both vehicles were then shown to elicit the expression of BDNF in MSCs from a bicistronic cassette. Non-virally induced neurotrophin expression may be a safe and easy method for adapting autologous stem cells for therapeutic treatment of diseases and neural system injuries.

  20. Binding of poly(amidoamine), carbosilane, phosphorus and hybrid dendrimers to thrombin-Constants and mechanisms.

    PubMed

    Shcharbin, Dzmitry; Pedziwiatr-Werbicka, Elzbieta; Vcherashniaya, Aliaksandra; Janaszewska, Anna; Marcinkowska, Monika; Goska, Piotr; Klajnert-Maculewicz, Barbara; Ionov, Maksim; Abashkin, Viktar; Ihnatsyeu-Kachan, Aliaksei; de la Mata, F Javier; Ortega, Paula; Gomez-Ramirez, Rafael; Majoral, Jean-Pierre; Bryszewska, Maria

    2017-03-31

    Thrombin is an essential part of the blood coagulation system; it is a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, and catalyzes many other coagulation-related reactions. Absorption at its surface of small nanoparticles can completely change the biological properties of thrombin. We have analyzed the influence on thrombin of 3 different kinds of small nanoparticles: dendrimers (phosphorus-based, carbosilane based and polyamidoamine) and 2 hybrid systems containing carbosilane, viologen and phosphorus dendritic scaffolds in one single molecule, bearing different flexibility, size and surface charge. There was significant alteration in the rigidity of the rigid dendrimers in contrast to flexible dendrimers. These differences in their action are important in understanding interactions taking place at a bio-nanointerface.

  1. Controlling Cellular Uptake and Toxicity of Polyphenylene Dendrimers by Chemical Functionalization.

    PubMed

    Hammer, Brenton; Wu, Yuzhou; Fischer, Stephan; Liu, Weina; Weil, Tanja; Müllen, Klaus

    2017-02-21

    Polyphenylene dendrimers (PPDs) represent a unique class of macromolecules based on their monodisperse and shape-persistent nature. These characteristics have enabled the synthesis of a new genre of "patched" surface dendrimers where their exterior can be functionalized with a variety of polar and unpolar substituents to yield lipophilic binding sites in a site-specific way. While such materials have proven capable of complexing biologically relevant molecules, shown high cellular uptake in various cell lines, and low to no toxicity; there is minimal understanding of the driving forces to these characteristics. Therefore, the present work aims at investigating whether it is the specific chemical functionalities, relative quantities of each moiety, or the "patched" surface patterning on the dendrimers that more significantly influences their behavior in biological media.

  2. Controlled delivery of Gemcitabine Hydrochloride using mannosylated poly(propyleneimine) dendrimers

    NASA Astrophysics Data System (ADS)

    Soni, Namrata; Jain, Keerti; Gupta, Umesh; Jain, N. K.

    2015-11-01

    The aim of the present investigation was to deliver Gemcitabine Hydrochloride (GmcH), an anticancer bioactive, specifically to lung tumor cells using mannosylated 4.0G poly(propyleneimine) dendrimers (M-PPI). 4.0G poly(propyleneimine) (PPI) dendrimers was synthesized using ethylenediamine as core and conjugated with mannose by ring opening reactions, followed by Schiff's reaction in the presence of sodium acetate buffer (pH 4.0). Synthesized PPI dendrimers and mannose-conjugated dendrimers were characterized using IR, NMR spectroscopy, and scanning electron microscopy. GmcH was loaded into PPI and M-PPI dendrimers using equilibrium dialysis method to develop the formulations, GmcH-PPI and GmcH-M-PPI, respectively. The developed formulations were evaluated for drug loading, in vitro release kinetics, in vitro stability, hemolytic toxicity, cytotoxicity, pharmacokinetic, and biodistribution studies. The dendrimeric formulation of GmcH showed pH-sensitive release with faster release at acidic pH, i.e., pH 4.0 in comparison with physiological pH 7.4. M-PPI conjugate showed significant reduction in hemolytic toxicity as compared to plain 4.0G PPI dendrimers towards human erythrocytes. In the cytotoxicity studies with A-549 lung adenocarcinoma cell line, the GmcH-M-PPI formulation showed the lowest IC50 value. Further, the pharmacokinetic and tissue distribution studies of free drug GmcH, GmcH-PPI, and GmcH-M-PPI in albino rats of Sprague-Dawley strain suggested the mean residence time of GmcH-M-PPI conjugate to be significantly higher (24.85 h) than free GmcH and GmcH-PPI. Deposition of drug (396.1 ± 4.7 after 2 h) in lung was found to be significantly higher with GmcH-M-PPI formulation in comparison with Gmch and GmcH-PPI.

  3. Emerging concepts in dendrimer-based nanomedicine: from design principles to clinical applications.

    PubMed

    Kannan, R M; Nance, E; Kannan, S; Tomalia, D A

    2014-12-01

    Dendrimers are discrete nanostructures/nanoparticles with 'onion skin-like' branched layers. Beginning with a core, these nanostructures grow in concentric layers to produce stepwise increases in size that are similar to the dimensions of many in vivo globular proteins. These branched tree-like concentric layers are referred to as 'generations'. The outer generation of each dendrimer presents a precise number of functional groups that may act as a monodispersed platform for engineering favourable nanoparticle-drug and nanoparticle-tissue interactions. These features have attracted significant attention in medicine as nanocarriers for traditional small drugs, proteins, DNA/RNA and in some instances as intrinsically active nanoscale drugs. Dendrimer-based drugs, as well as diagnostic and imaging agents, are emerging as promising candidates for many nanomedicine applications. First, we will provide a brief survey of recent nanomedicines that are either approved or in the clinical approval process. This will be followed by an introduction to a new 'nanoperiodic' concept which proposes nanoparticle structure control and the engineering of 'critical nanoscale design parameters' (CNDPs) as a strategy for optimizing pharmocokinetics, pharmocodynamics and site-specific targeting of disease. This paradigm has led to the emergence of CNDP-directed nanoperiodic property patterns relating nanoparticle behaviour to critical in vivo clinical translation issues such as cellular uptake, transport, elimination, biodistribution, accumulation and nanotoxicology. With a focus on dendrimers, these CNDP-directed nanoperiodic patterns are used as a strategy for designing and optimizing nanoparticles for a variety of drug delivery and imaging applications, including a recent dendrimer-based theranostic nanodevice for imaging and treating cancer. Several emerging preclinical dendrimer-based nanotherapy concepts related to inflammation, neuro-inflammatory disorders, oncology and infectious

  4. EXAFS Characterization of Dendrimer-Derived Pt/γ-Al2O3

    NASA Astrophysics Data System (ADS)

    Siani, A.; Alexeev, O. S.; Williams, C. T.; Ploehn, H. J.; Amiridis, M. D.

    2007-02-01

    The various steps involved in the preparation of a Pt/γ-Al2O3 material using hydroxyl-terminated generation four (G4OH) PAMAM dendrimers as templates were monitored by EXAFS. The results indicate that Cl ligands in the Pt precursors (H2PtCl6 and K2PtCl4) were partially replaced by aquo ligands upon hydrolysis to form [PtCl3(H2O)3]+ and [PtCl2(H2O)2] species. After interaction of such species with G4OH, Cl ligands from the first coordination shell of Pt were further replaced by nitrogen atoms from the dendrimer interior, indicating the complexation of Pt with the dendrimer. This process was accompanied by a transfer of the electron density from the dendrimer to Pt, indicating that the former plays the role of a ligand. Following treatment of the H2PtCl6/G4OH and K2PtCl4/G4OH composites with NaBH4, no substantial changes were detecteded in the electronic or coordination environment of Pt, and no formation of metal nanoparticles was observed. However, when the reduction treatment was performed with H2, the formation of extremely small Pt clusters incorporating no more than 4 Pt atoms was observed. These Pt species remained strongly bonded to the dendrimer and their nuclearity depends on the length of the H2 treatment. Formation of Pt nanoparticles with an average diameter of approximately 10 Å was finally observed after the deposition of H2PtCl6/G4OH on γ-Al2O3 and drying, suggesting that their formation may be related to the collapse of the dendrimer structure. The Pt nanoparticles formed appear to have high mobility, since subsequent thermal treatment in O2/H2 led to further sintering.

  5. Manganese G8 Dendrimers Targeted to Oxidation-Specific Epitopes: In vivo MR imaging of Atherosclerosis

    PubMed Central

    Nguyen, Tuyen H.; Bryant, Henry; Shapsa, Ari; Street, Hannah; Mani, Venkatesh; Fayad, Zahi A.; Frank, Joseph A.; Tsimikas, Sotirios; Briley-Saebo, Karen C.

    2014-01-01

    Objective To determine if manganese (Mn) G8 dendrimers targeted to oxidation-specific epitopes (OSE) allow for in vivo detection of atherosclerotic lesions. Background OSE have been identified as key factors in atherosclerotic plaque progression and destabilization. Mn offers a potentially clinically translatable alternative to gadolinium-based agents when bioretention and potential toxicity of gadolinium is anticipated. However, to be effective, high payloads of Mn must accumulate intracellularly in macrophages. It was hypothesized that G8 dendrimers targeted to OSE may allow delivery of high Mn payloads, thereby enabling in vivo detection of macrophage rich plaques. Methods G8 dendrimers were modified to allow conjugation with MnDTPA (758 Mn ion) and the antibody MDA2 that is targeted to malondialdehyde (MDA)-lysine epitopes. Both the untargeted and targeted G8 dendrimers were characterized and their in vivo efficacy evaluated in apoE-/- mice over a 96-hour time period after bolus administration of a 0.05 mmol Mn/kg dose using a clinical MR system (3 Tesla). Results Significant enhancement (normalized enhancement >60%, p=0.0013) of atherosclerotic lesions was observed within a 72-hour time period following administration of the targeted dendrimers. The presence of Mn within atherosclerotic lesions was confirmed using spectroscopic methods (>8 μg Mn/g). Limited signal attenuation (<18%) and Mn deposition (< 1 μg Mn/g) was observed in the arterial wall following injection of the untargeted material. Conclusions This study demonstrates that manganese labeled dendrimers, allowing a high Mn payload, targeted to OSE may allow in vivo image of atherosclerotic lesions. PMID:24610640

  6. Mechanism of Cooperativity and Nonlinear Release Kinetics in Multivalent Dendrimer-Atropine Complexes.

    PubMed

    Mukherjee, Jhindan; Wong, Pamela T; Tang, Shengzhuang; Gam, Kristina; Coulter, Alexa; Baker, James R; Choi, Seok Ki

    2015-12-07

    Despite extensive studies on drug delivery using multivalent complexation systems, the biophysical basis for release kinetics remains poorly defined. The present study addresses this aspect involved in the complexation of a fifth generation poly(amidoamine) (PAMAM) dendrimer with atropine, an essential antidote used for treating organophosphate poisoning. First, we designed (1)H NMR titration studies for determining the molecular basis of the drug complexation with a glutarate-modified anionic dendrimer. These provide evidence pointing to a combination of electrostatic and hydrophobic interactions as the driving forces for dendrimer complexation with the alkaloid drug molecule. Second, using LC-MS/MS spectrometry, we determined the dissociation constants (KD) at steady state and also measured the drug release kinetics of atropine complexes with four negatively charged dendrimer types. Each of these dendrimers has a high payload capacity for up to ∼ 100 atropine molecules. However, the affinity of the atropine to the carrier was highly dependent on the drug to dendrimer ratio. Thus, a complex made at a lower loading ratio (≤ 0.1) displayed greater atropine affinity (KD ≈ μM) than other complexes prepared at higher ratios (>10), which showed only mM affinity. This negative cooperative variation in affinity is tightly associated with the nonlinear release kinetics observed for each complex in which drug release occurs more slowly at the later time phase at a lower loading ratio. In summary, the present study provides novel insights on the cooperativity as the mechanistic basis for nonlinear release kinetics observed in multivalent carrier systems.

  7. 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.

  8. 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

  9. The use of dendrimers as high-performance shells for round-trip energy transfer: efficient trans-cis photoisomerization from an excited triplet state produced within a dendrimer shell.

    PubMed

    Miura, Yousuke; Momotake, Atsuya; Takeuchi, Keiichirou; Arai, Tatsuo

    2011-01-01

    A series of stilbene-cored poly(benzyl ether) dendrimers with benzophenone peripheries were synthesized and their photophysical and photochemical properties were studied. Fluorescence studies revealed that singlet-singlet energy transfer (SSET) from the stilbene core to the benzophenone units took place efficiently in dendrimers of all generations. Similarly, phosphorescence and time-resolved spectroscopic measurements indicated efficient triplet-triplet energy transfer (TTET) from the benzophenone periphery to the stilbene core. Upon excitation at 310 nm, the stilbene core isomerizes via an energy round trip within the dendrimer shell. The quantum yields for the energy round trip (Φ(ERT)), defined as the product of the quantum yields of SSET, intersystem crossing, and TTET (Φ(ERT) = Φ(SS)Φ(isc)Φ(TT)), were extremely high for all generations--99%, 95% and 94% for G1, G2, and G3, respectively--which means that the excitation energy of the dendrimer core was transferred to the dendrimer periphery and back to the core almost quantitatively. The quantum yield for photoisomerization of G1-G3 via an energy round trip was higher than for other stilbene-cored dendrimers, which mainly isomerize from the excited singlet state. Photostability in the dendrimers was also demonstrated and discussed.

  10. Magnetic layering transitions in a polyamidoamine (PAMAM) dendrimer nano-structure: Monte Carlo study

    NASA Astrophysics Data System (ADS)

    Ziti, S.; Aouini, S.; Labrim, H.; Bahmad, L.

    2017-02-01

    We study the magnetic layering transitions in a polyamidoamine (PAMAM) dendrimer nano-structure, under the effect of an external magnetic field. We examine the magnetic properties, of this model of the spin S=1 Ising ferromagnetic in real nanostructure used in several scientific domains. For T=0, we give and discuss the ground state phase diagrams. At non null temperatures, we applied the Monte Carlo simulations giving important results summarized in the form of the phase diagrams. We also analyzed the effect of varying the external magnetic field, and found the layering transitions in the polyamidoamine (PAMAM) dendrimer nano-structure.

  11. Encapsulation of anilinonaphthalenesulfonates in carboxylate-terminated PAMAM dendrimer at the polarized water|1,2-dichloroethane interface.

    PubMed

    Nagatani, Hirohisa; Sakamoto, Tsutomu; Torikai, Taishi; Sagara, Takamasa

    2010-11-16

    Molecular encapsulation of water-soluble anionic fluorescent dye molecules, 8-anilino-1-naphthalenesulfonic acid (ANS), and its bimolecular derivative (bis-ANS), in the generation 3.5 polyamidoamine (G3.5 PAMAM) dendrimer was investigated in the bulk aqueous phase and at the polarized water|1,2-dichloroethane interface. ANS(-) was electrostatically incorporated in the dendrimer, and the fluorescence enhancement with a blue shift of the emission maximum was observed at pH values <6, where the interior of the dendrimer was positively charged. The fluorescence enhancement of ANS was maximized around pH 3 and then decreased under more acidic conditions. The potential dependences of the molecular encapsulation and the interfacial mechanism were studied in detail by means of potential modulated fluorescence (PMF) spectroscopy. Under acidic conditions, the dendrimer incorporated ANS(-) at the positively polarized interface as well as in the aqueous phase. ANS(-) was released from the dendrimer at the intrinsic transfer potential and independently transferred across the interface. Bis-ANS exhibited relatively strong interaction with the dendrimer over a wide pH range (1 < pH < 8), and a negative shift of the transfer potential was observed under the corresponding pH condition. The PMF analysis clearly demonstrated that the interfacial mechanism of the dendrimer involves transfer and adsorption processes depending on the pH condition and the Galvani potential difference.

  12. 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".

  13. 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.

  14. Gradient shape-persistent pi-conjugated dendrimers for light-harvesting: synthesis, photophysical properties, and energy funneling.

    PubMed

    Wang, Jin-Liang; Yan, Jing; Tang, Zheng-Ming; Xiao, Qi; Ma, Yuguo; Pei, Jian

    2008-07-30

    A new class of pi-conjugated dendrimers G0, G1, and G2 was developed through a double-stage divergent/convergent growth approach, in which 5,5,10,10,15,15-hexahexyltruxene was employed as the node and oligo(thienylethynylene)s (OTEs) with different lengths as the branching moieties. The dendrimers were fully characterized by (1)H and (13)C NMR, elemental analysis, gel permeation chromatography, and MALDI-TOF MS. Also, by using atomic force microscopy, it was observed that dendrimer G2 laid nearly flat on the mica surface as a single molecule. Dynamic light scattering results showed that the molecule retained its relatively flat shape in solution. To our best knowledge, dendrimer G2, with a radius approaching 10 nm and a molecular weight of 27 072 Da, was the largest among reported second generation dendrimers. The energy gradient in G2 was constructed by linking OTEs of increasing effective conjugation lengths from the dendritic rim to the core. The intramolecular energy transfer process was studied using steady-state UV-vis absorption and photoluminescent spectroscopies, as well as time-resolved fluorescence spectroscopy. Our structurally extended dendrimers showed an excellent energy funneling ability (their energy transfer efficiencies were all over 95%). All results demonstrate that these dendrimers are promising candidates as light-harvesting materials for optoelectronic devices.

  15. 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.

  16. Polypropyleneimine and polyamidoamine dendrimer mediated enhanced solubilization of bortezomib: Comparison and evaluation of mechanistic aspects by thermodynamics and molecular simulations.

    PubMed

    Chaudhary, Sonam; Gothwal, Avinash; Khan, Iliyas; Srivastava, Shubham; Malik, Ruchi; Gupta, Umesh

    2017-03-01

    Bortezomib (BTZ) is the first proteasome inhibitor approved by the US-FDA is majorly used for the treatment of newly diagnosed and relapsed multiple myeloma including mantle cell lymphoma. BTZ is hydrophobic in nature and is a major cause for its minimal presence as marketed formulations. The present study reports the design, development and characterization of dendrimer based formulation for the improved solubility and effectivity of bortezomib. The study also equally focuses on the mechanistic elucidation of solubilization by two types of dendrimers i.e. fourth generation of poly (amidoamine) dendrimers (G4-PAMAM-NH2) and fifth generation of poly (propylene) imine dendrimers (G5-PPI-NH2). It was observed that aqueous solubility of BTZ was concentration and pH dependent. At 2mM G5-PPI-NH2 concentration, the fold increase in bortezomib solubility was 1152.63 times in water, while approximately 3426.69 folds increase in solubility was observed at pH10.0, respectively (p<0.05). The solubility of the drug was increased to a greater extent with G5-PPI-NH2 dendrimers because it has more hydrophobic interior than G4-PAMAM-NH2 dendrimers. The release of BTZ from G5-PPI-NH2 complex was comparatively slower than G4-PAMAM-NH2. The thermodynamic treatment of data proved that dendrimer drug complexes were stable at all pH with values of ΔG always negative. The experimental findings were also proven by molecular simulation studies and by calculating RMSD and intermolecular hydrogen bonding through Schrodinger software. It was concluded that PPI dendrimers were able to solubilize the drug more effectively than PAMAM dendrimers through electrostatic interactions.

  17. New Dendrimer-Based Nanoparticles Enhance Curcumin Solubility.

    PubMed

    Falconieri, Maria Cristina; Adamo, Mauro; Monasterolo, Claudio; Bergonzi, Maria Camilla; Coronnello, Marcella; Bilia, Anna Rita

    2017-03-01

    Curcumin, the main curcuminoid of the popular Indian spice turmeric, is a potent chemopreventive agent and useful in many different diseases. A major limitation of applicability of curcumin as a health promoting and medicinal agent is its extremely low bioavailability due to efficient first pass metabolism, poor gastrointestinal absorption, rapid elimination, and poor aqueous solubility. In the present study, nanotechnology was selected as a choice approach to enhance the bioavailability of the curcuminis. A new polyamidoamine dendrimer (G0.5) was synthesized, characterized, and tested for cytotoxicity in human breast cancer cells (MCF-7). No cytotoxicity of G0.5 was found in the range between 10(-3) and 3 × 10(-8) M. Consequently, G0.5 was used to prepare spherical nanoparticles of ca. 150 nm, which were loaded with curcumin [molar ratio G0.5/curcumin 1 : 1 (formulation 1) and 1 : 0.5 (formulation 2)]. Remarkably, the occurrence of a single population of nanoparticles having an excellent polydispersity index (< 0.20) was found in both formulations. Formulation 1 was selected to test in vitro drug release because it was superior in terms of encapsulation efficiency (62 %) and loading capacity (32 %). The solubility of curcumin was increased ca. 415 and 150 times with respect to the unformulated drug, respectively, for formulation 1 and formulation 2. The release of curcumin from the nanoparticles showed an interesting prolonged and sustained release profile.

