These are representative sample records from Science.gov related to your search topic.
For comprehensive and current results, perform a real-time search at Science.gov.
1

LHRH-targeted nanogels as a delivery system for cisplatin to ovarian cancer.  

PubMed

Targeted drug delivery using multifunctional polymeric nanocarriers is a modern approach for cancer therapy. Our purpose was to prepare targeted nanogels for selective delivery of chemotherapeutic agent cisplatin to luteinizing hormone-releasing hormone (LHRH) receptor overexpressing tumor in vivo. Building blocks of such delivery systems consisted of innovative soft block copolymer nanogels with ionic cores serving as a reservoir for cisplatin (loading 35%) and a synthetic analogue of LHRH conjugated to the nanogels via poly(ethylene glycol) spacer. Covalent attachment of (D-Lys6)-LHRH to nanogels was shown to be possible without loss in either the ligand binding affinity or the nanogel drug incorporation ability. LHRH-nanogel accumulation was specific to the LHRH-receptor positive A2780 ovarian cancer cells and not toward LHRH-receptor negative SKOV-3 cells. The LHRH-nanogel cisplatin formulation was more effective and less toxic than equimolar doses of free cisplatin or untargeted nanogels in the treatment of receptor-positive ovarian cancer xenografts in mice. Collectively, the study indicates that LHRH mediated nanogel-cisplatin delivery is a promising formulation strategy for therapy of tumors that express the LHRH receptor. PMID:23957812

Nukolova, Natalia V; Oberoi, Hardeep S; Zhao, Yi; Chekhonin, Vladimir P; Kabanov, Alexander V; Bronich, Tatiana K

2013-10-01

2

Multifunctional quantum dot-polypeptide hybrid nanogel for targeted imaging and drug delivery  

NASA Astrophysics Data System (ADS)

A new type of multifunctional quantum dot (QD)-polypeptide hybrid nanogel with targeted imaging and drug delivery properties has been developed by metal-affinity driven self-assembly between artificial polypeptides and CdSe-ZnS core-shell QDs. On the surface of QDs, a tunable sandwich-like microstructure consisting of two hydrophobic layers and one hydrophilic layer between them was verified by capillary electrophoresis, transmission electron microscopy, and dynamic light scattering measurements. Hydrophobic and hydrophilic drugs can be simultaneously loaded in a QD-polypeptide nanogel. In vitro drug release of drug-loaded QD-polypeptide nanogels varies strongly with temperature, pH, and competitors. A drug-loaded QD-polypeptide nanogel with an arginine-glycine-aspartic acid (RGD) motif exhibited efficient receptor-mediated endocytosis in ?v?3 overexpressing HeLa cells but not in the control MCF-7 cells as analyzed by confocal microscopy and flow cytometry. In contrast, non-targeted QD-polypeptide nanogels revealed minimal binding and uptake in HeLa cells. Compared with the original QDs, the QD-polypeptide nanogels showed lower in vitro cytotoxicity for both HeLa cells and NIH 3T3 cells. Furthermore, the cytotoxicity of the targeted QD-polypeptide nanogel was lower for normal NIH 3T3 cells than that for HeLa cancer cells. These results demonstrate that the integration of imaging and drug delivery functions in a single QD-polypeptide nanogel has the potential for application in cancer diagnosis, imaging, and therapy.A new type of multifunctional quantum dot (QD)-polypeptide hybrid nanogel with targeted imaging and drug delivery properties has been developed by metal-affinity driven self-assembly between artificial polypeptides and CdSe-ZnS core-shell QDs. On the surface of QDs, a tunable sandwich-like microstructure consisting of two hydrophobic layers and one hydrophilic layer between them was verified by capillary electrophoresis, transmission electron microscopy, and dynamic light scattering measurements. Hydrophobic and hydrophilic drugs can be simultaneously loaded in a QD-polypeptide nanogel. In vitro drug release of drug-loaded QD-polypeptide nanogels varies strongly with temperature, pH, and competitors. A drug-loaded QD-polypeptide nanogel with an arginine-glycine-aspartic acid (RGD) motif exhibited efficient receptor-mediated endocytosis in ?v?3 overexpressing HeLa cells but not in the control MCF-7 cells as analyzed by confocal microscopy and flow cytometry. In contrast, non-targeted QD-polypeptide nanogels revealed minimal binding and uptake in HeLa cells. Compared with the original QDs, the QD-polypeptide nanogels showed lower in vitro cytotoxicity for both HeLa cells and NIH 3T3 cells. Furthermore, the cytotoxicity of the targeted QD-polypeptide nanogel was lower for normal NIH 3T3 cells than that for HeLa cancer cells. These results demonstrate that the integration of imaging and drug delivery functions in a single QD-polypeptide nanogel has the potential for application in cancer diagnosis, imaging, and therapy. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr03058c

Yang, Jie; Yao, Ming-Hao; Wen, Lang; Song, Ji-Tao; Zhang, Ming-Zhen; Zhao, Yuan-Di; Liu, Bo

2014-09-01

3

Near-infrared light-responsive core-shell nanogels for targeted drug delivery.  

PubMed

A near-infrared light-responsive drug delivery platform based on Au-Ag nanorods (Au-Ag NRs) coated with DNA cross-linked polymeric shells was constructed. DNA complementarity has been applied to develop a polyacrylamide-based sol-gel transition system to encapsulate anticancer drugs into the gel scaffold. The Au-Ag NR-based nanogels can also be readily functionalized with targeting moieties, such as aptamers, for specific recognition of tumor cells. When exposed to NIR irradiation, the photothermal effect of the Au-Ag NRs leads to a rapid rise in the temperature of the surrounding gel, resulting in the fast release of the encapsulated payload with high controllability. In vitro study confirmed that aptamer-functionalized nanogels can be used as drug carriers for targeted drug delivery with remote control capability by NIR light with high spatial/temporal resolution. PMID:21542633

Kang, Huaizhi; Trondoli, Anna Carolina; Zhu, Guizhi; Chen, Yan; Chang, Ya-Jen; Liu, Haipeng; Huang, Yu-Fen; Zhang, Xiaoling; Tan, Weihong

2011-06-28

4

Nanogels for Oligonucleotide Delivery to the Brain  

PubMed Central

Systemic delivery of oligonucleotides (ODN) to the central nervous system is needed for development of therapeutic and diagnostic modalities for treatment of neurodegenerative disorders. Macromolecules injected in blood are poorly transported across the blood–brain barrier (BBB) and rapidly cleared from circulation. In this work we propose a novel system for ODN delivery to the brain based on nanoscale network of cross-linked poly(ethylene glycol) and polyethylenimine (“nanogel”). The methods of synthesis of nanogel and its modification with specific targeting molecules are described. Nanogels can bind and encapsulate spontaneously negatively charged ODN, resulting in formation of stable aqueous dispersion of polyelectrolyte complex with particle sizes less than 100 nm. Using polarized monolayers of bovine brain microvessel endothelial cells as an in vitro model this study demonstrates that ODN incorporated in nanogel formulations can be effectively transported across the BBB. The transport efficacy is further increased when the surface of the nanogel is modified with transferrin or insulin. Importantly the ODN is transported across the brain microvessel cells through the transcellular pathway; after transport, ODN remains mostly incorporated in the nanogel and ODN displays little degradation compared to the free ODN. Using mouse model for biodistribution studies in vivo, this work demonstrated that as a result of incorporation into nanogel 1 h after intravenous injection the accumulation of a phosphorothioate ODN in the brain increases by over 15 fold while in liver and spleen decreases by 2-fold compared to the free ODN. Overall, this study suggests that nanogel is a promising system for delivery of ODN to the brain. PMID:14733583

Vinogradov, Serguei V.; Batrakova, Elena V.; Kabanov, Alexander V.

2009-01-01

5

Triple-responsive expansile nanogel for tumor and mitochondria targeted photosensitizer delivery.  

PubMed

A pH, thermal, and redox potential triple-responsive expansile nanogel system (TRN), which swells at acidic pH, temperature higher than its transition temperature, and reducing environment, has been developed. TRN quickly expands from 108 nm to over 1200 nm (in diameter), achieving more than 1000-fold size enlargement (in volume), within 2 h in a reducing environment at body temperature. Sigma-2 receptor targeting-ligand functionalized TRN can effectively target head and neck tumor, and help Pc 4 targeting mitochondria inside cancer cells to achieve enhanced photodynamic therapy efficacy. PMID:25154666

He, Huacheng; Cattran, Alexander W; Nguyen, Tu; Nieminen, Anna-Liisa; Xu, Peisheng

2014-11-01

6

Polymer nanogels: a versatile nanoscopic drug delivery platform  

PubMed Central

In this review we put the spotlight on crosslinked polymer nanogels, a promising platform that has the characteristics of an “ideal” drug delivery vehicle. Some of the key aspects of drug delivery vehicle design like stability, response to biologically relevant stimuli, passive targeting, active targeting, toxicity and ease of synthesis are discussed. We discuss several delivery systems in this light and highlight some examples of systems, which satisfy some or all of these design requirements. In particular, we point to the advantages that crosslinked polymeric systems bring to drug delivery. We review some of the synthetic methods of nanogel synthesis and conclude with the diverse applications in drug delivery where nanogels have been fruitfully employed. PMID:22342438

Chacko, Reuben T.; Ventura, Judy; Zhuang, Jiaming; Thayumanavan, S.

2012-01-01

7

Smart stimuli sensitive nanogels in cancer drug delivery and imaging: a review.  

PubMed

Nanogels are nanosized hydrogel particles formed by physical or chemical cross-linked polymer networks. The advantageous properties of nanogels related to the ability of retaining considerable amount of water, the biocompatibility of the polymers used, the ability to encapsulate and protect a large quantity of payload drugs within the nanogel matrix, the high stability in aqueous media, their stimuli responsively behavior potential, and the versatility in release drugs in a controlled manner make them very attractive for use in the area of drug delivery. The materials used for the preparation of nanogels ranged from natural polymers like ovalbumin, pullulan, hyaluronic acid, methacrylated chondroitin sulfate and chitosan, to synthetic polymers like poly (N-isopropylacrylamide), poly (Nisopropylacrylamide- co-acrylic acid) and poly (ethylene glycol)-b-poly (methacrylic acid). The porous nanogels have been finding application as anti-cancer drug and imaging agent reservoirs. Smart nanogels responding to external stimuli such as temperature, pH etc can be designed for diverse therapeutic and diagnostic applications. The nanogels have also been surface functionalized with specific ligands aiding in targeted drug delivery. This review focus on stimuli-sensitive, multi-responsive, magnetic and targeted nanogels providing a brief insight on the application of nanogels in cancer drug delivery and imaging in detail. PMID:23489200

Maya, S; Sarmento, Bruno; Nair, Amrita; Rejinold, N Sanoj; Nair, Shantikumar V; Jayakumar, R

2013-01-01

8

Self-reinforced endocytoses of smart polypeptide nanogels for "on-demand" drug delivery.  

PubMed

The pH and reduction dual-responsive polypeptide nanogels with self-reinforced endocytoses were prepared through ring-opening polymerization of l-glutamate N-carboxyanhydrides, deprotection of benzyl group and subsequent quaternization reaction between ?-2-chloroethyl-l-glutamate unit in polypeptide block and 2,2'-dithiobis(N,N-dimethylethylamine). The nanogels were revealed to exhibit smart pH and reduction dual-responsiveness, and excellent biocompatibilities, which expressed great potential as antitumor drug nanocarriers. Doxorubicin (DOX) as a model antitumor drug was loaded into nanogels through dispersion. DOX-loaded nanogels displayed a stable core-cross-linked structure under normal physiological condition (pH7.4), while rapidly releasing the payloads in the mimicking endosomal (pH5.3), tumor tissular (pH6.8) or intracellular reductive microenvironments (10.0mM glutathione). Confocal fluorescence microscopy demonstrated that DOX-loaded nanogels could deliver DOX into HepG2 cells (a human hepatoma cell line) more efficiently than the parent DOX-loaded micelle and free DOX. The enhanced cellular internalizations of DOX-loaded nanogels were more significant under tumor tissular acidic condition (pH6.8) ascribed to the quaternary ammonium groups in the cores. In addition, DOX-loaded nanogels exhibited improved in vitro and in vivo antitumor activities, and in vivo securities compared with DOX-loaded micelle and free DOX. These excellent features of the smart nanogels with quaternary ammonium groups were endowed with a bright prospect for intracellular targeting antitumor drug delivery. PMID:23742879

Ding, Jianxun; Xu, Weiguo; Zhang, Ying; Sun, Diankui; Xiao, Chunsheng; Liu, Donghong; Zhu, Xiaojuan; Chen, Xuesi

2013-12-10

9

Multifunctional chitin nanogels for simultaneous drug delivery, bioimaging, and biosensing.  

PubMed

In this work, we developed biodegradable chitin nanogels (CNGs) by controlled regeneration method. For multifunctionalization, we have conjugated CNGs with MPA-capped-CdTe-QDs (QD-CNGs) for the in vitro cellular localization studies. In addition, the Bovine Serum Albumin (BSA) was loaded on to QD-CNGs (BSA-QD-CNGs). The CNGs, QD-CNGs, and BSA-QD-CNGs were well-characterized by SEM and AFM, which shows that the nanogels are in the range of <100 nm. These were further characterized by FT-IR and Cyclic Voltametry. The cytocompatibility assay showed that the nanogels are nontoxic to L929, NIH-3T3, KB, MCF-7, PC3, and VERO cells. The cell uptake studies of the QD-CNGs were analyzed, which showed retention of these nanogels inside the cells (L929, PC3, and VERO). In addition, the protein loading efficiency of the nano gels has also been analyzed. Our preliminary studies reveal that these multifunctionalized nanogels could be useful for drug delivery with simultaneous imaging and biosensing. PMID:21863797

Rejinold N, Sanoj; Chennazhi, Krishna Prasad; Tamura, Hiroshi; Nair, Shantikumar V; Rangasamy, Jayakumar

2011-09-01

10

Click hydrogels, microgels and nanogels: emerging platforms for drug delivery and tissue engineering.  

PubMed

Hydrogels, microgels and nanogels have emerged as versatile and viable platforms for sustained protein release, targeted drug delivery, and tissue engineering due to excellent biocompatibility, a microporous structure with tunable porosity and pore size, and dimensions spanning from human organs, cells to viruses. In the past decade, remarkable advances in hydrogels, microgels and nanogels have been achieved with click chemistry. It is a most promising strategy to prepare gels with varying dimensions owing to its high reactivity, superb selectivity, and mild reaction conditions. In particular, the recent development of copper-free click chemistry such as strain-promoted azide-alkyne cycloaddition, radical mediated thiol-ene chemistry, Diels-Alder reaction, tetrazole-alkene photo-click chemistry, and oxime reaction renders it possible to form hydrogels, microgels and nanogels without the use of potentially toxic catalysts or immunogenic enzymes that are commonly required. Notably, unlike other chemical approaches, click chemistry owing to its unique bioorthogonal feature does not interfere with encapsulated bioactives such as living cells, proteins and drugs and furthermore allows versatile preparation of micropatterned biomimetic hydrogels, functional microgels and nanogels. In this review, recent exciting developments in click hydrogels, microgels and nanogels, as well as their biomedical applications such as controlled protein and drug release, tissue engineering, and regenerative medicine are presented and discussed. PMID:24674460

Jiang, Yanjiao; Chen, Jing; Deng, Chao; Suuronen, Erik J; Zhong, Zhiyuan

2014-06-01

11

Polymeric nanogel formulations of nucleoside analogs  

PubMed Central

Nanogels are colloidal microgel carriers that have been introduced recently as a prospective drug delivery system for nucleotide therapeutics. The crosslinked protonated polymer network of nanogels binds oppositely charged drug molecules, encapsulating them into submicron particles with a core-shell structure. The nanogel network also provides a suitable template for chemical engineering, surface modification and vectorisation. This review reveals recent attempts to develop novel drug formulations of nanogels with antiviral and antiproliferative nucleoside analogs in the active form of 5?-triphosphates; discusses structural approaches to the optimisation of nanogel properties, and; discusses the development of targeted nanogel drug formulations for systemic administration. Notably, nanogels can improve the CNS penetration of nucleoside analogs that are otherwise restricted from passing across the blood–brain barrier. The latest findings reviewed here demonstrate an efficient intracellular release of nucleoside analogs, encouraging further applications of nanogel carriers for targeted drug delivery. PMID:17184158

Vinogradov, Serguei V

2008-01-01

12

Icam-1 targeted nanogels loaded with dexamethasone alleviate pulmonary inflammation.  

PubMed

Lysozyme dextran nanogels (NG) have great potential in vitro as a drug delivery platform, combining simple chemistry with rapid uptake and cargo release in target cells with "stealth" properties and low toxicity. In this work, we study for the first time the potential of targeted NG as a drug delivery platform in vivo to alleviate acute pulmonary inflammation in animal model of LPS-induced lung injury. NG are targeted to the endothelium via conjugation with an antibody (Ab) directed to Intercellular Adhesion Molecule-1(ICAM-NG), whereas IgG conjugated NG (IgG-NG) are used for control formulations. The amount of Ab conjugated to the NG and distribution in the body after intravenous (IV) injection have been quantitatively analyzed using a tracer isotope-labeled [125I]IgG. As a proof of concept, Ab-NG are loaded with dexamethasone, an anti-inflammatory therapeutic, and the drug uptake and release kinetics are measured by HPLC. In vivo studies in mice showed that: i) ICAM-NG accumulates in mouse lungs (?120% ID/g vs ?15% ID/g of IgG-NG); and, ii) DEX encapsulated in ICAM-NG, but not in IgG-NG practically blocks LPS-induced overexpression of pro-inflammatory cell adhesion molecules including ICAM-1 in the pulmonary inflammation. PMID:25019304

Ferrer, M Carme Coll; Shuvaev, Vladimir V; Zern, Blaine J; Composto, Russell J; Muzykantov, Vladimir R; Eckmann, David M

2014-01-01

13

ICAM-1 Targeted Nanogels Loaded with Dexamethasone Alleviate Pulmonary Inflammation  

PubMed Central

Lysozyme dextran nanogels (NG) have great potential in vitro as a drug delivery platform, combining simple chemistry with rapid uptake and cargo release in target cells with “stealth” properties and low toxicity. In this work, we study for the first time the potential of targeted NG as a drug delivery platform in vivo to alleviate acute pulmonary inflammation in animal model of LPS-induced lung injury. NG are targeted to the endothelium via conjugation with an antibody (Ab) directed to Intercellular Adhesion Molecule-1(ICAM-NG), whereas IgG conjugated NG (IgG-NG) are used for control formulations. The amount of Ab conjugated to the NG and distribution in the body after intravenous (IV) injection have been quantitatively analyzed using a tracer isotope-labeled [125I]IgG. As a proof of concept, Ab-NG are loaded with dexamethasone, an anti-inflammatory therapeutic, and the drug uptake and release kinetics are measured by HPLC. In vivo studies in mice showed that: i) ICAM-NG accumulates in mouse lungs (?120% ID/g vs ?15% ID/g of IgG-NG); and, ii) DEX encapsulated in ICAM-NG, but not in IgG-NG practically blocks LPS-induced overexpression of pro-inflammatory cell adhesion molecules including ICAM-1 in the pulmonary inflammation. PMID:25019304

Coll Ferrer, M. Carme; Shuvaev, Vladimir V.; Zern, Blaine J.; Composto, Russell J.; Muzykantov, Vladimir R.; Eckmann, David M.

2014-01-01

14

Synthesis and characterization of novel dual-responsive nanogels and their application as drug delivery systems  

NASA Astrophysics Data System (ADS)

In this study, a temperature/pH dual-response nanogel based on NIPAm, MAA, and PEGMA was synthesized via emulsion polymerization and characterized by 1H-NMR, FT-IR, TEM and DLS. By introducing a novel initiator, through which PEG-AIBN-PEG was synthesized, it was revealed that the PEG segments from PEG-AIBN-PEG with a dosage of initiator had a significant influence over the macro-state and stability of the nanogels. In order to optimize the feeding prescription for better application as a drug delivery system, the effect of the co-monomer contents on the response to stimuli (temperature and pH value) and cytotoxicity of the nanogels has been studied in detail. The results demonstrated that the responsiveness, reversibility and volume phase transition critical value of the nanogels could be controlled by adjusting the feeding ratio of the co-monomers in the synthesis process. MTT assay results revealed that nanogels with appropriate compositions showed good biocompatibility and relatively low toxicity. Most importantly, by studying the drug loading behavior, it was found that the dimensions of the drug molecules had a considerable influence on the drug loading efficiency and loading capacity of the nanogels, and that the mechanism by which drug molecule sizes influence the drug loading behavior of nanogels needs further investigation. The results indicated that such PNMP nanogels might have potential applications in drug delivery and other medical applications, but that the drug loading mechanism must be further developed.

Peng, Jinrong; Qi, Tingting; Liao, Jinfeng; Fan, Min; Luo, Feng; Li, He; Qian, Zhiyong

2012-03-01

15

Methacrylic-based nanogels for the pH-sensitive delivery of 5-Fluorouracil in the colon  

PubMed Central

Methacrylic-based copolymers in drug-delivery systems demonstrate a pH-sensitive drug-releasing behavior in the colon. In this study, copolymers of methacrylic acid and 2-ethyl hexyl acrylate were prepared using a microemulsion polymerization technique. The purified copolymer was characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and differential scanning calorimetry. 5-Fluorouracil (5-FU) was entrapped within methacrylic-based copolymers by a solvent evaporation method. The size of the nanogels formed was characterized by transmission electron microscopy and atomic force microscopy. In vitro drug-release studies using phosphate-buffered saline at different pH levels demonstrated the sustained release of 5-FU and its pH dependence. Cell proliferation assay of a human colon tumor colon cancer cell line (HCT-116) was performed and showed that the nanogels containing 5-FU exhibited considerable cytotoxicity in comparison with free 5-FU. Cell uptake of the nanogels was also monitored using confocal microscopy. Western blot analysis and flow cytometry studies confirmed that the nanogels could be successfully used as an efficient vector for pH-sensitive and controlled delivery of drugs specifically targeted to the colon. PMID:23172988

Ashwanikumar, N; Kumar, Nisha Asok; Nair, S Asha; Kumar, GS Vinod

2012-01-01

16

Intracellular microenvironment-responsive label-free autofluorescent nanogels for traceable gene delivery.  

PubMed

Gene therapy presents a unique opportunity for the treatment of genetic diseases, but the lack of multifunctional delivery systems has hindered its clinical applications. Here, a new delivery vector, autofluorescent polyethyleneimine (PEI) nanogels, for highly efficient and traceable gene delivery is developed. Different from commercial high-molecular-weight PEI, the cationic nanogels are noncytotoxic and able to be fragmented due to their unique intracellular microenvironment-responsive structures. The biodegradable nanogels can effectively load plasmid DNA (pDNA), and the self-assembled polyplexes can be cleaved after cellular uptake to improve gene transfection efficiency. Most importantly, the nanogels and the nanogel/pDNA polyplexes are autofluorescent. The fluorescence is stable in blood plasma and responsive to the intracellular microenvironment. The breakup of the nanogels or polyplexes leads to the loss of fluorescence, and thus the gene delivery and carrier biodegradation processes can be monitored. The reported multifunctional system demonstrates excellent biocompatibility, high transfection efficiency, responsive biodegradability, controlled gene release, label-free and simultaneous fluorescence tracking, which will provide a new platform for future scientific investigation and practical implications in gene therapy. PMID:24965262

Shi, Bingyang; Zhang, Hu; Qiao, Shi Zhang; Bi, Jingxiu; Dai, Sheng

2014-11-01

17

Naphthalene-hydrophobized ?-1,3-glucan nanogel for doxorubicin delivery to immunocytes.  

PubMed

A water soluble ?-1,3-glucan schizophyllan (SPG) can be recognized by an immunocyte receptor called dectin-1. When we introduced naphthalene into the side chain of SPG (nSPG), it formed nanogel by physical cross-link and gained capability to ingest hydrophobic compounds such as doxorubicin. Our in vitro assay revealed that this nanogel can be used as specific delivery of anti-cancer drugs to immunocytes. PMID:24684841

Maeda, Kazuya; Mochizuki, Shinichi; Sanada, Yusuke; Sakurai, Kazuo

2014-04-15

18

Enhanced topical delivery and anti-inflammatory activity of methotrexate from an activated nanogel  

Microsoft Academic Search

This work examined the effect of sodium carbonate (Na2CO3) on the topical delivery of methotrexate (MTX) from a loaded nanogel in vitro and the modulation of prostaglandin E2 (PGE2) production in skin ex vivo. A nanogel based on co-polymerised N-isopropylacrylamide (NIPAM) and butylacrylate (BA) was synthesized, characterized and loaded with MTX. Finite doses were then applied to excised porcine epidermal

Gillian S. Leslie Singka; Nor Abu Samah; Mohd H. Zulfakar; Aysu Yurdasiper; Charles M. Heard

2010-01-01

19

Nanogel-based immunologically stealth vaccine targets macrophages in the medulla of lymph node and induces potent antitumor immunity.  