  18. Thermodynamic Properties of Carbosilane Dendrimers of the Sixth Generation with Ethylene Oxide Terminal Groups.

    PubMed

    Sologubov, Semen S; Markin, Alexey V; Smirnova, Natalia N; Novozhilova, Natalia A; Tatarinova, Elena A; Muzafarov, Aziz M

    2015-11-12

    The temperature dependences of heat capacities of carbosilane dendrimers of the sixth generation with ethyleneoxide terminal groups, denoted as G6[(OCH2CH2)1OCH3]256 and G6[(OCH2CH2)3OCH3]256, were measured in the temperature range from T = (6 to 520) K by precision adiabatic calorimetry and differential scanning calorimetry (DSC). In the above temperature range the physical transformations, such as glass transition and high-temperature relaxation transition, were detected. The standard thermodynamic characteristics of the revealed transformations were determined and analyzed. The standard thermodynamic functions, namely, heat capacity Cp°(T), enthalpy H°(T) - H°(0), entropy S°(T) - S°(0), and Gibbs energy G°(T) - H°(0) for the range from T → 0 to 520 K, and the standard entropies of formation ΔfS° of the investigated dendrimers in the devitrified state at T = 298.15 K, were calculated per corresponding moles of the notional structural units. The standard thermodynamic properties of dendrimers under study were discussed and compared with literature data for carbosilane dendrimers with different functional terminal groups.

  19. Controllable synthesis of hydroxyapatite nanocrystals via a dendrimer-assisted hydrothermal process

    SciTech Connect

    Zhou Zhuohua; Zhou, Ping-Le; Yang Shiping . E-mail: shipingy@shnu.edu.cn; Yu Xibin; Yang Liangzhun

    2007-09-04

    The morphology and size of hydroxyapatite Ca{sub 10}(PO{sub 4}){sub 6}(OH){sub 2} (denoted HAP) can be controlled under hydrothermal treatment assisted with different dendrimers, such as carboxylic terminated poly(amidoamine) (PAMAM) and polyhydroxy terminated PAMAM. The structure and morphology were characterized by X-ray diffraction (XRD), infrared spectroscopy (IR) and transmission electron microscopy (TEM). IR spectra were also used to investigate the complexation of Ca{sup 2+} with PAMAM. The results revealed that the inner cores of the PAMAM dendrimers are hydrophilic and potentially open to calcium ions, since interior nitrogen moieties serve as complexation sites, especially in case of the polyhydroxy terminated PAMAM. And the reasonable mechanism of crystallization was proposed that it can be attributed to the localization of nucleation site: external or interior PAMAM. Additionally, the PAMAM dendrimer with carboxylic and polyhydroxy groups has an effective influence on the size and shape of hydroxyapatite (HAP) nanostructures. Different crystal morphology was accomplished by adsorption of different dendrimers onto specific faces of growing crystals, altering the relative growth rates of the different crystallographic faces and leading to different crystal habits.

  20. 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.

  1. Fabrication of dendrimer porogen-capsulated mesoporous silica via sol-gel process of silatrane precursor.

    PubMed

    Tanglumlert, Walairat; Wongkasemjit, Sujitra; Imae, Toyoko

    2009-03-01

    Mesoporous silica materials with ordered structures were prepared from a silatrane precursor and a poly(amido amine) dendrimer porogen under the dilute acidic condition via the sol-gel process. With decreasing the concentration of the dendrimer and adding much water, the production of undesirable amorphous silica was diminished and spherical particles with smooth surface became in majority. Two kinds of crystal arrays were found to be produced in the silica particles. Although pore diameters were within sizes of shrank and extended dendrimers, center-to-center distance of template pores was different each other for two arrays, and the difference was close to a molecular length of silatrane. These results indicate that one molecule of silatrane constructed polysiloxane wall in the first array and origomeric silatranes formed wall in the second array. It was referred that the intrinsic (hydrogen bonding) character of hydroxyl groups in the hydrolyzed silatrane resulted in hydrogen bonded oligomers and reinforced the hydrogen bonding interaction with dendrimer porogen as well as electrostatic interaction, giving rise to two types of template arrays.

  2. Osteogenic differentiation of mesenchymal stem cells using PAMAM dendrimers as gene delivery vectors.

    PubMed

    Santos, José Luís; Oramas, Elena; Pêgo, Ana Paula; Granja, Pedro Lopes; Tomás, Helena

    2009-03-04

    This paper reports the use of different generations of polyamidoamine (PAMAM) dendrimers for the in vitro transfection of mesenchymal stem cells (MSCs). A systematic study was carried out on the transfection efficiency achieved by the PAMAM dendrimers using a beta-galactosidase reporter gene system. Transfection results were shown to be dependent upon the generation of dendrimers, the amine to phosphate group ratio and the cell passage number. In all cases, the transfection efficiency was very low. Nevertheless, it was hypothesized that a low transfection level could be sufficient to promote the in vitro differentiation of MSCs towards the osteoblastic lineage. To address this possibility, dendrimers carrying the human bone morphogenetic protein-2 (hBMP-2) gene-containing plasmid were used. All quantitative (alkaline phosphatase activity, osteocalcin secretion and calcium deposition) and qualitative (von Kossa staining) osteogenic markers were significantly stronger in transfected cells when compared to non-transfected ones. This study not only clearly demonstrates that a low transfection level can be sufficient for inducing in vitro differentiation of MSCs to the osteoblast phenotype but also highlights the importance of focusing research on the development of gene delivery vectors in the concrete application.

  3. Structure-Dependent Photophysics of First-Generation; Phenyl-Cored Thiophene Dendrimers

    SciTech Connect

    Mitchell, W. J.; Ferguson, A. J.; Kose, M. E.; Rupert, B. L.; Ginley, D. S.; Rumbles, G.; Shaheen, S. E.; Kopidakis, N.

    2009-01-01

    We have prepared two series of first-generation thiophene-bridge dendrimers, with either three (3G1) or four (4G1) arms attached to a phenyl core, to elucidate their structure-property relationships. Optical properties were investigated with a combination of steady-state and time-resolved spectroscopic techniques. Steady-state spectroscopic data for the 3-arm dendrimers suggests that the exciton is delocalized over the {alpha}-conjugated thiophene segment and the phenyl core, but that the meta-linking of the dendrons prevents their electronic communication. In contrast, conjugation through the core to dendrons in the ortho and para positions is permitted in the 4-arm dendrimers, although the data suggest that the conjugation length does not extend over the full length of the {alpha}-conjugated sections of two coupled dendrons. This observation is due to steric interactions between neighboring arms, which forces the arms to twist and bend out of the plane of the phenyl core, and is particularly prevalent in disrupting the conjugation through the ortho positions. As expected, our results show that an increase in the bridge length results in an increase in the conjugation length for both dendrimers, and a subsequent red-shift of the absorption and emission. In addition, an increase in the dendron length results in an increase in the photoluminescence quantum yield and lifetime, suggesting that the ground and excited-state geometries are very similar and that the electronic transition is coupled to fewer vibrational modes.

  4. Multifunctional Dendrimer Ligands for High-Efficiency, Solution-Processed Quantum Dot Light-Emitting Diodes.

    PubMed

    Cho, Ikjun; Jung, Heeyoung; Jeong, Byeong Guk; Chang, Jun Hyuk; Kim, Younghoon; Char, Kookheon; Lee, Doh C; Lee, Changhee; Cho, Jinhan; Bae, Wan Ki

    2017-01-24

    We present multifunctional dendrimer ligands that serve as the charge injection controlling layer as well as the adhesive layer at the interfaces between quantum dots (QDs) and the electron transport layer (ETL) in quantum dot light-emitting diodes (QLEDs). Specifically, we use primary amine-functionalized dendrimer ligands (e.g., a series of poly(amidoamine) dendrimers (PADs, also referred to PAMAM)) that bind to the surface of QDs by replacing the native ligands (oleic acids) and also to the surface of ZnO ETL. PAD ligands control the electron injection rate from ZnO ETL into QDs by altering the electronic energy levels of the surface of ZnO ETL and thereby improve the charge balance within QDs in devices, leading to the enhancement of the device efficiency. As an ultimate achievement, the device efficiency (peak external quantum efficiency) improves by a factor of 3 by replacing the native ligands (3.86%) with PAD ligands (11.36%). In addition, multibranched dendrimer ligands keep the QD emissive layer intact during subsequent solution processing, enabling us to accomplish solution-processed QLEDs. The approach and results in the present study emphasize the importance of controlling the ligands of QDs to enhance QLED performance and also offer simple yet effective chemical mean toward all-solution-processed QLEDs.

  5. Drug delivery investigations of quaternised poly(propylene imine) dendrimer using nimesulide as a model drug.

    PubMed

    Murugan, E; Geetha Rani, D P; Yogaraj, V

    2014-02-01

    This study describes the demonstration of quaternized poly(propylene imine) dendrimer of generation-3, QPPI (G3) as a drug carrier for poorly soluble drug nimesulide (NMD, an anti-inflammatory drug). QPPI (G3) was prepared by treating the surface amine groups of poly(propylene imine) dendrimer with glycidyltrimethyl ammonium chloride and it was characterized with FTIR, (1)H and (13)C NMR and MALDI-TOF mass spectral techniques. The drug carrying potential of QPPI (G3) was assessed by analyzing drug solubility, in vitro release and cytotoxicity studies. The observed results reveal that the aqueous solubility of NMD has been dramatically increased in the presence of QPPI (G3) and also can sustain the release of NMD. It is further noticed that the complexation of NMD with QPPI (G3) is responsible for increased solubility and sustained release. This complexation was evidenced through NMR ((1)H & 2D) and UV-vis spectral techniques, DSC and DLS studies. Cytotoxicity study through MTT assay on Vero and HBL-100 cell lines reveal that this dendrimer increase the biocompatibility and the tolerance concentration of NMD in drug-dendrimer formulations. The observed results prove that the QPPI (G3) is one of the new promising candidate for effective delivery of NMD.

  6. Understanding AuNP interaction with low-generation PAMAM dendrimers: a CIELab and deconvolution study

    NASA Astrophysics Data System (ADS)

    Jimenez-Ruiz, A.; Carnerero, J. M.; Castillo, P. M.; Prado-Gotor, R.

    2017-01-01

    Low-generation polyamidoamine (PAMAM) dendrimers are known to adsorb on the surface of gold nanoparticles (AuNPs) causing aggregation and color changes. In this paper, a thorough study of this affinity using absorption spectroscopy, colorimetric, and emission methods has been carried out. Results show that, for citrate-capped gold nanoparticles, interaction with the dendrimer is not only of an electrostatic character but instead occurs, at least in part, through the dendrimer's uncharged internal amino groups. The possibilities of the CIELab chromaticity system parameters' evolution have also been explored in order to quantify dendrimer interaction with the red-colored nanoparticles. By measuring and quantifying 17 nm citrate-capped AuNP color changes, which are strongly dependant on their aggregation state, binding free energies are obtained for the first time for these systems. Results are confirmed via an alternate fitting method which makes use of deconvolution parameters from absorbance spectra. Binding free energies obtained through the use of both means are in good agreement with each other.

  7. Optimization and In Vivo Toxicity Evaluation of G4.5 Pamam Dendrimer-Risperidone Complexes

    PubMed Central

    Prieto, Maria Jimena; del Rio Zabala, Nahuel Eduardo; Marotta, Cristian Hernán; Carreño Gutierrez, Hector; Arévalo Arévalo, Rosario; Chiaramoni, Nadia Silvia; Alonso, Silvia del Valle

    2014-01-01

    Risperidone is an approved antipsychotic drug belonging to the chemical class of benzisoxazole. This drug has low solubility in aqueous medium and poor bioavailability due to extensive first-pass metabolism and high protein binding (>90%). Since new strategies to improve efficient treatments are needed, we studied the efficiency of anionic G4.5 PAMAM dendrimers as nanocarriers for this therapeutic drug. To this end, we explored dendrimer-risperidone complexation dependence on solvent concentration, pH and molar relationship. The best dendrimer-risperidone incorporation (46 risperidone molecules per dendrimer) was achieved with a mixture of chloroform:methanol 50∶50 v/v solution pH 3. In addition, to explore the possible effects of this complex, in vivo studies were carried out in the zebrafish model. Changes in the development of dopaminergic neurons and motoneurons were studied using tyrosine hydroxylase and calretinin, respectively. Physiological changes were studied through histological sections stained with hematoxylin-eosin to observe possible morphological brain changes. The most significant changes were observed when larvae were treated with free risperidone, and no changes were observed when larvae were treated with the complex. PMID:24587349

  8. Poly(amidoamine) Dendrimer-Drug Conjugates with Disulfide Linkages for Intracellular Drug Delivery

    PubMed Central

    Kurtoglu, Yunus E.; Navath, Raghavendra S.; Wang, Bing; Kannan, Sujatha; Romero, Robert; Kannan, Rangaramanujam M.

    2009-01-01

    Understanding and improving drug release kinetics from dendrimer-drug conjugates is a key step to improving their in vivo efficacy. N-Acetylcysteine (NAC) is an anti-inflammatory agent with significant potential for clinical use in the treatment of neuroinflammation, stroke and cerebral palsy. There is a need for delivery of NAC which can enhance its efficacy, reduce dosage and prevent it from binding plasma proteins. For this purpose, 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. The results indicate that the prepared conjugate can deliver ~60% of its NAC payload within 1 hour at intracellular GSH concentrations at physiological pH, whereas the conjugate did not release any drug at plasma GSH levels. The stability of the conjugate in the presence of bovine serum albumin at plasma concentrations was also demonstrated. The efficacy of the dendrimer-NAC conjugate was measured in activated microglial cells (target cells in vivo) using the reactive oxygen species (ROS) assay. 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. PMID:19171376

  9. 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.

  10. Exciton migration in conjugated dendrimers: a joint experimental and theoretical study.

    PubMed

    Köse, Muhammet E; Graf, Peter; Kopidakis, Nikos; Shaheen, Sean E; Kim, Kwiseon; Rumbles, Garry

    2009-12-21

    We report a joint experimental and theoretical investigation of exciton diffusion in phenyl-cored thiophene dendrimers. Experimental exciton diffusion lengths of the dendrimers vary between 8 and 17 nm, increasing with the size of the dendrimer. A theoretical methodology is developed to estimate exciton diffusion lengths for conjugated small molecules in a simulated amorphous film. The theoretical approach exploits Fermi's Golden Rule to estimate the energy transfer rates for a large ensemble of bimolecular complexes in random relative orientations. Utilization of Poisson's equation in the evaluation of the Coulomb integral leads to very efficient calculation of excitonic couplings between the donor and the acceptor chromophores. Electronic coupling calculations with delocalized transition densities revealed efficient coupling pathways in the bulk of the material, but do not result in strong couplings between the chromophores which are calculated for more localized transition densities. The molecular structures of dendrimers seem to be playing a significant role in the magnitude of electronic coupling between chromophores. Simulated diffusion lengths correlate well with the experimental data. The chemical structure of the chromophore, the shape of the transition densities and the exciton lifetime are found to be the most important factors in determining the size of the exciton diffusion length in amorphous films of conjugated materials.

  11. 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.

  12. Synthesis and Relaxometric Studies of a Dendrimer-Based pH-Responsive MRI Contrast Agent

    PubMed Central

    Ali, M. Meser; Woods, Mark; Caravan, Peter; Opina, Ana C. L.; Spiller, Marga; Fettinger, James C.

    2009-01-01

    The design of effective pH responsive MRI contrast agents is a key goal in the development of new diagnostic methods for conditions such as kidney disease and cancer. A key factor determining the effectiveness of an agent is the difference between the relaxivity of the “on” state compared to that of the “off” state. In this paper, we demonstrate that it is possible to improve the pH-responsive action of a low molecular weight agent by conjugating it to a macromolecular construct. The synthesis of a bifunctional pH responsive agent is reported. As part of that synthetic pathway we examine the Ing–Manske reaction, identifying an undesirable by-product and establishing effective conditions for promoting a clean and effective reaction. Reaction of the bifunctional pH responsive agent with a G5-PAMAM dendrimer yielded a product with an average of 96 chelates per dendrimer. The relaxivity of the dendrimer conjugate rises from 10.8 mm−1 s−1 (pH 9) to 24.0 mm−1 s−1 (pH 6) per Gd3+ ion. This more than doubles the relaxivity pH response, Δr1, of our agent from just 51% for the original low molecular weight chelate to 122% for the dendrimer. PMID:18601236

  13. Fluorescent properties of a hybrid cadmium sulfide-dendrimer nanocomposite and its quenching with nitromethane.

    PubMed

    Campos, Bruno B; Algarra, Manuel; Esteves da Silva, Joaquim C G

    2010-01-01

    A fluorescent hybrid cadmium sulphide quantum dots (QDs) dendrimer nanocomposite (DAB-CdS) synthesised in water and stable in aqueous solution is described. The dendrimer, DAB-G5 dendrimer (polypropylenimine tetrahexacontaamine) generation 5, a diaminobutene core with 64 amine terminal primary groups. The maximum of the excitation and emission spectra, Stokes' shift and the emission full width of half maximum of this nanocomposite are, respectively: 351, 535, 204 and 212 nm. The fluorescence time decay was complex and a four component decay time model originated a good fit (chi = 1.20) with the following lifetimes: tau (1) = 657 ps; tau (2) = 10.0 ns; tau (3) = 59.42 ns; and tau (4) = 265 ns. The fluorescence intensity of the nanocomposite is markedly quenched by the presence of nitromethane with a dynamic Stern-Volmer constant of 25 M(-1). The quenching profiles show that about 81% of the CdS QDs are located in the external layer of the dendrimer accessible to the quencher. PARAFAC analysis of the excitation emission matrices (EEM) acquired as function of the nitromethane concentration showed a trilinear data structure with only one linearly independent component describing the quenching which allows robust estimation of the excitation and emission spectra and of the quenching profiles. This water soluble and fluorescent nanocomposite shows a set of favourable properties to its use in sensor applications.

  14. 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

  15. Anionic linear-globular dendrimers: biocompatible hybrid materials with potential uses in nanomedicine.

    PubMed

    Alavidjeh, Mohammad Shafiee; Haririan, Ismaeil; Khorramizadeh, Mohammad Reza; Ghane, Zohre Zarei; Ardestani, Mehdi Shafiee; Namazi, Hassan

    2010-04-01

    The use of dendrimers as nano-sized excipients/vectors in biological and pharmaceutical systems is dependent on the investigation of their toxicological profiles in biological media. In this study, a series of mechanistic in vitro structure-associated cell toxicity evaluations was performed on the two generations of an anionic linear-globular dendrimer G1 and G2 (where PEG is the core, and citric acid is the periphery) each of which has a different size, charge, and MW. In vitro cytotoxicity behavior of the dendrimers with the methods like crystal violet staining, methyl thiazolyl tetrazolium (MTT), and lactate dehydrogenase (LDH) assays was analyzed. The cell death mechanisms (apoptosis-necrosis) induced by the dendrimers were also evaluated in HT1080 cell line. The impact of the dendrimers on the release of the pro-inflammatory cytokines like TNF-alpha (tumor necrosis factor alpha) and IL1-beta (interleukin 1 beta) was assessed in THP-1 cell line. Hemolysis assay and coagulation studies such as PT (prothrombin time) and APTT (activated partial thromboplastin time) on human blood samples were conducted to examine the interactions of the dendrimers with such bio-environments. The results of cell cytotoxicity experiments and the amounts of IL1-beta and TNF-alpha secretions from THP-1 cell line were consistent with the hemoglobin release from the erythrocytes and the results gained from the coagulation studies. In fact, no significant harmful effect was observed for the dendrimers up to the concentration of 0.5 mg/ml. Both apoptosis and necrosis were ascribed to cell death. The G1 with more flexibility, less negative charge, and greater poly dispersity in size versus the G2 displayed more toxicity than the G2 at the concentration of 1 mg/ml and above in most of the experiments. As a whole, these results suggest a biocompatible range for these hybrid structures up to the concentration of 0.5 mg/ml. Therefore, the potentiality for these structures to be employed in the

  16. 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.

  17. 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.

  18. Structural characterization of new defective molecules in poly(amidoamide) dendrimers by combining mass spectrometry and nuclear magnetic resonance.

    PubMed

    Tintaru, Aura; Ungaro, Rémi; Liu, Xiaoxiuan; Chen, Chao; Giordano, Laurent; Peng, Ling; Charles, Laurence

    2015-01-01

    A new side-reaction occurring during divergent synthesis of PAMAM dendrimers (generations G0-G2) was revealed by mass spectrometric detection of defective molecules with a net gain of a single carbon atom as compared to expected compounds. Combining MS/MS experiments performed on different electrosprayed precursor ions (protonated molecules and lithiated adducts) with NMR analyses allowed the origin of these by-products to be elucidated. Modification of one ethylenediamine end-group of perfect dendrimers into a cyclic imidazolidine moiety was induced by formaldehyde present at trace level in the methanol solvent used as the synthesis medium. Dendrimers studied here were purposely constructed from a triethanolamine core to make them more flexible, as compared to NH3- or ethylenediamine-core PAMAM, and hence improve their interaction with DNA. Occurrence of this side-reaction would be favored by the particular flexibility of the dendrimer branches.

  19. Guiding the self-assembly of a second-generation polyphenylene dendrimer into well-defined patterns.

    PubMed

    Heyen, An J J Ver; Buron, Cédric C; Tianshi, Qin; Bauer, Roland; Jonas, Alain M; Müllen, Klaus; De Schryver, Frans C; De Feyter, Steven

    2008-08-01

    A second-generation polyphenylene dendrimer 1 is shown to self-assemble into nanofibers. To guide the formation of the dendrimer fibers into well-defined patterns, 1H,1H,2H,2H-perfluorodecyltrichlorosilane is grafted in the gas phase onto a silicon substrate. De-wetting of the solution on the nanopatterned surface results in the formation of a nanostructured template, into which fiber growth subsequently occurs under the constraints set by the de-wetted morphology.

  20. A peptide derivatized cellulosic aerogel from cotton as a point of care diagnostic protease sensor

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Lightweight aerogels are highly porous with usually very small pore size making them suitable for a variety of potential applications as sensors including deformation strain, humidity, organic vapors, thermal, and optical sensing properties. However, little has been reported on their use as biosenso...

  1. Effective targeting of gemcitabine to pancreatic cancer through PEG-cored Flt-1 antibody-conjugated dendrimers.

    PubMed

    Öztürk, Kıvılcım; Esendağlı, Güneş; Gürbüz, Mustafa Ulvi; Tülü, Metin; Çalış, Sema

    2017-01-30

    Tumor-targeted delivery of anticancer drugs using dendrimers has been recognized as a promising strategy to increase efficiency and reduce adverse effects of chemotherapy. Herein, we developed a dendrimer-based drug delivery system targeting Flt-1 (a receptor for vascular endothelial growth factors (VEGF)) receptor to improve therapeutic efficacy of gemcitabine in pancreatic cancer. Synthesized polyethylene glycol (PEG)-cored PAMAM dendrimers, which bear anionic carboxylic acid groups on the surface were modified with PEG chains, which were then conjugated with Flt-1 antibody. Following structural and chemical characterization studies, gemcitabine HCl-dendrimer inclusion complexes were successfully prepared. These complexes were efficiently engulfed by Flt-1 expressing pancreatic cancer cells, which enhanced the cytotoxicity of gemcitabine. Moreover, pancreatic tumors established in mice were highly targeted by PEG-cored Flt-1 antibody-conjugated dendrimers and increased accumulation of these gemcitabine-loaded complexes exhibited satisfactory in vivo anti-cancer efficacy. In conclusion, dendrimer-based targeted delivery of chemotherapeutics may serve as a promising approach for the treatment of malignancies such as pancreatic cancer that do not benefit from conventional chemotherapy.

  2. 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.

  3. Synthesis of cationic carbosilane dendrimers via click chemistry and their use as effective carriers for DNA transfection into cancerous cells.

    PubMed

    Arnáiz, Eduardo; Doucede, Lorena I; García-Gallego, Sandra; Urbiola, Koldo; Gómez, Rafael; Tros de Ilarduya, Conchita; de la Mata, F Javier

    2012-03-05

    New amine-terminated carbosilane dendrimers have been prepared by a Huisgen cycloaddition ("click chemistry" reaction) of azide-terminated carbosilane dendrimers with two different propargyl amines. The corresponding cationic derivatives with peripheral ammonium groups were obtained by subsequent addition of MeI. Quaternized dendrimers are soluble and stable in water or other protic solvents for long time periods, and have been studied as nonviral vectors for the transfection of DNA to cancer cells. In this study DNA-dendrimeric nanoparticles (dendriplexes) formulated with two different families of cationic carbosilane dendrimers (family 1 (G1, G2 and G3) and family 2 (G1, G2)) were characterized and evaluated for their ability to transfect cells in vitro and in vivo. Dendriplex derived from second generation dendrimer of family 1 (F1G2 5/1 (+/-)) increased the efficiency of plasmid-mediated gene transfer in HepG2 cells as compared to naked DNA and the commercial control dendrimer. Also, intravenously administered dendriplex F1G3 20/1 (+/-) is superior in terms of gene transfer efficiency in vivo.

  4. 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

    2016-07-05

    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.

  5. Fabrication and characterization of dendrimer-functionalized nano-hydroxyapatite and its application in dentin tubule occlusion.

    PubMed

    Lin, Xuandong; Xie, Fangfang; Ma, Xueling; Hao, Yuhong; Qin, Hejia; Long, Jindong

    2017-03-31

    The occlusion of dentinal tubules is an effective method to alleviate the symptoms of dentin hypersensitivity. In this paper, we successfully modified nano-hydroxyapatite (n-HAP) with carboxyl-terminated polyamidoamine dendrimers by an aqueous-based chemical method and verified by fourier transform infrared spectroscopy (FTIR) and transmission electron microscope (TEM). Then the demineralization dentin discs were randomly divided into 4 groups, corresponding to subsequent brushing experiments: deionized water and kept in artificial saliva (AS), dendrimer-functionalized n-HAP and stored in AS, n-HAP and saved in AS, dendrimer-functionalized n-HAP and stored in deionized water. After 7 days of simulated brushing, dentin discs followed the in vitro characterization using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy and microhardness test. These data suggested that dendrimer-functionalized n-HAP could crosslink with collagen fibers and resulted in effective dentinal tubule occlusion. Moreover, the new material can induce the HAP formation with the help of superficial carboxyl and fill the spaces in dentinal tubules furtherly. The microhardness of dendrimer-functionalized n-HAP-treated specimens was significantly higher than others. In summary, dendrimer-functionalized n-HAP can be a new therapeutic material for the treatment of dentin hypersensitivity.

  6. Ligand accessibility and bioactivity of a hormone–dendrimer conjugate depend on pH and pH history

    SciTech Connect

    Kim, Sung Hoon; Madak-Erdogan, Zeynep; Bae, Sung Chul; Carlson, Kathryn E.; Mayne, Christopher G.; Granick, Steve; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.

    2015-07-17

    Estrogen conjugates with a polyamidoamine (PAMAM) dendrimer have shown remarkably selective regulation of the nongenomic actions of estrogens in target cells in this paper. In response to pH changes, however, these estrogen–dendrimer conjugates (EDCs) display a major morphological transition that alters the accessibility of the estrogen ligands that compromises the bioactivity of the EDC. A sharp break in dynamic behavior near pH 7 occurs for three different ligands on the surface of a PAMAM-G6 dendrimer: a fluorophore (tetramethylrhodamine [TMR]) and two estrogens (17α-ethynylestradiol and diphenolic acid). Collisional quenching and time-resolved fluorescence anisotropy experiments with TMR–PAMAM revealed high ligand shielding above pH 7 and low shielding below pH 7. Furthermore, when the pH was cycled from 8.5 (conditions of ligand–PAMAM conjugation) to 4.5 (e.g., endosome/lysosome) and through 6.5 (e.g., hypoxic environment) back to pH 8.5, the 17α-ethynylestradiol– and diphenolic acid–PAMAM conjugates experienced a dramatic, irreversible loss in cell stimulatory activity; dynamic NMR studies indicated that the hormonal ligands had become occluded within the more hydrophobic core of the PAMAM dendrimer. Thus, the active state of these estrogen–dendrimer conjugates appears to be metastable. Finally, this pH-dependent irreversible masking of activity is of considerable relevance to the design of drug conjugates with amine-bearing PAMAM dendrimers.

  7. A controllable aptamer-based self-assembled DNA dendrimer for high affinity targeting, bioimaging and drug delivery.

    PubMed

    Zhang, Huimin; Ma, Yanli; Xie, Yi; An, Yuan; Huang, Yishun; Zhu, Zhi; Yang, Chaoyong James

    2015-05-11

    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.

  8. 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

  9. 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

  10. Low cytotoxicity fluorescent PAMAM dendrimer as gene carriers for monitoring the delivery of siRNA

    NASA Astrophysics Data System (ADS)

    Guan, Lingmei; Huang, Saipeng; Chen, Zhao; Li, Yanchao; Liu, Ke; Liu, Yang; Du, Libo

    2015-09-01

    Visual detection of gene vectors has attracted a great deal of attention due to the application of these vectors in monitoring and evaluating the effect of gene carriers in living cells. A non-viral vector, the fluorescent PAMAM dendrimer (F-PAMAM), was synthesized through conjugation of PAMAM dendrimers and fluorescein. In vitro and ex vivo experiments show that F-PAMAM exhibits superphotostability, low cytotoxicity and facilitates endocytosis by A549 cells. The vector has a high siRNA binding affinity and it increases the efficiency of cy5-siRNA delivery in A549 cells, in comparison with a cy5-siRNA monomer. Our results provide a new method for simultaneously monitoring the delivery of siRNA and its non-viral carriers in living cells.

  11. 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.

  12. 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.

  13. Nanoparticles and cancer therapy: A concise review with emphasis on dendrimers

    PubMed Central

    Bharali, Dhruba J; Khalil, Marianne; Gurbuz, Mujgan; Simone, Tessa M; Mousa, Shaker A

    2009-01-01

    The emergence of nanotechnology has had a profound effect on many areas of healthcare and scientific research. Having grown exponentially, the focus of nanotechnology has been on engineering diversified novel applications that even go beyond therapeutic activity; nanotechnology also offers the ability to detect diseases, such as cancer, much earlier than ever imaginable. Often, patients diagnosed with breast, lung, colon, prostate, and ovarian cancer have hidden or overt metastatic colonies. With the advent of diagnostic nanotechnology, these numbers are expected to greatly diminish. This review provides a brief description of nanoparticle (liposome, quantum dot, and dendrimer)-mediated cancer therapy in the last decade with an emphasis on the development and use of dendrimers in cancer therapeutics. PMID:19421366

  14. High-Resolution Imaging of Dendrimers Used in Drug Delivery via Scanning Probe Microscopy.

    PubMed

    Shi, Lifang; Fleming, Christopher J; Riechers, Shawn L; Yin, Nai-Ning; Luo, Juntao; Lam, Kit S; Liu, Gang-Yu

    2011-01-01

    Dendrimers and telodendrimer micelles represent two new classes of vehicles for drug delivery that have attracted much attention recently. Their structural characterization at the molecular and submolecular level remains a challenge due to the difficulties in reaching high resolution when imaging small particles in their native media. This investigation offers a new approach towards this challenge, using scanning tunneling microscopy (STM) and atomic force microscopy (AFM). By using new sample preparation protocols, this work demonstrates that (a) intramolecular features such as drug molecules and dendrimer termini can be resolved; and (b) telodendrimer micelles can be immobilized on the surface without compromising structural integrity, and as such, high resolution AFM imaging may be performed to attain 3D information. This high-resolution structural information should enhance our knowledge of the nanocarrier structure and nanocarrier-drug interaction and, therefore, facilitate design and optimization of the efficiency in drug delivery.

  15. Direct TLC/MALDI-MS coupling for modified polyamidoamine dendrimers analyses.

    PubMed

    Leriche, Emma-Dune; Hubert-Roux, Marie; Grossel, Martin C; Lange, Catherine M; Afonso, Carlos; Loutelier-Bourhis, Corinne

    2014-01-15

    Polyamidoamine (PAMAM) are synthetic dendrimers which present attractive properties for the biological and biomedical fields, as they proved to be efficient drug and gene carriers. In order to increase their transfection efficiency, chemical modifications of the amino end-groups had been reported. In this work, the synthesis of the ammonia-cored G1(N) PAMAM and the consecutive chemical modification with glycine or phenylalanine amino-acids were monitored using the coupling of thin layer chromatography (TLC) with matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS). Thus, the monitoring of the PAMAM synthesis included the identification of the by-products such as defective structures of PAMAM dendrimers as well as the study of phenylalanine-grafted PAMAM oligomer distribution.

  16. 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.

  17. Effective strategies and applications of dendrimers in the treatment of ovarian cancer.

    PubMed

    Kesavan, Akila; Babu, Pakala Suresh; Kumar, Rayala Suresh; Venkatraman, Ganesh

    2017-02-23

    Ovarian cancer, the worldwide leading cause of gynecological cancer-related death, is primarily treated by surgery followed by platinum chemotherapy. Though the tumor initially responds to the treatment, only 30% of 5 year survival period has been recorded and this is mainly attributed to the acquired chemo resistance and frequent recurrence of tumor. Combination chemotherapy as well, led to therapeutic failure due to non-specificity and subsequent side effects. However, polymer mediated drug delivery aids in overcoming these impediments. In particular, three dimensional macromolecule "Dendrimer" with its unique properties and numerous functionalities offer various advantages over the conventional approach and may improve the treatment outcome in patients with ovarian cancer. The present review highlights the various strategies employed using dendrimers to achieve targeted drug delivery and enhanced therapeutic efficacy in ovarian cancer.

  18. Electrochemical one-electron oxidation of low-generation polyamidoamine-type dendrimers with a 1,4-phenylenediamine core.

    PubMed

    Hammerich, Ole; Hansen, Thomas; Thorvildsen, Asbjørn; Christensen, Jørn B

    2009-08-03

    A series of polyamidoamine (PAMAM)-type dendrimers with a 1,4-phenylenediamine (PD) core is prepared from PD by procedures including Michael addition of methyl acrylate followed by aminolysis with 1,2-ethanediamine. Their one-electron oxidation potentials are determined by differential pulse voltammetry (DPV) in methanol, acetonitrile, dichloromethane, and dimethyl sulfoxide. The dendrimers are more difficult to oxidize than N,N,N',N'-tetramethyl-p-phenylenediamine (TMePD). The oxidation potentials decrease with increasing dendrimer generation up to G0.5, after which the potential is essentially constant up to G2.0. The structures of both the neutral species and the radical cations are studied by DFT calculations at the B3LYP/6-31G(d,p) level of theory, which include a series of simple PDs for comparison. The data show that the structural arrangement close to the PD core is similar to that of N,N,N',N'-tetra-n-alkyl-p-phenylenediamines, including a planar arrangement of the atoms linked to the two PD nitrogen atoms. Thus, the effect of chain size on the oxidation potential appears to be caused primarily by a simple electronic effect. The calculations indicate considerable reorientation of the dendrimer side chains on oxidation, presumably caused by interactions between the positive charge centered at the core and the neighboring ester or amide dipoles. The relative ease of oxidation of TMePD and the lowest members of the series of the dendrimers can be reproduced theoretically only when solvation was included in the calculations. The DPV peak heights vary approximately as predicted from the Stokes-Einstein-Sutherland equation, but the variation of the relative effective radii with the size of the dendrimer is much larger than predicted from the radii obtained by the DFT calculations, that is, the dendrimers exist in solution mainly as aggregates.

  19. 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.

  20. Dendrimer-modified solid supports: nanostructured materials with potential drug allergy diagnostic applications.

    PubMed

    Ruiz-Sanchez, A J; Montañez, M I; Mayorga, C; Torres, M J; Kehr, N S; Vida, Y; Collado, D; Najera, F; De Cola, L; Perez-Inestrosa, E

    2012-01-01

    Complex functional materials consisting of bioactive molecules immobilized on solid supports present potential applications in biosensoring. Advances in the fabrication of these surface materials are of growing interest for antibody-based diagnosis. This work exploits dendrimers as versatile nanostructures for templating sensor surfaces and the critical role of the immobilization protocol in the solid supports cellulose and zeolites, of organic and inorganic composition respectively. The fabrication and characterization, including the degree of functionalization and reproducibility, of different nanostructured materials are described. To validate the approach, the fabricated supports were further used as a solid phase for developing a radioimmunoassay to detect immunoglobulin E (IgE) specific to penicillin, the antibody involved in immediate allergy responses to this drug. The dendrimer-modified supports provide assays with significantly enhanced sensitivity, as well as increase the availability of biomolecules for specific interaction and minimize nonspecific adsorptions through appropriate functionalization protocols in each case. The manufacturing methodology involved the use of a long, flexible hydrophilic spacer in the cellulose materials, and a higher surface density of the immobilized dendrimers in the zeolite crystals. The ability of hybrid zeolite materials in such biosensing applications was evaluated for the first time. The assays were validated in human serum samples from patients allergic to penicillin and from non-allergic controls. The specificity and improved sensitivity of the dendrimer- modified supports make these strategies versatile for different bioactive molecules and could have significant implications for the quantification of a wide range of specific IgE antibodies and other biomolecules of diagnostic interest.

  1. G3.5 PAMAM Dendrimers Enhance Transepithelial Transport of SN38 while minimizing Gastrointestinal Toxicity

    PubMed Central

    Goldberg, Deborah S.; Vijayalakshmi, Nirmalkumar; Swaan, Peter W.; Ghandehari, Hamidreza

    2011-01-01

    Poly(amido amine) (PAMAM) dendrimers have shown promise in oral drug delivery. Conjugation of SN38 to PAMAM dendrimers has the potential to improve its oral absorption while minimizing gastrointestinal toxicity. In this work we evaluated G3.5 PAMAM dendrimer-SN38 conjugates with ester-linked glycine and β-alanine spacers for their suitability in oral therapy of hepatic colorectal cancer metastases. G3.5-βAlanine-SN38 was mostly stable while G3.5-Glycine-SN38 showed 10%, 20%, and 56% SN38 release in simulated gastric, intestinal and liver environments for up to 6, 24 and 48 hours, respectively. Short-term treatment of Caco-2 cells with G3.5-SN38 conjugates did not reduce cell viability, while comparable concentrations of SN38 caused significant cytotoxicity. G3.5-Glycine-SN38 and G3.5-βAlanine-SN38 showed IC50 values of 0.60 and 3.59 μM, respectively, in HT-29 cells treated for 48 hours, indicating the efficacy of the drug delivery system in colorectal cancer cells with longer incubation time. Both conjugates increased SN38 transepithelial transport compared to the free drug. Transport of G3.5-Glycine-SN38 was highly concentration-dependent whereas transport of G3.5-βAlanine-SN38 was concentration-independent, highlighting the influence of drug loading and spacer chemistry on transport mechanism. Together these results show that PAMAM dendrimers have the potential to improve the oral bioavailability of potent anti-cancer drugs. PMID:21115079

  2. Dendrimer/methyl methacrylate co-polymers: residual methyl methacrylate and degree of conversion.

    PubMed

    Viljanen, Eeva K; Skrifvars, Mikael; Vallittu, Pekka K

    2005-01-01

    Dendrimer/methyl methacrylate co-polymers were studied for use in dental composites. The aim was to determine the effects of methyl methacrylate concentration in the resin mixture and polymerization method on the degree of conversion and residual monomer content of the copolymers. Two dendrimers were studied, D12 with 12 reactive methacrylate groups and D24 with 24 reactive groups. The concentration of methyl methacrylate varied from 20 wt% to 50 wt% of monomers. Camphorquinone (CQ) was used as the light-activation initiator and 2-(N,N-dimethylamino)ethyl methacrylate (DMAEMA) as the activator, both in the quantity of 3.0 wt%. Three polymerization methods were used: photo-polymerization, photo-polymerized immediately followed by post-polymerization at 120 degrees C for 15 min, and photo-polymerization followed by postpolymerization after 7 days. The degree of conversion was determined using FT-IR. Residual monomers were extracted with tetrahydrofuran and methanol and analyzed with HPLC. The highest degrees of conversion were 65 and 62%, and the lowest residual monomer contents 1.0 and 1.5% for D12 and D24, respectively. These were measured after heat-induced post-polymerization. For D12, increasing the proportion of methyl methacrylate decreased the degree of conversion and increased the residual monomer content after photo-polymerization. Post-polymerization enhanced the polymerization of the dendrimer co-polymers in respect of degree of conversion and residual monomer content. The present study suggested that the tested dendrimer/methyl methacrylate copolymers require heat-induced polymerization to reach the generally accepted levels of degree of conversion and residual monomers.