PubMed

Because existing therapeutic cancer vaccines provide only a limited clinical benefit, a different vaccination strategy is necessary to improve vaccine efficacy. We developed a nanoparticulate cancer vaccine by encapsulating a synthetic long peptide antigen within an immunologically inert nanoparticulate hydrogel (nanogel) of cholesteryl pullulan (CHP). After subcutaneous injection to mice, the nanogel-based vaccine was efficiently transported to the draining lymph node, and was preferentially engulfed by medullary macrophages but was not sensed by other macrophages and dendritic cells (so-called "immunologically stealth mode"). Although the function of medullary macrophages in T cell immunity has been unexplored so far, these macrophages effectively cross-primed the vaccine-specific CD8(+) T cells in the presence of a Toll-like receptor (TLR) agonist as an adjuvant. The nanogel-based vaccine significantly inhibited in vivo tumor growth in the prophylactic and therapeutic settings, compared to another vaccine formulation using a conventional delivery system, incomplete Freund's adjuvant. We also revealed that lymph node macrophages were highly responsive to TLR stimulation, which may underlie the potency of the macrophage-oriented, nanogel-based vaccine. These results indicate that targeting medullary macrophages using the immunologically stealth nanoparticulate delivery system is an effective vaccine strategy. PMID:25180962

Muraoka, Daisuke; Harada, Naozumi; Hayashi, Tae; Tahara, Yoshiro; Momose, Fumiyasu; Sawada, Shin-ichi; Mukai, Sada-atsu; Akiyoshi, Kazunari; Shiku, Hiroshi

2014-09-23

20

Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines  

NASA Astrophysics Data System (ADS)

Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel (`nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.

Nochi, Tomonori; Yuki, Yoshikazu; Takahashi, Haruko; Sawada, Shin-Ichi; Mejima, Mio; Kohda, Tomoko; Harada, Norihiro; Kong, Il Gyu; Sato, Ayuko; Kataoka, Nobuhiro; Tokuhara, Daisuke; Kurokawa, Shiho; Takahashi, Yuko; Tsukada, Hideo; Kozaki, Shunji; Akiyoshi, Kazunari; Kiyono, Hiroshi

2010-07-01

21

A novel crosslinked hyaluronic Acid nanogel for drug delivery.  

PubMed

An amphiphilic hyaluronic acid conjugate is successfully developed based on grafting a thiolated hydrophobic molecule to the polysaccharide backbone. The engineered conjugate is capable of assembling into nanostructures once dispersed in water, with average diameter of 80.2?±?0.4?nm (n?=?5), stable up to 6 months. The thiolated HyA conjugate is reticulated by dissulfide bond with a homofunctional crosslinker-1,4-Bis(3-[2-pyridyldithio]propionamido)butane (DPDPB). The drug loading efficiency of the reticulated and non-reticulated nanogel is accessed with two hydrophobic drugs, curcumin and simvastatin. Results suggest that crosslinked nanogel exhibit higher stability upon dilution and drug loading efficiency and proves to be a redox sensitive material. The nanogels hold great potential as stealth carriers of lipophilic drugs. PMID:25088667

Pedrosa, Sílvia Santos; Gonçalves, Catarina; David, Laurent; Gama, Miguel

2014-11-01

22

Modular 'Click-in-Emulsion' Bone-Targeted Nanogels  

PubMed Central

A new class of nanogel demonstrates modular biodistribution and affinity for bone. Nanogels, 67 nm in diameter and synthesized via an astoichiometric click-chemistry-inemulsion method, controllably display residual, free click-able functional groups. Functionalization with a bisphosphonate ligand results in significant binding to bone on the inner walls of marrow cavities, liver avoidance, and anti-osteoporotic effects. PMID:23280931

Heller, Daniel A.; Levi, Yair; Pelet, Jeisa M.; Doloff, Joshua C.; Wallas, Jasmine; Pratt, George W.; Jiang, Shan; Sahay, Gaurav; Schroeder, Avi; Schroeder, Josh E.; Chyan, Yieu; Zurenko, Christopher; Querbes, William; Manzano, Miguel; Kohane, Daniel S.; Langer, Robert; Anderson, Daniel G.

2013-01-01

23

Polypeptide nanogels with hydrophobic moieties in the cross-linked ionic cores: Synthesis, characterization and implications for anticancer drug delivery  

PubMed Central

Polymer nanogels have gained considerable attention as a potential platform for drug delivery applications. Here we describe the design and synthesis of novel polypeptide-based nanogels with hydrophobic moieties in the cross-linked ionic cores. Diblock copolymer, poly(ethylene glycol)-b-poly(L-glutamic acid), hydrophobically modified with L-phenylalanine methyl ester moieties was used for controlled template synthesis of nanogels with small size (ca. 70 nm in diameter) and narrow particle size distribution. Steady-state and time-resolved fluorescence studies using coumarin C153 indicated the existence of hydrophobic domains in the ionic cores of the nanogels. Stable doxorubicin-loaded nanogels were prepared at high drug capacity (30 w/w%). We show that nanogels are enzymatically-degradable leading to accelerated drug release under simulated lysosomal acidic pH. Furthermore, we demonstrate that the nanogel-based formulation of doxorubicin is well tolerated and exhibit an improved antitumor activity compared to a free doxorubicin in an ovarian tumor xenograft mouse model. Our results signify the point to a potential of these biodegradable nanogels as attractive carriers for delivery of chemotherapeutics. PMID:23998716

Kim, Jong Oh; Oberoi, Hardeep S.; Desale, Swapnil; Kabanov, Alexander V.; Bronich, Tatiana K.

2014-01-01

24

Enhanced topical delivery and anti-inflammatory activity of methotrexate from an activated nanogel.  

PubMed

This work examined the effect of sodium carbonate (Na(2)CO(3)) on the topical delivery of methotrexate (MTX) from a loaded nanogel in vitro and the modulation of prostaglandin E(2) (PGE(2)) production in skin ex vivo. A nanogel based on co-polymerised N-isopropylacrylamide (NIPAM) and butylacrylate (BA) was synthesized, characterized and loaded with MTX. Finite doses were then applied to excised porcine epidermal membranes mounted in Franz diffusion cells, followed by the addition of saturated aqueous Na(2)CO(3). For comparison, the addition of half-saturated Na(2)CO(3) was examined along with loaded nanogel alone. The same treatments were applied to Silastic membrane and full-thickness porcine ear skin ex vivo, which was then treated with radioimmunoprecipitation buffer and probed for levels of PGE(2) using a commercial enzyme immunoassay kit. The MTX-loaded nanogel, which demonstrated de-swelling by 7% over the range 25-37°C, provided a MTX flux of 1.4±0.3ngcm(-2)h(-1); this increased to 3.1±0.22ngcm(-2)h(-1) upon the addition of saturated aqueous Na(2)CO(3) (p<0.05). Lag times were 6 and ?0h, respectively. Similar results were obtained using half-saturated aqueous Na(2)CO(3). No permeation was detected across Silastic membrane. PGE(2) levels for water (control) and saturated aqueous Na(2)CO(3) were similar, but reduced by 33% when the MTX-loaded nanogel was applied, and by 57% when this was followed by the application of saturated aqueous Na(2)CO(3) (p<0.01). A novel mechanism is proposed whereby the change in temperature experienced by the nanogel as it penetrated skin induced de-swelling and expulsion of MTX in situ. The added Na(2)CO(3) lead to further solubilisation and MTX release, hence increasing the concentration gradient, flux and reducing PGE(2) production. PMID:20600884

Singka, Gillian S Leslie; Samah, Nor Abu; Zulfakar, Mohd H; Yurdasiper, Aysu; Heard, Charles M

2010-10-01

25

Novel core shell magnetic nanogels synthesized in an emulsion-free aqueous system under UV irradiation for targeted radiopharmaceutical applications  

NASA Astrophysics Data System (ADS)

Novel core-shell poly(acrylamide) magnetic nanogels with controllable particle size produced via a photochemical method in an emulsion-free aqueous system at room temperature have been developed for the first time. After Hoffmann elimination of carbonyl, nanogels with amino groups, or poly(acrylamide-vinyl amine) magnetic nanogels, were also obtained. Particle size, size distributions and zeta potential of the magnetic nanogels before and after Hoffmann elimination were measured by photo-correlation spectroscopy (PCS). The structure and morphology of the magnetic nanogels were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The higher dispersibility and stability of the magnetic nanogels suggest promising potential applications in targeted radiopharmaceuticals carriers for cancer therapy, and in biological and medical studies as well.

Sun, Hanwen; Yu, Jiahui; Gong, Peijun; Xu, Dongmei; Zhang, Chunfu; Yao, Side

2005-07-01

26

A magnetic nanogel based on O-carboxymethylchitosan for antitumor drug delivery: synthesis, characterization and in vitro drug release.  

PubMed

This paper studied the synthesis, characterization and use of the magnetic chitosan nanogel for carrying meleimidic compounds. The hydrogel polymer was prepared using O-carboxymethylchitosan, which was crosslinked with epichlorohydrin for subsequent incorporation of iron oxide magnetic nanoparticles. The characterization revealed that the magnetic material comprises about 10% of the hydrogel. This material is comprised of magnetite and maghemite and exhibits ferro-ferrimagnetic behavior. The average particle size is 4.2 nm. There was high incorporation efficiency of maleimides in the magnetic nanogel. The release was of sustained character and there was a greater release when an external magnetic field was applied. The mathematical model that best explained the process of drug release by the magnetic hydrogel was that of Peppas-Sahlin. The magnetic nanogel proved to be an excellent candidate for use in drug-delivery systems. PMID:24647530

Demarchi, Carla Albetina; Debrassi, Aline; Buzzi, Fátima de Campos; Corrêa, Rogério; Filho, Valdir Cechinel; Rodrigues, Clovis Antonio; Nedelko, Nataliya; Demchenko, Pavlo; ?lawska-Waniewska, Anna; D?u?ewski, Piotr; Greneche, Jean-Marc

2014-05-21

27

Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for targeting of CD44-positive and drug-resistant tumors  

PubMed Central

Many drug-resistant tumors and cancer stem cells (CSC) express elevated levels of CD44 receptor, a cellular glycoprotein binding hyaluronic acid (HA). Here, we report the synthesis of nanogel-drug conjugates based on membranotropic cholesteryl-HA (CHA) for efficient targeting and suppression of drug-resistant tumors. These conjugates significantly increased the bioavailability of poorly soluble drugs with previously reported activity against CSC, such as etoposide, salinomycin, and curcumin. The small nanogel particles (diam. 20–40 nm) with a hydrophobic core and high drug loads (up to 20%) formed after ultrasonication and demonstrated a sustained drug release following the hydrolysis of biodegradable ester linkage. Importantly, CHA-drug nanogels demonstrated 2–7 times higher cytotoxicity in CD44-expressing drug-resistant human breast and pancreatic adenocarcinoma cells compared to free drugs and non-modified HA-drug conjugates. These nanogels were efficiently internalized via CD44 receptor-mediated endocytosis and simultaneous interaction with the cancer cell membrane. Anchoring by cholesterol moieties in the cellular membrane after nanogel unfolding evidently caused more efficient drug accumulation in cancer cells compared to non-modified HA-drug conjugates. CHA-drug nanogels were able to penetrate multicellular cancer spheroids and displayed higher cytotoxic effect in the system modeling tumor environment than both free drugs and HA-drug conjugates. In conclusion, the proposed design of nanogel-drug conjugates allowed us to significantly enhance drug bioavailability, cancer cell targeting, and the treatment efficacy against drug-resistant cancer cells and multicellular spheroids. PMID:23547842

Wei, Xin; Senanayake, Thulani H.; Warren, Galya; Vinogradov, Serguei V.

2013-01-01

28

Novel pH-responsive dextrin nanogels for doxorubicin delivery to cancer cells with reduced cytotoxicity to cardiomyocytes and stem cells.  

PubMed

The aim of this study was to develop pH-responsive dextrin nanogels (DNGs) capable of triggered intracellular DOX release at the lower pH of cancer cells. DNGs were prepared by an emulsion cross-linking method using glyoxal as cross-linker to create an acid-labile bond. A higher molecular weight of dextrin with increasing mole ratio of dextrin to glyoxal decreased the average diameter of DNGs. DNGs showed slightly negative surface charge and pH-responsive behavior. The in vitro drug release was slow at pH 7.4 and increased with decreasing pH (pH 5>6.8). The cytotoxicity of DOX-loaded DNGs in mesenchymal stem cells and cardiomyocytes was lower than that of free DOX. Moreover, DOX-loaded DNGs were efficiently internalized by tumor cells with rapid release of DOX into the nucleus. Thus, DOX-loaded DNGs were successful for intracellular targeted anti-tumor drug delivery and reducing side-effects to non-tumor cells such as cardiomyocytes and stem cells. PMID:25263867

Manchun, Somkamol; Cheewatanakornkool, Kamonrak; Dass, Crispin R; Sriamornsak, Pornsak

2014-12-19

29

Water soluble folate-chitosan nanogels crosslinked by genipin.  

PubMed

Folate-chitosan conjugates were prepared by a concurrent functionalization and crosslinking reaction with the natural crosslinker genipin. Genipin molecule was employed simultaneously as crosslinker agent and spacer molecule in order to allow the functionalization with folic acid for active tumor targeting. The reaction was carried out in reverse microemulsion which provided colloidal size and monodisperse particle size distribution. The water solubility of the obtained folate-genipin-chitosan nanogels was studied as function of the pH of the medium and all nanoparticles were totally dispersible at physiological pH. The enzymatic degradability of the nanogels in a lysozyme solution was evaluated at acidic and physiological pH. QELS analyses of the swelling behavior of the nanogels with the pH did not show a clear pH-sensitivity. However, the study on the loading and release capacity of 5-fluorouracil revealed an interesting pH-responsive behavior of the nanogels that makes them promising as nanodevices for targeted anticancer drug delivery. PMID:24299756

Pujana, Maite Arteche; Pérez-Álvarez, Leyre; Iturbe, L Carlos Cesteros; Katime, Issa

2014-01-30

30

Nanoparticles for Targeted Drug Delivery  

E-print Network

Nanoparticles were synthesized and modified for target drug delivery. The research involved the aqueous synthesis of near infrared (NIR) sensitive Au-Au2S nanoparticles. An anti-cancer drug (cis-platin) ...

Chow, Gan-Moog

31

TARGETED DELIVERY OF INHALED PROTEINS  

EPA Science Inventory

ETD-02-047 (Martonen) GPRA # 10108 TARGETED DELIVERY OF INHALED PROTEINS T. B. Martonen1, J. Schroeter2, Z. Zhang3, D. Hwang4, and J. S. Fleming5 1Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Research Triangle Park...

32

Efficient siRNA delivery based on PEGylated and partially quaternized polyamine nanogels: Enhanced gene silencing activity by the cooperative effect of tertiary and quaternary amino groups in the core  

Microsoft Academic Search

For the development of an siRNA delivery system using polyion complexes (PICs) based on PEGylated nanogel consisting of a cross-linked poly[2-(N,N-diethylaminoethyl) methacrylate] (PEAMA) gel core and tethered poly(ethylene glycol) (PEG) chains, quaternary ammonium groups were introduced in the polyamine gel core to enhance the binding ability with siRNA and the stability of the PICs. Consequently, the quaternization of the polyamine

Atsushi Tamura; Motoi Oishi; Yukio Nagasaki

2010-01-01

33

Delivery of chemotropic proteins and improvement of dopaminergic neuron outgrowth through a thixotropic hybrid nano-gel.  

PubMed

Chemotropic proteins guide neuronal projections to their final target during embryo development and are useful to guide axons of neurons used in transplantation therapies. Site-specific delivery of the proteins however is needed for their application in the brain to avoid degradation and pleiotropic affects. In the present study we report the use of Poly (ethylene glycol)-Silica (PEG-Si) nanocomposite gel with thixotropic properties that make it injectable and suitable for delivery of the chemotropic protein semaphorin 3A. PEG-Si gel forms a functional gradient of semaphorin that enhances axon outgrowth of dopaminergic neurons from rat embryos or differentiated from stem cells in culture. It is not cytotoxic and its properties allowed its injection into the striatum without inflammatory response in the short term. Long term implantation however led to an increase in macrophages and glial cells. The inflammatory response could have resulted from non-degraded silica particles, as observed in biodegradation assays. PMID:21744103

Tamariz, Elisa; Wan, Andrew C A; Pek, Y Shona; Giordano, Magda; Hernández-Padrón, Genoveva; Varela-Echavarría, Alfredo; Velasco, Iván; Castaño, Víctor M

2011-09-01

34

The effects of topically applied polyNIPAM-based nanogels and their monomers on skin cyclooxygenase expression, ex vivo.  

PubMed

Stimulus-responsive nanogels have potential as carriers for drugs targeting the skin. It is important to estimate the biocompatibility of such materials with the skin since they are directly in contact upon application and may induce irritation or inflammation. In the current work, blank (drug-free) polyN-isopropylacrylamide (polyNIPAM), poly(NIPAM copolymerized butyl acrylate) [poly(NIPAM-co-BA)], and poly(NIPAM copolymerized with 5% w/v acrylic acid) [poly(NIPAM-co-AAc)(5%)] nanogels were dosed onto freshly excised full-thickness porcine ear skin and the effects on the expression of cyclooxygenase-2 (COX-2) determined ex vivo by Western blotting. Modulated COX-2 expression was indicative that the material had penetrated the skin and keratinocytes of the viable epidermis. The poly(NIPAM-co-BA) nanogel was found to exert a proinflammatory response when applied topically, as reflected by 67% higher COX-2 expression relative to the control treatment (p = 0.0035). The data obtained for the poly(NIPAM-co-AAc)(5%) nanogel, on the other hand, indicated no significant modulation in the expression of COX-2 (p = 0.1578), suggesting the particles are compatible with skin. This was even the case in the presence of co-administered aqueous citric acid solution. Overall the data support the use of the multi-responsive poly(NIPAM-co-AAc)(5%) nanogel for triggered or controlled topical drug delivery applications. PMID:23194376

Abu Samah, Nor H; Heard, Charles M

2014-02-01

35

Aptamer-targeted Antigen Delivery  

PubMed Central

Effective therapeutic vaccines often require activation of T cell-mediated immunity. Robust T cell activation, including CD8 T cell responses, can be achieved using antibodies or antibody fragments to direct antigens of interest to professional antigen presenting cells. This approach represents an important advance in enhancing vaccine efficacy. Nucleic acid aptamers present a promising alternative to protein-based targeting approaches. We have selected aptamers that specifically bind the murine receptor, DEC205, a C-type lectin expressed predominantly on the surface of CD8?+ dendritic cells (DCs) that has been shown to be efficient at facilitating antigen crosspresentation and subsequent CD8+ T cell activation. Using a minimized aptamer conjugated to the model antigen ovalbumin (OVA), DEC205-targeted antigen crosspresentation was verified in vitro and in vivo by proliferation and cytokine production by primary murine CD8+ T cells expressing a T cell receptor specific for the major histocompatibility complex (MHC) I-restricted OVA257–264 peptide SIINFEKL. Compared with a nonspecific ribonucleic acid (RNA) of similar length, DEC205 aptamer-OVA-mediated antigen delivery stimulated strong proliferation and production of interferon (IFN)-? and interleukin (IL)-2. The immune responses elicited by aptamer-OVA conjugates were sufficient to inhibit the growth of established OVA-expressing B16 tumor cells. Our results demonstrate a new application of aptamer technology for the development of effective T cell-mediated vaccines. PMID:24682172

Wengerter, Brian C; Katakowski, Joseph A; Rosenberg, Jacob M; Park, Chae Gyu; Almo, Steven C; Palliser, Deborah; Levy, Matthew

2014-01-01

36

Targeted Drug Delivery in Pancreatic Cancer  

PubMed Central

Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor and antibody has been a success in recent pre-clinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer, and provides important information on potential therapeutic targets for pancreatic cancer treatment. PMID:19853645

Yu, Xianjun; Zhang, Yuqing; Chen, Changyi; Yao, Qizhi; Li, Min

2009-01-01

37

Polymers for Colon Targeted Drug Delivery  

PubMed Central

The colon targeted drug delivery has a number of important implications in the field of pharmacotherapy. Oral colon targeted drug delivery systems have recently gained importance for delivering a variety of therapeutic agents for both local and systemic administration. Targeting of drugs to the colon via oral administration protect the drug from degradation or release in the stomach and small intestine. It also ensures abrupt or controlled release of the drug in the proximal colon. Various drug delivery systems have been designed that deliver the drug quantitatively to the colon and then trigger the release of drug. This review will cover different types of polymers which can be used in formulation of colon targeted drug delivery systems. PMID:21969739

Rajpurohit, H.; Sharma, P.; Sharma, S.; Bhandari, A.

2010-01-01

38

Nanogel scavengers for drugs: local anesthetic uptake by thermoresponsive nanogels.  

PubMed

The use of functional nanogels based on poly(N-isopropylacrylamide) for effectively scavenging compounds (here, the model drug bupivacaine) is demonstrated using an in vitro cell-based assay. Nanogels containing higher loadings of acidic functional groups or more core-localized functional group distributions bound more bupivacaine, while nanogel size had no significant effect on drug binding. Increasing the dose of nanogel applied also facilitated more bupivacaine binding for all nanogel compositions tested. Binding was driven predominantly by acid-base interactions between the nanogels (anionic) and bupivacaine (cationic) at physiological pH, although both non-specific absorption and hydrophobic partitioning also contributed to drug scavenging. Nanogels exhibited minimal cytotoxicity to multiple cell types and were well tolerated in vivo via peritoneal injections, although larger nanogels caused limited splenic toxicity at higher concentrations. The cell-based assay described herein is found to facilitate more robust drug uptake measurements for nanogels than conventional centrifugation-based assays, in which nanogels can be compressed (and thus drug released) during the measurement. PMID:22244983

Hoare, Todd; Sivakumaran, Daryl; Stefanescu, Cristina F; Lawlor, Michael W; Kohane, Daniel S

2012-04-01

39

Nanogel scavengers for drugs: Local anesthetic uptake by thermoresponsive nanogels  

PubMed Central

The use of functional nanogels based on poly(N-isopropylacrylamide) for effectively scavenging compounds (here, the model drug bupivacaine) is demonstrated using an in vitro cell-based assay. Nanogels containing higher loadings of acidic functional groups or more core-localized functional group distributions bound more bupivacaine, while nanogel size had no significant effect on drug binding. Increasing the dose of nanogel applied also facilitated more bupivacaine binding for all nanogel compositions tested. Binding was driven predominantly by acid-base interactions between the nanogels (anionic) and bupivacaine (cationic) at physiological pH, although both non-specific absorption and hydrophobic partitioning also contributed to drug scavenging. Nanogels exhibited minimal cytotoxicity to multiple cell types and were well-tolerated in vivo via peritoneal injections, although larger nanogels caused limited splenic toxicity at higher concentrations. The cell-based assay described herein is found to facilitate more robust drug uptake measurements for nanogels than conventional centrifugation-based assays, in which nanogels can be compressed (and thus drug released) during the measurement. PMID:22244983

Hoare, Todd; Sivakumaran, Daryl; Stefanescu, Cristina; Lawlor, Michael W.; Kohane, Daniel S.

2012-01-01

40

Superparamagnetic hollow hybrid nanogels as a potential guidable vehicle system of stimuli-mediated MR imaging and multiple cancer therapeutics.  

PubMed

Hollow hybrid nanogels were prepared first by the coassembly of the citric acid-coated superparamagnetic iron oxide nanoparticles (SPIONs, 44 wt %) with the graft copolymer (56 wt %) comprising acrylic acid and 2-methacryloylethyl acrylate units as the backbone and poly(ethylene glycol) and poly(N-isopropylacrylamide) as the grafts in the aqueous phase of pH 3.0 in the hybrid vesicle structure, followed by in situ covalent stabilization via the photoinitiated polymerization of MEA residues within vesicles. The resultant hollow nanogels, though slightly swollen, satisfactorily retain their structural integrity while the medium pH is adjusted to 7.4. Confining SPION clusters to such a high level (44 wt %) within the pH-responsive thin gel layer remarkably enhances the transverse relaxivity (r2) and renders the MR imaging highly pH-tunable. For example, with the pH being adjusted from 4.0 to 7.4, the r2 value can be dramatically increased from 138.5 to 265.5 mM(-1) s(-1). The DOX-loaded hybrid nanogels also exhibit accelerated drug release in response to both pH reduction and temperature increase as a result of the substantial disruption of the interactions between drug molecules and copolymer components. With magnetic transport guidance toward the target and subsequent exposure to an alternating magnetic field, this DOX-loaded nanogel system possessing combined capabilities of hyperthermia and stimuli-triggered drug release showed superior in vitro cytotoxicity against HeLa cells as compared to the case with only free drug or hyperthermia alone. This work demonstrates that the hollow inorganic/organic hybrid nanogels hold great potential to serve as a multimodal theranostic vehicle functionalized with such desirable features as the guidable delivery of stimuli-mediated diagnostic imaging and hyperthermia/chemotherapies. PMID:23627806

Chiang, Wen-Hsuan; Ho, Viet Thang; Chen, Hsin-Hung; Huang, Wen-Chia; Huang, Yi-Fong; Lin, Sung-Chyr; Chern, Chorng-Shyan; Chiu, Hsin-Cheng

2013-05-28

41

Targeted delivery of drugs for liver fibrosis.  

PubMed

Liver fibrosis and its end stage disease cirrhosis are a major cause of mortality and morbidity around the world. There is no effective pharmaceutical intervention for liver fibrosis at present. Many drugs that show potent antifibrotic activities in vitro often show only minor effects in vivo because of insufficient concentrations of drugs accumulating around the target cell and their adverse effects as a result of affecting other non-target cells. Hepatic stellate cells (HSC) play a critical role in the fibrogenesis of liver, so they are the target cells of antifibrotic therapy. Several kinds of targeted delivery system that could target the receptors expressed on HSC have been designed, and have shown an attractive targeted potential in vivo. After being carried by these delivery systems, many agents showed a powerful antifibrotic effect in animal models of liver fibrosis. These targeted delivery systems provide a new pathway for the therapy of liver fibrosis. The characteristics of theses targeted carriers are reviewed in this paper. PMID:19413460

Li, Feng; Wang, Ji-yao

2009-05-01

42

Targeted drug delivery for brain cancer treatment  

Microsoft Academic Search

The blood brain barrier (BBB) and the systemic toxicity of conventional chemotherapy present obstacles to the success of future blood-borne drug therapies of brain tumors. The work with polymer-encapsulated cancer drugs suggests an alternative and more focused treatment approach. Our experimental strategy integrates direct intracerebral drug delivery, sustained drug release from liposomes or polymer implants, and increased targeting of the

Robert L Gutman; Gina Peacock; D. Robert Lu

2000-01-01

43

Antitumor effects of heparin-polyethyleneimine nanogels delivering claudin-3-targeted short hairpin RNA combined with low-dose cisplatin on ovarian cancer.  