  3. Dendrimer-entrapped gold nanoparticles as potential CT contrast agents for blood pool imaging

    NASA Astrophysics Data System (ADS)

    Wang, Han; Zheng, Linfeng; Guo, Rui; Peng, Chen; Shen, Mingwu; Shi, Xiangyang; Zhang, Guixiang

    2012-03-01

    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.

  4. Surface-induced dissociation of singly and multiply protonated polypropylenamine dendrimers.

    PubMed

    de Maaijer-Gielbert, J; Gu, C; Somogyi, A; Wysocki, V H; Kistemaker, P G; Weeding, T L

    1999-05-01

    The ease of fragmentation of various charge states of protonated polypropylenamine (POPAM) dendrimers is investigated by surface-induced dissociation. Investigated are the protonated diaminobutane propylenamines [DAB(PA)n] DAB(PA)8 (1+ and 2+), DAB(PA)16 (2+ and 3+), and DAB(PA)32 (3+ and 4+). These ions have been proposed to fragment by charge-directed intramolecular nucleophilic substitution (SNi) reactions. Differences in relative fragment ion abundances between charge states can be related to the occupation of different protonation sites. These positions can be rationalized based on estimates of Coulomb energies and gas-phase basicities of the protonation/fragmentation sites. The laboratory collision energies at which the fragment ion current is approximately 50% of the total ion current were found to increase with the size, but to be independent of charge state of the protonated POPAM dendrimers. It is suggested that intramolecular Coulomb repulsion within the multiply protonated POPAM dendrimers selected for activation does not readily result in easier fragmentation, which is in accordance with the proposed fragmentation mechanism.

  5. Formulation and characterization of antimicrobial quaternary ammonium dendrimer in poly(methyl methcarylate) bone cement.

    PubMed

    Abid, C K V Zainul; Jain, Swati; Jackeray, Richa; Chattopadhyay, Sruti; Singh, Harpal

    2017-04-01

    The use of novel antimicrobial molecules in bone cement can improve efficiency of recuperation after arthroplasty or joint replacement surgeries, avoiding the risks associated with antibiotic resistant antimicrobial agents. Nanomaterials particularly dendrimers are particularly useful for making broad spectrum killing agents owing to their large surface areas and functionalities. Therefore, we have synthesized generation 1 quaternary ammonium dendrimer of tripropylene glycol diacrylate (TPGDA) using octyl iodide (OI) [TPGDA G1.0 (=) quaternary octyl iodide (QOI)] and capitalized on their capabilities of contact killing based mechanism. We formulated different TPGDA G1.0 (=) QOI antimicrobial agent loaded liquid component composed of methyl methacrylate monomer and N,N-dimethyl-p-toluidine coinitiator. Different polymethyl methacrylate (PMMA) based experimental bone cement formulations were made and dendrimer concentration was optimized. Mechanical strength and compressive modulus of modified bone cement decreased on increasing concentrations and 10% was optimized for further analysis. The mechanical strength of bone cement yield the similar trend in wet conditions bone cement immersed in artificially created stimulated body fluids. Ten percent TPGDA G1.0 (=) QOI in bone cement was sufficient to kill gram positive and negative bacteria and its property is retained even after a period of 30 days. Thus novel dendritic structures show promise for clinical antimicrobial activity while retaining mechanical properties of bone cements. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 521-530, 2017.

  6. Microscopic Basis for the Mesoscopic Extensibility of Dendrimer-Compacted DNA

    PubMed Central

    Mills, Maria; Orr, Brad; Banaszak Holl, Mark M.; Andricioaei, Ioan

    2010-01-01

    Abstract The mechanism of DNA compaction by dendrimers is key to the design of nanotechnologies that can deliver genetic material into cells. We present atomistic simulations, mesoscopic modeling and single-molecule pulling experiments describing DNA dendrimer interactions. All-atom molecular dynamics were used to characterize pulling-force-dependent interactions between DNA and generation-3 PAMAM amine-terminated dendrimers, and a free energy profile and mean forces along the interaction coordinate are calculated. The energy, force, and geometry parameters computed at the atomic level are input for a Monte Carlo model yielding mesoscopic force-extension curves. Actual experimental single-molecule curves obtained with optical tweezers are also presented, and they show remarkable agreement with the virtual curves from our model. The calculations reveal the microscopic origin of the hysteresis observed in the phase transition underlying compaction. A broad range of ionic and pulling parameters is sampled, and suggestions for windows of conditions to probe new single-molecule behavior are made. PMID:20197037

  7. Effect of diblock copolymer properties on the photophysical properties of dendrimer silicon phthalocyanine nanoconjugates

    NASA Astrophysics Data System (ADS)

    Chen, Kuizhi; Pan, Sujuan; Zhuang, Xuemei; Lv, Hafei; Que, Shoulin; Xie, Shusen; Yang, Hongqin; Peng, Yiru

    2016-07-01

    1-2 generation poly(benzyl aryl ether) dendrimer silicon phthalocyanines with axially disubstituted cyano terminal functionalities (G n -DSiPc(CN)4 n , (G n = n-generation dendrimer, n = 1-2)) were synthesized. Their structures were characterized by elemental analysis, IR, 1H NMR, and ESI-MS. Polymeric nanoparticles (G n -DSiPc(CN)4 n /m) were formed through encapsulating G n -DSiPc(CN)4 n into three monomethoxyl poly(ethylene glycol)-poly(ɛ-caprolactone) diblock copolymers (MPEG-PCL) with different hydrophilic/hydrophobic proportion, respectively. The effect of dendritic generation and the hydrophilic/hydrophobic proportion of diblock copolymers on the UV/Vis and fluorescence spectra of G n -DSiPc(CN)4 n and G n -DSiPc(CN)4 n /m were studied. The photophysical properties of polymeric nanoparticles exhibited dendritic generation and hydrophilic/hydrophobic proportion dependence. The fluorescence intensities and lifetimes of G n -DSiPc(CN)4 n /m were lower than the corresponding free dendrimer phthalocyanines. G n -DSiPc(CN)4 n encapsulated into MPEG-PCL with hydrophilic/hydrophobic molecular weight ratio 2000:4000 exhibited excellent photophysical property. The mean diameter of MPEG2000-PCL2000 micelles was about 70 nm, which decreased when loaded with G n -DSiPc(CN)4 n .

  8. 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.

  9. 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.

  10. Multivalent Conjugation of Antibody to Dendrimers for the Enhanced Capture and Regulation on Colon Cancer Cells

    PubMed Central

    Xie, Jingjing; Wang, Jichuang; Chen, Hongning; Shen, Weiyu; Sinko, Patrick J.; Dong, Haiyan; Zhao, Rongli; Lu, Yusheng; Zhu, Yewei; Jia, Lee

    2015-01-01

    Circulation tumor cells (CTCs) in the bloodstream of early-stage cancer patients carry the important information about valuable biomarkers and biological properties of primary tumor. However, detection and capture of CTCs are challenging owing to their low concentrations. Traditional technologies have the limited detection sensitivity and the low capture efficiency. We, herein, report an effective approach to specifically bind and capture colon cancer HT29 cells by using multiple Sialyl Lewis X antibodies (aSlex)-conjugated PAMAM dendrimers. The conjugation was characterized by using atom force microscope, UV and fluorescence measurements. The capturing and regulating HT29 cells by the aSlex-coated dendrimer conjugate were analyzed by microscopy and flow cytometry. The results indicated that the conjugate showed the enhanced capture of HT29 cells in a concentration-dependent manner and the maximum capture efficiency of 77.88% was obtained within 1 h-exposure. G6-5aSlex-FITC conjugate showed capture efficiency better than FITC-G6-COOH-5aSlex conjugate. G6-5aSlex-FITC conjugate could specifically capture HT29 cells even when the target HT29 cells were diluted with the interfering cells (e.g., RBCs) to a low concentration. The capture resulted in a concentration-dependent restraint of the cell activity. In conclusion, the aSlex-coated dendrimer conjugate displayed the great potential in capturing and restraining colorectal CTCs in blood. PMID:25819426

  11. 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.

  12. 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.

  13. Regulation of dendrimer:dextran material performance by altered tissue microenvironment in inflammation and neoplasia

    PubMed Central

    Oliva, Nuria; Carcole, Maria; Beckerman, Margarita; Seliktar, Sivan; Hayward, Alison; Stanley, Butch; Parry, Nicola Maria Anne; Edelman, Elazer R.; Artzi, Natalie

    2015-01-01

    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 prior to 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

  14. An amperometric chloramphenicol immunosensor based on cadmium sulfide nanoparticles modified-dendrimer bonded conducting polymer.

    PubMed

    Kim, Dong-Min; Rahman, Md Aminur; Do, Minh Hien; Ban, Changill; Shim, Yoon-Bo

    2010-03-15

    An amperometric chloramphenicol (CAP) immunosensor was fabricated by covalently immobilizing anti-chloramphenicol acetyl transferase (anti-CAT) antibody on cadmium sulfide nanoparticles (CdS) modified-dendrimer that was bonded to the conducting polymer (poly 5, 2': 5', 2''-terthiophene-3'-carboxyl acid (poly-TTCA)) layer. The AuNPs, dendrimers, and CdS nanoparticles were deposited onto the polymer layer in order to enhance the sensitivity of the sensor probes. The particle sizes were determined using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The immobilization of dendrimers, CdS, and anti-CAT were confirmed using energy disruptive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and quartz crystal microbalance (QCM) techniques. The detection of CAP was based on the competitive immuno-interaction between the free- and labeled-CAP for active sites of the anti-CAT. Hydrazine was used as the label for CAP, and it electrochemically catalyzed the reduction of H(2)O(2) at -0.35 V vs. Ag/AgCl. Under optimized conditions, the proposed immunosensor exhibited a linear range of CAP detection between 50 pg/mL and 950 pg/mL, and the detection limit was 45 pg/mL. The immunosensor was examined in real meat samples for the analysis of CAP.

  15. PAMAM Dendrimers Cross the Blood–Brain Barrier When Administered through the Carotid Artery in C57BL/6J Mice

    PubMed Central

    Srinageshwar, Bhairavi; Peruzzaro, Sarah; Andrews, Melissa; Johnson, Kayla; Hietpas, Allison; Clark, Brittany; McGuire, Crystal; Petersen, Eric; Kippe, Jordyn; Stewart, Andrew; Lossia, Olivia; Al-Gharaibeh, Abeer; Antcliff, Aaron; Culver, Rebecca; Swanson, Douglas; Dunbar, Gary; Sharma, Ajit; Rossignol, Julien

    2017-01-01

    Drug delivery into the central nervous system (CNS) is challenging due to the blood–brain barrier (BBB) and drug delivery into the brain overcoming the BBB can be achieved using nanoparticles such as dendrimers. The conventional cationic dendrimers used are highly toxic. Therefore, the present study investigates the role of novel mixed surface dendrimers, which have potentially less toxicity and can cross the BBB when administered through the carotid artery in mice. In vitro experiments investigated the uptake of amine dendrimers (G1-NH2 and G4-NH2) and novel dendrimers (G1-90/10 and G4-90/10) by primary cortical cultures. In vivo experiments involved transplantation of G4-90/10 into mice through (1) invasive intracranial injections into the striatum; and (2) less invasive carotid injections. The animals were sacrificed 24-h and 1-week post-transplantations and their brains were analyzed. In vivo experiments proved that the G4-90/10 can cross the BBB when injected through the carotid artery and localize within neurons and glial cells. The dendrimers were found to migrate through the corpus callosum 1-week post intracranial injection. Immunohistochemistry showed that the migrating cells are the dendrimer-infected glial cells. Overall, our results suggest that poly-amidoamine (PAMAM) dendrimers may be used as a minimally invasive means to deliver biomolecules for treating neurological diseases or disorders PMID:28335421

  16. PAMAM Dendrimers Cross the Blood-Brain Barrier When Administered through the Carotid Artery in C57BL/6J Mice.

    PubMed

    Srinageshwar, Bhairavi; Peruzzaro, Sarah; Andrews, Melissa; Johnson, Kayla; Hietpas, Allison; Clark, Brittany; McGuire, Crystal; Petersen, Eric; Kippe, Jordyn; Stewart, Andrew; Lossia, Olivia; Al-Gharaibeh, Abeer; Antcliff, Aaron; Culver, Rebecca; Swanson, Douglas; Dunbar, Gary; Sharma, Ajit; Rossignol, Julien

    2017-03-14

    Drug delivery into the central nervous system (CNS) is challenging due to the blood-brain barrier (BBB) and drug delivery into the brain overcoming the BBB can be achieved using nanoparticles such as dendrimers. The conventional cationic dendrimers used are highly toxic. Therefore, the present study investigates the role of novel mixed surface dendrimers, which have potentially less toxicity and can cross the BBB when administered through the carotid artery in mice. In vitro experiments investigated the uptake of amine dendrimers (G1-NH₂ and G4-NH₂) and novel dendrimers (G1-90/10 and G4-90/10) by primary cortical cultures. In vivo experiments involved transplantation of G4-90/10 into mice through (1) invasive intracranial injections into the striatum; and (2) less invasive carotid injections. The animals were sacrificed 24-h and 1-week post-transplantations and their brains were analyzed. In vivo experiments proved that the G4-90/10 can cross the BBB when injected through the carotid artery and localize within neurons and glial cells. The dendrimers were found to migrate through the corpus callosum 1-week post intracranial injection. Immunohistochemistry showed that the migrating cells are the dendrimer-infected glial cells. Overall, our results suggest that poly-amidoamine (PAMAM) dendrimers may be used as a minimally invasive means to deliver biomolecules for treating neurological diseases or disorders.

  17. 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.

  18. Topical gene silencing by iontophoretic delivery of an antisense oligonucleotide-dendrimer nanocomplex: the proof of concept in a skin cancer mouse model

    NASA Astrophysics Data System (ADS)

    Venuganti, , Venkata Vamsi K.; Saraswathy, Manju; Dwivedi, Chandradhar; Kaushik, Radhey S.; Perumal, Omathanu P.

    2015-02-01

    The study was aimed at investigating the feasibility of using a poly (amidoamine) (PAMAM) dendrimer as a carrier for topical iontophoretic delivery of an antisense oligonucleotide (ASO). Bcl-2, an anti-apoptotic protein implicated in skin cancer, was used as the model target protein to demonstrate the topical gene silencing approach. Confocal laser scanning microscopy studies demonstrated that the iontophoretically delivered ASO-dendrimer complex can reach the viable epidermis in porcine skin. In contrast, passively delivered free or dendrimer complexed ASO was mainly localized to the stratum corneum. The cell uptake of ASO was significantly enhanced by the dendrimer complex and the complex suppressed Bcl-2 levels in the cell. In the skin cancer mouse model, the iontophoretically delivered ASO-dendrimer complex reduced the tumor volume by 45% and was consistent with the reduction in Bcl-2 protein levels. The iontophoretically delivered ASO-dendrimer complex caused significant apoptosis in skin tumor. Overall, the findings from this study demonstrate that dendrimers are promising nanocarriers for developing topical gene silencing approaches for skin diseases.The study was aimed at investigating the feasibility of using a poly (amidoamine) (PAMAM) dendrimer as a carrier for topical iontophoretic delivery of an antisense oligonucleotide (ASO). Bcl-2, an anti-apoptotic protein implicated in skin cancer, was used as the model target protein to demonstrate the topical gene silencing approach. Confocal laser scanning microscopy studies demonstrated that the iontophoretically delivered ASO-dendrimer complex can reach the viable epidermis in porcine skin. In contrast, passively delivered free or dendrimer complexed ASO was mainly localized to the stratum corneum. The cell uptake of ASO was significantly enhanced by the dendrimer complex and the complex suppressed Bcl-2 levels in the cell. In the skin cancer mouse model, the iontophoretically delivered ASO-dendrimer complex

  19. Matrix-assisted resonant infrared pulsed laser ablation of electroluminescent dendrimers

    NASA Astrophysics Data System (ADS)

    Torres-Pagan, Ricardo Daniel

    The deposition techniques for polymer thin films in organic light emitting diodes are limited to wet methods since molecular pyrolysis prevents the use of dry vacuum thermal evaporation methods. Wet methods have critical limitations such as poor thickness control, drying patterns and re-dissolution of previous layers. In this work, a novel approach, Matrix-Assisted Resonant Infrared Pulsed Laser Ablation (RIM-PLA) has been studied as an alternative deposition method for electroluminescent polymer films. RIM-PLA was successfully used for the deposition of two model dendrimers: fluorescent and phosphorescent Ir-cored. A free-electron laser was tuned to resonance frequencies for the vibrational modes of two solid matrix solvents: chloroform (C-H stretch; C-H bending) and toluene (C-H stretch; C=C stretch). The temperature-dependent absorption coefficients for each resonance mode were measured. Targets made from flash-frozen, low-concentration solutions of the dendrimers were irradiated at each frequency while varying fluence and exposure times. The molecular structure integrity of the targets was characterized. The deposited films were characterized to assess structure fidelity, roughness and topography, and luminance. All RIM-PLA deposited films were compared with spin-coated films. The ablation characteristics for each mode were found to be dependent on the solvent and not the dendrimer. Calculations from a temperature-rise model show that FEL pulsed-irradiation results in heating rates on the order of 108--109 K/s, resulting in metastable condensed targets. Thermodynamic and kinetic relations were used to calculate the relevance of three ablation mechanisms: normal vaporization, normal boiling and phase explosion. The latter mechanism has a critical threshold (> 0.8 Tc) for each solvent, and proceeds through spinodal decay followed by rapid homogeneous nucleation of vapor bubbles within the focal volume. For both chloroform modes, the primary ablation mechanism was

  20. 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

  1. 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

  2. Triblock copolymers encapsulated poly (aryl benzyl ether) dendrimer zinc(II) phthalocyanine nanoparticles for enhancement in vitro photodynamic efficacy.

    PubMed

    Huang, Yide; Yu, Huizhen; Lv, Huafei; Zhang, Hong; Ma, Dongdong; Yang, Hongqin; Xie, Shusen; Peng, Yiru

    2016-12-01

    A novel series of nanoparticles formed via an electrostatic interaction between the periphery of negatively charged 1-2 generation aryl benzyl ether dendrimer zinc (II) phthalocyanines and positively charged poly(L-lysin) segment of triblock copolymer, poly(L-lysin)-block-poly(ethylene glycol)-block-poly(L-lysin), was developed for the use as an effective photosensitizers in photodynamic therapy. The dynamic light scattering, atomic force microscopy showed that two nanoparticles has a relevant size of 80-150nm. The photophysical properties and singlet oxygen quantum yields of free dendrimer phthalocyanines and nanoparticles exhibited generation dependence. The intracellular uptake of dendrimer phthalocyanines in Hela cells was significantly elevated as they were incorporated into the micelles, but was inversely correlated with the generation of dendrimer phthalocyanines. The photocytotoxicity of dendrimer phthalocyanines incorporated into polymeric micelles was also increased. The presence of nanoparticles induced efficient cell death. Using a mitochondrial-sepcific dye rhodamine 123 (Rh123), our fluorescence microscopic result indicated that nanoparticles localized to the mitochondria.

  3. p-Hydroxy benzoic acid-conjugated dendrimer nanotherapeutics as potential carriers for targeted drug delivery to brain: an in vitro and in vivo evaluation

    NASA Astrophysics Data System (ADS)

    Swami, Rajan; Singh, Indu; Kulhari, Hitesh; Jeengar, Manish Kumar; Khan, Wahid; Sistla, Ramakrishna

    2015-06-01

    Dendrimers which are discrete nanostructures/nanoparticles are emerging as promising candidates for many nanomedicine applications. Ligand-conjugated dendrimer facilitate the delivery of therapeutics in a targeted manner. Small molecules such as p-hydroxyl benzoic acid (pHBA) were found to have high affinity for sigma receptors which are prominent in most parts of central nervous system and tumors. The aim of this study was to synthesize pHBA-dendrimer conjugates as colloidal carrier for site-specific delivery of practically water insoluble drug, docetaxel (DTX) to brain tumors and to determine its targeting efficiency. pHBA, a small molecule ligand was coupled to the surface amine groups of generation 4-PAMAM dendrimer via a carbodiimide reaction and loaded with DTX. The conjugation was confirmed by 1HNMR and FT-IR spectroscopy. In vitro release of drug from DTX-loaded pHBA-conjugated dendrimer was found to be less as compared to unconjugated dendrimers. The prepared drug delivery system exhibited good physico-chemical stability and decrease in hemolytic toxicity. Cell viability and cell uptake studies were performed against U87MG human glioblastoma cells and formulations exerted considerable anticancer effect than plain drug. Conjugation of dendrimer with pHBA significantly enhanced the brain uptake of DTX which was shown by the recovery of a higher percentage of the dose from the brain following administration of pHBA-conjugated dendrimers compared with unconjugated dendrimer or formulation in clinical use (Taxotere®). Therefore, pHBA conjugated dendrimers could be an efficient delivery vehicle for the targeting of anticancer drugs to brain tumors.

  4. Not Only Columns: High Hole Mobility in a Discotic Nematic Mesophase Formed by Metal-Containing Porphyrin-Core Dendrimers.

    PubMed

    Concellón, Alberto; Marcos, Mercedes; Romero, Pilar; Serrano, José Luis; Termine, Roberto; Golemme, Attilio

    2017-01-24

    We report a new family of multifunctional liquid-crystalline porphyrin-core dendrimers that have coumarin functional groups around the porphyrin core. Porphyrin metalation strongly affects the photophysical properties, and therefore Zn(II) and Cu(II) derivatives have also been prepared. All the synthesized dendrimers form a nematic discotic mesophase. Their high tendency for homeotropic alignment makes these dendrimers excellent candidates for device applications, owing to their easy processability, spontaneous alignment between electrodes, and self-healing of defects because of their dynamic nature. The charge mobility values of these materials are the highest ever reported for a nematic discotic phase. Moreover, these values are similar to the highest values reported for ordered columnar mesophases, and this shows that a supramolecular organization in columns is not necessary to achieve high charge mobility.

  5. Amperometric enzyme electrodes for aerobic and anaerobic glucose monitoring prepared by glucose oxidase immobilized in mixed ferrocene-cobaltocenium dendrimers.

    PubMed

    Alonso, Beatriz; Armada, Pilar García; Losada, José; Cuadrado, Isabel; González, Blanca; Casado, Carmen M

    2004-07-15

    The enzyme glucose oxidase (GOx) has been immobilized electrostatically onto carbon and platinum electrodes modified with mixed ferrocene-cobaltocenium dendrimers. The ferrocene units have been used successfully as mediators between the GOx and the electrode under anaerobic conditions. In experiments carried out in the presence of oxygen, the cobaltocenium moieties act as electrocatalysts in the reduction of the oxygen in the solution, thus making possible the determination of the oxygen variation due to the enzymatic reaction, with high sensitivity. The current response of the electrode was determined by measuring steady-state current values obtained applying a constant potential. The effect of the substrate concentration, the dendrimer generation, the thickness of the dendrimer layer, interferences, and storage on the response of the sensors were investigated.

  6. Dendrimer brain uptake and targeted therapy for brain injury in a large animal model of hypothermic circulatory arrest.

    PubMed

    Mishra, Manoj K; Beaty, Claude A; Lesniak, Wojciech G; Kambhampati, Siva P; Zhang, Fan; Wilson, Mary A; Blue, Mary E; Troncoso, Juan C; Kannan, Sujatha; Johnston, Michael V; Baumgartner, William A; Kannan, Rangaramanujam M

    2014-03-25

    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.

  7. Ligand accessibility and bioactivity of a hormone–dendrimer conjugate depend on pH and pH history

    DOE PAGES

    Kim, Sung Hoon; Madak-Erdogan, Zeynep; Bae, Sung Chul; ...

    2015-07-17

    Estrogen conjugates with a polyamidoamine (PAMAM) dendrimer have shown remarkably selective regulation of the nongenomic actions of estrogens in target cells in this paper. In response to pH changes, however, these estrogen–dendrimer conjugates (EDCs) display a major morphological transition that alters the accessibility of the estrogen ligands that compromises the bioactivity of the EDC. A sharp break in dynamic behavior near pH 7 occurs for three different ligands on the surface of a PAMAM-G6 dendrimer: a fluorophore (tetramethylrhodamine [TMR]) and two estrogens (17α-ethynylestradiol and diphenolic acid). Collisional quenching and time-resolved fluorescence anisotropy experiments with TMR–PAMAM revealed high ligand shielding abovemore » pH 7 and low shielding below pH 7. Furthermore, when the pH was cycled from 8.5 (conditions of ligand–PAMAM conjugation) to 4.5 (e.g., endosome/lysosome) and through 6.5 (e.g., hypoxic environment) back to pH 8.5, the 17α-ethynylestradiol– and diphenolic acid–PAMAM conjugates experienced a dramatic, irreversible loss in cell stimulatory activity; dynamic NMR studies indicated that the hormonal ligands had become occluded within the more hydrophobic core of the PAMAM dendrimer. Thus, the active state of these estrogen–dendrimer conjugates appears to be metastable. Finally, this pH-dependent irreversible masking of activity is of considerable relevance to the design of drug conjugates with amine-bearing PAMAM dendrimers.« less

  8. Continuous flow atomic force microscopy imaging reveals fluidity and time-dependent interactions of antimicrobial dendrimer with model lipid membranes.

    PubMed

    Lind, Tania Kjellerup; Zielińska, Paulina; Wacklin, Hanna Pauliina; Urbańczyk-Lipkowska, Zofia; Cárdenas, Marité

    2014-01-28

    In this paper, an amphiphilic peptide dendrimer with potential applications against multi-resistant bacteria such as Staphylococcus aureus was synthesized and studied on model cell membranes. The combination of quartz crystal microbalance and atomic force microscopy imaging during continuous flow allowed for in situ monitoring of the very initial interaction processes and membrane transformations on longer time scales. We used three different membrane compositions of low and high melting temperature phospholipids to vary the membrane properties from a single fluid phase to a pure gel phase, while crossing the phase coexistence boundaries at room temperature. The interaction mechanism of the dendrimer was found to be time-dependent and to vary remarkably with the fluidity and coexistence of liquid-solid phases in the membrane. Spherical micelle-like dendrimer-lipid aggregates were formed in the fluid-phase bilayer and led to partial solubilization of the membrane, while in gel-phase membranes, the dendrimers caused areas of local depressions followed by redeposition of flexible lipid patches. Domain coexistence led to a sequence of events initiated by the formation of a ribbon-like network and followed by membrane solubilization via spherical aggregates from the edges of bilayer patches. Our results show that the dendrimer molecules were able to destroy the membrane integrity through different mechanisms depending on the lipid phase and morphology and shed light on their antimicrobial activity. These findings could have an impact on the efficacy of the dendrimers since lipid membranes in certain bacteria have transition temperatures very close to the host body temperature.

  9. Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy.

    PubMed

    Kaminskas, Lisa M; McLeod, Victoria M; Ryan, Gemma M; Kelly, Brian D; Haynes, John M; Williamson, Mark; Thienthong, Neeranat; Owen, David J; Porter, Christopher J H

    2014-06-10

    Direct administration of chemotherapeutic drugs to the lungs significantly enhances drug exposure to lung resident cancers and may improve chemotherapy when compared to intravenous administration. Direct inhalation of uncomplexed or unencapsulated cytotoxic drugs, however, leads to bolus release and unacceptable lung toxicity. Here, we explored the utility of a 56kDa PEGylated polylysine dendrimer, conjugated to doxorubicin, to promote the controlled and prolonged exposure of lung-resident cancers to cytotoxic drug. After intratracheal instillation to rats, approximately 60% of the dendrimer was rapidly removed from the lungs (within 24h) via mucociliary clearance and absorption into the blood. This was followed by a slower clearance phase that reflected both absorption from the lungs (bioavailability 10-13%) and biodegradation of the dendrimer scaffold. After 7days, approximately 15% of the dose remained in the lungs. A syngeneic rat model of lung metastasised breast cancer was subsequently employed to compare the anticancer activity of the dendrimer with a doxorubicin solution formulation after intravenous and pulmonary administration. Twice weekly intratracheal instillation of the dendrimer led to a >95% reduction in lung tumour burden after 2weeks in comparison to IV administration of doxorubicin solution which reduced lung tumour burden by only 30-50%. Intratracheal instillation of an equivalent dose of doxorubicin solution led to extensive lung-related toxicity and death withinseveral days of a single dose. The data suggest that PEGylated dendrimers have potential as inhalable drug delivery systems to promote the prolonged exposure of lung-resident cancers to chemotherapeutic drugs and to improve anti-cancer activity.

  10. 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

  11. Low temperature synthesis of ordered mesoporous stable anatase nanocrystals: the phosphorus dendrimer approach

    NASA Astrophysics Data System (ADS)

    Brahmi, Younes; Katir, Nadia; Ianchuk, Mykhailo; Collière, Vincent; Essassi, El Mokhtar; Ouali, Armelle; Caminade, Anne-Marie; Bousmina, Mosto; Majoral, Jean Pierre; El Kadib, Abdelkrim

    2013-03-01

    The scarcity of low temperature syntheses of anatase nanocrystals prompted us to explore the use of surface-reactive fourth generation phosphorus-dendrimers as molds to control the nucleation and growth of titanium-oxo-species during the sol-gel mineralization process. Unexpectedly, the dendritic medium provides at low temperature, discrete anatase nanocrystals (4.8 to 5.2 nm in size), in marked contrast to the routinely obtained amorphous titanium dioxide phase under standard conditions. Upon thermal treatment, heteroatom migration from the branches to the nanoparticle surface and the ring opening polymerization of the cyclophosphazene core provide stable, interpenetrating mesoporous polyphosphazene-anatase hybrid materials (-P&z.dbd;N-)n-TiO2. The steric hindrance of the dendritic skeleton, the passivation of the anatase surface by heteroatoms and the ring opening of the core limit the crystal growth of anatase to 7.4 nm and prevent, up to 800 °C, the commonly observed anatase-to-rutile phase transformation. Performing this mineralization in the presence of similar surface-reactive but non-dendritic skeletons (referred to as branch-mimicking dendrimers) failed to generate crystalline anatase and to efficiently limit the crystal growth, bringing thus clear evidence of the virtues of phosphorus dendrimers in the design of novel nanostructured materials.The scarcity of low temperature syntheses of anatase nanocrystals prompted us to explore the use of surface-reactive fourth generation phosphorus-dendrimers as molds to control the nucleation and growth of titanium-oxo-species during the sol-gel mineralization process. Unexpectedly, the dendritic medium provides at low temperature, discrete anatase nanocrystals (4.8 to 5.2 nm in size), in marked contrast to the routinely obtained amorphous titanium dioxide phase under standard conditions. Upon thermal treatment, heteroatom migration from the branches to the nanoparticle surface and the ring opening polymerization of

  12. 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

  13. Energetics of dendrimer binding to HIV-1 gp120-CD4 complex and mechanismic aspects of its role as an entry-inhibitor

    NASA Astrophysics Data System (ADS)

    Saurabh, Suman; Sahoo, Anil Kumar; Maiti, Prabal K.

    2016-10-01

    Experiments and computational studies have established that de-protonated dendrimers (SPL7013 and PAMAM) act as entry-inhibitors of HIV. SPL7013 based Vivagel is currently under clinical development. The dendrimer binds to gp120 in the gp120-CD4 complex, destabilizes it by breaking key contacts between gp120 and CD4 and prevents viral entry into target cells. In this work, we provide molecular details and energetics of the formation of the SPL7013-gp120-CD4 ternary complex and decipher modes of action of the dendrimer in preventing viral entry. It is also known from experiments that the dendrimer binds weakly to gp120 that is not bound to CD4. It binds even more weakly to the CD4-binding region of gp120 and thus cannot directly block gp120-CD4 complexation. In this work, we examine the feasibility of dendrimer binding to the gp120-binding region of CD4 and directly blocking gp120-CD4 complex formation. We find that the process of the dendrimer binding to CD4 can compete with gp120-CD4 binding due to comparable free energy change for the two processes, thus creating a possibility for the dendrimer to directly block gp120-CD4 complexation by binding to the gp120-binding region of CD4.

  14. Dendrimer nanocarriers for transport modulation across models of the pulmonary epithelium.

    PubMed

    Bharatwaj, Balaji; Mohammad, Abdul Khader; Dimovski, Radovan; Cassio, Fernando L; Bazito, Reinaldo C; Conti, Denise; Fu, Qiang; Reineke, Joshua; da Rocha, Sandro R P

    2015-03-02

    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.

  15. Solution-processed bulk heterojunction photovoltaic cells from gradient pi-conjugated thienylene vinylene dendrimers.

    PubMed

    Wang, Jin-Liang; Zhong, Chengmei; Tang, Zheng-Ming; Wu, Hongbin; Ma, Yuguo; Cao, Yong; Pei, Jian

    2010-01-04

    A series of gradient pi-conjugated dendrimers and their corresponding models based on 5,5,10,10,15,15-hexahexyltruxene moieties as nodes and oligo(thienylene vinylene) (OTVs) units with different lengths as branching arms are synthesized in good yields through Wittig-Horner reactions. All new compounds are fully characterized by (1)H and (13)C NMR spectroscopy, elemental analysis, and MALDI-TOF MS or ESI-MS. Investigation of their photophysical properties reveals that the gradient dendritic scaffold not only results in a higher molar absorption coefficient and broader absorption region than those of their corresponding model compounds, but also improves the PL quantum yields relative to the corresponding OTVs. The suitable HOMO and LUMO levels as well as excellent film forming properties make these molecules potential candidates for organic solar cells. Solution-processed bulk heterojunction solar cells using these dendrimers as donor and [6,6]-phenyl-C(61) butyric acid methyl ester as acceptor are prepared and tested. The power conversion efficiency of the devices based on G0-4-2 is 0.40 % under illumination of air mass 1.5 and 100 mW cm(-2). This is the highest record value for OTV-based materials to date. Although the absorption band of dendrimer G0-4-2 is much narrower than that of poly(3-hexylthienylene vinylene) (P3HTV), the efficiency of its solar cell device is almost twice that of the device based on P3HTV. This result shows clearly the advantage of gradient dendritic structures as active materials for photovoltaic cells.

  16. Efficient light harvesting and energy transfer in a red phosphorescent iridium dendrimer.

    PubMed

    Cho, Yang-Jin; Hong, Seong Ahn; Son, Ho-Jin; Han, Won-Sik; Cho, Dae Won; Kang, Sang Ook

    2014-12-15

    A series of red phosphorescent iridium dendrimers of the type [Ir(btp)2(pic-PCn)] (Ir-Gn; n = 0, 1, 2, and 3) with two 2-(benzo[b]thiophen-2-yl)pyridines (btp) and 3-hydroxypicolinate (pic) as the cyclometalating and ancillary ligands were prepared in good yields. Dendritic generation was grown at the 3 position of the pic ligand with 4-(9H-carbazolyl)phenyl dendrons connected to 3,5-bis(methyleneoxy)benzyloxy branches (PCn; n = 0, 2, 4, and 8). The harvesting photons on the PCn dendrons followed by efficient energy transfer to the iridium center resulted in high red emissions at ∼600 nm by metal-to-ligand charge transfer. The intensity of the phosphorescence gradually increased with increasing dendrimer generation. Steady-state and time-resolved spectroscopy were used to investigate the energy-transfer mechanism. On the basis of the fluorescence quenching rate constants of the PCn dendrons, the energy-transfer efficiencies for Ir-G1, Ir-G2, and Ir-G3 were 99, 98, and 96%, respectively. The energy-transfer efficiency for higher-generation dendrimers decreased slightly because of the longer distance between the PC dendrons and the core iridium(III) complex, indicating that energy transfer in Ir-Gn is a Förster-type energy transfer. Finally, the light-harvesting efficiencies for Ir-G1, Ir-G2, and Ir-G3 were determined to be 162, 223, and 334%, respectively.

  17. 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.

  18. POxylated Polyurea Dendrimers: Smart Core-Shell Vectors with IC50 Lowering Capacity.

    PubMed

    Restani, Rita B; Conde, João; Pires, Rita F; Martins, Pedro; Fernandes, Alexandra R; Baptista, Pedro V; Bonifácio, Vasco D B; Aguiar-Ricardo, Ana

    2015-08-01

    The design and preparation of highly efficient drug delivery platforms using green methodologies is at the forefront of nanotherapeutics research. POxylated polyurea dendrimers are efficiently synthesized using a supercritical-assisted polymerization in carbon dioxide. These fluorescent, pH-responsive and water-soluble core-shell smart nanocarriers show low toxicity in terms of cell viability and absence of glutathione depletion, two of the major side effect limitations of current vectors. The materials are also found to act as good transfection agents, through a mechanism involving an endosomal pathway, being able to reduce 100-fold the IC50 of paclitaxel.

  19. Electrochemical biosensors for biocontaminant detection consisting of carbon nanotubes, platinum nanoparticles, dendrimers, and enzymes.

    PubMed

    Siriviriyanun, Ampornphan; Imae, Toyoko; Nagatani, Naoki

    2013-12-15

    The presented approach provides the advanced development of effective, rapid, and versatile electrochemical sensors for a small amount of analytes on potential, cheap, and disposable printed chips. The electrocatalytic activity of this biosensor revealed the feasible detection of hydrogen peroxide at low potential (~0.09 V) and the detection of a biocontaminant inhibitor (organophosphorus pesticide) in a wide range of concentrations. This efficiency comes from the chemical immobilization of catalysts (Pt nanoparticles) and electron transfer-enlarging materials (carbon nanotubes) on an electrode. Especially, dendrimers raise the stable conjugation of enzymes (acetylcholinesterase/choline oxidase/peroxidase) as well as nanoparticles and carbon nanotubes on an electrode.

  20. Covalent immobilization of invertase on PAMAM-dendrimer modified superparamagnetic iron oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Uzun, K.; Çevik, E.; Şenel, M.; Sözeri, H.; Baykal, A.; Abasıyanık, M. F.; Toprak, M. S.

    2010-10-01

    In this study, polyamidoamine (PAMAM) dendrimer was synthesized on the surface of superparamagnetite nanoparticles to enhance invertase immobilization. The amount of immobilized enzyme on the surface-hyperbranched magnetite nanoparticle was up to 2.5 times (i.e., 250%) as much as that of magnetite nanoparticle modified with only amino silane. Maximum reaction rate ( V max) and Michaelis-Menten constant ( K m) were determined for the free and immobilized enzymes. Various characteristics of immobilized invertase such as; the temperature activity, thermal stability, operational stability, and storage stability were evaluated and results revealed that stability of the enzyme is improved upon immobilization.

  1. Constructing metal nanoparticle multilayers with polyphenylene dendrimer/gold nanoparticles via "click" chemistry.

    PubMed

    Li, Huiqiang; Li, Zhanxian; Wu, Linzhi; Zhang, Yuna; Yu, Mingming; Wei, Liuhe

    2013-03-26

    Multilayer films composed of azide-functional polymer and polyphenylene dendrimer-stabilized gold nanoparticles with alkynes in their peripheries have been fabricated using a layer-by-layer (LBL) approach via "click" chemistry. This method permits facile covalent linking of the polymer/nanoparticle interlayers in the mixture of DMF and water, which provides a general and powerful technique for preparing uniform nanoparticle (NP) thin films. The deposition process is linearly related to the number of bilayers as monitored by UV-vis spectroscopy. The multilayer structure and morphology have been characterized by X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and contact angle.

  2. Zero-field-cooled/field-cooled magnetization study of Dendrimer model

    NASA Astrophysics Data System (ADS)

    Arejdal, M.; Bahmad, L.; Benyoussef, A.

    2017-01-01

    Being motivated by Dendrimer model with mixed spins σ=3 and S=7/2, we investigated the magnetic nanoparticle system in this study. We analyzed and discussed the ground-state phase diagrams and the stable phases. Then, we elaborated and explained the magnetic properties of the system by using Monte Carlo Simulations (MCS) in the framework of the Ising model. In this way, we determined the blocking temperature, which is deduced through studying the partial-total magnetization and susceptibility as a function of the temperature, and we established the effects of both the exchange coupling interaction and the crystal field on the hysteresis loop.

  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. Multifunctional supramolecular dendrimers with an s-triazine ring as the central core: liquid crystalline, fluorescence and photoconductive properties.