PubMed

Cisplatin is normally administered in chemotherapy for ovarian cancer, but is accompanied by severe dose-dependent toxicity. The combination of cisplatin with other antitumor agents may be a useful alternative for achieving higher antitumor efficiency and lower toxicity. Claudin-3 (CLDN3), a commonly upregulated gene in 90% of ovarian cancers, has been identified as a novel therapeutic target of ovarian cancer. Therefore, in the present study, we constructed a recombinant plasmid carrying an shRNA targeting CLDN3 (pshCLDN3), and investigated the antitumor effects of the combination therapy of pshCLDN3 and a low-dose of cisplatin for the treatment of ovarian cancer. Heparin-polyethyleneimine (HPEI) nanogel, a novel gene carrier with superior biodegradability, excellent blood compatibility and low-toxicity, was used to deliver pshCLDN3 into ovarian cancer cells. The knockdown efficiency was determined by western blot analysis and CLDN3 immunostaining. Nude mice bearing intraperitoneal ovarian carcinomas were treated with pshCLDN3/HPEI complexes, low-dose cisplatin, pshCLDN3/HPEI plus low-dose cisplatin or control agents, respectively. The results showed that pshCLDN3/HPEI effectively suppressed the expression of CLDN3 in ovarian cancer. The combination therapy of pshCLDN3/HPEI and low-dose cisplatin exhibited enhanced antitumor activity, when compared with either agent alone, as evidenced by mean tumor weight analysis, Ki-67 immunostaining analysis and TUNEL assay, without obvious systemic toxicity. These results indicate that pshCLDN3/HPEI combined with low-dose cisplatin demonstrates apparent synergistic antitumor activity without marked toxicity. Our study offers a novel therapeutic strategy for the treatment of ovarian cancer. PMID:24482188

Liu, Lili; Gou, Maling; Yi, Tao; Bai, Yu; Wei, Yuquan; Zhao, Xia

2014-04-01

44

Bioresorbable polymersomes for targeted delivery of cisplatin.  

PubMed

Nontoxic bioresorbable polymersomes have been developed that efficiently and site-selectively tether targeting peptides under mild conditions with no toxic catalysts. The binding and release properties of these polymersomes have been evaluated when targeting DLD-1 human colon cancer cells overexpressing the ?(5)?(1) integrin. The delivery efficacy to these cells is markedly improved over commonly used RGD targeting peptides by use of an ?(5)?(1)-specific targeting peptide, PR_b. Release profiles in buffered solution from pH 7.4 to 4.5 were evaluated and compared to release after binding to cells, and enzymatic degradation was identified as a major cause of rapid payload release in the cell. Intracellular trafficking and release were imaged via confocal microscopy in live cells and colocalization with organelles was evaluated quantitatively over time. Finally, the anticancer drug cisplatin was encapsulated in the PR_b functionalized polymersomes and the presence of PR_b greatly improved delivery efficacy, with increased cisplatin-induced losses to targeted DLD-1 colon cancer cell viability. When delivered to CACO-2 model human epithelial cells expressing low levels of ?(5)?(1) integrin, low toxicity was maintained, suggesting that targeting was specific to ?(5)?(1) overexpressing cells. These results demonstrate that PR_b-functionalized bioresorbable polymersomes may be an attractive route to minimizing the dose-limiting side effects associated with existing approaches to cisplatin chemotherapy. PMID:23521104

Petersen, Matthew A; Hillmyer, Marc A; Kokkoli, Efrosini

2013-04-17

45

AS1411 aptamer for targetable photosensitizer delivery  

Microsoft Academic Search

A specialized G-quadruplex DNA aptamer with nucleolin targeting ability, AS1411, has been studied for cancer therapy. In this study, we report a novel delivery strategy for chemo-photodynamic combined treatment using AS1411 aptamer conjugated with tetra-(N-methyl-4-pyridyl)-porphine by intercalation and outside binding. Our results show that the apt-TMP complex exhibited higher TMPyP4 accumulation in nucleolin over-expressing MCF-7 breast cancer cells than in

M. J. Shieh; Y. A. Shieh; P. S. Lai

2009-01-01

46

Comparison of Nanogel Drug Carriers and their Formulations with Nucleoside 5?-Triphosphates  

Microsoft Academic Search

\\u000a Purpose  The aim of the study is to synthesize and characterize nanogel carriers composed of amphiphilic polymers and cationic polyethylenimine\\u000a for encapsulation and delivery of cytotoxic nucleoside analogs 5?-triphosphates (NTPs) into cancer cells.\\u000a \\u000a \\u000a \\u000a Methods  Nanogels were synthesized by a novel micellar approach and compared with carriers prepared by the emulsification\\/evaporation\\u000a method. Complexes of nanogels with NTP were prepared; particle size and in

Serguei V. Vinogradov; Ekta Kohli; Arin D. Zeman

2006-01-01

47

New Approaches to Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

For targeted drug delivery, one of the primary drawbacks lies with the inability to design a delivery system that can be loaded with a variety of drugs and biomolecules. Motivated by this challenge, we will present data showing 400 nm liposomes loaded via the novel method of lysenin pores. These pores are approximately 3 nm in diameter and can be closed with divalent and trivalent ions in addition to charged polymers. This new method allows for the controllable passage of large biomolecules such as DNA and protein without the inherent problems common to active and passive loading methods. We will show proof-of-concept results of this method using fluorescent calcein as a drug simulator. Furthermore, data demonstrating current attempts at loading DNA will also be presented.

Cooper, James; Oliver, William; Fologea, Daniel

2013-03-01

48

Macromolecules in drug delivery Macromolecular targeting agents, carriers, and drugs  

E-print Network

Macromolecules in drug delivery Macromolecular targeting agents, carriers, and drugs 1gauthier@emt.inrs.ca #12;Why macromolecules in drug delivery? 2gauthier@emt.inrs.ca Classic chemotherapy Drug delivery? Targeting A carrier for small drugs A release mechanism (if necessary) Protection of drug cargo #12;How? 3

Barthelat, Francois

49

Colloidal microgels in drug delivery applications  

PubMed Central

Colloidal microgels have recently received attention as environmentally responsive systems and now are increasingly used in applications as carriers for therapeutic drugs and diagnostic agents. Synthetic microgels consist of a crosslinked polymer network that provides a depot for loaded drugs, protection against environmental hazards and template for post-synthetic modification or vectorization of the drug carriers. The aim of this manuscript is to review recent attempts to develop new microgel formulations for oral drug delivery, to design metal-containing microgels for diagnostic and therapeutic applications, and to advance approaches including the systemic administration of microgels. Novel nanogel drug delivery systems developed in the authors’ laboratory are discussed in details including aspects of their synthesis, vectorization and recent applications for encapsulation of low molecular weight drugs or formulation of biological macromolecules. The findings reviewed here are encouraging for further development of the nanogels as intelligent drug carriers with such features as targeted delivery and triggered drug release. PMID:17168773

Vinogradov, Serguei V.

2005-01-01

50

Targeted estrogen delivery reverses the metabolic syndrome  

PubMed Central

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases. PMID:23142820

Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Muller, Timo D; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C; Garcia-Caceres, Cristina; Kabra, Dhiraj G; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrabe; Tiano, Joseph P; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D; Tschop, Matthias H

2013-01-01

51

Formulations of biodegradable Nanogel carriers with 5?-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity  

PubMed Central

Therapies including nucleoside analogs are associated with severe toxic side effects and acquirement of drug resistance. We have previously reported the drug delivery in the form of 5?-triphosphates (NTP) encapsulated in cross-linked cationic networks of polyethylenimine (PEI) and PEG/Pluronic® polymers (Nanogels). In this study, Nanogels, containing biodegradable PEI that could easily dissociate in reducing cytosolic environment and form products with minimal toxicity, were synthesized and displayed low cytotoxicity. Toxicity of Nanogels was clearly dependent on the total positive charge of carriers and was 5–6-fold lower for carriers loaded with NTP. Though intracellular ATP level was immediately reduced by ca. 50% following the treatment with Nanogels, it was largely restored 24 h later. Effect of Nanogels on various respiratory components of cells was reversible too, and, therefore, resulted in low immediate cell death. Nanogel alone and formulations with AZT-TP demonstrated a much lower mitochondrial toxicity than AZT. As an example of potential antiviral applications of low-toxic Nanogel carriers, a 5?-triphosphorylated Ribavirin-Nanogel formulation was prepared that demonstrated a 30-fold decrease in effective drug concentration (EC90) and, totally, a 10-fold increase in selectivity index compared to the drug alone in MDCK cells infected with influenza A virus. PMID:17509713

Kohli, Ekta; Han, Huai-Yun; Zeman, Arin D.; Vinogradov, Serguei V.

2007-01-01

52

Progress in aptamer-mediated drug delivery vehicles for cancer targeting and its implications in addressing chemotherapeutic challenges.  

PubMed

Aptamers are novel oligonucleotides with flexible three-dimensional configurations that recognize and bind to their cognate targets, including tumor surface receptors, in a high-affinity and highly specific manner. Because of their unique intrinsic properties, a variety of aptamer-mediated nanovehicles have been developed to directionally transport anti-cancer drugs to tumor sites to minimize systemic cytotoxicity and to enhance permeation by these tumoricidal agents. Despite advances in the selection and synthesis of aptamers and in the conjugation and self-assembly of nanotechnologies, current chemotherapy and drug delivery systems face great challenges. These challenges are due to the limitations of aptamers and vehicles and because of complicated tumor mechanisms, including heterogeneity, anti-cancer drug resistance, and hypoxia-induced aberrances. In this review, we will summarize current approaches utilizing tumor surface hallmarks and aptamers and their roles and mechanisms in therapeutic nanovehicles targeting tumors. Delivery forms include nanoparticles, nanotubes, nanogels, aptamer-drug conjugates, and novel molecular trains. Moreover, the obstacles posed by the aforementioned issues will be highlighted, and possible solutions will be acknowledged. Furthermore, future perspectives will be presented, including cutting-edge integration with RNA interference nanotechnology and personalized chemotherapy, which will facilitate innovative approaches to aptamer-based therapeutics. PMID:25057317

Zhu, Jie; Huang, He; Dong, Shiwu; Ge, Liang; Zhang, Yuan

2014-01-01

53

Progress in Aptamer-Mediated Drug Delivery Vehicles for Cancer Targeting and Its Implications in Addressing Chemotherapeutic Challenges  

PubMed Central

Aptamers are novel oligonucleotides with flexible three-dimensional configurations that recognize and bind to their cognate targets, including tumor surface receptors, in a high-affinity and highly specific manner. Because of their unique intrinsic properties, a variety of aptamer-mediated nanovehicles have been developed to directionally transport anti-cancer drugs to tumor sites to minimize systemic cytotoxicity and to enhance permeation by these tumoricidal agents. Despite advances in the selection and synthesis of aptamers and in the conjugation and self-assembly of nanotechnologies, current chemotherapy and drug delivery systems face great challenges. These challenges are due to the limitations of aptamers and vehicles and because of complicated tumor mechanisms, including heterogeneity, anti-cancer drug resistance, and hypoxia-induced aberrances. In this review, we will summarize current approaches utilizing tumor surface hallmarks and aptamers and their roles and mechanisms in therapeutic nanovehicles targeting tumors. Delivery forms include nanoparticles, nanotubes, nanogels, aptamer-drug conjugates, and novel molecular trains. Moreover, the obstacles posed by the aforementioned issues will be highlighted, and possible solutions will be acknowledged. Furthermore, future perspectives will be presented, including cutting-edge integration with RNA interference nanotechnology and personalized chemotherapy, which will facilitate innovative approaches to aptamer-based therapeutics. PMID:25057317

Zhu, Jie; Huang, He; Dong, Shiwu; Ge, Liang; Zhang, Yuan

2014-01-01

54

Liposome-templated supramolecular assembly of responsive alginate nanogels.  

PubMed

Nanosized gel particles (nanogels) are of interest for a variety of applications, including drug delivery and single-molecule encapsulation. Here, we employ the cores of nanoscale liposomes as reaction vessels to template the assembly of calcium alginate nanogels. For our experiments, a liposome formulation with a high bilayer melting temperature (Tm) is selected, and sodium alginate is encapsulated in the liposomal core. The liposomes are then placed in an aqueous buffer containing calcium chloride, and the temperature is raised up to Tm. This allows permeation of Ca2+ ions through the bilayer and into the core, whereupon these ions gel the encapsulated alginate. Subsequently, the lipid bilayer covering the gelled core is removed by the addition of a detergent. The resulting alginate nanogels have a size distribution consistent with that of the template liposomes (ca. 120-200 nm), as confirmed by transmission electron microscopy and light scattering. Nanogels of different average sizes can be synthesized by varying the template dimensions, and the gel size can be further tuned after synthesis by the addition of monovalent salt to the solution. PMID:18338908

Hong, Jennifer S; Vreeland, Wyatt N; Lacerda, Silvia H DePaoli; Locascio, Laurie E; Gaitan, Michael; Raghavan, Srinivasa R

2008-04-15

55

Toward Intracellular Targeted Delivery of Cancer Therapeutics  

PubMed Central

A number of anti-cancer drugs have their targets localized to particular intracellular compartments. These drugs reach the targets mainly through diffusion, dependent on biophysical and biochemical forces that allow cell penetration. This means that both cancer cells and normal cells will be subjected to such diffusion; hence many of these drugs, like chemotherapeutics, are potentially toxic and the concentration achieved at the site of their action is often suboptimal. The same relates to radiation that indiscriminately affects normal and diseased cells. However, nature-designed systems enable compounds present in the extracellular environment to end up inside the cell and even travel to more specific intracellular compartments. For example, viruses and bacterial toxins can more or less specifically recognize eukaryotic cells, enter these cells, and direct some protein portions to designated intracellular areas. These phenomena have led to creative thinking, such as employing viruses or bacterial toxins for cargo delivery to cells and, more specifically, to cancer cells. Proteins can be genetically engineered in order to not only mimic what viruses and bacterial toxins can do, but also to add new functions, extending or changing the intracellular routes. It is possible to make conjugates or, more preferably, single-chain proteins that recognize cancer cells and deliver cargo inside the cells, even to the desired subcellular compartment. These findings offer new opportunities to deliver drugs/labels only to cancer cells and only to their site of action within the cells. The development of such dual-specificity vectors for targeting cancer cells is an attractive and potentially safer and more efficacious way of delivering drugs. We provide examples of this approach for delivering brain cancer therapeutics, using a specific biomarker on glioblastoma tumor cells. PMID:22671766

Pandya, Hetal; Debinski, Waldemar

2013-01-01

56

Thermoresponsive hyaluronic acid nanogels as hydrophobic drug carrier to macrophages.  

PubMed

Delivery systems for macrophages are particularly attractive since these phagocytic cells play a important role in immunological and inflammatory responses, also acting as host cells for microorganisms that are involved in deadly infectious diseases, such as leishmaniasis. Hyaluronic acid (HA) is specifically recognized by macrophages that are known to express HA receptors. Therefore, in this study, we focused on HA-based nanogels as drug carriers for these cells. The drug delivery was validated in an in vivo study on mice using intravital two-photon laser scanning microscopy. HA derivatives were modified with a biocompatible oligo(ethylene glycol)-based thermoresponsive polymer to form nanogels. These HA conjugates were readily prepared by varying the molar mass of initial HA and the degree of substitution via radical-mediated thiol-ene chemistry in aqueous solution. The derivatives were shown to self-assemble into spherical gel particles with diameters ranging from 150 to 214nm above 37°C. A poorly water-soluble two-photon dye was successfully loaded into the nanogels during this self-assembly process. In vitro cellular uptake tests using a RAW 264.7 murine macrophage cell line showed successful intracellular delivery of the hydrophobic dye. After intravenous injection in mice, the nanogels circulated freely in the blood but were rapidly phagocytized within 13min by circulating macrophages and stored in the liver and spleen, as observed by two-photon microscopy. Benefit can be thus expected in using such a delivery system for the liver and spleen macrophage-associated diseases. PMID:25110287

Fernandes Stefanello, Talitha; Szarpak-Jankowska, Anna; Appaix, Florence; Louage, Benoit; Hamard, Lauriane; De Geest, Bruno G; van der Sanden, Boudewijn; Nakamura, Celso Vataru; Auzély-Velty, Rachel

2014-11-01

57

Expert Review Functionalized Micellar Systems for Cancer Targeted Drug Delivery  

E-print Network

Expert Review Functionalized Micellar Systems for Cancer Targeted Drug Delivery Damon Sutton,1 targeting; cancer nanomedicine; micelle pharmacokinetics; polymer micelles; responsive drug release with greatly improved drug pharmacokinetics and efficacious response in cancer treatment. Typical

Gao, Jinming

58

Thermoresponsive nanogels for prolonged duration local anesthesia  

PubMed Central

Nanogels based on poly(N-isopropylacrylamide) are attractive vehicles for prolonged duration local anesthesia because of their tunable size, number of functional groups, thermoresponsiveness, and their anionic charge. Nerve block durations of up to nine hours were achieved using acrylic acid-loaded nanogels loaded with bupivacaine. Increasing the anionic charge density of the nanogels or (for more highly acid-functionalized nanogels) decreasing the nanogel size facilitated longer duration anesthetic release. Small (<300 nm diameter) nanogels formed dense aggregates upon injection in vivo and induced only mild inflammatory responses, while large (>500 nm diameter) nanogels typically remained as liquid-like residues in vivo and induced more severe inflammatory reactions. PMID:22732383

Hoare, Todd; Young, Stuart; Lawlor, Michael W.; Kohane, Daniel S.

2012-01-01

59

[Research advances in brain-targeted nanoscale drug delivery system].  

PubMed

The blood-brain barrier (BBB) exerts its central nervous system (CNS) protective function as it hinders the delivery of diagnostic and therapeutic agents to the brain. With the development of nanotechnology during the last thirty years, the nanocarriers for delivering drugs make it possible to transport drugs across the BBB. The brain-targeted drug delivery system usually consists of two parts: nanocarriers and brain-targeted strategies. In this review, several kinds of nanocarriers are introduced for brain-targeted drug delivery. We focus on several possible strategies for brain-targeting and comment on their advantages and disadvantages in application. PMID:24417079

Liu, Yang; Jiang, Chen

2013-10-01

60

Synthesis of galactosyl compounds for targeted gene delivery  

Microsoft Academic Search

Cell-specific DNA delivery offers a great potential for targeted gene therapy. Toward this end, we have synthesized a series of compounds carrying galactose residues as a targeting ligand for asialoglycoprotein receptors of hepatocytes and primary amine groups as a functional domain for DNA binding. Biological activity of these galactosyl compounds in DNA delivery was evaluated in HepG2 and BL-6 cells

Tan Ren; Guisheng Zhang; Dexi Liu

2001-01-01

61

Targeting delivery of drugs in the vascular system  

PubMed Central

Delivery and effects of therapeutics remain suboptimal. Most drugs do not have affinity to their targets. Biotherapeutics including enzymes and genetic materials require specific sub-cellular addressing not attainable naturally. Endothelium, lining the luminal surface of blood vessels, represents a key therapeutic target in many diseases. Studies in cell culture and animal models revealed that targeted delivery of therapeutics to, into and across endothelium can be achieved using carriers targeted to specific molecules expressed on the surface of the endothelial cells. For example, cell adhesion molecules represent attractive targets for drug delivery. Rational design of the drug delivery systems (e.g., selection of optimal geometry and affinity to specific epitopes) provides an unprecedented level of control of such parameters of drug delivery as pharmacokinetics, circulation in blood, binding to selected endothelial cell phenotypes, anchoring on cell surface or internalization into the endothelium, subsequent intracellular addressing and duration of the effects. We discusse here key aspects of design of endothelium-targeted drug delivery systems with potential for translation into the clinical domain.

Muzykantov, Vladimir; Muro, Silvia

2014-01-01

62

Targeted Content Delivery for Social Media Content  

Microsoft Academic Search

Spotting contextually relevant keywords is fundamental to eective content suggestions on the Web. In this regard, misspellings, entity variations and o-topic discussions in content from Social Media pose unique challenges. Here, we present an algorithm that assists content delivery systems by identifying contextually relevant keywords and eliminating o-topic

Meenakshi Nagarajan; Kamal Baid

63

A Fluorescent Responsive Hybrid Nanogel for Closed-Loop Control of Glucose  

PubMed Central

Background The concept of closed-loop control of glucose, in which continuous glucose sensing is coupled to a fully automated insulin delivery device, without human input, has been an attractive idea for diabetes management. This study presents a new class of hybrid nanogels that can integrate glucose sensing and glucose-responsive insulin release into a single nano-object. Methods Zinc oxide@poly[N-isopropylacrylamide (NIPAM)-acrylamide (AAm)- 2-aminomethyl-5-fluorophenylboronic acid (FPBA)] hybrid nanogels were synthesized and investigated for size, morphology, volume phase transition, photoluminescence properties, and in vitro insulin release under different glucose concentrations. Glucose sensing was performed both in phosphate-buffered saline (PBS) and in blood samples. The insulin release in PBS of varying glucose levels, as well as a stepwise treatment between two glucose levels (126.0 and 270.0 mg/dl), was performed to test the glucose-responsive insulin release ability of the hybrid nanogels. Results Zinc oxide@poly(NIPAM-AAm-FPBA) hybrid nanogels can sensitively and selectively detect glucose in highly reproducible fluorescent signals over the clinically relevant glucose concentration range of 18?540 mg/dl. The glucose-responsive volume phase transition of the nanogels can further regulate the release of the preloaded insulin. The insulin release from the nanogels exhibits the slowest rate (~5% released in 76 h) at a normal glucose level (108.0 mg/dl) but becomes quicker and quicker as the glucose increases to higher and higher levels. Conclusions The rationally designed hybrid nanogel can optically signal the glucose level with high sensitivity and selectivity and simultaneously regulate the insulin release rate in response to the glucose reading, which shows a promising concept toward the development of a miniaturized closed-loop glycemic control system. PMID:22920816

Wu, Weitai; Chen, Shoumin; Hu, Yumei; Zhou, Shuiqin

2012-01-01

64

Subcellular targeting strategies for drug design and delivery  

Microsoft Academic Search

Many drug targets are localized to particular subcellular compartments, yet current drug design strategies are focused on bioavailability and tissue targeting and rarely address drug delivery to specific intracellular compartments. Insights into how the cell traffics its constituents to these different cellular locations could improve drug design. In this Review, we explore the fundamentals of membrane trafficking and subcellular organization,

Lawrence Rajendran; Hans-Joachim Knölker; Kai Simons

2010-01-01

65

Tumor-targeting drug delivery of new-generation taxoids  

PubMed Central

A long-standing problem of conventional cancer chemotherapy is the lack of tumor specificity. Tumor-targeting drug-delivery systems have been explored to overcome this problem. These systems combine a powerful cytotoxic anticancer agent with a tumor-targeting molecule via a ‘smart’ linker to form highly efficacious drug conjugates. These drug conjugates can deliver potent cytotoxic drugs specifically to tumors and tumor cells with minimal systemic toxicity. This review describes our groups’ research on the molecular approaches to the design and development of a novel drug-delivery system bearing highly potent new-generation taxoids for tumor-targeting chemotherapy in our laboratory. PMID:22168163

Ojima, Iwao; Zuniga, Edison S; Berger, William T; Seitz, Joshua D

2012-01-01

66

Tumor-targeting drug delivery of new-generation taxoids.  

PubMed

A long-standing problem of conventional cancer chemotherapy is the lack of tumor specificity. Tumor-targeting drug-delivery systems have been explored to overcome this problem. These systems combine a powerful cytotoxic anticancer agent with a tumor-targeting molecule via a 'smart' linker to form highly efficacious drug conjugates. These drug conjugates can deliver potent cytotoxic drugs specifically to tumors and tumor cells with minimal systemic toxicity. This review describes our groups' research on the molecular approaches to the design and development of a novel drug-delivery system bearing highly potent new-generation taxoids for tumor-targeting chemotherapy in our laboratory. PMID:22168163

Ojima, Iwao; Zuniga, Edison S; Berger, William T; Seitz, Joshua D

2012-01-01

67

Receptor-targeted nanocarriers for therapeutic delivery to cancer  

PubMed Central

Efficient and site-specific delivery of therapeutic drugs is a critical challenge in clinical treatment of cancer. Nano-sized carriers such as liposomes, micelles, and polymeric nanoparticles have been investigated for improving bioavailability and pharmacokinetic properties of therapeutics via various mechanisms, for example, the enhanced permeability and retention (EPR) effect. Further improvement can potentially be achieved by conjugation of targeting ligands onto nanocarriers to achieve selective delivery to the tumour cell or the tumour vasculature. Indeed, receptor-targeted nanocarrier delivery has been shown to improve therapeutic responses both in vitro and in vivo. A variety of ligands have been investigated including folate, transferrin, antibodies, peptides and aptamers. Multiple functionalities can be incorporated into the design of nanoparticles, e.g., to enable imaging and triggered intracellular drug release. In this review, we mainly focus on recent advances on the development of targeted nanocarriers and will introduce novel concepts such as multi-targeting and multi-functional nanoparticles. PMID:21028937

YU, BO; TAI, HENG CHIAT; XUE, WEIMING; LEE, L. JAMES; LEE, ROBERT J.

2013-01-01

68

Antiproliferative activity of fucan nanogel.  

PubMed

Sulfated fucans comprise families of polydisperse natural polysaccharides based on sulfated L-fucose. Our aim was to investigate whether fucan nanogel induces cell-specific responses. To that end, a non toxic fucan extracted from Spatoglossum schröederi was chemically modified by grafting hexadecylamine to the polymer hydrophilic backbone. The resulting modified material (SNFuc) formed nanosized particles. The degree of substitution with hydrophobic chains was close to 100%, as estimated by elemental analysis. SNFfuc in aqueous media had a mean diameter of 123 nm and zeta potential of -38.3 ± 0.74 mV, as measured by dynamic light scattering. Nanoparticles conserved their size for up to 70 days. SNFuc cytotoxicity was determined using the MTT assay after culturing different cell lines for 24 h. Tumor-cell (HepG2, 786, H-S5) proliferation was inhibited by 2.0%-43.7% at nanogel concentrations of 0.05-0.5 mg/mL and rabbit aorta endothelial cells (RAEC) non-tumor cell line proliferation displayed inhibition of 8.0%-22.0%. On the other hand, nanogel improved Chinese hamster ovary (CHO) and monocyte macrophage cell (RAW) non-tumor cell line proliferation in the same concentration range. The antiproliferative effect against tumor cells was also confirmed using the BrdU test. Flow cytometric analysis revealed that the fucan nanogel inhibited 786 cell proliferation through caspase and caspase-independent mechanisms. In addition, SNFuc blocks 786 cell passages in the S and G2-M phases of the cell cycle. PMID:23118717

Dantas-Santos, Nednaldo; Almeida-Lima, Jailma; Vidal, Arthur Anthunes Jacome; Gomes, Dayanne Lopes; Oliveira, Ruth Medeiros; Santos Pedrosa, Silvia; Pereira, Paula; Gama, Francisco Miguel; Oliveira Rocha, Hugo Alexandre

2012-09-01

69

Antiproliferative Activity of Fucan Nanogel  

PubMed Central

Sulfated fucans comprise families of polydisperse natural polysaccharides based on sulfated L-fucose. Our aim was to investigate whether fucan nanogel induces cell-specific responses. To that end, a non toxic fucan extracted from Spatoglossum schröederi was chemically modified by grafting hexadecylamine to the polymer hydrophilic backbone. The resulting modified material (SNFuc) formed nanosized particles. The degree of substitution with hydrophobic chains was close to 100%, as estimated by elemental analysis. SNFfuc in aqueous media had a mean diameter of 123 nm and zeta potential of ?38.3 ± 0.74 mV, as measured by dynamic light scattering. Nanoparticles conserved their size for up to 70 days. SNFuc cytotoxicity was determined using the MTT assay after culturing different cell lines for 24 h. Tumor-cell (HepG2, 786, H-S5) proliferation was inhibited by 2.0%–43.7% at nanogel concentrations of 0.05–0.5 mg/mL and rabbit aorta endothelial cells (RAEC) non-tumor cell line proliferation displayed inhibition of 8.0%–22.0%. On the other hand, nanogel improved Chinese hamster ovary (CHO) and monocyte macrophage cell (RAW) non-tumor cell line proliferation in the same concentration range. The antiproliferative effect against tumor cells was also confirmed using the BrdU test. Flow cytometric analysis revealed that the fucan nanogel inhibited 786 cell proliferation through caspase and caspase-independent mechanisms. In addition, SNFuc blocks 786 cell passages in the S and G2-M phases of the cell cycle. PMID:23118717

Dantas-Santos, Nednaldo; Almeida-Lima, Jailma; Vidal, Arthur Anthunes Jacome; Gomes, Dayanne Lopes; Oliveira, Ruth Medeiros; Santos Pedrosa, Silvia; Pereira, Paula; Gama, Francisco Miguel; Oliveira Rocha, Hugo Alexandre

2012-01-01

70

Functionalized Nanosystems for Targeted Mitochondrial Delivery  

PubMed Central

Mitochondrial dysfunction including oxidative stress and DNA mutations underlies the pathology of various diseases including Alzheimer’s disease and diabetes, necessitating the development of mitochondria targeted therapeutic agents. Nanotechnology offers unique tools and materials to target therapeutic agents to mitochondria. As discussed in this paper, a variety of functionalized nanosystems including polymeric and metallic nanoparticles as well as liposomes are more effective than plain drug and non-functionalized nanosystems in delivering therapeutic agents to mitochondria. Although the field is in its infancy, studies to date suggest the superior therapeutic activity of functionalized nanosystems for treating mitochondrial defects. PMID:22138492

Durazo, Shelley A.; Kompella, Uday B.

2011-01-01

71

Synthetic LDL as targeted drug delivery vehicle  

DOEpatents

The present invention provides a synthetic LDL nanoparticle comprising a lipid moiety and a synthetic chimeric peptide so as to be capable of binding the LDL receptor. The synthetic LDL nanoparticle of the present invention is capable of incorporating and targeting therapeutics to cells expressing the LDL receptor for diseases associated with the expression of the LDL receptor such as central nervous system diseases. The invention further provides methods of using such synthetic LDL nanoparticles.

Forte, Trudy M. (Berkeley, CA); Nikanjam, Mina (Richmond, CA)

2012-08-28

72

Nanoparticles for oral delivery: Targeted nanoparticles with peptidic ligands for oral protein delivery  

PubMed Central

As the field of biotechnology has advanced, oral protein delivery has also made significant progress. Oral delivery is the most common method of drug administration with high levels of patient acceptance. Despite the preference of oral delivery, administration of therapeutic proteins has been extremely difficult. Increasing the bioavailability of oral protein drugs to the therapeutically acceptable level is still a challenging goal. Poor membrane permeability, high molecular weight, and enzymatic degradation of protein drugs have remained unsolved issues. Among diverse strategies, nanotechnology has provided a glimpse of hope in oral delivery of protein drugs. Nanoparticles have advantages, such as small size, high surface area, and modification using functional groups for high capacity or selectivity. Nanoparticles with peptidic ligands are especially worthy of notice because they can be used for specific targeting in the gastrointestinal (GI) tract. This article reviews the transport mechanism of the GI tract, barriers to protein absorption, current status and limitations of nanotechnology for oral protein delivery system. PMID:23123292

Yun, Yeonhee; Cho, Yong Woo; Park, Kinam

2012-01-01

73

Targeting the Delivery of Army Advertisements on Television.  

National Technical Information Service (NTIS)

The U.S. Army uses advertisements to affect the knowledge, attitudes, and behavioral intentions of youth to effectively recruit manpower. Both the message content and the delivery of the message are targeted to recruit soldiers who are most likely to prov...

T. Ellig

1988-01-01

74

Integrated nanoplasmonic-nanofluidic biosensors with targeted delivery of analytes  

E-print Network

Integrated nanoplasmonic-nanofluidic biosensors with targeted delivery of analytes Ahmet Ali Yanik the effective analyte transport. To overcome this limitation, we propose and demonstrate a nanoplasmonic-nanofluidic layers of microfluidic channels through plasmonic/nanofluidic holes. To implement the proposed sensor

75

Self-Assembling Peptide Amphiphiles for Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

The systemic delivery of therapeutics is currently limited by off-target side effects and poor drug uptake into the cells that need to be treated. One way to circumvent these issues is to target the delivery and release of therapeutics to the desired location while limiting systemic toxicity. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures for the development of targeted therapies. Specifically, the research has focused on the interrelationships between presentation of targeting moeities and the control of nanostructure morphology in the context of systemic delivery for targeting cancer and vascular injuries. The self-assembly region of the PA was systematically altered to achieve control of nanostructure widths, from 100 nm to 10 nm, by the addition of valine-glutamic acid dimers into the chemical structure, subsequently increasing the degree of nanostructure twist. For the targeting of tumors, a homing PA was synthesized to include a dimeric, cyclic peptide sequence known to target the cancer-specific, death receptor 5 (DR5) and initiate apoptosis through the oligomerization of DR5. This PA presented a multivalent display of DR5-binding peptides, resulting in improved binding affinity measured by surface plasmon resonance. The DR5-targeting PA also showed enhanced efficacy in both in vitro and in vivo tumor models relative to non-targeted controls. Alternative modifications to the PA-based antitumor therapies included the use of a cytotoxic, membrane-lytic PA coassembled with a pegylated PA, which showed enhanced biodistribution and in vivo activity after coassembly. The functionalization of the hydrophobic core was also accomplished through the encapsulation of the chemotherapy camptothecin, which was shown to be an effective treatment in vivo. Additionally, a targeted PA nanostructure was designed to bind to the site of vascular intervention by targeting collagen IV. Following balloon angioplasty, targeted PA nanofibers showed enhanced binding by fluorescence relative to spherical micelles with the same targeting sequence, demonstrating the importance of nanostructure shape for vascular binding. Nitric oxide was functionalized onto the PA nanostructure through the S-nitrosylation (SNO) of a cysteine residue. Two weeks after vascular injury, the SNO-functionalized, targeted nanofibers showed significantly decreased levels of restenosis. In all treatment methods described, the control of multivalency through the tuning of supramolecular structure was essential to achieve optimal binding. Understanding the role of dynamic, supramolecular structures for the systemic delivery of peptide therapeutics should be an important focus of future work.

Moyer, Tyson

76

Targeting homeostasis in drug delivery using bioresponsive hydrogel microforms.  

PubMed

A drug delivery platform comprising a biocompatible, bioresponsive hydrogel and possessing a covalently tethered peptide-drug conjugate was engineered to achieve stasis, via a closed control loop, of the external biochemical activity of the actuating protease. The delivery platform contains a peptide-drug conjugate covalently tethered to the hydrogel matrix, which in the presence of the appropriate protease, was cleaved and the drug released into the bathing environment. This platform was developed and investigated in silico using a finite element modeling (FEM) approach. Firstly, the primary governing phenomena guiding drug release profiles were investigated, and it was confirmed that under transport-limited conditions, the diffusion of the enzyme within the hydrogel and the coupled enzyme kinetics accurately model the system and are in agreement with published results. Secondly, the FEM model was used to investigate the release of a competitive protease inhibitor, MAG283, via cleavage of Acetyl-Pro-Leu-Gly|Leu-MAG-283 by MMP9 in order to achieve targeted homeostasis of MMP-9 activity, such as in the pathophysiology of chronic wounds, via closed-loop feedback control. The key engineering parameters for the delivery device are the radii of the hydrogel microspheres and the concentration of the peptide-inhibitor conjugate. Homeostatic drug delivery, where the focus turns away from the drug release rate and turns toward achieving targeted control of biochemical activity within a biochemical pathway, is an emerging approach in drug delivery methodologies for which the potential has not yet been fully realized. PMID:24333901

Wilson, A Nolan; Guiseppi-Elie, Anthony

2014-01-30

77

Prostate cancer relevant antigens and enzymes for targeted drug delivery.  

PubMed

Chemotherapy is one of the most widely used approaches in combating advanced prostate cancer, but its therapeutic efficacy is usually insufficient due to poor specificity and associated toxicity. Lack of targeted delivery to prostate cancer cells is also the primary obstacles in achieving feasible therapeutic effect of other promising agents including peptide, protein, and nucleic acid. Consequently, there remains a critical need for strategies to increase the selectivity of anti-prostate cancer agents. This review will focus on various prostate cancer-relevant antigens and enzymes that could be exploited for prostate cancer targeted drug delivery. Among various targeting strategies, active targeting is the most advanced approach to specifically deliver drugs to their designated cancer cells. In this approach, drug carriers are modified with targeting ligands that can specifically bind to prostate cancer-specific antigens. Moreover, there are several specific enzymes in the tumor microenvironment of prostate cancer that can be exploited for stimulus-responsive drug delivery systems. These systems can specifically release the active drug in the tumor microenvironment of prostate cancer, leading to enhanced tumor penetration efficiency. PMID:24878184

Barve, Ashutosh; Jin, Wei; Cheng, Kun

2014-08-10

78

Colon targeting: an emerging frontier for oral insulin delivery.  

PubMed

Subcutaneous administration of insulin is associated with several limitations such as discomfort, local pain, irritation, infections, immune reactions and lipoatrophy as well as lipohypertrophy manifestations at the injection site. To overcome these drawbacks, enormous research is currently going on worldwide for designing of an alternative noninvasive route of administration. Pulmonary and oral route seem to be the most promising ones, with respect to the market value. However, after the letdown by pulmonary delivery of insulin, oral colon targeted delivery of insulin has gained tremendous interest among researchers. Although bioavailability remains a challenge for oral colon specific delivery of insulin, the employment of protease inhibitors, permeation enhancers and polymeric delivery systems have proved to be advantageous to overcome the said problem. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the strategies employed for attaining non-erratic bioavailability of insulin, and to highlight some of the formulation technologies that have been developed for attaining oral colon-specific delivery of insulin. PMID:23521062

Patel, Mayur Mahendrakumar

2013-06-01

79

Responsive polymer-fluorescent carbon nanoparticle hybrid nanogels for optical temperature sensing, near-infrared light-responsive drug release, and tumor cell imaging  

NASA Astrophysics Data System (ADS)

Fluorescent carbon nanoparticles (FCNPs) have been successfully immobilized into poly(N-isopropylacrylamide-co-acrylamide) [poly(NIPAM-AAm)] nanogels based on one-pot precipitation copolymerization of NIPAM monomers with hydrogen bonded FCNP-AAm complex monomers in water. The resultant poly(NIPAM-AAm)-FCNP hybrid nanogels can combine functions from each building block for fluorescent temperature sensing, cell imaging, and near-infrared (NIR) light responsive drug delivery. The FCNPs in the hybrid nanogels not only emit bright and stable photoluminescence (PL) and exhibit up-conversion PL properties, but also increase the loading capacity of the nanogels for curcumin drug molecules. The reversible thermo-responsive swelling/shrinking transition of the poly(NIPAM-AAm) nanogel can not only modify the physicochemical environment of the FCNPs to manipulate the PL intensity for sensing the environmental temperature change, but also regulate the releasing rate of the loaded anticancer drug. In addition, the FCNPs embedded in the nanogels can convert the NIR light to heat, thus an exogenous NIR irradiation can further accelerate the drug release and enhance the therapeutic efficacy. The hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells upon laser excitation. The demonstrated hybrid nanogels with nontoxic and optically active FCNPs immobilized in responsive polymer nanogels are promising for the development of a new generation of multifunctional materials for biomedical applications.Fluorescent carbon nanoparticles (FCNPs) have been successfully immobilized into poly(N-isopropylacrylamide-co-acrylamide) [poly(NIPAM-AAm)] nanogels based on one-pot precipitation copolymerization of NIPAM monomers with hydrogen bonded FCNP-AAm complex monomers in water. The resultant poly(NIPAM-AAm)-FCNP hybrid nanogels can combine functions from each building block for fluorescent temperature sensing, cell imaging, and near-infrared (NIR) light responsive drug delivery. The FCNPs in the hybrid nanogels not only emit bright and stable photoluminescence (PL) and exhibit up-conversion PL properties, but also increase the loading capacity of the nanogels for curcumin drug molecules. The reversible thermo-responsive swelling/shrinking transition of the poly(NIPAM-AAm) nanogel can not only modify the physicochemical environment of the FCNPs to manipulate the PL intensity for sensing the environmental temperature change, but also regulate the releasing rate of the loaded anticancer drug. In addition, the FCNPs embedded in the nanogels can convert the NIR light to heat, thus an exogenous NIR irradiation can further accelerate the drug release and enhance the therapeutic efficacy. The hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells upon laser excitation. The demonstrated hybrid nanogels with nontoxic and optically active FCNPs immobilized in responsive polymer nanogels are promising for the development of a new generation of multifunctional materials for biomedical applications. Electronic supplementary information (ESI) available: Fig. S1-S5. See DOI: 10.1039/c4nr01030b

Wang, Hui; Ke, Fuyou; Mararenko, Anton; Wei, Zengyan; Banerjee, Probal; Zhou, Shuiqin

2014-06-01

80

Synthesis of galactosyl compounds for targeted gene delivery.  

PubMed

Cell-specific DNA delivery offers a great potential for targeted gene therapy. Toward this end, we have synthesized a series of compounds carrying galactose residues as a targeting ligand for asialoglycoprotein receptors of hepatocytes and primary amine groups as a functional domain for DNA binding. Biological activity of these galactosyl compounds in DNA delivery was evaluated in HepG2 and BL-6 cells and compared with respect to the number of galactose residues as well as primary amine groups in each molecule. Transfection experiments using a firefly luciferase gene as a reporter revealed that compounds with multivalent binding properties were more active in DNA delivery. An optimal transfection activity in HepG2 cells requires seven primary amine groups and a minimum of two galactose residues in each molecule. The transfection activity of compounds carrying multi-galactose residues can be inhibited by asialofetuin, a natural substrate for asialoglycoprotein receptors of hepatocytes, suggesting that gene transfer by these galactosyl compounds is asialoglycoprotein receptor-mediated. These results provide direct evidence in support of our new strategy for the use of small and synthetic compounds for cell specific and targeted gene delivery. PMID:11597478

Ren, T; Zhang, G; Liu, D

2001-11-01

81

Polypropylene nanogel: “Myth or reality”  

NASA Astrophysics Data System (ADS)

The objective of this work is the investigation of the nanogel and microgel formation in modified PP. The modified PP in pellets was synthesized by gamma irradiation of pristine PP under a crosslinking atmosphere of acetylene in dose of 5, 12.5 and 20 kGy, followed by thermal treatment for radical recombination and annihilation of the remaining radicals. The thin film gel of the polypropylenes was obtained by extraction in boiling xylene for period of 12 h at 138 °C, followed by decantation in beaker at room temperature of 25 °C with the total volatilization of the xylene and deposition of dried material film on glass substrate under agitation by Settling process. The thin film gel formed of pristine PP and modified PP (i.e., irradiated) was characterized using scanning electron microscopy (SEM), field emission scanning electron microscopy (FESEM) and differential scanning calorimetry (DSC). The PP morphology indicated the nanogels and microgel formation with increase of spherulitic concentration and crystallinity at dose of 12.5 kGy.

Oliani, W. L.; Parra, D. F.; Riella, H. G.; Lima, L. F. C. P.; Lugao, A. B.

2012-09-01

82

Targeted delivery of doxorubicin using stealth liposomes modified with transferrin.  

PubMed

Site-specific delivery of drugs and therapeutics can significantly reduce drug toxicity and increase the therapeutic effect. Transferrin (Tf) is one suitable ligand to be conjugated to drug delivery systems to achieve site-specific targeting, due to its specific binding to transferrin receptors (TfR), highly expressed on the surfaces of tumor cells. Stealth liposomes are effective vehicles for drugs, genes and vaccines and can be easily modified with proteins, antibodies, and other appropriate ligands, resulting in attractive formulations for targeted drug delivery. In this study, we prepared doxorubicin-loaded stealth liposomes (Tf-SL-DOX) by film dispersion followed by ammonium sulphate gradient method, then conjugated Tf to the liposome surface by an amide bound between DSPE-PEG(2000)-COOH and Tf. The results of the intracellular uptake study indicated that Tf-modified SL was able to enhance the intracellular uptake of the entrapped DOX by HepG2 cells compared to SL-DOX. We studied tissue distribution and therapeutic effects of Free DOX, SL-DOX and Tf-SL-DOX in tumor-bearing mice and pharmacokinetics in rats. The pharmacokinetic behavior of Tf-SL-DOX in the plasma was closed to SL-DOX. Administration of Tf-SL-DOX to tumor-bearing mice could be used to deliver DOX effectively to the targeted site, significantly increasing DOX concentration in tumor and decreasing DOX concentration in heart and kidney. In summary, our study indicated that the Tf-coupled PEG liposomes (Tf-SL) could be as the targeted carriers to facilitate the delivery of the encapsulated anticancer drugs into tumor cells by receptor-mediated way. PMID:19429296

Li, XueMing; Ding, Liyan; Xu, Yuanlong; Wang, Yonglu; Ping, QiNeng

2009-05-21

83

Multifunctional Inorganic Nanoparticles for Imaging, Targeting, and Drug Delivery  

PubMed Central

Drug delivery, magnetic resonance and fluorescence imaging, magnetic manipulation, and cell targeting are simultaneously possible using a multifunctional mesoporous silica nanoparticle. Superparamagnetic iron oxide nanocrystals were encapsulated inside mesostructured silica spheres that were labeled with fluorescent dye molecules and coated with hydrophilic groups to prevent aggregation. Water-insoluble anticancer drugs were delivered into human cancer cells; surface conjugation with cancer-specific targeting agents increased the uptake into cancer cells relative to that in non-cancerous fibroblasts. The highly versatile multifunctional nanoparticles could potentially be used for simultaneous imaging and therapeutic applications. PMID:19206485

Liong, Monty; Lu, Jie; Kovochich, Michael; Xia, Tian; Ruehm, Stefan G.; Nel, Andre E.; Tamanoi, Fuyuhiko; Zink, Jeffrey I.

2009-01-01

84

Magnetic nanoparticles as targeted delivery systems in oncology  

PubMed Central

Background Many different types of nanoparticles, magnetic nanoparticles being just a category among them, offer exciting opportunities for technologies at the interfaces between chemistry, physics and biology. Some magnetic nanoparticles have already been utilized in clinical practice as contrast enhancing agents for magnetic resonance imaging (MRI). However, their physicochemical properties are constantly being improved upon also for other biological applications, such as magnetically-guided delivery systems for different therapeutics. By exposure of magnetic nanoparticles with attached therapeutics to an external magnetic field with appropriate characteristics, they are concentrated and retained at the preferred site which enables the targeted delivery of therapeutics to the desired spot. Conclusions The idea of binding chemotherapeutics to magnetic nanoparticles has been around for 30 years, however, no magnetic nanoparticles as delivery systems have yet been approved for clinical practice. Recently, binding of nucleic acids to magnetic nanoparticles has been demonstrated as a successful non-viral transfection method of different cell lines in vitro. With the optimization of this method called magnetofection, it will hopefully become another form of gene delivery for the treatment of cancer. PMID:22933928

Prijic, Sara; Sersa, Gregor

2011-01-01

85

Multifunctional Particles for Melanoma-Targeted Drug Delivery  

PubMed Central

New magnetic-based core-shell particles (MBCSP) were developed to target skin cancer cells while delivering chemotherapeutic drugs in a controlled fashion. MBCSP consist of a thermo-responsive shell of poly(N-isopropylacrylamide-acrylamide-allylamine) and a core of poly(lactic-co-glycolic acid) (PLGA) embedded with magnetite nanoparticles. To target melanoma cancer cells, MBCSP were conjugated with Gly-Arg-Gly-Asp-Ser (GRGDS) peptides that specifically bind to the ?5?3+ receptor of melanoma cell. MBCSP consist of unique multifunctional and controlled drug delivery characteristics. Specially, they can provide dual drug release mechanisms (a sustained release of drugs through degradation of PLGA core and a controlled release in response to changes in temperature via thermo-responsive polymer shell), and dual targeting mechanisms (magnetic localization and receptor-mediated targeting). Results from in vitro studies indicate that GRGDS-conjugated MBCSP has an average diameter of 296 nm and exhibit no cytotoxicity towards human dermal fibroblasts up to 500 ?g ml?1. Further, a sustained release of curcumin from the core and a temperature-dependent release of doxorubicin from the shell of MBCSP were observed. The particles also produced a dark contrast signal in magnetic resonance imaging. Finally, the particles were accumulated at the tumor site in a B16F10 melanoma orthotopic mouse model, especially in presence of a magnet. Results indicate great potential of MBCSP as a platform technology to target, treat, and monitor melanoma for targeted drug delivery to reduce side effects of chemotherapeutic reagents. PMID:22561668

Wadajkar, Aniket S.; Bhavsar, Zarna; Ko, Cheng-Yu; Koppolu, Bhanuprasanth; Cui, Weina; Tang, Liping; Nguyen, Kytai T.

2012-01-01

86

Inorganic nanomaterials for bioimaging, targeted drug delivery and therapeutics.  

PubMed

Inorganic nanomaterials including gold nanoparticles, mesoporous silica nanoparticles, graphene, magnetic nanoparticles, quantum dots and layered double hydroxides have become one of the most active research fields in biochemistry, biotechnology and biomedicine. Benefiting from the facile synthesis/modification, intrinsically physicochemical properties and good biocompatibility, inorganic nanomaterials have shown great potential in bioimaging, targeted drug delivery and cancer therapies. This Feature Article summarizes recent progress on various inorganic nanocarriers, including the background, synthesis, modification, cytotoxicity, physicochemical properties as well as their applications in biomedicine. PMID:24955443

Liang, Ruizheng; Wei, Min; Evans, David G; Duan, Xue

2014-10-21

87

An Efficient Targeted Drug Delivery through Apotransferrin Loaded Nanoparticles  

PubMed Central

Background Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. Methodology/Principal Findings Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano) have diameters of 25–50 ?m, which increase to 60–80 ?m upon direct loading of drug (direct-nano), and showed further increase in dimension (75–95 ?m) in conjugated nanoparticles (conj-nano). The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a) localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus) (b) pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c) the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in regression of hepatocellular carcinoma with negligible toxicity to kidney and liver. Conclusions The present study thus demonstrates that the direct-nano is highly efficacious in delivery of drug in a target specific manner with lower toxicity to heart, liver and kidney. PMID:19806207

Kishore, Golla; Kondapi, Anand Kumar

2009-01-01

88

Hepatic-targeted gene delivery using cationic mannan vehicle.  