    PubMed

    Bucoş, Madalina; Sierra, Teresa; Golemme, Attilio; Termine, Roberto; Barberá, Joaquín; Giménez, Raquel; Serrano, José Luis; Romero, Pilar; Marcos, Mercedes

    2014-08-04

    Novel liquid crystal (LC) dendrimers have been synthesised by hydrogen bonding between an s-triazine as the central core and three peripheral dendrons derived from bis(hydroxymethyl)propionic acid. Symmetric acid dendrons bearing achiral promesogenic units have been synthesised to obtain 3:1 complexes with triazine that exhibit LC properties. Asymmetric dendrons that combine the achiral promesogenic unit and an active moiety derived from coumarin or pyrene structures have been synthesised in order to obtain dendrimers with photophysical and electrochemical properties. The formation of the complexes was confirmed by IR and NMR spectroscopy data. The liquid crystalline properties were investigated by differential scanning calorimetry, polarising optical microscopy and X-ray diffractometry. All complexes displayed mesogenic properties, which were smectic in the case of symmetric dendrons and their complexes and nematic in the case of asymmetric dendrons and their dendrimers. A supramolecular model for the lamellar mesophase, based mainly on X-ray diffraction studies, is proposed. The electrochemical behaviour of dendritic complexes was investigated by cyclic voltammetry. The UV/Vis absorption and emission properties of the compounds and the photoconductive properties of the dendrons and dendrimers were also investigated.

  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. Multifunctional dendrimer-based nanoparticles for in vivo MR/CT dual-modal molecular imaging of breast cancer

    PubMed Central

    Li, Kangan; Wen, Shihui; Larson, Andrew C; Shen, Mingwu; Zhang, Zhuoli; Chen, Qian; Shi, Xiangyang; Zhang, Guixiang

    2013-01-01

    Development of dual-mode or multi-mode imaging contrast agents is important for accurate and self-confirmatory diagnosis of cancer. We report a new multifunctional, dendrimer-based gold nanoparticle (AuNP) as a dual-modality contrast agent for magnetic resonance (MR)/computed tomography (CT) imaging of breast cancer cells in vitro and in vivo. In this study, amine-terminated generation 5 poly(amidoamine) dendrimers modified with gadolinium chelate (DOTA-NHS) and polyethylene glycol monomethyl ether were used as templates to synthesize AuNPs, followed by Gd(III) chelation and acetylation of the remaining dendrimer terminal amine groups; multifunctional dendrimer-entrapped AuNPs (Gd-Au DENPs) were formed. The formed Gd-Au DENPs were used for both in vitro and in vivo MR/CT imaging of human MCF-7 cancer cells. Both MR and CT images demonstrate that MCF-7 cells and the xenograft tumor model can be effectively imaged. The Gd-Au DENPs uptake, mainly in the cell cytoplasm, was confirmed by transmission electron microscopy. The cell cytotoxicity assay, cell morphology observation, and flow cytometry show that the developed Gd-Au DENPs have good biocompatibility in the given concentration range. Our results clearly suggest that the synthetic Gd-Au DENPs are amenable for dual-modality MR/CT imaging of breast cancer cells. PMID:23888113

  7. 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.

  8. 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 ...

  9. Optimisation of synthetic vector systems for cancer gene therapy - the role of the excess of cationic dendrimer under physiological conditions.

    PubMed

    Santander-Ortega, M J; de la Fuente, M; Lozano, M V; Tsui, M L; Bolton, K; Uchegbu, I F; Schätzlein, A G

    2014-01-01

    We have previously demonstrated in a therapeutic study that a single systemic course of DAB-Am16 dendriplexes loaded with plasmid expressing TNFα over a period of time of 10 days led to a regression of 100% of tumours and to long term cures of up to 80% of animals. However, the formulation had a relatively low colloidal stability requiring administration soon after nanoparticle preparation. Similar to other cationic polyplex and dendrimer DNA delivery systems, DAB-AM16 dendrimer formulations contained a substantial proportion of free polymer; this free polymer is present independently of the specific polymer:DNA ratio and increases with increasing proportion of polymer (N:P charge ratio) in the formulation. It has previously been shown for this and other systems that the excess of polymer plays a role in promoting the transfection efficiency of synthetic vectors. This has been linked to effects of the polymer on the efficiency of intracellular processing, e.g. endosomal release. However, the free polymer may have additional effects that are relevant to the efficiency of the formulation. This study therefore considered the effect of free dendrimer on the colloidal stability of the complexes, the interaction of the complex with the formulation medium, and with biological components, i.e. electrolytes and serum proteins after administration. Analysis of the total potential of interaction shows that, even at high N:P ratios, the excess of free dendrimer in the medium is not enough to induce the aggregation of the formulation due to depletion forces. This finding is unusual and can be attributed to the particularly low Mw of these dendrimers (1.6 kDa). On the other hand, formulations are highly sensitive to the strength of the dendrimer:DNA interactions. These can be controlled by the degree of protonation (α) of the dendrimer which is strongly dependent on bulk pH. Modulation of the protonation level to α≥0.4 allows reproducible production of colloidally stable

  10. 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

  11. Tumor targeting using polyamidoamine dendrimer-cisplatin nanoparticles functionalized with diglycolamic acid and herceptin.

    PubMed

    Kesavan, Akila; Ilaiyaraja, P; Sofi Beaula, W; Veena Kumari, Vuttaradhi; Sugin Lal, J; Arunkumar, C; Anjana, G; Srinivas, Satish; Ramesh, Anita; Rayala, Suresh Kumar; Ponraju, D; Venkatraman, Ganesh

    2015-10-01

    Polymer mediated drug delivery system represents a novel promising platform for tumor-targeting with reduced systemic side effects and improved chemotherapeutical efficacy. In this study, we report the preparation and characterization of herceptin targeted, diglycolamic acid (DGA) functionalized polyamidoamine (PAMAM) dendrimer as a potent drug carrier for cisplatin. DGA dendrimers carrying cisplatin demonstrated enhanced anticancer activity when targeted with herceptin. In vitro cell line studies with herceptin-DGA-G4-cisplatin in HER-2 +ve and HER-2 -ve human ovarian cancer cell lines showed that these nanoparticles possessed remarkable features such as lower IC50 value, improved S-phase arrest, and enhanced apoptosis due to increased cellular uptake and accumulation than the untargeted DGA-G4-cisplatin and free cisplatin. Furthermore, in vivo results in SCID mice bearing SKOV-3 tumor xenografts, herceptin-DGA-G4-cisplatin, appeared to be more effective in inducing tumor regression as compared to free cisplatin. Collectively, these results indicate that herceptin targeted DGA functionalized PAMAM-cisplatin conjugates serve as better anti-tumor agents than individual therapeutic agents.

  12. Generation 9 polyamidoamine dendrimer encapsulated platinum nanoparticle mimics catalase size, shape, and catalytic activity.

    PubMed

    Wang, Xinyu; Zhang, Yincong; Li, Tianfu; Tian, Wende; Zhang, Qiang; Cheng, Yiyun

    2013-04-30

    Poly(amidoamine) (PAMAM) encapsulated platinum nanoparticles were synthesized and used as catalase mimics. Acetylated generation 9 (Ac-G9) PAMAM dendrimer with a molecular size around 10 nm was used as a template to synthesize platinum nanoparticles. The feeding molar ratio of Pt(4+) and Ac-G9 is 2048, and the synthesized platinum nanoparticle (Ac-G9/Pt NP) has an average size of 3.3 nm. Ac-G9/Pt NP has a similar molecular size and globular shape with catalase (~11 nm). The catalytic activity of Ac-G9/Pt NP on the decomposition of H2O2 is approaching that of catalase at 37 °C. Ac-G9/Pt NP shows differential response to the changes of pH and temperature compared with catalase, which can be explained by different catalytic mechanisms of Ac-G9/Pt NP and catalase. Ac-G9/Pt NP also shows horseradish peroxidase activity and is able to scavenge free radicals such as di(phenyl)-(2,4,6-trinitrophenyl)iminoazanium (DPPH). Furthermore, Ac-G9/Pt NP shows excellent biocompatibility on different cell lines and can down-regulate H2O2-induced intracellular reactive oxygen species (ROS) in these cells. These results suggest that dendrimers are promising mimics of proteins with different sizes and Ac-G9/Pt NP can be used as an alternative candidate of catalase to decrease oxidation stress in cells.

  13. Ultrathin dendrimer-graphene oxide composite film for stable cycling lithium-sulfur batteries.

    PubMed

    Liu, Wen; Jiang, Jianbing; Yang, Ke R; Mi, Yingying; Kumaravadivel, Piranavan; Zhong, Yiren; Fan, Qi; Weng, Zhe; Wu, Zishan; Cha, Judy J; Zhou, Henghui; Batista, Victor S; Brudvig, Gary W; Wang, Hailiang

    2017-04-04

    Lithium-sulfur batteries (Li-S batteries) have attracted intense interest because of their high specific capacity and low cost, although they are still hindered by severe capacity loss upon cycling caused by the soluble lithium polysulfide intermediates. Although many structure innovations at the material and device levels have been explored for the ultimate goal of realizing long cycle life of Li-S batteries, it remains a major challenge to achieve stable cycling while avoiding energy and power density compromises caused by the introduction of significant dead weight/volume and increased electrochemical resistance. Here we introduce an ultrathin composite film consisting of naphthalimide-functionalized poly(amidoamine) dendrimers and graphene oxide nanosheets as a cycling stabilizer. Combining the dendrimer structure that can confine polysulfide intermediates chemically and physically together with the graphene oxide that renders the film robust and thin (<1% of the thickness of the active sulfur layer), the composite film is designed to enable stable cycling of sulfur cathodes without compromising the energy and power densities. Our sulfur electrodes coated with the composite film exhibit very good cycling stability, together with high sulfur content, large areal capacity, and improved power rate.

  14. Photomanipulation of the anchoring strength using a spontaneously adsorbed layer of azo dendrimers.

    PubMed

    Nádasi, Hajnalka; Stannarius, Ralf; Eremin, Alexey; Ito, Atsuki; Ishikawa, Ken; Haba, Osamu; Yonetake, Koichiro; Takezoe, Hideo; Araoka, Fumito

    2017-03-15

    We systematically studied the photoinduced anchoring transition in a nematic liquid crystal containing azo dendrimers. Because the azo dendrimers in the trans-isomer state were spontaneously adsorbed at substrate surfaces, which was confirmed by optical second-harmonic generation (SHG), a homeotropic orientation was established at the first stage. Ultraviolet (UV) light irradiation triggered a transition into a planar state which was accompanied by a suppression of the SH generation. The monotonic decrease of the effective scalar order parameter with increasing UV light intensity was determined by polarized attenuated total reflection infrared (ATR-IR) spectroscopy. The variation of anchoring strength and extrapolation length was evaluated by observing the Fréedericksz transition as a function of UV light intensity at a certain visible (VIS) light intensity. Such a photoinduced variation can be interpreted as a variation of the anchoring strength depending on the trans/cis ratio at the surfaces based on a modified Rapini-Papoular model. Thus, this system provides the opportunity for a controlled change in the anchoring strength.

  15. 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.

  16. A Systematic Investigation of p-Nitrophenol Reduction by Bimetallic Dendrimer Encapsulated Nanoparticles

    PubMed Central

    2013-01-01

    We demonstrate that the reduction of p-nitrophenol to p-aminophenol by NaBH4 is catalyzed by both monometallic and bimetallic nanoparticles (NPs). We also demonstrate a straightforward and precise method for the synthesis of bimetallic nanoparticles using poly(amido)amine dendrimers. The resulting dendrimer encapsulated nanoparticles (DENs) are monodisperse, and the size distribution does not vary with different elemental combinations. Random alloys of Pt/Cu, Pd/Cu, Pd/Au, Pt/Au, and Au/Cu DENs were synthesized and evaluated as catalysts for p-nitrophenol reduction. These combinations are chosen in order to selectively tune the binding energy of the p-nitrophenol adsorbate to the nanoparticle surface. Following the Brønsted–Evans–Polanyi (BEP) relation, we show that the binding energy can reasonably predict the reaction rates of p-nitrophenol reduction. We demonstrate that the measured reaction rate constants of the bimetallic DENs is not always a simple average of the properties of the constituent metals. In particular, DENs containing metals with similar lattice constants produce a binding energy close to the average of the two constituents, whereas DENs containing metals with a lattice mismatch show a bimodal distribution of binding energies. Overall, in this work we present a uniform method for synthesizing pure and bimetallic DENs and demonstrate that their catalytic properties are dependent on the adsorbate’s binding energy. PMID:23616909

  17. 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.

  18. Evaluation of Jeffamine®-cored PAMAM dendrimers as an efficient in vitro gene delivery system.

    PubMed

    Aydin, Zeynep; Akbas, Fahri; Senel, Mehmet; Koc, S Naci

    2012-10-01

    In this study, we investigated gene delivery properties of Jeffamine-cored polyamidoamine (PAMAM) dendrimers (JCPDs). The effects of dendrimer concentration, generation, and core size on the gene delivery have been analyzed. The experimental results showed that the JCPD effectively delivered plasmid DNA inside the HeLa cells, and the transfection efficiency improved considerably as the number of generation increased. The cytotoxicity of JCPD in different concentration was tested for HeLa cell line. JCPD was complexed with a lacZ gene carrying plasmid and tested for transfection efficiency using quantitative β-galactosidase expression assay. Additionally, confocal microscopy results revealed that JCPD effectively delivered green fluorescent protein-expressing plasmid into HeLa cells and produced fluorescent signal with satisfactory efficiency. The highest transfection efficiency was obtained from JCPDs G4 and G5, which mixed with expression plasmid vectors at a 10/1 weight ratio. These results indicated that under optimized conditions, JCPD can be considered as an efficient transfection reagent and can be effectively used for gene delivery applications.

  19. A Systematic Investigation of p-Nitrophenol Reduction by Bimetallic Dendrimer Encapsulated Nanoparticles.

    PubMed

    Pozun, Zachary D; Rodenbusch, Stacia E; Keller, Emily; Tran, Kelly; Tang, Wenjie; Stevenson, Keith J; Henkelman, Graeme

    2013-04-18

    We demonstrate that the reduction of p-nitrophenol to p-aminophenol by NaBH4 is catalyzed by both monometallic and bimetallic nanoparticles (NPs). We also demonstrate a straightforward and precise method for the synthesis of bimetallic nanoparticles using poly(amido)amine dendrimers. The resulting dendrimer encapsulated nanoparticles (DENs) are monodisperse, and the size distribution does not vary with different elemental combinations. Random alloys of Pt/Cu, Pd/Cu, Pd/Au, Pt/Au, and Au/Cu DENs were synthesized and evaluated as catalysts for p-nitrophenol reduction. These combinations are chosen in order to selectively tune the binding energy of the p-nitrophenol adsorbate to the nanoparticle surface. Following the Brønsted-Evans-Polanyi (BEP) relation, we show that the binding energy can reasonably predict the reaction rates of p-nitrophenol reduction. We demonstrate that the measured reaction rate constants of the bimetallic DENs is not always a simple average of the properties of the constituent metals. In particular, DENs containing metals with similar lattice constants produce a binding energy close to the average of the two constituents, whereas DENs containing metals with a lattice mismatch show a bimodal distribution of binding energies. Overall, in this work we present a uniform method for synthesizing pure and bimetallic DENs and demonstrate that their catalytic properties are dependent on the adsorbate's binding energy.

  20. Polyphenylenepyridyl dendrimers as stabilizing and controlling agents for CdS nanoparticle formation.

    PubMed

    Kuchkina, Nina V; Morgan, David Gene; Stein, Barry D; Puntus, Lada N; Sergeev, Alexander M; Peregudov, Alexander S; Bronstein, Lyudmila M; Shifrina, Zinaida B

    2012-04-07

    Semiconductor nanoparticles (NPs) are being actively explored for applications in medical diagnostics and therapy and numerous electronic devices including solar cells. In this paper we demonstrate the influence of the third generation rigid polyphenylenepyridyl dendrimers (PPPDs) of a different architecture on the formation of well-defined CdS NPs. A high temperature approach to the synthesis of novel CdS/PPPD nanocomposites is feasible due to the high thermal stability of PPPDs. The PPPD architecture affects the CdS NP formation: larger NPs are obtained in the presence of dendrimers with 1,3,5-triphenylbenzene cores compared to those with tetrakis(4-ethynylphen-1-yl)methane cores. The reaction conditions such as concentrations of PPPDs and NP precursors and the temperature regime also influence the CdS NP sizes. For the first time, we elucidated a mechanism of CdS NP formation in a non-coordinating solvent through the CdO redispersion in the presence of PPPDs. Interesting optical properties of these CdS/PPPD nanocomposites make them promising candidates for imaging applications.

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. Bioconjugates of PAMAM dendrimers with trans-retinal, pyridoxal, and pyridoxal phosphate

    PubMed Central

    Filipowicz, A; Wołowiec, S

    2012-01-01

    Background Bioconjugates of a polyamidoamine (PAMAM) G3 dendrimer and an aldehyde were synthesized as carriers for vitamins A and B6, and the bioavailability of these vitamins for skin nutrition was investigated. Methods Nuclear magnetic resonance (NMR) and ultraviolet-visible methods were used to characterize the structure of the bioconjugates and for monitoring release of pyridoxal (Pyr) and pyridoxal phosphate (PLP) from these bioconjugates in vitro. A skin model permeation of bioconjugates was also studied in a Franz chamber. Results A transdermal G3 PAMAM dendrimer was used to synthesize bioconjugates with trans-retinal (Ret), pyridoxal (Pyr), or PLP. These nanomolecules, containing up to four covalently linked Ret, Pyr, or PLP (G34Ret, G34Pyr, and G34PLP), were able to permeate the skin, as demonstrated in vitro using a model skin membrane. PLP and Pyr bound to a macromolecular vehicle were active cofactors for glutamic pyruvic transaminase, as shown by 1H NMR spectral monitoring of the progress of the L-alanine + α-ketoglutarate → glutamic acid + pyruvic acid reaction. Conclusion PAMAM-PLP, PAMAM-Pyr, and PAMAM-Ret bioconjugates are able to permeate the skin. PLP and Pyr are available as cofactors for glutamic pyruvic transaminase. PMID:22973101

  6. 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

  7. Synthesis of ethylene diamine-based ferrocene terminated dendrimers and their application as burning rate catalysts.

    PubMed

    Zain-Ul-Abdin; Wang, Li; Yu, Haojie; Saleem, Muhammad; Akram, Muhammad; Khalid, Hamad; Abbasi, Nasir M; Yang, Xianpeng

    2017-02-01

    Ferrocene-based derivatives are widely used as ferrocene-based burning rate catalysts (BRCs) for ammonium perchlorate (AP)-based propellant. However, in long storage, small ferrocene-based derivatives migrate to the surface of the propellant, which results in changes in the designed burning parameters and finally causes unstable combustion. To retard the migration of ferrocene-based BRCs in the propellant and to increase the combustion of the solid propellant, zero to third generation ethylene diamine-based ferrocene terminated dendrimers (0G, 1G, 2G and 3G) were synthesized. The synthesis of these dendrimers was confirmed by (1)H NMR and FT-IR spectroscopy. The electrochemical behavior of 0G, 1G, 2G and 3G was investigated by cyclic voltammetry (CV) and the burning rate catalytic activity of 0G, 1G, 2G and 3G on thermal disintegration of AP was examined by thermogravimetry (TG) and differential thermogravimetry (DTG) techniques. Anti-migration studies show that 1G, 2G and 3G exhibit improved anti-migration behavior in the AP-based propellant.

  8. Synthesis of nanoparticle-cored dendrimers by convergent dendritic functionalization of monolayer-protected nanoparticles.

    PubMed

    Shon, Young-Seok; Choi, Daeock; Dare, Jonathan; Dinh, Tuong

    2008-06-01

    This article presents a synthesis method for nanoparticle-cored dendrimers (NCDs), which have dendritic architectures around a monolayer-protected gold nanoparticle. The synthesis method is based on a strategy in which the synthesis of monolayer-protected nanoparticles is followed by adding dendrons on functionalized nanoparticles by a single coupling reaction. NMR spectroscopy, IR spectroscopy, and thermogravimetric analysis (TGA) characterizations confirmed the successful coupling reaction between dendrons with different generations ([G1], [G2], and [G3]) and COOH-functionalized nanoparticles ( approximately Au201L71). The dendrimer wedge density also could be controlled by reacting nanoparticles having different loading of COOH groups ( approximately 60 and approximately 10% COOH of the 71 ligands per gold nanoparticle) with functionalized dendrons. Transmission electron microscope results showed that this synthesis strategy maintains the average size of the nanoparticle core during dendron coupling reactions. This control over the composition and core size makes the systematic study of NCDs with different generations possible. The chemical stability of NCDs was found to be affected by dendron generation around the nanoparticle core. The current-potential response of NCD films on microelectrode arrays exhibited better electrical conductivity for NCDs with lower dendron generation.