PubMed

The incidence of hepatic diseases continuously increases worldwide and causes significant mortality because of inefficient pharmacotherapy. Gene therapy is a new strategy in the treatment of hepatic diseases, but the disadvantages of insufficient retention in the liver and undesirable side effects hinder its application. In this study, we developed a novel nonviral vehicle targeted to liver. Mannan was cationized with spermine at varying grafted ratios to deliver the gene and was optimized in cytotoxicity and transfection in vitro. A spermine-mannan (SM)-based delivery system was proven to be hepatic targeted and was capable of prolonging the gene retention period in the liver. Moreover, SM at N/P of 20 was confirmed to be less interfered with by the serum. Optimized SM vehicle has relatively high hepatic transfection with almost no toxicity induction in the liver, which highlighted its potential in the treatment of hepatic diseases. PMID:24735422

Ruan, Gui-Xin; Zhang, Tian-Yuan; Li, Li-Ming; Zhang, Xing-Guo; Shen, You-Qing; Tabata, Yasuhiko; Gao, Jian-Qing

2014-10-01

89

Nanostructured porous Si-based nanoparticles for targeted drug delivery  

PubMed Central

One of the backbones in nanomedicine is to deliver drugs specifically to unhealthy cells. Drug nanocarriers can cross physiological barriers and access different tissues, which after proper surface biofunctionalization can enhance cell specificity for cancer therapy. Recent developments have highlighted the potential of mesoporous silica (PSiO2) and silicon (PSi) nanoparticles for targeted drug delivery. In this review, we outline and discuss the most recent advances on the applications and developments of cancer therapies by means of PSiO2 and PSi nanomaterials. Bio-engineering and fine tuning of anti-cancer drug vehicles, high flexibility and potential for sophisticated release mechanisms make these nanostructures promising candidates for “smart” cancer therapies. As a result of their physicochemical properties they can be controllably loaded with large amounts of drugs and coupled to homing molecules to facilitate active targeting. The main emphasis of this review will be on the in vitro and in vivo studies. PMID:23507894

Shahbazi, Mohammad-Ali; Herranz, Barbara; Santos, Helder A.

2012-01-01

90

Synergistic Antitumor Activity from Two-Stage Delivery of Targeted Toxins and Endosome-Disrupting Nanoparticles  

E-print Network

Plant-derived Type I toxins are candidate anticancer therapeutics requiring cytosolic delivery into tumor cells. We tested a concept for two-stage delivery, whereby tumor cells precoated with an antibody-targeted gelonin ...

Su, Xingfang

91

Targeted drug delivery and enhanced intracellular release using functionalized liposomes  

NASA Astrophysics Data System (ADS)

The ability to target cancer cells using an appropriate drug delivery system can significantly reduce the associated side effects from cancer therapies and can help in improving the overall quality of life, post cancer survival. Integrin alpha5beta1 is expressed on several types of cancer cells, including colon cancer and plays an important role in tumor growth and metastasis. Thus, the ability to target the integrin alpha 5beta1 using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth and reducing tumor metastasis. The work in this thesis focuses on designing and optimizing, functionalized stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that specifically target the integrin alpha5beta1. The PEG provides a steric barrier allowing the liposomes to circulate in the blood for longer duration and the functionalizing moiety, PR_b peptide specifically recognizes and binds to integrin alpha5beta1 expressing cells. The work demonstrates that by optimizing the amount of PEG and PR_b on the liposomal interface, nano-vectors can be engineered that bind to CT26.WT colon cancer cells in a specific manner and internalize through alpha 5beta1-mediated endocytosis. To further improve the efficacy of the system, PR_b functionalized pH-sensitive stealth liposomes that exhibit triggered release under mild acidic conditions present in endocytotic vesicles were designed. The study showed that PR_b functionalized pH-sensitive stealth liposomes, undergo destabilization under mildly acidic conditions and incorporation of the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b functionalized pH-sensitive stealth liposomes bind to CT26.WT colon carcinoma cells that express integrin alpha5beta 1, undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. PR_b-targeted pH-sensitive stealth liposomes encapsulating 5-fluorouracil (5-FU) show significantly higher cytotoxicity than the PR_b-targeted inert stealth liposomes and the non-targeted stealth liposomes (both pH-sensitive and inert). The studies demonstrated that optimized PR_b functionalized pH sensitive liposomes have the potential to deliver a payload, such as chemotherapeutic agents, directly to colon cancer cells in an efficient and specific manner.

Garg, Ashish

92

Luminescent/magnetic hybrid nanoparticles with folate-conjugated peptide composites for tumor-targeted drug delivery.  

PubMed

We developed a novel chitosan-based luminescent/magnetic hybrid nanoparticles with folate-conjugated tetrapeptide composites (CLMNPs-tetrapeptide-FA) by conjugation in situ. First, chitosan, CdTe quantum dots (QDs), and superparamagnetic iron oxide were directly gelled into ternary hybrid nanogels. Subsequently, tetrapeptides (GFFG and LGPV) and folate were conjugated orderly into the hybrid nanoparticles. The morphology, composition, and properties of the as-prepared copolymers have also been characterized and determined using TEM, EDX, XRD, FTIR spectra, DLS, fluorescence spectroscopy, VSM, and fluorescence microscopy imaging studies. The size range of the end product CLMNPs-tetrapeptide-FA copolymers was from 150 to 190 nm under simulated physiological environment. In vivo, the experimental results of magnetic accumulation showed that the copolymers could be trapped in the tumor tissue under magnetic guidance. Under the present experimental conditions, the loading efficiencies of CPT were approximately 8.6 wt % for CLMNPs-GFFG-FA and 1.1 wt % for CLMNPs-LGPV-FA, respectively. The CPT cumulative release under dialysis condition mainly occurred for the first 28 h, and could reach 55% at pH 5.3 and 46% at pH 7.4 from CPT-loaded CLMNPs-GFFG-FA, and 69% at pH 5.3 and 57% at pH 7.4 from CPT-loaded CLMNPs-LGPV-FA within 28 h, respectively. The hemolysis percentages (<2%) and coagulation properties of blank and CPT-loaded copolymers were within the scope of safe values. Compared to free CPT, the CPT-loaded CLMNPs-tetrapeptide-FA copolymers showed specific targeting to A549 cells in vitro. More than 75% viability in L02 cells were seen in CLMNPs-GFFG-FA and CLMNPs-LGPV-FA copolymer concentration of 500 ?g/mL, respectively. It was found that the two kinds of copolymers were transported into the A549 cells by a folate-receptor-mediated endocytosis mechanism. These results indicate that the multifunctional CLMNPs-tetrapeptide-FA copolymers possess a moderate CPT loading efficiency, low cytotoxicity, and favorable biocompatibility, and are promising candidates for tumor-targeted drug delivery. PMID:22486419

Shen, Jian-Min; Guan, Xing-Mei; Liu, Xiao-Yan; Lan, Jing-Feng; Cheng, Ting; Zhang, Hai-Xia

2012-05-16

93

The ability of retention, drug release and rheological properties of nanogel bioadhesives based on cellulose derivatives.  

PubMed

The rheological and drug release behavior of biopolymer nanocomposite gels based on the cellulose derivatives, formulated as the bioadhesive drug delivery platforms, were investigated. The bioadhesive gel is composed of the microcrystalline cellulose, sodium carboxymethyl cellulose and phosphate buffered saline (pH?=?7.4 at 20?°C) as the dissolution and release medium. The reinforcing nanofillers such as MMT-clay, fumed porous silica and porous starch were used as additives in the nanogel bioadhesive. The constant steady state viscosities of this nanogels upon incorporation of various nanofillers into the systems is the sign of structural stability. Hence, this system is suitable for use in the controlled drug delivery systems in contact with the biological tissues. Based on the rheological measurements, the shear flow properties (i.e. zero shear viscosity and yield stress) were influenced by the concentration of polymers and nanoparticles. The results indicate that the nonlinear rheological data are fitted properly by the Giesekus model. Furthermore, the results showed that the nonlinear viscoelastic parameters (? and ?) are highly affected by the biogel and nanoparticles concentrations. Finally, the drug release was measured, and the results indicated that the biopolymer-clay nanocomposites have appropriate release pattern as the release is better controlled compared to the other nanogel formulations. PMID:24160773

Keshavarz, M; Kaffashi, B

2014-12-01

94

Magnetic/NIR-thermally responsive hybrid nanogels for optical temperature sensing, tumor cell imaging and triggered drug release  

NASA Astrophysics Data System (ADS)

The paper demonstrates a class of multifunctional core-shell hybrid nanogels with fluorescent and magnetic properties, which have been successfully developed for simultaneous optical temperature sensing, tumor cell imaging and magnetic/NIR-thermally responsive drug carriers. The as-synthesized hybrid nanogels were designed by coating bifunctional nanoparticles (BFNPs, fluorescent carbon dots embedded in the porous carbon shell and superparamagnetic iron oxide nanocrystals clustered in the core) with a thermo-responsive poly(N-isopropylacrylamide-co-acrylamide) [poly(NIPAM-AAm)]-based hydrogel as the shell. The BFNPs in hybrid nanogels not only demonstrate excellent photoluminescence (PL) and photostability due to the fluorescent carbon dots embedded in the porous carbon shell, but also has targeted drug accumulation potential and a magnetic-thermal conversion ability due to the superparamagnetic iron oxide nanocrystals clustered in the core. The thermo-responsive poly(NIPAM-AAm)-based gel shell can not only modify the physicochemical environment of the BFNPs core to manipulate the fluorescence intensity for sensing the variation of the environmental temperature, but also regulate the release rate of the loaded anticancer drug (curcumin) by varying the local temperature of environmental media. In addition, the carbon layer of BFNPs can adsorb and convert the NIR light to heat, leading to a promoted drug release under NIR irradiation and improving the therapeutic efficacy of drug-loaded hybrid nanogels. Furthermore, the superparamagnetic iron oxide nanocrystals in the core of BFNPs can trigger localized heating using an alternating magnetic field, leading to a phase change in the polymer gel to trigger the release of loaded drugs. Finally, the multifunctional hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells. The demonstrated hybrid nanogels would be an ideal system for the biomedical applications due to their excellent optical properties, magnetic properties, high drug loading capacity and responsive drug release behavior.The paper demonstrates a class of multifunctional core-shell hybrid nanogels with fluorescent and magnetic properties, which have been successfully developed for simultaneous optical temperature sensing, tumor cell imaging and magnetic/NIR-thermally responsive drug carriers. The as-synthesized hybrid nanogels were designed by coating bifunctional nanoparticles (BFNPs, fluorescent carbon dots embedded in the porous carbon shell and superparamagnetic iron oxide nanocrystals clustered in the core) with a thermo-responsive poly(N-isopropylacrylamide-co-acrylamide) [poly(NIPAM-AAm)]-based hydrogel as the shell. The BFNPs in hybrid nanogels not only demonstrate excellent photoluminescence (PL) and photostability due to the fluorescent carbon dots embedded in the porous carbon shell, but also has targeted drug accumulation potential and a magnetic-thermal conversion ability due to the superparamagnetic iron oxide nanocrystals clustered in the core. The thermo-responsive poly(NIPAM-AAm)-based gel shell can not only modify the physicochemical environment of the BFNPs core to manipulate the fluorescence intensity for sensing the variation of the environmental temperature, but also regulate the release rate of the loaded anticancer drug (curcumin) by varying the local temperature of environmental media. In addition, the carbon layer of BFNPs can adsorb and convert the NIR light to heat, leading to a promoted drug release under NIR irradiation and improving the therapeutic efficacy of drug-loaded hybrid nanogels. Furthermore, the superparamagnetic iron oxide nanocrystals in the core of BFNPs can trigger localized heating using an alternating magnetic field, leading to a phase change in the polymer gel to trigger the release of loaded drugs. Finally, the multifunctional hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells. The demonstrated hybrid nanogels would be an ide

Wang, Hui; Yi, Jinhui; Mukherjee, Sumit; Banerjee, Probal; Zhou, Shuiqin

2014-10-01

95

Transcranial Route of Brain Targeted Delivery of Methadone in Oil  

PubMed Central

The unique anatomical arrangement of blood vessels and sinuses in the human skull and the brain, the prevalence of a high density of skin appendages in the scalp, extracranial vessels of the scalp communicating with the brain via emissary veins and most importantly, the way that the scalp is used in Ayurvedic medical system in treating diseases associated with the brain show that a drug could be transcranially delivered and targeted to the brain through the scalp. The present study was to investigate by measuring the antinociceptive effect on rats whether the opioid analgesic methadone could be delivered and targeted to the brain by transcranial delivery route. A non aqueous solution of methadone base in sesame oil was used for the application on the scalp. Animal studies were carried out using six groups of male rats consisting of group 1, the oral control treated with distilled water 1 ml; group 2, the oral positive control treated with methadone hydrochloride solution 316.5 ?g/ml; group 3, the negative control treated transcranially with the blank sesame oil 0.2 ml and three test groups 4, 5 and 6 treated with three different dose levels of the transcranial oil formulation of methadone base, 41.6 ?g/0.2 ml, 104 ?g/0.2 ml and 208 ?g/0.2 ml, respectively. The antinociceptive effects were examined by subjecting the rats to the hot plate and tail flick tests. The two higher concentrations of the three transcranial methadone formulations yielded response vs time curves showing nearly equal maximum antinociceptive effects similar to that of the oral positive control. Maximum analgesic effect after transcranial administration was observed between 1st and 2nd h and declined up to 6th hour. The results indicate that the transcranial brain targeted delivery of methadone base in the form of an oil based non aqueous solution results in statistically significant antinociceptive effects under experimental conditions. Therefore, it is possible to deliver central nervous system drugs through the proposed transcranial route when suitably formulated. PMID:20490292

Pathirana, W.; Abhayawardhana, P.; Kariyawasam, H.; Ratnasooriya, W. D.

2009-01-01

96

Magnetic/NIR-thermally responsive hybrid nanogels for optical temperature sensing, tumor cell imaging and triggered drug release.  

PubMed

The paper demonstrates a class of multifunctional core-shell hybrid nanogels with fluorescent and magnetic properties, which have been successfully developed for simultaneous optical temperature sensing, tumor cell imaging and magnetic/NIR-thermally responsive drug carriers. The as-synthesized hybrid nanogels were designed by coating bifunctional nanoparticles (BFNPs, fluorescent carbon dots embedded in the porous carbon shell and superparamagnetic iron oxide nanocrystals clustered in the core) with a thermo-responsive poly(N-isopropylacrylamide-co-acrylamide) [poly(NIPAM-AAm)]-based hydrogel as the shell. The BFNPs in hybrid nanogels not only demonstrate excellent photoluminescence (PL) and photostability due to the fluorescent carbon dots embedded in the porous carbon shell, but also has targeted drug accumulation potential and a magnetic-thermal conversion ability due to the superparamagnetic iron oxide nanocrystals clustered in the core. The thermo-responsive poly(NIPAM-AAm)-based gel shell can not only modify the physicochemical environment of the BFNPs core to manipulate the fluorescence intensity for sensing the variation of the environmental temperature, but also regulate the release rate of the loaded anticancer drug (curcumin) by varying the local temperature of environmental media. In addition, the carbon layer of BFNPs can adsorb and convert the NIR light to heat, leading to a promoted drug release under NIR irradiation and improving the therapeutic efficacy of drug-loaded hybrid nanogels. Furthermore, the superparamagnetic iron oxide nanocrystals in the core of BFNPs can trigger localized heating using an alternating magnetic field, leading to a phase change in the polymer gel to trigger the release of loaded drugs. Finally, the multifunctional hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells. The demonstrated hybrid nanogels would be an ideal system for the biomedical applications due to their excellent optical properties, magnetic properties, high drug loading capacity and responsive drug release behavior. PMID:25243783

Wang, Hui; Yi, Jinhui; Mukherjee, Sumit; Banerjee, Probal; Zhou, Shuiqin

2014-10-01

97

Reversible masking using low-molecular-weight neutral lipids to achieve optimal-targeted delivery.  

PubMed

Intravenous injection of therapeutics is required to effectively treat or cure metastatic cancer, certain cardiovascular diseases, and other acquired or inherited diseases. Using this route of delivery allows potential uptake in all disease targets that are accessed by the bloodstream. However, normal tissues and organs also have the potential for uptake of therapeutic agents. Therefore, investigators have used targeted delivery to attempt delivery solely to the target cells; however, use of ligands on the surface of delivery vehicles to target specific cell surface receptors is not sufficient to avoid nonspecific uptake. PEGylation has been used for decades to try to avoid nonspecific uptake but suffers from many problems known as "The PEGylation Dilemma." We have solved this dilemma by replacing PEGylation with reversible masking using low-molecular-weight neutral lipids in order to achieve optimal-targeted delivery solely to target cells. Our paper will focus on this topic. PMID:22655199

Templeton, Nancy Smyth; Senzer, Neil

2012-01-01

98

Reversible Masking Using Low-Molecular-Weight Neutral Lipids to Achieve Optimal-Targeted Delivery  

PubMed Central

Intravenous injection of therapeutics is required to effectively treat or cure metastatic cancer, certain cardiovascular diseases, and other acquired or inherited diseases. Using this route of delivery allows potential uptake in all disease targets that are accessed by the bloodstream. However, normal tissues and organs also have the potential for uptake of therapeutic agents. Therefore, investigators have used targeted delivery to attempt delivery solely to the target cells; however, use of ligands on the surface of delivery vehicles to target specific cell surface receptors is not sufficient to avoid nonspecific uptake. PEGylation has been used for decades to try to avoid nonspecific uptake but suffers from many problems known as “The PEGylation Dilemma.” We have solved this dilemma by replacing PEGylation with reversible masking using low-molecular-weight neutral lipids in order to achieve optimal-targeted delivery solely to target cells. Our paper will focus on this topic. PMID:22655199

Templeton, Nancy Smyth; Senzer, Neil

2012-01-01

99

Targeted Stimuli-Responsive Dextran Conjugates for Doxorubicin Delivery to Hepatocytes  

E-print Network

A targeted, stimuli-responsive, polymeric drug delivery vehicle is being developed in our lab to help alleviate severe side-effects caused by narrow therapeutic window drugs. Targeting specific cell types or organs via ...

Zaman, Noreen T.

100

Role of nanotechnology in targeted drug delivery and imaging: a concise review  

Microsoft Academic Search

The use of nanotechnology in drug delivery and imaging in vivo is a rapidly expanding field. The emphases of this review are on biophysical attributes of the drug delivery and imaging platforms as well as the biological aspects that enable targeting of these platforms to injured and diseased tissues and cells. The principles of passive and active targeting of nanosized

Otilia M. Koo; Israel Rubinstein; Hayat Onyuksel

2005-01-01

101

Targeted delivery of oligodeoxynucleotides to parenchymal liver cells in vivo.  

PubMed Central

Anti-sense oligodeoxynucleotides (ODNs) hold great promise for correcting the biosynthesis of clinically relevant proteins. The potential of ODNs for modulating liver-specific genes might be increased by preventing untimely elimination and by improving the local bioavailability of ODNs in the target tissue. In the present study we have assessed whether the local ODN concentration can be enhanced by the targeted delivery of ODNs through conjugation to a ligand for the parenchymal liver cell-specific asialoglycoprotein receptor. A capped ODN (miscellaneous 20-mer sequence) was derivatized with a ligand with high affinity for this receptor, N2-[N2-(N2,N6-bis¿N-[p-(beta-d-galactopyranosyloxy) anilino] thiocarbamyl¿-L-lysyl)-N6-(N-¿p-[beta-D -galactopyranosyloxy] anilino¿ thiocarbamyl)-L-lysyl]-N6-[N- (p-¿beta-D-galactopyranosyloxy¿anilino)thiocarbamyl]-L-lysine (L3G4) (Kd 6.5+/-0.2 nM, mean+/-S.D.). Both the uptake studies in vitro and the confocal laser scan microscopy studies demonstrated that L3G4-ODN was far more efficiently bound to and taken up by parenchymal liver cells than underivatized ODN. Studies in vivo in rats showed that hepatic uptake could be greatly enhanced from 19+/-1% to 77+/-6% of the injected dose after glycoconjugation. Importantly, specific ODN accumulation of ODN into parenchymal liver cells was improved almost 60-fold after derivatization with L3G4, and could be attributed to the asialoglycoprotein receptor. In conclusion, the scavenger receptor-mediated elimination pathway for miscellaneous ODN sequences can be circumvented by direct conjugation to a synthetic tag for the asialoglycoprotein receptor. In this manner a crucial requisite is met towards the application of ODNs in vivo to modulate the biosynthesis of parenchymal liver cell-specific genes such as those for apolipoprotein (a), cholesterol ester transfer protein and viral proteins. PMID:10359665

Biessen, E A; Vietsch, H; Rump, E T; Fluiter, K; Kuiper, J; Bijsterbosch, M K; van Berkel, T J

1999-01-01

102

Mucoadhesive platforms for targeted delivery to the colon.  

PubMed

A novel platform system, comprising a mucoadhesive core and a rapid release carrier, was designed for targeted drug delivery to the colon. Prednisolone pellets containing different carbomers, including Carbopol 971P, Carbopol 974P and Polycarbophil AA-1, with or without organic acids, were produced by extrusion-spheronization. Mucoadhesive pellets were coated with a new enteric double-coating system, which dissolves at pH 7. This system comprises an inner layer of partially neutralized Eudragit S and buffer salt and an outer coating of standard Eudragit S. A single layer of standard Eudragit S was also applied for comparison purposes. Dissolution of the coated pellets was assessed in USP II apparatus in 0.1N HCl followed by Krebs bicarbonate buffer pH 7.4. Visualization of the coating dissolution process was performed by confocal laser scanning microscopy using fluorescent markers in both layers. The mucoadhesive properties of uncoated, single-coated and-double coated pellets were evaluated ex vivo on porcine colonic mucosa. Mucoadhesive pellets coated with a single layer of Eudragit S release its cargo after a lag time of 120 min in Krebs buffer. In contrast, drug release from the double-coated mucoadhesive pellets was significantly accelerated, starting at 75 min. In addition, the mucoadhesive properties of the core of the double coated pellets were higher than those from single-coated pellets after the core had been exposed to the buffer medium. This novel platform technology has the potential to target the colon and overcome the variability in transit and harmonize drug release and bioavailability. PMID:21856393

Varum, Felipe J O; Veiga, Francisco; Sousa, João S; Basit, Abdul W

2011-11-25

103

Transporter targeted gatifloxacin prodrugs: Synthesis, permeability, and topical ocular delivery  

PubMed Central

Purpose To design and synthesize prodrugs of gatifloxacin targeting OCT, MCT, and ATB (0, +) transporters and to identify a prodrug with enhanced delivery to the back of the eye. Method Dimethylamino-propyl, carboxy-propyl, and amino-propyl(2-methyl) derivatives of gatifloxacin (GFX), DMAP-GFX, CP-GFX, and APM-GFX, were designed and synthesized to target OCT, MCT, and ATB (0, +) transporters, respectively. LC-MS method was developed to analyze drug and prodrug levels in various studies. Solubility and Log D (pH 7.4) were measured for prodrugs and the parent drug. Permeability of the prodrugs was determined in cornea, conjunctiva, and sclera-choroidretinal pigment epitheluim (SCRPE) and compared with gatifloxacin using Ussing chamber assembly. Permeability mechanisms were elucidated by determining the transport in the presence of transporter specific inhibitors. 1-Methyl-4-phenylpyridinium iodide (MPP+), nicotinic acid sodium salt, and ?-methyl-DL-tryptophan were used to inhibit OCT, MCT, and ATB (0, +) transporters, respectively. A prodrug selected based on in vitro studies was administered as an eye drop to pigmented rabbits and the delivery to various eye tissues including vitreous humor was compared with gatifloxacin dosing. Results DMAP-GFX exhibited 12.8-fold greater solubility than GFX. All prodrugs were more lipophilic, with the measured Log D (pH 7.4) values ranging from 0.05 to 1.04, when compared to GFX (Log D: -1.15). DMAP-GFX showed 1.4-, 1.8-, and 1.9-fold improvement in permeability across cornea, conjunctiva, as well as SCRPE when compared to GFX. Moreover, it exhibited reduced permeability in the presence of MPP+ (competitive inhibitor of OCT), indicating OCT-mediated transport. CP-GFX showed 1.2-, 2.3- and 2.5-fold improvement in permeability across cornea, conjunctiva and SCRPE, respectively. In the presence of nicotinic acid (competitive inhibitor of MCT), permeability of CP-GFX was reduced across conjunctiva. However, cornea and SCRPE permeability of CP-GFX was not affected by nicotinic acid. APM-GFX did not show any improvement in permeability when compared to GFX across cornea, conjunctiva, and SCRPE. Based on solubility and permeability, DMAP-GFX was selected for in vivo studies. DMAP-GFX showed 3.6- and 1.95-fold higher levels in vitreous humor and CRPE compared to that of GFX at 1 hour after topical dosing. In vivo conversion of DMAP-GFX prodrug to GFX was quantified in tissues isolated at 1 hour after dosing. Prodrug-to-parent drug ratio was 8, 70, 24, 21, 29, 13, 55, and 60 % in cornea, conjunctiva, iris-ciliary body, aqueous humor, sclera, CRPE, retina, and vitreous humor, respectively. Conclusions DMAP-GFX prodrug enhanced solubility, Log D, as well as OCT mediated delivery of gatifloxacin to the back of the eye. PMID:23003105

Vooturi, Sunil K.; Kadam, Rajendra S.; Kompella, Uday B.

2013-01-01

104

Analysis on the current status of targeted drug delivery to tumors  

PubMed Central

Targeted drug delivery to tumor sites is one of the ultimate goals in drug delivery. Recent progress in nanoparticle engineering has certainly improved drug targeting, but the results are not as good as expected. This is largely due to the fact that nanoparticles, regardless of how advanced they are, find the target as a result of blood circulation, like the conventional drug delivery systems do. Currently, the nanoparticle-based drug delivery to the target tumor tissues is based on wrong assumptions that most of the nanoparticles, either PEGylated or not, reach the target by the enhanced permeation and retention (EPR) effect. Studies have shown that so-called targeting moieties, i.e., antibodies or ligands, on the nanoparticle surface do not really improve delivery to target tumors. Targeted drug delivery to tumor sites is associated with highly complex biological, mechanical, chemical and transport phenomena, of which characteristics vary spatiotemporally. Yet, most of the efforts have been focused on design and surface manipulation of the drug carrying nanoparticles with relatively little attention to other aspects. This article examines the current misunderstandings and the main difficulties in targeted drug delivery. PMID:22800574

Kwon, Il Keun; Lee, Sang Cheon; Han, Bumsoo; Park, Kinam

2013-01-01

105

Degradable thermoresponsive nanogels for protein encapsulation and controlled release.  