  9. Preparation and characterization of dendrimer-templated Ag-Cu bimetallic nanoclusters.

    PubMed

    Li, Guoping; Luo, Yunjun

    2008-01-07

    Ag-Cu bimetallic nanoclusters with different shapes were prepared by a co-complexation method in the presence of PAMAM dendrimers. Small and evenly sized spherical Ag-Cu bimetallic nanoparticles were obtained with N2H4.H2O as the reducing agent, and long rod-shaped bimetallic nanoclusters were prepared with NaBH4 as the reducing agent. The mechanisms of formation of Ag-Cu bimetallic nanolusters with different shapes were discussed. The different shapes of the cluster were likely caused by the differences in the reduction rate of metal ions with NaBH4 and N2H4.H2O. Structure characterization by TEM, UV-vis spectra, EDX, and TGA showed that, in the presence of PAMAM dendrimers, Ag-Cu alloy bimetallic nanorods were obtained with NaBH4 reduction, and Ag-Cu bimetallic nanoparticles were prepared with N2H4.H2O as the reducing agent.

  10. PEGylated Dendrimers as Drug Delivery Vehicles for the Photosensitizer Silicon Phthalocyanine Pc 4 for Candidal Infections.

    PubMed

    Hutnick, Melanie A; Ahsanuddin, Sayeeda; Guan, Linna; Lam, Minh; Baron, Elma D; Pokorski, Jonathan K

    2017-02-13

    Fungi account for billions of infections worldwide. The second most prominent causative agent for fungal infections is Candida albicans (C. albicans). As strains of fungi become resistant to antifungal medications, new treatment modalities must be investigated to combat these infections. One approach is to employ photodynamic therapy (PDT). PDT utilizes a photosensitizer, light, and cellular O2 to produce reactive oxygen species (ROS), which then induce oxidative stress resulting in apoptosis. Silicon phthalocyanine Pc 4 is a photosensitizer that has exhibited success in clinical trials for a myriad of skin diseases. The hydrophobic nature of Pc 4, however, poses significant formulation and delivery challenges in the use of this therapy. To mitigate these concerns, a drug delivery vehicle was synthesized to better formulate Pc 4 into a viable PDT agent for treating fungal infections. Utilizing poly(amidoamine) dendrimers as the framework for the vehicle, ∼13% of the amine chain ends were PEGylated to promote water solubility and deter nonspecific adsorption. In vitro studies with C. albicans demonstrate that the potency of Pc 4 was not hindered by the dendrimer vehicle. Encapsulated Pc 4 was able to effectively generate ROS and obliterate fungal pathogens upon photoactivation. The results presented within describe a nanoparticulate delivery vehicle for Pc 4 that readily kills drug-resistant C. albicans and eliminates solvent toxicity, thus, improving formulation characteristics for the hydrophobic photosensitizer.

  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. Tumour regression and improved gastrointestinal tolerability from controlled release of SN-38 from novel polyoxazoline-modified dendrimers.

    PubMed

    England, Richard M; Hare, Jennifer I; Barnes, Jennifer; Wilson, Joanne; Smith, Aaron; Strittmatter, Nicole; Kemmitt, Paul D; Waring, Michael J; Barry, Simon T; Alexander, Cameron; Ashford, Marianne B

    2017-02-10

    Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 l-lysine dendrimer that has been part-modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan. By conjugating SN-38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half-lives of 2.5h, 21h, and 72h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half-life of 21h achieved sustained SN-38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN-38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72h release half-lives did not achieve an anti-tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN-38, which are associated with gastrointestinal toxicity. Administration of the 21h release dendrimer conjugate did not produce a high initial Cmax of SN-38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4mg SN-38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximised efficacy and minimised adverse side effects.

  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

    2015-03-04

    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.

  14. 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

  15. Platinum and Other Transition Metal Nanoclusters (Pd, Rh) Stabilized by PAMAM Dendrimer as Excellent Heterogeneous Catalysts: Application to the Methylcyclopentane (MCP) Hydrogenative Isomerization.

    PubMed

    Deraedt, Christophe; Melaet, Gérôme; Ralston, Walter T; Ye, Rong; Somorjai, Gabor A

    2017-03-08

    Pt, Rh, and Pd nanoclusters stabilized by PAMAM dendrimer are used for the first time in a gas flow reactor at high temperature (150-250 °C). Pt nanoclusters show a very high activity for the hydrogenation of the methylcyclopentane (MCP) at 200-225 °C with turnover freqency (TOF) up to 334 h(-1) and selectivity up to 99.6% for the ring opening isomerization at very high conversion (94%). Rh nanoclusters show different selectivity for the reaction, that is, ring opening isomerization at 175 °C and cracking at higher temperature whereas Pd nanoclusters perform ring enlargement plus dehydrogenation, while maintaining a high activity. The difference in these results as compared to unsupported/uncapped nanoparticles, demonstrates the crucial role of dendrimer. The tunability of the selectivity of the reaction as well as the very high activity of the metal nanoclusters stabilized by dendrimer under heterogeneous conditions open a new application for dendrimer catalysts.

  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. Development of Topical Treatment for Pseudomonas aeruginosa Wound Infections by Quorum-Sensing Inhibitors Mediated by Poly(amidoamine) (PAMAM) Dendrimers

    DTIC Science & Technology

    2013-01-01

    allowed to stir overnight for encapsulation to complete. The resulting encapsulated dendrimer product was obtained by membrane filtration through a 10...solid product of the encapsulated QSI-PAMAM was obtained by lyophilization. Characterization of encapsulated dendrimer species was carried out by HPLC...PAMAM on PqsA activity PqsA is the first enzyme in quinolone synthetic pathway (3). Anthranilic acid (AA) is a substrate for PqsA. AA analogs

  18. Gd3+-DTPA-bis (N-methylamine) - anionic linear globular Dendrimer-G1; a more efficient MRI contrast media.

    PubMed

    Ghalandarlaki, N; Mohammadi, T D; Agha Babaei, R; Tabasi, M A; Keyhanvar, P; Mehravi, B; Yaghmaei, P; Cohan, R A; Ardestani, M S

    2014-02-01

    By advancing of molecular imaging techniques, magnetic resonance imaging (MRI) is becoming an increasingly important tool in early diagnosis. Researchers have found new ways to increase contrast of MRI images.Therefore some types of drug known as contrast media are produced. Contrast media improve the visibility of internal body structures in MRI images. Gadodiamide (Omniscan®) is one of these contrast media which is produced commercially and used clinically. In this study Gadodiamide was first synthesized and then qualitative and quantitative methods were carried out to ensure the proper synthesis of this drug then to increase the efficiency of this contrast medium use dendrimer that is one kind of nano particle. This dendrimer has a polyethylene glycol (PEG) core and citric acid branches. After dendrimer attached to Gadodiamide to ensure the proper efficient connection between them the stability studies were carried out and cytotoxicity of the drug was evaluated. Finally, after ensuring the non-toxicity of the drug, in vivo studies (injected into mice) MR imaging was performed to examine the impact of synthesis drug on the resolution of image.The result obtained from this study demonstrated that the attachment of Gadodiamide to dendrimer reduces its cytotoxicity and also improved resolution of image. Also the new contrast media (Gd3+-DTPA- bis [N-methylamine] - Dendrimer) - unlike Omniscan® - is biodegradable and able to enter the HEPG2 cell line. The results confirm the hypothesis that using dendrimer to synthesize this new nano contrast medium increases its effectiveness.

  19. Tailored control and optimisation of the number of phosphonic acid termini on phosphorus-containing dendrimers for the ex-vivo activation of human monocytes.

    PubMed

    Rolland, Olivier; Griffe, Laurent; Poupot, Mary; Maraval, Alexandrine; Ouali, Armelle; Coppel, Yannick; Fournié, Jean-Jacques; Bacquet, Gérard; Turrin, Cédric-Olivier; Caminade, Anne-Marie; Majoral, Jean-Pierre; Poupot, Rémy

    2008-01-01

    The syntheses of a series of phosphonic acid-capped dendrimers is described. This collection is based on a unique set of dendritic structural parameters-cyclo(triphosphazene) core, benzylhydrazone branches and phosphonic acid surface-and was designed to study the influence of phosphonate (phosphonic acid) surface loading towards the activation of human monocytes ex vivo. Starting from the versatile hexachloro-cyclo(triphosphazene) N(3)P(3)Cl(6), six first-generation dendrimers were obtained, bearing one to six full branches, that lead to 4, 8, 12, 16, 20 and 24 phosphonate termini, respectively. The surface loading was also explored at the limit of dense packing by means of a first-generation dendrimer having a cyclo(tetraphosphazene) core and bearing 32 termini, and with a first-generation dendrimer based on a AB(2)/CD(5) growing pattern and bearing 60 termini. Human monocyte activation by these dendrimers confirms the requirement of the whole dendritic structure for bioactivity and identifies the dendrimer bearing four branches, thus 16 phosphonate termini, as the most bioactive.

  20. Pharmacokinetics of Chiral Dendrimer-Triamine-Coordinated Gd-MRI Contrast Agents Evaluated by in Vivo MRI and Estimated by in Vitro QCM.

    PubMed

    Miyake, Yuka; Ishikawa, Syungo; Kimura, Yu; Son, Aoi; Imai, Hirohiko; Matsuda, Tetsuya; Yamada, Hisatsugu; Toshimitsu, Akio; Kondo, Teruyuki

    2015-12-18

    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 (K(a)) 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 K(a) 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.

  1. Complex dendrimer-lyotropic liquid crystalline systems: structural behavior and interactions.

    PubMed

    Bitan-Cherbakovsky, Liron; Libster, Dima; Aserin, Abraham; Garti, Nissim

    2011-10-27

    The incorporation of dendrimer into three lyotropic liquid crystalline (LLCs) mesophases is demonstrated for the first time. A second generation (G2) of poly(propylene imine) dendrimer (PPI) was solubilized into lamellar, diamond reverse cubic, and reverse hexagonal LLCs composed of glycerol monooleate (GMO), and water (and D-α-tocopherol in the H(II) system). The combination of PPI with LLCs may provide an advantageous drug delivery system. Cross-polarized light microscope, small-angle X-ray scattering (SAXS), and attenuated total reflectance Fourier transform infrared (ATR-FTIR) were utilized to study the structural behavior of the mesophases, the localization of PPI within the system, and the interactions between the guest molecule and the system's components. It was revealed that PPI-G2 functioned as a "water pump", competing with the lipid headgroups for water binding. As a result, L(α)→H(II) and Q(224)→H(II) structural shifts were detected (at 10 wt % PPI-G2 content), probably caused by the dehydration of monoolein headgroups and subsequent increase of the lipid's critical packing parameter (CPP). In the case of H(II), as a result of the balance between the dehydration of the monoolein headgroups and the significant presence of PPI within the interfacial region, increasing the quantity of hydrogen bonds, no structural transitions occurred. ATR-FTIR analysis demonstrated a downward shift of the H-O-H (water), as a result of PPI-G2 embedment, suggesting an increase in the mean water-water H-bond angle resulting from binding PPI-G2 to the water network. Additionally, the GMO hydroxyl groups at β- and γ-C-OH positions revealed a partial interaction of hydrogen bonds with N-H functional groups of the protonated PPI-G2. Other GMO interfacial functional groups were shown to interact with the PPI-G2, in parallel with the GMO dehydration phenomenon. In the future, these outcomes can be used to design advanced drug delivery systems, allowing administration of

  2. Subconjunctival injectable dendrimer-dexamethasone gel for the treatment of corneal inflammation.

    PubMed

    Soiberman, Uri; Kambhampati, Siva P; Wu, Tony; Mishra, Manoj K; Oh, Yumin; Sharma, Rishi; Wang, Jiangxia; Al Towerki, Abdul Elah; Yiu, Samuel; Stark, Walter J; Kannan, Rangaramanujam M

    2017-05-01

    Corneal inflammation is often encountered as a key pathological event in many corneal diseases. Current treatments involve topical corticosteroids which require frequent instillations due to rapid tear turnover, causing side-effects such as corneal toxicity and elevated intraocular pressure (IOP). Hence, new interventions that can reduce side effects, dosing frequency, and increase patient compliance can be highly beneficial. In this study, we explore a subconjunctival injectable gel based on G4-PAMAM dendrimer and hyaluronic acid, cross-linked using thiol-ene click chemistry, incorporated with dendrimer dexamethasone (D-Dex) conjugates as a potential strategy for sustained delivery and enhanced bioavailability of corticosteroids. The efficacy of the injectable gel formulation was evaluated in a rat mild alkali burn model. Fluorescently-labelled dendrimers (D-Cy5) incorporated in the gel release D-Cy5 in vivo. The released D-Cy5 selectively targets and localizes within corneal macrophages in inflamed rat cornea but not in healthy controls. This pathology dependent biodistribution was exploited for drug delivery, by incorporating D-Dex in the injectable gel. The attenuation of corneal inflammation by D-Dex gels was assessed using various clinical and biochemical parameters over a 2-week period. Subconjunctival D-Dex gel treatment resulted in favorable clinically-relevant outcomes with reduced central corneal thickness and improved corneal clarity compared to free-Dex and placebo gel controls. The extent of corneal neovascularization was significantly reduced in the D-Dex group. These findings suggest that D-Dex attenuates corneal inflammation more effectively than free-Dex by attenuating macrophage infiltration and pro-inflammatory cytokines expression. A significant elevation in IOP was not observed in the D-Dex group but was observed in the free-Dex group. This novel injectable D-Dex gel may be a potential drug delivery platform for the treatment of many

  3. Site-selective Cu deposition on Pt dendrimer-encapsulated nanoparticles: correlation of theory and experiment.

    PubMed

    Carino, Emily V; Kim, Hyun You; Henkelman, Graeme; Crooks, Richard M

    2012-03-07

    The voltammetry of Cu underpotential deposition (UPD) onto Pt dendrimer-encapsulated nanoparticles (DENs) containing an average of 147 Pt atoms (Pt(147)) is correlated to density functional theory (DFT) calculations. Specifically, the voltammetric peak positions are in good agreement with the calculated energies for Cu deposition and stripping on the Pt(100) and Pt(111) facets of the DENs. Partial Cu shells on Pt(147) are more stable on the Pt(100) facets, compared to the Pt(111) facets, and therefore, Cu UPD occurs on the 4-fold hollow sites of Pt(100) first. Finally, the structures of Pt DENs having full and partial monolayers of Cu were characterized in situ by X-ray absorption spectroscopy (XAS). The results of XAS studies are also in good agreement with the DFT-optimized models.

  4. Covalent immobilization of lipases on monodisperse magnetic microspheres modified with PAMAM-dendrimer

    NASA Astrophysics Data System (ADS)

    Zhu, Weiwei; Zhang, Yimei; Hou, Chen; Pan, Duo; He, Jianjun; Zhu, Hao

    2016-02-01

    This paper reported an immobilization of Candida rugosa lipase (CRL) onto PAMAM-dendrimer-grafted magnetic nanoparticles synthesized by a modified solvothermal reduction method. The dendritic magnetic nanoparticles were amply characterized by several instrumental measurements, and the CRL was covalently anchored on the three generation supports with glutaraldehyde as coupling reagent. The amount of immobilized enzyme was up to 150 mg/g support and the factors related with the enzyme activity were investigated. The immobilization of lipase improved their performance in wider ranges of pH and temperature. The immobilized lipase exhibited excellent thermal stability and reusability in comparison with free enzyme and can be reused 10 cycles with the enzymatic activity remained above 90 %. The properties of lipase improved obviously after being immobilized on the dendritic supports. The inactive immobilized lipase could be regenerated with glutaraldehyde and Cu2+, respectively. This synthetic strategy was facile and eco-friendly for applications in lipase immobilization.

  5. 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

  6. Biocompatible nanomaterials based on dendrimers, hydrogels and hydrogel nanocomposites for use in biomedicine

    NASA Astrophysics Data System (ADS)

    Khoa Nguyen, Cuu; Quyen Tran, Ngoc; Phuong Nguyen, Thi; Hai Nguyen, Dai

    2017-03-01

    Over the past decades, biopolymer-based nanomaterials have been developed to overcome the limitations of other macro- and micro- synthetic materials as well as the ever increasing demand for the new materials in nanotechnology, biotechnology, biomedicine and others. Owning to their high stability, biodegradability, low toxicity, and biocompatibility, biopolymer-based nanomaterials hold great promise for various biomedical applications. The pursuit of this review is to briefly describe our recent studies regarding biocompatible biopolymer-based nanomaterials, particularly in the form of dendrimers, hydrogels, and hydrogel composites along with the synthetic and modification approaches for the utilization in drug delivery, tissue engineering, and biomedical implants. Moreover, in vitro and in vivo studies for the toxicity evaluation are also discussed.

  7. Facile sol-gel synthesis of porous silicas using poly(propylene)imine dendrimers as templates

    SciTech Connect

    Larsen, Gustavo; Lotero, Edgar; Marquez, Manuel

    2000-08-01

    Commercially available poly(propylene)imine (DAB-Am-32 and DAB-Am-64) dendrimers were used as single-molecule templates to tailor the porosity of silicas via a nonacidic sol-gel method. X-ray diffraction on both the as-prepared (oven-dried at 373 K) and the calcined (833 K) materials revealed that modest contraction took place on template removal and that the cavities created did not achieve three-dimensional ordering under the current synthesis conditions. Transmission electron microscopy of ''Pt-stained'' samples supported this picture. A modified Horvath-Kawazoe analysis of the argon adsorption isotherms indicated that DAB-Am-64 is a much more effective template than DAB-Am-32. Pyrolysis and oxidation protocols for template removal are also presented. (c) 2000 Materials Research Society.

  8. Sugar-sensitive dendrimer films as a sacrificial layer for the preparation of freestanding multilayer films.

    PubMed

    Sato, Fumiya; Anzai, Jun-Ichi

    2017-03-01

    Multilayer thin films composed of poly(vinyl alcohol) (PVA) and phenylboronic acid-bearing poly(amidoamine) dendrimer (PBA-PAMAM) were used as a sacrificial layer for constructing freestanding polyelectrolyte films consisting of poly(styrenesulfonate) (PSS) and poly(allylamine hydrochloride) (PAH). Freestanding (PSS/PAH)15 films were successfully released from substrate by exposing composite (PVA/PBA-PAMAM)n/(PSS/PAH)15 films (n=5 and 10) to sorbitol solutions under mild conditions at pH7.0-9.0. The film release was accelerated in solutions of higher sorbitol concentrations at pH9.0 as well as in solutions with lower concentration of NaCl. The results were rationalized based on the scission of boronate ester bonds between PBA-PAMAM and PVA in the (PVA/PBA-PAMAM)n layer due to a competitive binding of sorbitol to PBA-PAMAM.

  9. 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.

  10. Reversible immobilization of BSA on Cu-chelated PAMAM dendrimer modified iron oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Demir, M.; Şenel, M.; Baykal, A.

    2014-09-01

    In this study, polyamidoamine (PAMAM) dendrimer coated superparamagnetite nanoparticles were synthesized by growing of PAMAM on amino-silane coated iron oxide nanoparticles. The PAMAM modified superparamagnetite nanoparticles were used as reversible protein immobilization host materials. During the reversible immobilization studies the effect of different metal ions such as; Cu+2, Zn+2, Co+2, Ni+2 on immobilization efficiency of BSA were evaluated. The maximum BSA adsorption capacity of the PAMAM-MNP- Cu+2 beads was observed to be 52.84 mg/g (BSA/PAMAM-MNP) at pH 7.0. Various characteristics of immobilized BSA such as; effect of generation, effect of pH, BSA concentration, temperature, salt concentration and reusability of PAMAM-MNP were evaluated.

  11. 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.

  12. Lateral flow immunoassay with the signal enhanced by gold nanoparticle aggregates based on polyamidoamine dendrimer.

    PubMed

    Shen, Guangyu; Xu, Hui; Gurung, Anant S; Yang, Yunhui; Liu, Guodong

    2013-01-01

    In order to amplify the signal in a gold nanoparticle-based lateral flow immunoassay, a simple and sensitive method utilizing gold nanoparticle aggregates as a colored reagent formed with a polyamidoamine dendrimer was developed. The results were compared with that achieved by employing the individual nanoparticles used in the conventional lateral flow immunoassay. Under the optimized experimental conditions, a detection limit of 0.1 ng mL⁻¹ for rabbit immunoglobulin G was achieved, which is almost 20-fold lower than that of the traditional method using individual gold nanoparticles. We believe that this simple, practical bioassay platform will be of interest for use in areas such as disease diagnostics, pathogen detection, and quality monitoring of food and water.

  13. Non-adiabatic excited state molecular dynamics of phenylene ethynylene dendrimer using a multiconfigurational Ehrenfest approach

    DOE PAGES

    Fernandez-Alberti, Sebastian; Makhov, Dmitry V.; Tretiak, Sergei; ...

    2016-03-10

    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. In conclusion, 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.

  14. Study of linear and nonlinear optical properties of dendrimers using density matrix renormalization group method

    NASA Astrophysics Data System (ADS)

    Mukhopadhyay, S.; Ramasesha, S.

    2009-08-01

    We have used the density matrix renormalization group (DMRG) method to study the linear and nonlinear optical responses of first generation nitrogen based dendrimers with donor acceptor groups. We have employed Pariser-Parr-Pople Hamiltonian to model the interacting π electrons in these systems. Within the DMRG method we have used an innovative scheme to target excited states with large transition dipole to the ground state. This method reproduces exact optical gaps and polarization in systems where exact diagonalization of the Hamiltonian is possible. We have used a correction vector method which tacitly takes into account the contribution of all excited states, to obtain the ground state polarizibility, first hyperpolarizibility, and two photon absorption cross sections. We find that the lowest optical excitations as well as the lowest excited triplet states are localized. It is interesting to note that the first hyperpolarizibility saturates more rapidly with system size compared to linear polarizibility unlike that of linear polyenes.

  15. Targeted Theranostic Approach for Glioma Using Dendrimer-Based Curcumin Nanoparticle

    PubMed Central

    Gamage, NH; Jing, Li; Worsham, MJ; Ali, MM

    2016-01-01

    The delivery of anti-cancer agents to brain tumors represent a challenge because the blood-brain tumor barrier (BBTB) effectively limits the delivery of many agents. A new generation 3 (G3) dendrimer-based curcumin (Curc) conjugate was synthesized. The synthesized G3-Curc conjugate demonstrated full solubility in aqueous media. The in vitro study revealed that G3-Curc nanoparticles were internalized into glioma U-251 cells. Systemic delivery of G3-Curc conjugate led to preferentially accumulation in an orthotopic preclinical glioma model minimizing systemic toxic effect. Multicolor microscopy images of the tumor tissue showed that G3-Curc particles were internalized inside tumor cells selectively and further localized within nuclei. Enhanced bioavailability of G3-Curc conjugate was also observed with improved therapeutic efficacy against different cancers cells. PMID:27699139

  16. Unambiguous detection of nitrated explosive vapours by fluorescence quenching of dendrimer films

    NASA Astrophysics Data System (ADS)

    Geng, Yan; Ali, Mohammad A.; Clulow, Andrew J.; Fan, Shengqiang; Burn, Paul L.; Gentle, Ian R.; Meredith, Paul; Shaw, Paul E.

    2015-09-01

    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.

  17. Nanoparticle corona for proteins: mechanisms of interaction between dendrimers and proteins.

    PubMed

    Shcharbin, Dzmitry; Ionov, Maksim; Abashkin, Viktar; Loznikova, Svetlana; Dzmitruk, Volha; Shcharbina, Natallia; Matusevich, Ludmila; Milowska, Katarzyna; Gałęcki, Krystian; Wysocki, Stanisław; Bryszewska, Maria

    2015-10-01

    Protein absorption at the surface of big nanoparticles and formation of 'protein corona' can completely change their biological properties. In contrast, we have studied the binding of small nanoparticles - dendrimers - to proteins and the formation of their 'nanoparticle corona'. Three different types of interactions were observed. (1) If proteins have rigid structure and active site buried deeply inside, the 'nanoparticle corona' is unaffected. (2) If proteins have a flexible structure and their active site is also buried deeply inside, the 'nanoparticle corona' affects protein structure, but not enzymatic activity. (3) The 'nanoparticle corona' changes both the structure and enzymatic activity of flexible proteins that have surface-based active centers. These differences are important in understanding interactions taking place at a bio-nanointerface.

  18. Study of linear and nonlinear optical properties of dendrimers using density matrix renormalization group method.

    PubMed

    Mukhopadhyay, S; Ramasesha, S

    2009-08-21

    We have used the density matrix renormalization group (DMRG) method to study the linear and nonlinear optical responses of first generation nitrogen based dendrimers with donor acceptor groups. We have employed Pariser-Parr-Pople Hamiltonian to model the interacting pi electrons in these systems. Within the DMRG method we have used an innovative scheme to target excited states with large transition dipole to the ground state. This method reproduces exact optical gaps and polarization in systems where exact diagonalization of the Hamiltonian is possible. We have used a correction vector method which tacitly takes into account the contribution of all excited states, to obtain the ground state polarizibility, first hyperpolarizibility, and two photon absorption cross sections. We find that the lowest optical excitations as well as the lowest excited triplet states are localized. It is interesting to note that the first hyperpolarizibility saturates more rapidly with system size compared to linear polarizibility unlike that of linear polyenes.

  19. Polyamidoamine dendrimer as a spacer for the immobilization of glucose oxidase in capillary enzyme microreactor.

    PubMed

    Wang, Siming; Su, Ping; Hongjun, E; Yang, Yi

    2010-10-15

    Polyamidoamine dendrimer (PAMAM) is one of a number of dendritic polymers with precise molecular structure, highly geometric symmetry, and a large number of terminal groups. In this study, different generations of PAMAM (G0-G4) were introduced onto the inner wall of fused-silica capillaries by microwave irradiation and a new type of glucose oxidase (GOx) capillary enzyme microreactor was developed based on enzyme immobilization in the prepared PAMAM-grafted fused-silica capillaries. The optimal enzymolysis conditions for beta-d-glucose in the microreactor were evaluated by capillary zone electrophoresis. In addition, the enzymolysis efficiencies of different generations of PAMAM-GOx capillary enzyme microreactor were compared. The results indicate that enzymolysis efficiency increased with increasing generations of PAMAM. The experimental results provide the possibility for the development and application of an online immobilized capillary enzyme microreactor.

  20. Wetting and layering transitions in a nano-dendrimer PAMAM structure: Monte Carlo study

    NASA Astrophysics Data System (ADS)

    Aouini, S.; Ziti, S.; Labrim, H.; Bahmad, L.

    2016-10-01

    This study is based on a nano-model of the dendrimer polyamidoamine (PAMAM). The idea is to examine the magnetic properties of such models in the context of wetting and the layering transitions. The studied system consists of spins σ ={1/2} Ising ferromagnetic in real nanostructure found in different scientific domains. To study this system, we perform Monte Carlo simulations leading to interesting results recapitulated in two classes. The former is the ground state phase diagrams study. The latter is the magnetic properties at non null temperatures. Also, we analyzed the effect of the terms present in the Hamiltonian governing our system such as the external magnetic field and the exchange couplings interactions.

  1. 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

  2. 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.

  3. Alkyl cross-linked low molecular weight polypropyleneimine dendrimers as efficient gene delivery vectors

    PubMed Central

    Ariaee, Faezeh Moghadam; Hashemi, Maryam; Farzad, Sara Amel; Abnous, Khalil; Ramezani, Mohammad

    2016-01-01

    Objective(s): In recent years, polypropyleneimine (PPI) dendrimers have attracted great interest as non-viral gene delivery systems because of their attractive features including highly branched architecture with number of reactive end groups. However, without being structurally modified, they are not efficient gene carriers. In the present study, generation 2 and 3 (G2 and G3) of PPI dendrimers were conjugated with alkylcarboxylate groups as linker to enhance the transfection efficiency while maintaining their low cell toxicity. Materials and Methods: First, 10-bromodecanoic acid was covalently attached to all available surface primary amines of PPI G2 and G3 to increase their lipophilicity. In the subsequent step, PPIs were conjugated to the alkylcarboxylate groups of alkylcarboxylate-PPI derivatives to increase the number of surface primary amines. Physicochemical properties of modified PPIs were determined. Transfection experiments (using both luciferase and green fluorescent protein (GFP)- expressing plasmids) and cytotoxicity assay were performed to evaluate the efficiency of the final derivatives. Results: Fabricated vectors condensed DNA effectively so that polyplexes with appropriate size (below 155 nm) and positive surface charge were constructed. Cross-linked low molecular weight PPIs (G2 or G3) with decanoate linkage increased transfection efficiency significantly while maintaining the low cytotoxicity. PPI G2 derivative exhibited increased buffering capacity which is believed to be responsible for better proton sponge mechanism leading to higher transfection efficiency. Conclusion: Our results indicated that oligomerization of low molecular weight PPI (PPI G2-alkyl-PPI G2 conjugate) could be an approach to increase the transfection efficiency and to lower the cytotoxicity of low molecular weight polycations. PMID:27872706

  4. Multiple antigen peptide dendrimer elicits antibodies for detecting rat and mouse growth hormone binding proteins

    PubMed Central

    Aguilar, Roberto M.; Talamantes, Frank J.; Bustamante, Juan J.; Muñoz, Jesus; Treviño, Lisa R.; Martinez, Andrew O.; Haro, Luis S.

    2009-01-01

    The membrane-bound rat growth hormone receptor (GH-R) and an alternatively spliced isoform, the soluble rat GH binding protein (GH-BP), are comprised of identical N-terminal GH binding domains, however, their C-terminal sequences differ. Immunological reagents are needed to distinguish between the two isoforms in order to understand their respective roles in mediating the actions of GH. Accordingly, a tetravalent multiple antigen peptide (MAP) dendrimer with four identical branches of a C-terminal peptide sequence of the rat GH-BP (GH-BP263-279) was synthesized and used as an immunogen in rabbits. Solid-phase peptide synthesis of four GH-BP263-279 segments onto a tetravalent Lys2-Lys-β-Ala-OH core peptide was carried out using N-(9-fluorenyl)methoxycarbonyl chemistry. The mass of the RP-HPLC purified synthetic product, 8398 Da, determined by ESI-MS, was identical to expected mass. Three anti-rat GH-BP263-279 MAP antisera, BETO-8039, BETO-8040 and BETO-8041, at dilutions of 10-3, recognized both the rat GH-BP263-279 MAP and recombinant mouse GH-BP with ED50s within a range of 5-10 fmol but did not cross-react with BSA in dot blot analyses. BETO-8041 antisera (10-3 dilution) recognized GH-BPs of rat serum and liver having Mrs ranging from 35-130 kDa but did not recognize full-length rat GH-Rs. The antisera also detected recombinant mouse GH-BPs. In summary, the tetravalent rat GH-BP263-279 MAP dendrimer served as an effective immunogenic antigen in eliciting high titer antisera specific for the C-termini of both rat and mouse GH-BPs. The antisera will facilitate studies aimed at improving our understanding of the biology of GH-BPs. PMID:19089805

  5. Dendrimer, liposomes, carbon nanotubes and PLGA nanoparticles: one platform assessment of drug delivery potential.

    PubMed

    Mody, Nishi; Tekade, Rakesh Kumar; Mehra, Neelesh Kumar; Chopdey, Prashant; Jain, Narendra Kumar

    2014-04-01

    Liposomes (LIP), nanoparticles (NP), dendrimers (DEN), and carbon nanotubes (CNTs), represent eminent classes of drug delivery devices. A study was carried out herewith by employing docetaxel (DTX) as model drug to assess their comparative drug delivery potentials. Under optimized conditions, highest entrapment of DTX was observed in CNT-based formulation (DTX-CNTs, 74.70 ± 4.9%) followed by nanoparticles (DTX-NP, 62.34 ± 1.5%), liposome (49.2 ± 1.51%), and dendrimers (28.26 ± 1.74%). All the formulations were found to be of nanometric size. In vitro release studies were carried out in PBS (pH 7.0 and 4.0), wherein all the formulations showed biphasic release pattern. Cytotoxicity assay in human cervical cancer SiHa cells inferred lowest IC50 value of 1,235.09 ± 41.93 nM with DTX-CNTs, followed by DTX-DEN, DTX-LIP, DTX-NP with IC50 values of 1,571.22 ± 151.27, 1,653.98 ± 72.89, 1,922.75 ± 75.15 nM, respectively. Plain DTX showed higher hemolytic toxicity of 22.48 ± 0.94%, however loading of DTX inside nanocarriers drastically reduced its hemolytic toxicity (DTX-DEN, 17.22 ± 0.48%; DTX-LIP, 4.13 ± 0.19%; DTX-NP, 6.43 ± 0.44%; DTX-CNTs, 14.87 ± 1.69%).

  6. Deposition of silver nanoparticles on dendrimer functionalized multiwalled carbon nanotubes: synthesis, characterization and antimicrobial activity.

    PubMed

    Neelgund, Gururaj M; Oki, Aderemi

    2011-04-01

    The nanohybrids composed of silver nanoparticles and aromatic polyamide functionalized multiwalled carbon nanotubes (MWCNTs) is successfully synthesized and tested for their antibacterial activity against different pathogens. Prior to deposition of silver nanoparticles, acid treated MWCNTs (MWCNTs-COOH) were successively reacted with p-phenylenediamine and methylmethacrylate to form series of NH2-terminated aromatic polyamide dendrimers on the surface of MWCNTs through Michael addition and amidation. Existence of high abundance of amine groups on the surface of functionalized MWCNTs (f-MWCNTs) provided sites for formation of silver nanoparticles by the reduction of aqueous solution of AgNO3. The silver nanoparticles formed in the resulted f-MWCNTs-Ag nanohybrids were determined to be face centered cubic (fcc) symmetry. The structure and nature of f-MWCNTs and f-MWCNTs-Ag nanohybrids were characterized by UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction analysis (XRD), Raman spectroscopy and thermogravimetric analysis (TGA). The dispersion state of f-MWCNTs and immobilization of silver nanoparticles on the surface of f-MWCNTs were investigated by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Elemental composition of f-MWCNTs-Ag nanohybrids was determined by energy dispersive X-ray spectroscopy (EDS). The antimicrobial activity of f-MWCNTs-Ag nanohybrids were estimated against E. coli, P. aeruginosa and S. aureu and compared with MWCNTs-COOH and f-MWCNTs. The results indicate that functionalization of MWCNTs with aromatic polyamide dendrimers and successive deposition of Ag nanoparticles could play an important role in the enhancement of antimicrobial activity.

  7. 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

  8. 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, Ji-Guang; 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).

  9. 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.

  10. Thiolated DAB dendrimers and CdSe quantum dots nanocomposites for Cd(II) or Pb(II) sensing.

    PubMed

    Algarra, M; Campos, B B; Alonso, B; Miranda, M S; Martínez, A M; Casado, C M; Esteves da Silva, J C G

    2012-01-15

    Four different generation of thiol-DAB dendrimers were synthesized, S-DAB-G(x) (x=1, 2, 3 and 5), and coupled with CdSe quantum dots, to obtain fluorescent nanocomposites as metal ions sensing. Cd(II) and Pb(II) showed the higher enhancement and quenching effects respectively towards the fluorescence of S-DAB-G(5)-CdSe nanocomposite. The fluorescence enhancement provoked by Cd(II) can be linearized using a Henderson-Hasselbalch type equation and the quenching provoked by Pb(II) can be linearized by a Stern-Volmer equation. The sensor responds to Cd(II) ion in the 0.05-0.7μM concentration range and to Pb(II) ion in the 0.01-0.15mM concentration range with a LOD of 0.06mM. The sensor has selectivity limitations but its dendrimer configuration has analytical advantages.

  11. Triggering hairpin-free chain-branching growth of fluorescent DNA dendrimers for nonlinear hybridization chain reaction.

    PubMed

    Xuan, Feng; Hsing, I-Ming

    2014-07-16

    We present a nonlinear hybridization chain reaction (HCR) system in which a trigger DNA initiates self-sustained assembly of quenched double-stranded substrates into fluorescent dendritic nanostructures. During the process, an increasing number of originally sequestered trigger sequences labeled with fluorescent reporters are freed up from quenched substrates, leading to chain-branching growth of the assembled DNA dendrimers and an exponential increase in the fluorescence intensity. The triggered assembly behavior was examined by PAGE analysis, and the morphologies of the grown dendrimers were verified by AFM imaging. The exponential kinetics of the fluorescence accumulation was also confirmed by time-dependent fluorescence spectroscopy. This method adopts a simple sequence design strategy, the concept of which could be adapted to program assembly systems with higher-order growth kinetics.

  12. 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

  13. Tuning polarity of polyphenylene dendrimers by patched surface amphiphilicity--precise control over size, shape, and polarity.

    PubMed

    Stangenberg, René; Saeed, Irfan; Kuan, Seah Ling; Baumgarten, Martin; Weil, Tanja; Klapper, Markus; Müllen, Klaus

    2014-01-01

    In the ideal case, a precise synthesis yields molecules with a constitutional as well as a conformational perfectness. Such a case of precision is demonstrated by the synthesis of semi-rigid amphiphilic polyphenylene dendrimers (PPDs). Polar sulfonate groups are precisely placed on their periphery in such a manner that patches of polar and non-polar regions are created. Key structural features are the semi-rigid framework and shape-persistent nature of PPDs since the limited flexibility introduces a nano-phase-separated amphiphilic rim of the dendrimer. This results in both attractive and repulsive interactions with a given solvent. Frustrated solvent structures then lead to a remarkable solubility in solvents of different polarity such as toluene, methanol, and water or their mixtures. Water solubility combined with defined surface structuring and variable hydrophobicity of PPDs that resemble the delicate surface textures of proteins are important prerequisites for their biological and medical applications based upon cellular internalization.

  14. Avoiding Steric’ Congestion in Dendrimer Growth through Proportionate Branching: A Twist on da Vinci’s Rule of Tree Branching

    PubMed Central

    Yue, Xuyi; Taraban, Marc B; Hyland, Laura L.

    2013-01-01

    Making defect-free macromolecules is a challenging issue in chemical synthesis. This challenge is especially pronounced in dendrimer synthesis where exponential growth quickly leads to steric congestion. To overcome this difficulty, proportionate branching in dendrimer growth is proposed. In proportionate branching, both the number and the length of branches increase exponentially, but in opposite directions to mimic tree growth. The effectiveness of this strategy is demonstrated through the synthesis of a fluorocarbon dendron containing 243 chemically identical fluorine atoms with a MW of 9,082 Da. Monodispersity is confirmed by nuclear magnetic resonance spectroscopy, mass spectrometry and small-angle X-ray scattering. Growing different parts proportionately, as nature does, could be a general strategy to achieve defect-free synthesis of macromolecules. PMID:23039185

  15. 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.

  16. Modulation of pro-inflammatory activation of monocytes and dendritic cells by aza-bis-phosphonate dendrimer as an experimental therapeutic agent

    PubMed Central

    2014-01-01

    Introduction Our objective was to assess the capacity of dendrimer aza-bis-phosphonate (ABP) to modulate phenotype of monocytes (Mo) and monocytes derived dendritic cells (MoDC) activated in response to toll-like receptor 4 (TLR4) and interferon γ (IFN- γ) stimulation. Methods Mo (n = 12) and MoDC (n = 11) from peripheral blood of healthy donors were prepared. Cells were preincubated or not for 1 hour with dendrimer ABP, then incubated with lipopolysaccharide (LPS; as a TLR4 ligand) and (IFN-γ) for 38 hours. Secretion of tumor necrosis factor α (TNFα), interleukin (IL) -1, IL-6, IL-12, IL-10 and IL-23 in the culture medium was measured by enzyme-linked immunosorbent assay (ELISA) and Cytokine Bead Array. Differentiation and subsequent maturation of MoDC from nine donors in the presence of LPS were analyzed by flow cytometry using CD80, CD86, CD83 and CD1a surface expression as markers. Results Mo and MoDC were orientated to a pro-inflammatory state. In activated Mo, TNFα, IL-1β and IL-23 levels were significantly lower after prior incubation with dendrimer ABP. In activated MoDC, dendrimer ABP promoted IL-10 secretion while decreasing dramatically the level of IL-12. TNFα and IL-6 secretion were significantly lower in the presence of dendrimer ABP. LPS driven maturation of MoDC was impaired by dendrimer ABP treatment, as attested by the significantly lower expression of CD80 and CD86. Conclusion Our data indicate that dendrimer ABP possesses immunomodulatory properties on human Mo and MoDC, in TLR4 + IFN-γ stimulation model, by inducing M2 alternative activation of Mo and promoting tolerogenic MoDC. PMID:24745366

  17. The effect of dendrimer generati