PubMed

Reversible addition-fragmentation chain transfer (RAFT) polymerization technique was used for the fabrication of stable core cross-linked micelles (CCL) with thermoresponsive and degradable cores. Well-defined poly(2-methacryloyloxyethyl phosphorylcholine), poly(MPC) macroRAFT agent, was first synthesized with narrow molecular weight distribution via the RAFT process. These CCL micelles (termed as nanogels) with hydrophilic poly(MPC) shell and thermoresponsive core consisting of poly(methoxydiethylene glycol methacrylate) (poly(MeODEGM) and poly(2-aminoethyl methacrylamide hydrochloride) (poly(AEMA) were then obtained in a one-pot process by RAFT polymerization in the presence of an acid degradable cross-linker. These acid degradable nanogels were efficiently synthesized with tunable sizes and low polydispersities. The encapsulation efficiencies of the nanogels with different proteins such as insulin, BSA, and ?-galactosidase were studied and found to be dependent of the cross-linker concentration, size of protein, and the cationic character of the nanogels imparted by the presence of AEMA in the core. The thermoresponsive nature of the synthesized nanogels plays a vital role in protein encapsulation: the hydrophilic core and shell of the nanogels at low temperature allow easy diffusion of the proteins inside out and, with an increase in temperature, the core becomes hydrophobic and the nanogels are easily separated out with entrapped protein. The release profile of insulin from nanogels at low pH was studied and results were analyzed using bicinchoninic assay (BCA). Controlled release of protein was observed over 48 h. PMID:22171688

Bhuchar, Neha; Sunasee, Rajesh; Ishihara, Kazuhiko; Thundat, Thomas; Narain, Ravin

2012-01-18

106

Exploring targeted pulmonary delivery for treatment of lung cancer  

PubMed Central

Lung cancer is the most malignant cancer today. The treatment of lung cancer continues to be a challenge for oncologists. The direct delivery of chemotherapeutic agents to the lungs could represent a novel therapeutic approach for patients with pulmonary metastases. The large alveolar surface area, the low thickness of the epithelial barrier, and an extensive vascularization make the pulmonary route an ideal route for administration of oncolytics. This paper reviews the research performed over the last and current decades on the delivery of various oncolytics for pulmonary delivery for the treatment of lung cancer. Inhaled drug delivery devices in cancer therapy are also discussed in the present manuscript. PMID:23799201

Goel, Amit; Baboota, Sanjula; Sahni, Jasjeet K; Ali, Javed

2013-01-01

107

Engineering targeted proteins for intracellular delivery of biotherapeutics  

E-print Network

Biotherapeutics have revolutionized medicine with their ability to achieve unprecedented molecular recognition and mediate complex biological responses. The intracellular delivery of biotherapeutics is an unmet scientific ...

Pirie, Christopher M

2011-01-01

108

Nanoparticle for delivery of antisense ?PNA oligomers targeting CCR5  

PubMed Central

The development of a new class of peptide nucleic acids (PNAs), i.e., gamma PNAs (?PNAs), creates the need for a general and effective method for its delivery into cells for regulating gene expression in mammalian cells. Here we report the antisense activity of a recently developed hydrophilic and biocompatible diethylene glycol (miniPEG)-based gamma peptide nucleic acid called MP?PNAs via its delivery by poly(lactide-co-glycolide) (PLGA)-based nanoparticle system. We show that MP?PNA oligomers designed to bind to the selective region of Chemokine Receptor 5 (CCR5) transcript, induce potent and sequence-specific antisense effects as compared with regular PNA oligomers. In addition, PLGA nanoparticle delivery of MP?PNAs is not toxic to the cells. The findings reported in this study provide a combination of ?PNA technology and PLGA-based nanoparticle delivery method for regulating gene expression in live cells via the antisense mechanism. PMID:23954968

Bahal, Raman; McNeer, Nicole Ali; Ly, Danith H.; Saltzman, W. Mark; Glazer, Peter M.

2013-01-01

109

Near Infrared-Sensitive Nanoparticles for Targeted Drug Delivery  

E-print Network

The invasive nature and undesirable side-effects related to conventional cancer therapy, such as surgery and chemotherapy, have led to the development of novel drug delivery systems (DDS). A minimally invasive DDS using ...

Tan, Mei Chee

110

Polyaspartic acid functionalized gold nanoparticles for tumor targeted doxorubicin delivery.  

PubMed

In this paper, we present polyaspartic acid, a biodegradable polymer as a reducing and functionalizing agent for the synthesis of doxorubicin loaded gold nanoparticles by a green process. Gold nanoparticles were stable to electrolytes and pH. Secondary amino groups of polyaspartic acid enabled reduction of gold chloride to form gold nanoparticles of size 55 +/-10 nm, with face centered cubic crystalline structure as confirmed by UV, TEM, SAED and XRD studies. Cationic doxorubicin was readily loaded onto anionic polyaspartic acid gold nanoparticles by ionic complexation. Fluorescence studies confirmed doxorubicin loading while FTIR spectra confirmed ionic complexation. Doxorubicin loading onto polyaspartic acid gold nanoparticles was studied at doxorubicin/polyaspartic acid molar ratios 1:10 to 1:1. As the molar ratio tended to unity, although loading up to 60% was achieved, colloidal instability resulted and is attributed to effective covering of negative charges of polyaspartic acid. Stable doxorubicin loaded polyaspartic acid gold nanoparticles of 105 +/- 15.1 nm with doxorubicin loading of 23.85% w/w and zeta potential value of -28 +/- 0.77 mV were obtained at doxorubicin/polyaspartic acid molar ratio 1:10. Higher doxorubicin release rate from the doxorubicin loaded polyaspartic acid gold nanoparticles in an acid medium (i.e., pH 5.5) as compared to that in pH 7.4 and deionized water is a desirable characteristic for tumor targeted delivery. Enhanced cytotoxicity and 3 fold higher uptake of doxorubicin loaded polyaspartic acid gold nanoparticles as compared to doxorubicin solution were seen in MCF-7 breast cancer cells while polyaspartic acid gold nanoparticles revealed no cytotoxicity confirming safety. Prominent regression in tumor size in-vivo in fibrosarcoma tumor induced mouse model was observed upto 59 days with doxorubicin loaded polyaspartic acid gold nanoparticles while doxorubicin solution treated mice showed regrowth beyond 23rd day. Moreover, a decrease of body weight of 35% indicating severe toxicity with doxorubicin solution as compared to only 20% with gradual recovery after day 30 in case of doxorubicin loaded polyaspartic acid gold nanoparticles confirmed their lower toxicity and enhanced efficacy. PMID:24724506

Khandekar, Sameera V; Kulkarni, M G; Devarajan, Padma V

2014-01-01

111

Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery  

Microsoft Academic Search

Skin is an attractive target for delivery of genetic therapies and vaccines. However, new approaches are needed to access this tissue more effectively. Here, we describe a new delivery technology based on arrays of structurally precise, micron-scale silicon projections, which we term microenhancer arrays (MEAs). In a human clinical study, these devices effectively breached the skin barrier, allowing direct access

Jason B. Alarcon; John M. Brittingham; Diane E. Sutter; Ronald J. Pettis; Noel G. Harvey; John A. Mikszta

2002-01-01

112

Mesenchymal Stem Cell as Targeted-Delivery Vehicle in Breast Cancer.  

National Technical Information Service (NTIS)

Mesenchymal stem cells (MSCs) have been proposed to be cellular vehicles for the targeted delivery and local production of biological agents in tumors. In this proposal we will stably transfect mesenchymal stem cells with a lentiviral vector containing a ...

Z. Cheng

2010-01-01

113

DEVELOPMENT OF A COLONIC TARGETING NANOSPHERE DELIVERY SYSTEM FOR CHEMOTHERAPEUTIC AGENTS.  

E-print Network

??Paclitaxel containing Eudragit nanospheres were investigated for use in target delivery applications. Nanospheres were successfully fabricated from Eudragit S and RS polymers. Electrostatic layer-by-layer self… (more)

Gentile, Martin

2008-01-01

114

Quantification of Mesenchymal Stem Cell (MSC) Delivery to a Target Site Using In Vivo Confocal Microscopy  

E-print Network

The ability to deliver cells to appropriate target tissues is a prerequisite for successful cell-based therapy. To optimize cell therapy it is therefore necessary to develop a robust method of in vivo cell delivery ...

Mortensen, Luke J.

115

Targeted delivery of a cisplatin prodrug for safer and more effective prostate cancer therapy in vivo  

E-print Network

Targeted delivery and controlled release of inactive platinum (Pt) prodrugs may offer a new approach to improve the efficacy and tolerability of the Pt family of drugs, which are used to treat 50% of all cancers today. ...

Dhar, Shanta

116

Cell-mediated Delivery and Targeted Erosion of Noncovalently Crosslinked Hydrogels  

NASA Technical Reports Server (NTRS)

A method for targeted delivery of therapeutic compounds from hydrogels is presented. The method involves administering to a cell a hydrogel in which a therapeutic compound is noncovalently bound to heparin.

Kiick, Kristi L. (Inventor); Yamaguchi, Nori (Inventor)

2013-01-01

117

Targeted Stimuli-Responsive Dextran Conjugates for Doxorubicin Delivery to Hepatocytes  

E-print Network

A targeted, stimuli-responsive, polymeric drug delivery vehicle has been developed to help alleviate the severe side-effects caused by narrow therapeutic window drugs. Doxorubicin, a commonly used chemotherapeutic agent ...

Zaman, Noreen T.

118

Bioengineered silk gene delivery system for nuclear targeting.  

PubMed

Gene delivery research has gained momentum with the use of lipophilic vectors that mimic viral systems to increase transfection efficiency. Maintaining cell viability with these systems remains a major challenge. Therefore, biocompatible biopolymers that are designed by combining non-immunological viral mimicking components with suitable carrier are explored to address these limitations. In the present study, dragline silk recombinant proteins are modified with DNA condensing units and the proton sponge endosomal escape pathway is utilized for enhanced delivery. Transfection efficiency in a COS-7 cell line is enhanced compared to lipofectamine and polyethyleneimine (PEI), as is cell viability. PMID:24889658

Yigit, Sezin; Tokareva, Olena; Varone, Antonio; Georgakoudi, Irene; Kaplan, D L

2014-09-01

119

Calcium-crosslinked LABL-TAT complexes effectively target gene delivery to ICAM-1 expressing cells  

PubMed Central

Targeted gene delivery using non-viral vectors is a highly touted scheme to reduce the potential for toxic or immunological side effects by reducing dose. In previous reports, TAT polyplexes with DNA have shown relatively poor gene delivery. The transfection efficiency has been enhanced by condensing TAT/DNA complexes to a small particle size using calcium. To explore the targetability of these condensed TAT complexes, LABL peptide targeting intercellular cell-adhesion molecule-1 (ICAM-1) was conjugated to TAT peptide using a polyethylene glycol (PEG) spacer. PEGylation reduced the transfection efficiency of TAT, but TAT complexes targeting ICAM-1 expressing cells regained much of the lost transfection efficiency. Targeted block peptides properly formulated with calcium offer promise for gene delivery to ICAM-1 expressing cells at sites of injury or inflammation. PMID:21473630

Khondee, Supang; Baoum, Abdulgader; Siahaan, Teruna J.; Berkland, Cory

2014-01-01

120

Synthetic aptamer-polymer hybrid constructs for programmed drug delivery into specific target cells.  

PubMed

Viruses have evolved specialized mechanisms to efficiently transport nucleic acids and other biomolecules into specific host cells. They achieve this by performing a coordinated series of complex functions, resulting in delivery that is far more efficient than existing synthetic delivery mechanisms. Inspired by these natural systems, we describe a process for synthesizing chemically defined molecular constructs that likewise achieve targeted delivery through a series of coordinated functions. We employ an efficient "click chemistry" technique to synthesize aptamer-polymer hybrids (APHs), coupling cell-targeting aptamers to block copolymers that secure a therapeutic payload in an inactive state. Upon recognizing the targeted cell-surface marker, the APH enters the host cell via endocytosis, at which point the payload is triggered to be released into the cytoplasm. After visualizing this process with coumarin dye, we demonstrate targeted killing of tumor cells with doxorubicin. Importantly, this process can be generalized to yield APHs that specifically target different surface markers. PMID:25290917

Oh, Seung Soo; Lee, Bongjae F; Leibfarth, Frank A; Eisenstein, Michael; Robb, Maxwell J; Lynd, Nathaniel A; Hawker, Craig J; Soh, H Tom

2014-10-22

121

Ultrasonically targeted delivery into endothelial and smooth muscle cells in ex vivo arteries  

PubMed Central

This study tested the hypothesis that ultrasound can target intracellular uptake of drugs into vascular endothelial cells (ECs) at low to intermediate energy and into smooth muscle cells (SMCs) at high energy. Ultrasound-enhanced delivery has been shown to enhance and target intracellular drug and gene delivery in the vasculature to treat cardiovascular disease, but quantitative studies of the delivery process are lacking. Viable ex vivo porcine carotid arteries were placed in a solution containing a model drug, TO-PRO®-1, and Optison® microbubbles. Arteries were exposed to ultrasound at 1.1 MHz and acoustic energies of 5.0, 66, or 630 J/cm2. Using confocal microscopy and fluorescent labeling of cells, the artery endothelium and media were imaged to determine the localization and to quantify intracellular uptake and cell death. At low to intermediate ultrasound energy, ultrasound was shown to target intracellular delivery into viable cells that represented 9 – 24% of exposed ECs. These conditions also typically caused 7 – 25% EC death. At high energy, intracellular delivery was targeted to SMCs, which was associated with denuding or death of proximal ECs. This work represents the first known in-depth study to evaluate intracellular uptake into cells in tissue. We conclude that significant intracellular uptake of molecules can be targeted into ECs and SMCs by ultrasound-enhanced delivery suggesting possible applications for treatment of cardivascular diseases and dysfunctions. PMID:17291619

Hallow, Daniel M.; Mahajan, Anuj D.; Prausnitz, Mark R.

2007-01-01

122

Stimuli responsive magnetic nanogels for biomedical application  

NASA Astrophysics Data System (ADS)

We report the synthesis and characterization of magnetic nanogels based on magnetite nanoparticles sterically stabilized by double layer oleic acid in water carrier and chemically cross linked poly (N-isopropylacril amide) (pNIPA) and poly (acrylic acid) (pAAc). In this structure the magnetite nanoparticles are attached to the flexible network chain by adhesive forces, resulting in a direct coupling between magnetic and elastic properties. Stable water suspensions of dual responsive magnetic nanogels based on temperature-responsive N-isopropyl acryl amide, pH responsive acrylic acid were obtained. The FTIR spectra of p(NIPA-AAc) ferrogel samples, showed the absorption region of the specific chemical groups associated with pNIPA, pAAc and the Fe3O4 magnetic nanoparticles. The morphology and the structure of the as prepared materials were confirmed by transmission electron microscopy (TEM) and the size distribution was determined by dynamic light scattering (DLS). The magnetic microgels have high magnetization and superparamagnetic behaviour being suitable materials for biomedical application.

Craciunescu, I.; Petran, A.; Daia, C.; Marinica, O.; Vekas, L.; Turcu, R.

2013-11-01

123

Protein engineering for targeted delivery of radionuclides to tumors  

E-print Network

Traditional cancer treatment strategies include systemic chemotherapy, external beam radiation, and surgical excision. Chemotherapy is nonspecific, and targets all rapidly dividing cells. External beam radiation and surgery ...

Orcutt, Kelly Davis

2010-01-01

124

Nanomicellar carriers for targeted delivery of anticancer agents  

PubMed Central

Clinical application of anticancer drugs is limited by problems such as low water solubility, lack of tissue-specificity and toxicity. Formulation development represents an important approach to these problems. Among the many delivery systems studied, polymeric micelles have gained considerable attention owing to ease in preparation, small sizes (10–100 nm), and ability to solubilize water-insoluble anticancer drugs and accumulate specifically at the tumors. This article provides a brief review of several promising micellar systems and their applications in tumor therapy. The emphasis is placed on the discussion of the authors’ recent work on several nanomicellar systems that have both a delivery function and antitumor activity, named dual-function drug carriers. PMID:24341817

Zhang, Xiaolan; Huang, Yixian; Li, Song

2014-01-01

125

Implications of nanoscale based drug delivery systems in delivery and targeting tubulin binding agent, noscapine in cancer cells.  

PubMed

Noscapine, a tubulin binding anticancer agent undergoing Phase I/II clinical trials, inhibits tumor growth in nude mice bearing human xenografts of breast, lung, ovarian, brain, and prostrate origin. The analogues of noscapine like 9-bromonoscapine (EM011) are 5 to 10-fold more active than parent compound, noscapine. Noscapinoids inhibit the proliferation of cancer cells that are resistant to paclitaxel and epothilone. Noscapine also potentiated the anticancer activity of doxorubicin in a synergistic manner against triple negative breast cancer (TNBC). However, physicochemical and pharmacokinetic (ED50˜300-600 mg/kg bodyweight) limitations of noscapine present hurdle in development of commercial anticancer formulations. Therefore, objectives of the present review are to summarize the chemotherapeutic potential of noscapine and implications of nanoscale based drug delivery systems in enhancing the therapeutic efficacy of noscapine in cancer cells. We have constructed noscapine-enveloped gelatin nanoparticles, NPs and poly (ethylene glycol) grafted gelatin NPs as well as inclusion complex of noscapine in ?-cyclodextrin (?-CD) and evaluated their physicochemical characteristics. The Fe3O4 NPs were also used to incorporate noscapine in its polymeric nanomatrix system where molecular weight of the polymer governed the encapsulation efficiency of drug. The enhanced noscapine delivery using ?PAR-targeted optical-MR imaging trackable NPs offer a great potential for image directed targeted delivery of noscapine. Human Serum Albumin NPs (150-300 nm) as efficient noscapine drug delivery systems have also been developed for potential use in breast cancer. PMID:22571485

Chandra, Ramesh; Madan, Jitender; Singh, Prashant; Chandra, Ankush; Kumar, Pradeep; Tomar, Vartika; Dass, Sujata K

2012-12-01

126

Cell Penetrating and Cell Targeting Peptides in Drug Delivery (revised version) Eric Vivs*, Julien Schmidt and Andr Plegrin.  

E-print Network

1 Cell Penetrating and Cell Targeting Peptides in Drug Delivery (revised version) Eric Vivès-penetrating peptide, cell-targeting peptide, cell delivery, drug. Abstract During the last decade, the potential of peptides for drug delivery into cells has been highlighted by the discovery of several cell

Paris-Sud XI, Université de

127

Improved dental adhesive formulations based on reactive nanogel additives.  

PubMed

Current challenges in adhesive dentistry include over-hydrophilic bonding formulations, which facilitate water percolation through the hybrid layer and result in unreliable bonded interfaces. This study introduces nanogel-modified adhesives as a way to control the material's hydrophobic character without changing the basic monomer formulation (keeping water-chasing capacity and operatory techniques unaltered). Nanogel additives of varied hydrophobicity were synthesized in solution, rendering 10- to 100-nm-sized particles. A model BisGMA/HEMA solvated adhesive was prepared (control), to which reactive nanogels were added. The increase in adhesive viscosity did not impair solvent removal by air-thinning. The degree of conversion in the adhesive was similar between control and nanogel-modified materials, while the bulk dry and, particularly, the wet mechanical properties were significantly improved through nanogel-based network reinforcement and reduced water solubility. As preliminary validation of this approach, short-term micro-tensile bond strengths to acid-etched and primed dentin were significantly enhanced by nanogel inclusion in the adhesive resins. PMID:22019910

Morães, R R; Garcia, J W; Wilson, N D; Lewis, S H; Barros, M D; Yang, B; Pfeifer, C S; Stansbury, J W

2012-02-01

128

The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers  

Microsoft Academic Search

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers

Carlee E. Ashley; Eric C. Carnes; Genevieve K. Phillips; David Padilla; Paul N. Durfee; Page A. Brown; Tracey N. Hanna; Juewen Liu; Brandy Phillips; Mark B. Carter; Nick J. Carroll; Xingmao Jiang; Darren R. Dunphy; Cheryl L. Willman; Dimiter N. Petsev; Deborah G. Evans; Atul N. Parikh; Bryce Chackerian; Walker Wharton; David S. Peabody; C. Jeffrey Brinker

2011-01-01

129

A proteomics-based methodology to investigate the protein corona effect for targeted drug delivery.  

PubMed

Here we introduce a proteomics methodology based on nanoliquid-chromatography tandem mass spectrometry (nanoLC/MS-MS) to investigate the "protein corona effect for targeted drug delivery", an innovative strategy, which exploits the "protein corona" that forms around nanoparticles in a physiological environment to target cells. PMID:25132011

Pozzi, D; Caracciolo, G; Capriotti, A L; Cavaliere, C; Piovesana, S; Colapicchioni, V; Palchetti, S; Riccioli, A; Laganà, A

2014-09-30

130

Targeted Delivery of siRNA-Generating DNA Nanocassettes Using Multifunctional Nanoparticles  

PubMed Central

Molecular therapy using a small interfering RNA (siRNA) has shown promise in the development of novel therapeutics. Various formulations have been used for in vivo delivery of siRNAs. However, the stability of short double-stranded RNA molecules in the blood and efficiency of siRNA delivery into target organs or tissues following systemic administration have been the major issues that limit applications of siRNA in human patients. In this study, multifunctional siRNA delivery nanoparticles are developed that combine imaging capability of nanoparticles with urokinase plasminogen activator receptor-targeted delivery of siRNA expressing DNA nanocassettes. This theranostic nanoparticle platform consists of a nanoparticle conjugated with targeting ligands and double-stranded DNA nanocassettes containing a U6 promoter and a shRNA gene for in vivo siRNA expression. Targeted delivery and gene silencing efficiency of firefly luciferase siRNA nanogenerators are demonstrated in tumor cells and in animal tumor models. Delivery of survivin siRNA expressing nanocassettes into tumor cells induces apoptotic cell death and sensitizes cells to chemotherapy drugs. The ability of expression of siRNAs from multiple nanocassettes conjugated to a single nanoparticle following receptor-mediated internalization should enhance the therapeutic effect of the siRNA-mediated cancer therapy. PMID:23292656

Cho, Y.-S.; Lee, G. Y.; Sajja, H. K.; Qian, W.; Cao, Z.; He, W.; Karna, P.; Chen, X.; Mao, H.; Wang, Y. A.; Yang, L.

2013-01-01

131

Vascular-targeted nanotherapy for obesity: unexpected passive targeting mechanism to obese fat for the enhancement of active drug delivery.  

PubMed

We previously reported that nanoparticles (NPs) modified with a prohibitin-homing peptide ligand via a short PEG(2kDa)-spacer could deliver its pay-load into the cytoplasm of endothelial cells in murine adipose tissue and escape from endosomes/lysosomes in vitro. We herein report, for the first time, on a dual-targeting strategy for mediating the enhanced targeting activity of NPs to adipose endothelial cells in diet-induced obesity (DIO). The targeted accumulation of prohibitin-targeted nanoparticles (PTNP), modified with a peptide ligand via a long PEG-linker, was significantly increased in white fat vessels of normal healthy mice compared to the other non-PEGylated targeted NPs, whereas the undesired accumulation of PTNP in the liver was considerably reduced. These results demonstrate that the PEGylation of targeted NPs is a critical factor in maximizing the in vivo targeted delivery of NPs and can be attributed to a significant decrease in recognition by the reticuloendothelial system. After systemic administration to DIO mice, PTNP exclusively accumulated in both adipose vessels and angiogenic clusters of obese fat cells. Surprisingly, PEGylated NPs with no active targeting moieties also accumulated in these clusters, demonstrating that the nanoscaled carriers passively accumulate in clusters via a mechanism similar to that for the enhanced permeability and retention effect, as has been well established in tumor targeting. Therefore, the enhanced delivery of PTNP appears to be mediated by both passive accumulation to angiogenic regions and active recognition by endothelial cells. Thus, the systemic administration of a proapoptotic peptide with the delivery via PTNP significantly reduced the body weight of DIO mice, as evidenced by the targeted ablation of adipose endothelial cells. These findings are potentially useful in terms of the design and development of vascular-targeted nanotherapy in the effective control of obesity. PMID:22982237

Hossen, Md Nazir; Kajimoto, Kazuaki; Akita, Hidetaka; Hyodo, Mamoru; Harashima, Hideyoshi

2012-10-28

132

Targeted delivery of carbon nanotubes to cancer cells  

Microsoft Academic Search

CD22 is broadly expressed on human B cell lymphomas. Monoclonal anti-CD22 antibodies (MAbs) alone, or coupled to toxins, have been used to selectively target these tumors both in severe combined immunodeficient (SCID) mice with xenografted human lymphomas and in patients. Single-walled carbon nanotubes (CNTs) attached to antibodies or peptides represent another approach to targeting cancer cells. CNTs convert absorbed near-infrared

Pavitra Chakravarty

2010-01-01

133

Colon Targeted Drug Delivery Systems: A Review on Primary and Novel Approaches  

PubMed Central

The colon is a site where both local and systemic delivery of drugs can take place. Local delivery allows topical treatment of inflammatory bowel disease. However, treatment can be made effective if the drugs can be targeted directly into the colon, thereby reducing the systemic side effects. This review, mainly compares the primary approaches for CDDS (Colon Specific Drug Delivery) namely prodrugs, pH and time dependent systems, and microbially triggered systems, which achieved limited success and had limitations as compared with newer CDDS namely pressure controlled colonic delivery capsules, CODESTM, and osmotic controlled drug delivery which are unique in terms of achieving in vivo site specificity, and feasibility of manufacturing process. PMID:22125706

Philip, Anil K.; Philip, Betty

2010-01-01

134

Cell-mediated delivery of nanoparticles: taking advantage of circulatory cells to target nanoparticles.  

PubMed

Cellular hitchhiking leverages the use of circulatory cells to enhance the biological outcome of nanoparticle drug delivery systems, which often suffer from poor circulation time and limited targeting. Cellular hitchhiking utilizes the natural abilities of circulatory cells to: (i) navigate the vasculature while avoiding immune system clearance, (ii) remain relatively inert until needed and (iii) perform specific functions, including nutrient delivery to tissues, clearance of pathogens, and immune system surveillance. A variety of synthetic nanoparticles attempt to mimic these functional attributes of circulatory cells for drug delivery purposes. By combining the advantages of circulatory cells and synthetic nanoparticles, many advanced drug delivery systems have been developed that adopt the concept of cellular hitchhiking. Here, we review the development and specific applications of cellular hitchhiking-based drug delivery systems. PMID:24747161

Anselmo, Aaron C; Mitragotri, Samir

2014-09-28

135

Multifunctional hybrid nanogel for integration of optical glucose sensing and self-regulated insulin release at physiological pH.  

PubMed

Optical detection of glucose, high drug loading capacity, and self-regulated drug delivery are simultaneously possible using a multifunctional hybrid nanogel particle under a rational design in a colloid chemistry method. Such hybrid nanogels are made of Ag nanoparticle (NP) cores covered by a copolymer gel shell of poly(4-vinylphenylboronic acid-co-2-(dimethylamino)ethyl acrylate) [p(VPBA-DMAEA)]. The introduction of the glucose sensitive p(VPBA-DMAEA) gel shell onto Ag NPs makes the polymer-bound Ag NPs responsive to glucose. While the small sized Ag cores (10 +/- 3 nm) provide fluorescence as an optical code, the responsive polymer gel shell can adapt to a surrounding medium of different glucose concentrations over a clinically relevant range (0-30 mM), convert the disruptions in homeostasis of glucose level into optical signals, and regulate release of preloaded insulin. This shows a new proof-of-concept for diabetes treatment that exploits the properties from each building block of a multifunctional nano-object. The highly versatile multifunctional hybrid nanogels could potentially be used for simultaneous optical diagnosis, self-regulated therapy, and monitoring of the response to treatment. PMID:20731458

Wu, Weitai; Mitra, Nivedita; Yan, Elsa C Y; Zhou, Shuiqin

2010-08-24

136

A polyvalent aptamer system for targeted drug delivery.  

PubMed

Poor efficacy and off-target systemic toxicity are major problems associated with current chemotherapeutic approaches to treat cancer. We developed a new form of polyvalent therapeutics that is composed of multiple aptamer units synthesized by rolling circle amplification and physically intercalated chemotherapy agents (termed as "Poly-Aptamer-Drug"). Using a leukemia cell-binding aptamer and doxorubicin as a model system, we have successfully constructed Poly-Aptamer-Drug systems and demonstrated that the Poly-Aptamer-Drug is significantly more effective than its monovalent counterpart in targeting and killing leukemia cells due to enhanced binding affinity (? 40 fold greater) and cell internalization via multivalent effects. We anticipate that our Poly-Aptamer-Drug approach will yield new classes of tunable therapeutics that can be utilized to effectively target and treat cancers while minimizing the side effects of chemotherapy. PMID:24044994

Zhang, Zhiqing; Ali, M Monsur; Eckert, Mark A; Kang, Dong-Ku; Chen, Yih Yang; Sender, Leonard S; Fruman, David A; Zhao, Weian

2013-12-01

137

Carboxymethyl starch and lecithin complex as matrix for targeted drug delivery: I. Monolithic mesalamine forms for colon delivery.  

PubMed

For drugs expected to act locally in the colon, and for successful treatment, a delivery device is necessary, in order to limit the systemic absorption which decreases effectiveness and causes important side effects. Various delayed release systems are currently commercialized; most of them based on pH-dependent release which is sensitive to gastrointestinal pH variation. This study proposes a novel excipient for colon delivery. This new preparation consists in the complexation between carboxymethyl starch (CMS) and Lecithin (L). As opposed to existing excipients, the new complex is pH-independent, inexpensive, and easy to manufacture and allows a high drug loading. FTIR, X-ray, and SEM structural analysis all support the hypothesis of the formation of a complex. By minor variation of the excipient content within the tablet, it is possible to modulate the release time and delivery at specific sites of the gastrointestinal tract. This study opens the door to a new pH-independent delivery system for mesalamine targeted administration. Our novel formulation fits well with the posology of mesalamine, used in the treatment of Inflammatory Bowel Disease (IBD), which requires repeated administrations (1g orally four times a day) to maintain a good quality of life. PMID:23562535

Mihaela Friciu, Maria; Canh Le, Tien; Ispas-Szabo, Pompilia; Mateescu, Mircea Alexandru

2013-11-01

138

Method for Targeted Therapeutic Delivery of Proteins into Cells  

Cancer.gov

Current methods to deliver proteins into cells (e.g., using retrovirus, DNA transfection, protein transduction, microinjection, complexing the protein with lipids, etc.) have many shortcomings, such as lack of target specificity toxicity, or unwanted random integration into the host chromosome.

139

Advances in lipid nanodispersions for parenteral drug delivery and targeting  

Microsoft Academic Search

Parenteral formulations, particularly intravascular ones, offer a unique opportunity for direct access to the bloodstream and rapid onset of drug action as well as targeting to specific organ and tissue sites. Triglyceride emulsions, liposomes and micellar solutions have been traditionally used to accomplish these tasks and there are several products on the market using these lipid formulations. The broader application

Panayiotis P. Constantinides; Mahesh V. Chaubal; Robert Shorr

2008-01-01

140

Methotrexate delivery via folate targeted dendrimer-based nanotherapeutic platform  

PubMed Central

This paper provides a synopsis of the advancements made in advancing a dendrimer-based nanomedicine towards human clinical trials by the Michigan Nanotechnology Institute for Medicine and Biological Sciences. A brief description of the synthesis and characterization of a targeted multifunctional therapeutic will demonstrate the simple yet delicate task of producing novel chemotherapeutic agents. The results obtained from in vitro and in vivo studies not only authenticate the potential of using nanoparticles to target therapeutics but also provide valuable insight towards the future directions of this technology. A fundamental, cross-disciplinary collaboration was necessary to achieve the synthesis and testing of this technology, and was the keystone to establishing this innovative invention. Throughout this paper, we will stress that the unique collaboration that facilitated the evolution of this technology is vital to the success of future developments in nanomedicine. PMID:20049813

Majoros, Istvan J.; Williams, Christopher R.; Becker, Andrew; Baker, James R.

2010-01-01

141

Receptor-targeted gene delivery using multivalent phagemid particles.  

PubMed

Although growth factor- and antibody-targeted filamentous phage have recently been demonstrated to transduce mammalian cells, there is a significant need to increase transduction efficiency so as to improve the usefulness of targeted phage vectors for gene therapy and ligand discovery. Here, we describe the use of multivalent phagemid vectors that are specifically designed for ligand-targeted mammalian cell transduction. This phagemid system has certain advantages over phage vectors, such as larger insert size and vector stability, and it retains the multivalent display necessary for efficient cell binding and internalization. Immunoblotting revealed that the most efficient multivalent display (exceeding that of a phage vector) was achieved in the phagemid system when epidermal growth factor (EGF) was fused to the C-terminal domain of the pIII coat protein. We compared phagemid particles displaying EGF at high or low valence by rescuing the vector with R408d3 (pIII deleted) or wild-type R408 helper phage, respectively. More efficient display of EGF correlated with increased internalization, vector potency, and transduction efficiency ( approximately 9%). The findings described here support our original hypothesis that phage-based vectors can be modified for more efficient gene transfer and suggest that directed evolution may be applied to increase their potential even further. PMID:11319907

Larocca, D; Jensen-Pergakes, K; Burg, M A; Baird, A

2001-04-01

142

Targeted delivery of doxorubicin: drug delivery system based on PAMAM dendrimers.  

PubMed

Polyamidoamine (PAMAM) dendrimers of the second generation (G2) are branched polymers containing 16 surface amino groups that allow them to be used as universal carriers on creating systems for drug delivery. G2 labeled with fluorescein isothiocyanate (FITC) efficiently bound with the surface of tumor cells at 4°C and was absorbed by the cells at 37°C. The covalent binding to G2-FITC of a vector protein, a recombinant fragment of the human alpha-fetoprotein receptor-binding domain (rAFP3D), increased the binding and endocytosis efficiency more than threefold. Covalent conjugates of G2 with doxorubicin (Dox) obtained by acid-labile linking of cis-aconitic anhydride (CAA) without the vector protein (G2-Dox) and with the vector protein rAFP3D (rAFP3D-G2-Dox) were accumulated by the tumor cells with high efficiency. However, a selective effect was observed only in rAFP3D-G2-Dox, which also demonstrated high cytotoxic activity against the human ovarian adenocarcinoma SKOV3 cells and low cytotoxicity against human peripheral blood lymphocytes. Based on these results, rAFP3D-G2 conjugate is promising for selective delivery of antitumor drugs. PMID:24228876

Yabbarov, N G; Posypanova, G A; Vorontsov, E A; Popova, O N; Severin, E S

2013-08-01

143

The application of carbon nanotubes in target drug delivery systems for cancer therapies  

PubMed Central

Among all cancer treatment options, chemotherapy continues to play a major role in killing free cancer cells and removing undetectable tumor micro-focuses. Although chemotherapies are successful in some cases, systemic toxicity may develop at the same time due to lack of selectivity of the drugs for cancer tissues and cells, which often leads to the failure of chemotherapies. Obviously, the therapeutic effects will be revolutionarily improved if human can deliver the anticancer drugs with high selectivity to cancer cells or cancer tissues. This selective delivery of the drugs has been called target treatment. To realize target treatment, the first step of the strategies is to build up effective target drug delivery systems. Generally speaking, such a system is often made up of the carriers and drugs, of which the carriers play the roles of target delivery. An ideal carrier for target drug delivery systems should have three pre-requisites for their functions: (1) they themselves have target effects; (2) they have sufficiently strong adsorptive effects for anticancer drugs to ensure they can transport the drugs to the effect-relevant sites; and (3) they can release the drugs from them in the effect-relevant sites, and only in this way can the treatment effects develop. The transporting capabilities of carbon nanotubes combined with appropriate surface modifications and their unique physicochemical properties show great promise to meet the three pre-requisites. Here, we review the progress in the study on the application of carbon nanotubes as target carriers in drug delivery systems for cancer therapies. PMID:21995320

2011-01-01

144

The application of carbon nanotubes in target drug delivery systems for cancer therapies  

NASA Astrophysics Data System (ADS)

Among all cancer treatment options, chemotherapy continues to play a major role in killing free cancer cells and removing undetectable tumor micro-focuses. Although chemotherapies are successful in some cases, systemic toxicity may develop at the same time due to lack of selectivity of the drugs for cancer tissues and cells, which often leads to the failure of chemotherapies. Obviously, the therapeutic effects will be revolutionarily improved if human can deliver the anticancer drugs with high selectivity to cancer cells or cancer tissues. This selective delivery of the drugs has been called target treatment. To realize target treatment, the first step of the strategies is to build up effective target drug delivery systems. Generally speaking, such a system is often made up of the carriers and drugs, of which the carriers play the roles of target delivery. An ideal carrier for target drug delivery systems should have three pre-requisites for their functions: (1) they themselves have target effects; (2) they have sufficiently strong adsorptive effects for anticancer drugs to ensure they can transport the drugs to the effect-relevant sites; and (3) they can release the drugs from them in the effect-relevant sites, and only in this way can the treatment effects develop. The transporting capabilities of carbon nanotubes combined with appropriate surface modifications and their unique physicochemical properties show great promise to meet the three pre-requisites. Here, we review the progress in the study on the application of carbon nanotubes as target carriers in drug delivery systems for cancer therapies.

Zhang, Wuxu; Zhang, Zhenzhong; Zhang, Yingge

2011-10-01

145

Click conjugated polymeric immuno-nanoparticles for targeted siRNA and antisense oligonucleotide delivery.  

PubMed

Efficient and targeted cellular delivery of small interfering RNAs (siRNAs) and antisense oligonucleotides (AONs) is a major challenge facing oligonucleotide-based therapeutics. The majority of current delivery strategies employ either conjugated ligands or oligonucleotide encapsulation within delivery vehicles to facilitate cellular uptake. Chemical modification of the oligonucleotides (ONs) can improve potency and duration of activity, usually as a result of improved nuclease resistance. Here we take advantage of innovations in both polymeric delivery vehicles and ON stabilization to achieve receptor-mediated targeted delivery of siRNAs or AONs for gene silencing. Polymeric nanoparticles comprised of poly(lactide-co-2-methyl, 2-carboxytrimethylene carbonate)-g-polyethylene glycol-furan/azide are click-modified with both anti-HER2 antibodies and nucleic acids on the exterior PEG corona. Phosphorothioate (PS), 2'F-ANA, and 2'F-RNA backbone chemical modifications improve siRNA and AON potency and duration of activity. Importantly, delivery of these nucleic acids on the exterior of the polymeric immuno-nanoparticles are as efficient in gene silencing as lipofectamine transfection without the associated potential toxicity of the latter. PMID:23932248

Chan, Dianna P Y; Deleavey, Glen F; Owen, Shawn C; Damha, Masad J; Shoichet, Molly S

2013-11-01

146

Targeted Drug Delivery Systems Mediated by a Novel Peptide in Breast Cancer Therapy and Imaging  

PubMed Central

Targeted delivery of drugs to tumors represents a significant advance in cancer diagnosis and therapy. Therefore, development of novel tumor-specific ligands or pharmaceutical nanocarriers is highly desirable. In this study, we utilized phage display to identify a new targeting peptide, SP90, which specifically binds to breast cancer cells, and recognizes tumor tissues from breast cancer patients. We used confocal and electron microscopy to reveal that conjugation of SP90 with liposomes enables efficient delivery of drugs into cancer cells through endocytosis. Furthermore, in vivo fluorescent imaging demonstrated that SP90-conjugated quantum dots possess tumor-targeting properties. In tumor xenograft and orthotopic models, SP90-conjugated liposomal doxorubicin was found to improve the therapeutic index of the chemotherapeutic drug by selectively increasing its accumulation in tumors. We conclude that the targeting peptide SP90 has significant potential in improving the clinical benefits of chemotherapy in the treatment and the diagnosis of breast cancer. PMID:23776619

Chiu, Chien-Yu; Lin, Wei-Chuan; Yan, Shin-Long; Wang, Yi-Ping; Kuo, Yuan-Sung; Yeh, Chen-Yun; Lo, Albert; Wu, Han-Chung

2013-01-01

147

Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery  

NASA Astrophysics Data System (ADS)

Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge density makes them toxic for in vivo applications. Here we describe the synthesis of a series of high molecular weight terpolymers with low charge density, and show that they exhibit efficient gene delivery, some surpassing the efficiency of the commercial transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymerization of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumour xenografts by one of the terpolymers results in significant inhibition of tumour growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high molecular weight and increased hydrophobicity, which compensates for their low charge density.

Zhou, Jiangbing; Liu, Jie; Cheng, Christopher J.; Patel, Toral R.; Weller, Caroline E.; Piepmeier, Joseph M.; Jiang, Zhaozhong; Saltzman, W. Mark

2012-01-01

148

Acoustic Molecular Imaging and Targeted Drug Delivery with Perfluorocarbon Nanoparticles  

NASA Astrophysics Data System (ADS)

Advances in molecular biology and cellular biochemistry are providing new opportunities for diagnostic medical imaging to "see" beyond the anatomical manifestations of disease to the earliest biochemical signatures of disease. Liquid perfluorocarbon nanoparticles provide inherent acoustic contrast when bound to targets, e.g., fibrin deposits in a thrombus, but unbound nanoparticles are undetectable. This nanoparticle platform may be further functionalized with paramagnetic metals, such as gadolinium, or radionuclides, with homing ligands, like anti-?v?3-integrins, and therapeutic agents. Acoustic imaging of densely distributed biomarkers, e.g., fibrin epitopes, is readily accommodated with fundamental imaging, but for sparse biomarkers, e.g., integrins, we have developed and implemented novel, nonlinear imaging techniques based upon information-theoretic receivers (i.e., thermodynamic receivers). These novel receivers allow sensitive direct imaging of contrast development.

Lanza, Gregory M.; Hughes, Michael. S.; Marsh, Jon N.; Scott, Michael J.; Zhang, Huiying; Lacy, Elizabeth K.; Allen, John S.; Wickline, Samuel A.

2005-03-01

149

Targeted delivery of carbon nanotubes to cancer cells  

NASA Astrophysics Data System (ADS)

CD22 is broadly expressed on human B cell lymphomas. Monoclonal anti-CD22 antibodies (MAbs) alone, or coupled to toxins, have been used to selectively target these tumors both in severe combined immunodeficient (SCID) mice with xenografted human lymphomas and in patients. Single-walled carbon nanotubes (CNTs) attached to antibodies or peptides represent another approach to targeting cancer cells. CNTs convert absorbed near-infrared (NIR) light into heat, which can thermally ablate cells in the vicinity of the CNTs. We have made MAb-CNT constructs where the MAb was either noncovalently or covalently coupled to CNTs, and investigated their ability to bind specifically to cells and to thermally ablate them after exposure to NIR light. The specific binding of these MAb-CNT constructs to antigen-positive and antigen-negative cells was demonstrated in vitro by using CD22+CD25 - Daudi cells, CD22-CD25+ phytohemagglutinin (PHA)-activated normal human peripheral blood mononuclear cells (PBMCs) and CNTs coupled non-covalently or covalently to either anti-CD22 or anti-CD25. We then demonstrated that the MAb-CNTs could bind to tumor cells expressing the relevant antigen but not to cells lacking the antigen. Furthermore we showed that, following exposure to NIR light, the cells could be thermally ablated. We also determined the stability of the MAb-CNTs in conditions designed to mimic the in vivo environment, i.e. mouse serum at 37°C. We then use the intrinsic Raman signature of CNTs to study the circulation and tissue distribution of intravenously injected MAb-CNTs in a murine xenograft model of lymphoma in vivo over a period of 24 hrs. We demonstrated that the MAb-CNTs have a short half-life in blood and that most of them are cleared by the reticuloendothelial system (RES). In the current embodiment, these constructs would therefore be of limited effectiveness in vivo.

Chakravarty, Pavitra

150

Targeting blood-brain barrier changes during inflammatory pain: an opportunity for optimizing CNS drug delivery  

PubMed Central

The blood–brain barrier (BBB) is the most significant obstacle to effective CNS drug delivery. It possesses structural and biochemical features (i.e., tight-junction protein complexes and, influx and efflux transporters) that restrict xenobiotic permeation. Pathophysiological stressors (i.e., peripheral inflammatory pain) can alter BBB tight junctions and transporters, which leads to drug-permeation changes. This is especially critical for opioids, which require precise CNS concentrations to be safe and effective analgesics. Recent studies have identified molecular targets (i.e., endogenous transporters and intracellular signaling systems) that can be exploited for optimization of CNS drug delivery. This article summarizes current knowledge in this area and emphasizes those targets that present the greatest opportunity for controlling drug permeation and/or drug transport across the BBB in an effort to achieve optimal CNS opioid delivery. PMID:22468221

Ronaldson, Patrick T; Davis, Thomas P

2012-01-01

151

NIR light controlled photorelease of siRNA and its targeted intracellular delivery based on upconversion  

E-print Network

limits its utility for gene therapy. In this work, a system of near- infrared (NIR) light-induced siNIR light controlled photorelease of siRNA and its targeted intracellular delivery based siRNA through electrostatic attractions and were easily internalized by living cells. Upon NIR light

Xing, Bengang

152

Towards multifunctional, targeted drug delivery systems using mesoporous silica nanoparticles - opportunities & challenges  

NASA Astrophysics Data System (ADS)

One of the big challenges of medicine today is to deliver drugs specifically to defected cells. Nanoparticulate drug carriers have the potential to answer to this call, as nanoparticles can cross physiological barriers and access different tissues, and also be provided in a targetable form aimed at enhancing cell specificity of the carrier. Recent developments within material science and strong collaborative efforts crossing disciplinary borders have highlighted the potential of mesoporous silica nanoparticles (MSNs) for such targeted drug delivery. Here we outline recent advances which in this sense push MSNs to the forefront of drug delivery development. Relatively straightforward inside-out tuning of the vehicles, high flexibility, and potential for sophisticated release mechanisms make these nanostructures promising candidates for targeted drug delivery such as `smart' cancer therapies. Moreover, due to the large surface area and the controllable surface functionality of MSNs, they can be controllably loaded with large amounts of drugs and coupled to homing molecules to facilitate active targeting, simultaneously carrying traceable (fluorescent or magnetically active) modalities, also making them highly interesting as theragnostic agents. However, the increased relative surface area and small size, and flexible surface functionalization which is beneficially exploited in nanomedicine, consequently also includes potential risks in their interactions with biological systems. Therefore, we also discuss some safety issues regarding MSNs and highlight how different features of the drug delivery platform influence their behaviour in a biological setting. Addressing these burning questions will facilitate the application of MSNs in nanomedicine.

Rosenholm, Jessica M.; Sahlgren, Cecilia; Lindén, Mika

2010-10-01

153

Folate-functionalized polymeric micelles for tumor targeted delivery of a potent multidrug-resistance  

E-print Network

Folate-functionalized polymeric micelles for tumor targeted delivery of a potent multidrug, polymeric micelles encoded with folic acid on the micelle surface were prepared with the encapsulation Mater Res 86A: 48­60, 2008 Key words: multidrug resistance; polymeric micelles; poly (ethylene glycol

Gao, Jinming

154

Depth-targeted transvascular drug delivery by using annular-shaped photomechanical waves  

NASA Astrophysics Data System (ADS)

Laser-based drug delivery is attractive for the targeting capability due to high spatial controllability of laser energy. Recently, we found that photomechanical waves (PMWs) can transiently increase the permeability of blood vessels in skin, muscle and brain of rats. In this study, we examined the use of annular-shaped PMWs to increase pressure at target depths due to superposition effect of pressure waves. This can increase the permeability of blood vessels located in the specific depth regions, enabling depth-targeted transvascular drug delivery. Annular PMWs were produced by irradiating a laser-absorbing material with annular-shaped pulsed laser beams that were produced by using an axicon lens. We first examined propagation and pressure characteristics of annular PMWs in tissue phantoms and confirmed an increased pressure at a target depth, which can be controlled by changing laser parameters. We injected Evans blue (EB) into a rat tail vein, and annular PMWs (inner diameter, 3 mm; outer diameter, 5 mm) were applied from the myofascial surface of the anterior tibialis muscle. After perfusion fixation, we observed fluorescence originating from EB in the tissue. We observed intense fluorescence at a target depth region of around 5 mm. These results demonstrate the capability of annular PMWs for depth-targeted transvascular drug delivery.

Akiyama, Takuya; Sato, Shunichi; Ashida, Hiroshi; Terakawa, Mitsuhiro

2011-02-01

155

Synthesis of Biomolecule-Modified Mesoporous Silica Nanoparticles for Targeted Hydrophobic Drug Delivery to Cancer Cells  

PubMed Central

Synthetic methodologies integrating hydrophobic drug delivery and biomolecular targeting with mesoporous silica nanoparticles are described. Transferrin and cyclic-RGD peptides are covalently attached to the nanoparticles utilizing different techniques and provide selectivity between primary and metastatic cancer cells. The increase in cellular uptake of the targeted particles is examined using fluorescence microscopy and flow cytometry. Transferrin-modified silica nanoparticles display enhancement in particle uptake by Panc-1 cancer cells over that of normal HFF cells. The endocytotic pathway for these particles is further investigated through plasmid transfection of the transferrin receptor into the normal HFF cell line, which results in an increase in particle endocytosis as compared to unmodified HFF cells. By designing and attaching a synthetic cyclic-RGD, selectivity between primary cancer cells (BT-549) and metastatic cancer cells (MDA-MB 435) is achieved with enhanced particle uptake by the metastatic cancer cell line. Incorporation of the hydrophobic drug Camptothecin into these two types of biomolecular-targeted nanoparticles causes an increase in mortality of the targeted cancer cells compared to that caused by both the free drug and nontargeted particles. These results demonstrate successful biomolecular-targeted hydrophobic drug delivery carriers that selectively target specific cancer cells and result in enhanced drug delivery and cell mortality. PMID:21595023

Ferris, Daniel P.; Lu, Jie; Gothard, Chris; Yanes, Rolando; Thomas, Courtney R.; Olsen, John-Carl; Stoddart, J. Fraser; Tamanoi, Fuyuhiko; Zink, Jeffrey I.

2011-01-01

156

Alveolar targeting of aerosol pentamidine. Toward a rational delivery system  

SciTech Connect

Nebulizer systems that deposit a high proportion of aerosolized pentamidine on large airways are likely to be associated with marked adverse side effects, which may lead to premature cessation of treatment. We have measured alveolar deposition and large airway-related side effects (e.g., cough, breathlessness, and effect on pulmonary function) after aerosolization of 150 mg pentamidine isethionate labeled with {sup 99m}Tc-Sn-colloid. Nine patients with AIDS were studied using three nebulizer systems producing different droplet size profiles: the Acorn System 22, Respirgard II, and Respirgard II with the inspiratory baffle removed. Alveolar deposition was greatest and side effects least with the nebulizer producing the smallest droplet size profile (Respirgard II), whereas large airway-related side effects were prominent and alveolar deposition lowest with the nebulizer producing the largest droplet size (Acorn System 22). Values for alveolar deposition and adverse airway effects were intermediate using the Respirgard with inspiratory baffle removed, thus indicating the importance of the baffle valve in determining droplet size. Addition of a similar baffle valve to the Acorn System 22 produced a marked improvement in droplet size profile. Selection of a nebulizer that produces an optimal droplet size range offers the advantage of enhancing alveolar targeting of aerosolized pentamidine while reducing large airway-related side effects.

Simonds, A.K.; Newman, S.P.; Johnson, M.A.; Talaee, N.; Lee, C.A.; Clarke, S.W. (Royal Free Hospital, London (England))

1990-04-01

157

Delivery  

MedlinePLUS

... your baby, your doctors will be working during labor and delivery to keep your blood glucose level under control. At ... what to expect during delivery, techniques to improve delivery and to relieve pain during labor, and how to care for your baby after ...

158

A facile route to synthesize nanogels doped with silver nanoparticles  

PubMed Central

In this work, we describe a simple method to prepare hybrid nanogels consisting of a biocompatible core-shell polymer host containing silver nanoparticles. First, the nanogels (NG, ~160 nm) containing a lysozyme rich core and a dextran rich shell, are prepared via Maillard and heat-gelation reactions. Second, silver nanoparticles (Ag NPs, ~5nm) are synthesized in situ in the NG solution without requiring additional reducing agents. This approach leads to stable Ag NPs located in the NG. Furthermore, we demonstrate that the amount of Ag NPs in the NG can be tuned by varying silver precursor concentration. Hybrid nanogels with silver nanoparticles have potential in antimicrobial, optical and therapeutic applications. PMID:23459266

Ferrer, M. Carme Coll; Ferrier, Robert C.; Eckmann, David M.; Composto, Russell J.

2012-01-01

159

Developing genetically engineered encapsulin protein cage nanoparticles as a targeted delivery nanoplatform.  

PubMed

Protein cage nanoparticles are excellent candidates for use as multifunctional delivery nanoplatforms because they are built from biomaterials and have a well-defined structure. A novel protein cage nanoparticle, encapsulin, isolated from thermophilic bacteria Thermotoga maritima, is prepared and developed as a versatile template for targeted delivery nanoplatforms through both chemical and genetic engineering. It is pivotal for multifunctional delivery nanoplatforms to have functional plasticity and versatility to acquire targeting ligands, diagnostic probes, and drugs simultaneously. Encapsulin is genetically engineered to have unusual heat stability and to acquire multiple functionalities in a precisely controlled manner. Hepatocellular carcinoma (HCC) cell binding peptide (SP94-peptide, SFSIIHTPILPL) is chosen as a targeting ligand and displayed on the surface of engineered encapsulin (Encap_loophis42C123) through either chemical conjugation or genetic insertion. The effective and selective targeted delivery of SP94-peptide displaying encapsulin (SP94-Encap_loophis42C123) to HepG2 cells is confirmed by fluorescent microscopy imaging. Aldoxorubicin (AlDox), an anticancer prodrug, is chemically loaded to SP94-Encap_loophis42C123 via thiol-maleimide Michael-type addition, and the efficacy of the delivered drugs is evaluated with a cell viability assay. SP94-Encap_loophis42C123-AlDox shows comparable killing efficacy with that of free drugs without the platform's own cytotoxicity. Functional plasticity and versatility of the engineered encapsulin allow us to introduce targeting ligands, diagnostic probes, and therapeutic reagents simultaneously, providing opportunities to develop multifunctional delivery nanoplatforms. PMID:25180761

Moon, Hyojin; Lee, Jisu; Min, Junseon; Kang, Sebyung

2014-10-13

160

Recent approaches of lipid-based delivery system for lymphatic targeting via oral route.  

PubMed

Abstract Lymphatic system is a key target in research field due to its distinctive makeup and huge contributing functions within the body. Intestinal lymphatic drug transport (chylomicron pathway) is intensely described in research field till date because it is considered to be the best for improving oral drug delivery by avoiding first pass metabolism. The lymphatic imaging techniques and potential therapeutic candidates are engaged for evaluating disease states and overcoming these conditions. The novel drug delivery systems such as self-microemulsifying drug delivery system, nanoparticles, liposomes, nano-lipid carriers, solid lipid carriers are employed for delivering drugs through lymphatic system via various routes such as subcutaneous route, intraperitoneal route, pulmonary route, gastric sub-mucosal injection, intrapleural and intradermal. Among these colloidal particles, lipid-based delivery system is considered to be the best for lymphatic delivery. From the last few decades, mesenteric lymph duct cannulation and thoracic lymph duct cannulation are followed to assess lymphatic uptake of drugs. Due to their limitations, chylomicrons inhibitors and in-vitro models are employed, i.e. lipolysis model and permeability model. Currently, research on this topic still continues and drainage system used to deliver the drugs against lymphatic disease as well as targeting other organs by modulating the chylomicron pathway. PMID:25148607

Chaudhary, Shilpa; Garg, Tarun; Murthy, R S R; Rath, Goutam; Goyal, Amit K

2014-12-01

161

A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy.  

PubMed

Targeted drug delivery vehicles with low immunogenicity and toxicity are needed for cancer therapy. Here we show that exosomes, endogenous nano-sized membrane vesicles secreted by most cell types, can deliver chemotherapeutics such as doxorubicin (Dox) to tumor tissue in BALB/c nude mice. To reduce immunogenicity and toxicity, mouse immature dendritic cells (imDCs) were used for exosome production. Tumor targeting was facilitated by engineering the imDCs to express a well-characterized exosomal membrane protein (Lamp2b) fused to ?v integrin-specific iRGD peptide (CRGDKGPDC). Purified exosomes from imDCs were loaded with Dox via electroporation, with an encapsulation efficiency of up to 20%. iRGD exosomes showed highly efficient targeting and Dox delivery to ?v integrin-positive breast cancer cells in vitro as demonstrated by confocal imaging and flow cytometry. Intravenously injected targeted exosomes delivered Dox specifically to tumor tissues, leading to inhibition of tumor growth without overt toxicity. Our results suggest that exosomes modified by targeting ligands can be used therapeutically for the delivery of Dox to tumors, thus having great potential value for clinical applications. PMID:24345736

Tian, Yanhua; Li, Suping; Song, Jian; Ji, Tianjiao; Zhu, Motao; Anderson, Gregory J; Wei, Jingyan; Nie, Guangjun

2014-02-01

162

Targeted Delivery of Doxorubicin Using a Colorectal Cancer-Specific ssDNA Aptamer.  

PubMed

Targeted drug delivery is particularly important in cancer treatment because many antitumor drugs are nonspecific and highly toxic to both cancerous and normal cells. The L33 aptamer is a single-stranded DNA (ssDNA) sequence that has the ability to recognize human colorectal cancer (CRC) cell line HCT116 specifically. In this study, we demonstrated that the L33 aptamer can selectively internalize into target HCT116 cells via receptor-mediated endocytosis. Based on this finding, we developed an aptamer-based drug delivery system using L33 as the carrier of the antitumor drug doxorubicin (Dox). The L33-Dox complex exhibited specific and high affinity (Kd ?=?14.3?±?2.2 nM) binding to HCT116 cells. The results of cytotoxicity assays revealed that the L33-Dox complex was capable of selectively delivering the drug to the target HCT116 cells and lowered the toxicity for nontarget CL187 cells. These findings indicate that the aptamer-based targeted drug delivery system has the potential to be used in clinical settings and may overcome drug resistance to a certain extent because high drug dosages can be directed toward target cells. Anat Rec, 297:2280-2288, 2014. © 2014 Wiley Periodicals, Inc. PMID:25044297

Li, Wanming; Chen, Hang; Yu, Min; Fang, Jin

2014-12-01

163

Targeted delivery of nano-therapeutics for major disorders of the central nervous system.  

PubMed

Major central nervous system (CNS) disorders, including brain tumors, Alzheimer’s disease, Parkinson’s disease, and stroke, are significant threats to human health. Although impressive advances in the treatment of CNS disorders have been made during the past few decades, the success rates are still moderate if not poor. The blood–brain barrier (BBB) hampers the access of systemically administered drugs to the brain. The development of nanotechnology provides powerful tools to deliver therapeutics to target sites. Anchoring them with specific ligands can endow the nano-therapeutics with the appropriate properties to circumvent the BBB. In this review, the potential nanotechnology-based targeted drug delivery strategies for different CNS disorders are described. The limitations and future directions of brain-targeted delivery systems are also discussed. PMID:23797465

Gao, Huile; Pang, Zhiqing; Jiang, Xinguo

2013-10-01

164

Drug transporters in the nasal epithelium: an overview of strategies in targeted drug delivery.  

PubMed

In this article, we discussed the expression of some ABC (e.g., P-glycoprortein, MRP and CFTR) and SLC (e.g., POT, DAT, OAT, OATP, OCT, EAAT2/GLT1 and GLUT) amino acid, metal and nucleoside transporters in the nasal mucosa. The localization and therapeutic targeting of these transporters are explored in detail. The wide array of transporters discovered so far in the nasal mucosa implies that a plethora of compounds can be delivered by targeting these transporters. The article concludes with a discussion of the potential challenges and delivery options for transporter-mediated drug targeting via the nasal route. PMID:25329195

Anand, Utkarshini; Parikh, Ankit; Ugwu, Malachy C; Agu, Remigius U

2014-08-01

165

Targeted delivery of cisplatin to lung cancer using ScFvEGFR-heparin-cisplatin nanoparticles.  

PubMed

The clinical application of cis-diamminedichloroplatinum(II) (DDP, cisplatin) for cancer therapy is limited by its nonspecific biodistribution and severe side effects. Here, we have developed EGFR-targeted heparin-DDP (EHDDP) nanoparticles for tumor-targeted delivery of DDP. This nanoparticle delivery system possesses the following unique properties: (i) succinic anhydride-modified heparin is biocompatible and biodegradable with no anticoagulant activity; (ii) single-chain variable fragment anti-EGFR antibody (ScFvEGFR) was conjugated to the nanoparticles as an EGFR-targeting ligand. Our results showed that EHDDP nanoparticles can significantly increase the intracellular concentrations of DDP and Pt-DNA adducts in EGFR-expressing non-small cell lung cancer H292 cells via an EGFR-mediated pathway. Compared to the free DDP, significantly prolonged blood circulation time and improved pharmacokinetics and biodistribution of Pt were observed after systemic delivery of the EHDDP nanoparticles. The new EHDDP nanoparticle delivery system significantly enhanced antitumor activity of DDP without weight loss or damage to the kidney and spleen in nude mice bearing H292 cell tumors. PMID:22032622

Peng, Xiang-Hong; Wang, Yiqing; Huang, Donghai; Wang, Yuxiang; Shin, Hyung Juc; Chen, Zhengjia; Spewak, Michael B; Mao, Hui; Wang, Xu; Wang, Ying; Chen, Zhuo Georgia; Nie, Shuming; Shin, Dong M

2011-12-27

166

Fluorine-Containing Taxoid Anticancer Agents and Their Tumor-Targeted Drug Delivery  

PubMed Central

A long-standing problem of conventional chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Consequently, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, including tumor-targeting drug delivery systems. In general, such a drug delivery system consists of a tumor recognition moiety and a cytotoxic “warhead” connected through a “smart” linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a “Trojan Horse” approach can be used for mass delivery of cytotoxic “warheads” to maximize the efficacy. Exploitation of the special properties of fluorine has proven successful in the development of new and effective biochemical tools as well as therapeutic agents. Fluorinated congeners can also serve as excellent probes for the investigation of biochemical mechanisms. 19F-NMR can provide unique and powerful tools for mechanistic investigations in chemical biology. This account presents our recent progress, in perspective, on the molecular approaches to the design and development of novel tumor-targeted drug delivery systems for new generation chemotherapy by exploiting the unique nature of fluorine. PMID:23935213

Seitz, Joshua; Vineberg, Jacob G.; Zuniga, Edison S.; Ojima, Iwao

2013-01-01

167

Peptide- and saccharide-conjugated dendrimers for targeted drug delivery: a concise review  

PubMed Central

Dendrimers comprise a category of branched materials with diverse functions that can be constructed with defined architectural and chemical structures. When decorated with bioactive ligands made of peptides and saccharides through peripheral chemical groups, dendrimer conjugates are turned into nanomaterials possessing attractive binding properties with the cognate receptors. At the cellular level, bioactive dendrimer conjugates can interact with cells with avidity and selectivity, and this function has particularly stimulated interests in investigating the targeting potential of dendrimer materials for the design of drug delivery systems. In addition, bioactive dendrimer conjugates have so far been studied for their versatile capabilities to enhance stability, solubility and absorption of various types of therapeutics. This review presents a brief discussion on three aspects of the recent studies to use peptide- and saccharide-conjugated dendrimers for drug delivery: (i) synthesis methods, (ii) cell- and tissue-targeting properties and (iii) applications of conjugated dendrimers in drug delivery nanodevices. With more studies to elucidate the structure–function relationship of ligand–dendrimer conjugates in transporting drugs, the conjugated dendrimers hold promise to facilitate targeted delivery and improve drug efficacy for discovery and development of modern pharmaceutics. PMID:23741608

Liu, Jie; Gray, Warren D.; Davis, Michael E.; Luo, Ying

2012-01-01

168

DNA and aptamer stabilized gold nanoparticles for targeted delivery of anticancer therapeutics  

NASA Astrophysics Data System (ADS)

Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further reduce toxicity by increasing targeted delivery towards malignant cells.Gold nanoparticles (GNPs) can be used as carriers of a variety of therapeutics. Ideally, drugs are released in the target cells in response to cell specific intracellular triggers. In this study, GNPs are loaded with doxorubicin or AZD8055, using a self-immolative linker which facilitates the release of anticancer therapeutics in malignant cells without modifications of the active compound. An additional modification with the aptamer AS1411 further increases the selectivity of GNPs towards cancer cells. Both modifications increase targeted delivery of therapeutics with GNPs. Whereas GNPs without anticancer drugs do not affect cell viability in all cells tested, AS1411 modified GNPs loaded with doxorubicin or AZD8055 show significant and increased reduction of cell viability in breast cancer and uveal melanoma cell lines. These results highlight that modified GNPs can be functionalized to increase the efficacy of cancer therapeutics and may further reduce toxicity by increasing targeted delivery towards malignant cells. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr00019f

Latorre, Alfonso; Posch, Christian; Garcimartín, Yolanda; Celli, Anna; Sanlorenzo, Martina; Vujic, Igor; Ma, Jeffrey; Zekhtser, Mitchell; Rappersberger, Klemens; Ortiz-Urda, Susana; Somoza, Álvaro

2014-06-01

169

Thermoresponsive bacterial cellulose whisker/poly(NIPAM-co-BMA) nanogel complexes: synthesis, characterization, and biological evaluation.  

PubMed

Dispersions of poly(N-isopropylacrylamide-co-butyl methacrylate) (PNB) nanogels are known to exhibit reversible thermosensitive sol-gel phase behavior and can consequently be used in a wide range of biomedical applications. However, some dissatisfactory mechanical properties of PNB nanogels can limit their applications. In this paper, bacterial cellulose (BC) whiskers were first prepared by sulfuric acid hydrolysis and then nanosized by high-pressure homogenization for subsequent use in the preparation of BC whisker/PNB nanogel complexes (designated as BC/PNB). The mechanical properties of PNB was successfully enhanced, resulting in good biosafety. The BC/PNB nanogel dispersions exhibited phase transitions from swollen gel to shrunken gel with increasing temperature. In addition, differential scanning calorimetry (DSC) data showed that the thermosensitivity of PNB nanogels was retained. Rheological tests also indicated that BC/PNB nanogel complexes had stronger gel strengths when compared with PNB nanogels. The concentrated dispersions showed shear thinning behavior and improved toughness, both of which can play a key role in the medical applications of nanogel complexes. Furthermore, the BC/PNB nanogel complexes were noncytotoxic according to cytotoxicity and hemolysis tests. Concentrated BC/PNB nanogel dispersion displayed gel a forming capacity in situ by catheter injection, which indicates potential for a wide range of medical applications. PMID:23458422

Wu, Lei; Zhou, Hui; Sun, Hao-Jan; Zhao, Yanbing; Yang, Xiangliang; Cheng, Stephen Z D; Yang, Guang

2013-04-01

170

Molecular design and nanoparticle-mediated intracellular delivery of functional proteins to target cellular pathways  

NASA Astrophysics Data System (ADS)

Intracellular delivery of specific proteins and peptides represents a novel method to influence stem cells for gain-of-function and loss-of-function. Signaling control is vital in stem cells, wherein intricate control of and interplay among critical pathways directs the fate of these cells into either self-renewal or differentiation. The most common route to manipulate cellular function involves the introduction of genetic material such as full-length genes and shRNA into the cell to generate (or prevent formation of) the target protein, and thereby ultimately alter cell function. However, viral-mediated gene delivery may result in relatively slow expression of proteins and prevalence of oncogene insertion into the cell, which can alter cell function in an unpredictable fashion, and non-viral delivery may lead to low efficiency of genetic delivery. For example, the latter case plagues the generation of induced pluripotent stem cells (iPSCs) and hinders their use for in vivo applications. Alternatively, introducing proteins into cells that specifically recognize and influence target proteins, can result in immediate deactivation or activation of key signaling pathways within the cell. In this work, we demonstrate the cellular delivery of functional proteins attached to hydrophobically modified silica (SiNP) nanoparticles to manipulate specifically targeted cell signaling proteins. In the Wnt signaling pathway, we have targeted the phosphorylation activity of glycogen synthase kinase-3beta (GSK-3beta) by designing a chimeric protein and delivering it in neural stem cells. Confocal imaging indicates that the SiNP-chimeric protein conjugates were efficiently delivered to the cytosol of human embryonic kidney cells and rat neural stem cells, presumably via endocytosis. This uptake impacted the Wnt signaling cascade, indicated by the elevation of beta-catenin levels, and increased transcription of Wnt target genes, such as c-MYC. The results presented here suggest that functional proteins can be delivered intracellularly in vitro using nanoparticles and used to target key signaling proteins and regulate cell signaling pathways. The same concept of naturally occurring protein-protein interactions can also be implemented to selectively bring intracellular protein targets in close proximity to proteasomal degradation machinery in cells and effect their depletion from the cellular compartments. This approach will be able to not only target entire pool of proteins to ubiquitination-mediated degradation, but also to specific sub-pools of posttranslationally modified proteins in the cell, provided peptides having distinct binding affinities are identified for posttranslational modifications. This system can then be tested for intracellular protein delivery using nanoparticle carriers to identify roles of different posttranslational modifications on the protein's activity. In future work, we propose to develop a cellular detection system, based on GFP complementation, which can be used to evaluate the efficiency of different protein delivery carriers to internalize proteins into the cell cytosol. We envision the application of nanoscale materials as intracellular protein delivery vehicles to target diverse cell signaling pathways at the posttranslational level, and subsequent metabolic manipulation, which may have interesting therapeutic properties and can potentially target stem cell fate.

Shah, Dhiral Ashwin

171

LIPOSOMAL MODULAR COMPLEXES FOR SIMULTANEOUS TARGETED DELIVERY OF BIOACTIVE GASES AND THERAPEUTICS  

PubMed Central

Intrinsically echogenic liposomes (ELIP) can be adapted to encapsulate nitric oxide to facilitate ultrasound-enhanced delivery of therapeutic agents to atherosclerotic plaques. However, the NO loading of targeted ELIP caused a 93% decrease of antibody (Ab) immunoreactivity. The following hypothesis was tested: biotin/avidin-mediated coupling of NO-ELIP and Ab-conjugated ELIP will enable co-delivery of bioactive gases and ELIP that can encapsulate other agents without loss of targeting efficiency. Complex formation was initiated by addition of excess streptavidin to equal proportions of biotinylated Ab-ELIP and NO-ELIP. Fluorescence deconvolution microscopy, Coulter Multisizer 3 analysis and flow cytometry demonstrated that the ELIP coupling procedure formed mixed aggregates of ?10 liposomes within 1 minute. Intravascular ultrasound imaging and ELISA showed that echogenicity and targeting efficiency were completely and 69–99% retained, respectively. When complexed to NO-ELIP, ELIP bifunctionally targeted to both CD34 and ICAM-1 (BF-ELIP) increased human mononuclear cell migration through human coronary artery endothelial cell monolayers in transwell plates 4-fold relative to a nonspecific IgG-ELIP control and 2-fold relative to BF-ELIP alone. It was concluded that this novel multi-functional conjugation methodology provides a platform technology for site-specific co-delivery of bioactive gases and other agents. PMID:19903503

Klegerman, Melvin E.; Wassler, Michael; Huang, Shao-Ling; Zou, Yuejiao; Kim, Hyunggun; Shelat, Harnath S.; Holland, Christy K.; Geng, Yong-Jian; McPherson, David D.

2010-01-01

172

Development of multiple-layer polymeric particles for targeted and controlled drug delivery  

PubMed Central

The purpose of this work was to develop multilayered particles consisting of a magnetic core and two encompassing shells made up of poly (N-isopropylacrylamide) (PNIPAAm) and poly(d,l-lactide-co-glycolide) (PLGA) for targeted and controlled drug delivery. Transmission electron microscopy confirmed that multilayered particles were obtained with PNIPAAm magnetic nanoparticles embedded within the PLGA shell. Factorial analysis studies also showed that the particle size was inversely proportional to the surfactant concentration and sonication power and directly proportional to the PLGA concentration. Drug-release results demonstrated that these multilayer particles produced an initial burst release and a subsequent sustained release of both bovine serum albumin (BSA) and curcumin loaded into the core and shell of the particle, respectively. BSA release was also affected by changes in temperature. In conclusion, our results indicate that the multilayered magnetic particles could be synthesized and used for targeted and controlled delivery of multiple drugs with different release mechanisms. PMID:19699325

Koppolu, Bhanuprasanth; Rahimi, Maham; Nattama, Sivaniarvindpriya; Wadajkar, Aniket; Nguyen, Kytai Truong

2010-01-01

173

pH-sensitive polymeric nanoparticles for tumor-targeting doxorubicin delivery: concept and recent advances.  

PubMed

Doxorubicin is a potent chemotherapeutic drug applied in the clinics for the treatment of various human cancers. It is typically administered as the hydrochloride salt or in liposomal forms, which are plagued with severe side effects. In recent years, pH-sensitive polymeric nanoparticles that are capable of retaining drug during circulation while actively releasing it at the tumor site and/or inside the target tumor cells have received an overwhelming interest for tumor-targeting cancer chemotherapy. This smart delivery approach has shown to elegantly resolve the in vivo stability versus intracellular drug release dilemma, as well as stealth versus tumor cell uptake dilemma. In this review, the concept and exciting new advances in pH-sensitive polymeric nanoparticles for doxorubicin delivery are presented and discussed. PMID:24746192

Meng, Fenghua; Zhong, Yinan; Cheng, Ru; Deng, Chao; Zhong, Zhiyuan

2014-03-01

174

Tumor-targeting multifunctional nanoparticles for siRNA delivery: recent advances in cancer therapy.  

PubMed

RNA interference (RNAi) is a naturally occurring regulatory process that controls posttranscriptional gene expression. Small interfering RNA (siRNA), a common form of RNAi-based therapeutics, offers new opportunities for cancer therapy via silencing specific genes, which are associated to cancer progress. However, clinical applications of RNAi-based therapy are still limited due to the easy degradation of siRNA during body circulation and the difficulty in the delivery of siRNA to desired tissues and cells. Thus, there have been many efforts to develop efficient siRNA delivery systems, which protect siRNA from serum nucleases and deliver siRNA to the intracellular region of target cells. Here, the recent advances in siRNA nanocarriers, which possess tumor-targeting ability are reviewed; various nanoparticle systems and their antitumor effects are summarized. The development of multifunctional nanocarriers for theranostics or combinatorial therapy is also discussed. PMID:24577795

Ku, Sook Hee; Kim, Kwangmeyung; Choi, Kuiwon; Kim, Sun Hwa; Kwon, Ick Chan

2014-08-01

175

Occlusion of retinal vessels using targeted delivery of a platelet aggregating agent.  

PubMed Central

Local laser targeted delivery of a platelet aggregating agent to occlude retinal and choroidal vessels was evaluated in rabbits and rats. Liposomes containing adenosine diphosphate (ADP) were administered intravenously and an argon laser was used to lyse the liposomes in main retinal arteries. Control vessels were treated with the same energy of laser without administering ADP. Fluorescein angiography performed 2 weeks later showed that all the control vessels were perfused. Ninety percent of the ADP-treated arteries showed complete or partial occlusion. Successful occlusion increased with the laser energy and decreased with increasing vessel diameter. Histopathology showed that occlusion was achieved in retinal as well as choroidal vessels. The inner retina remained relatively unaffected at the treatment site but the outer retina was thermally damaged. These preliminary results suggest that targeted delivery of a platelet aggregating agent holds promise for occluding vessels in the fundus. Images PMID:8494860

Ogura, Y; Guran, T; Takahashi, K; Zeimer, R

1993-01-01

176

Escort Aptamers: New Tools for the Targeted Delivery of Therapeutics into Cells  

PubMed Central

Escort aptamers are DNA or RNA sequences with high affinity to certain cell-surface proteins, which can be used for targeted delivery of various agents into cells of a definite type. The peculiarities of the selection of escort aptamers are discussed in this review. The methods used in selection of escort aptamers via the SELEX technique are considered, including selection against isolated cell-surface proteins, cell fragments, living eukaryotic cells, and bacteria. Particular attention is given to the design and chemical modification of escort aptamers. The different fields of application of escort aptamers are described, including the targeted delivery of siRNAs, nanoparticles, toxins, and photoagents, as well as the identification of specific cell markers and the detection or isolation of cells of a definite type. The potential for the application of escort aptamers in the development of new therapeutic agents and diagnostic systems is also discussed. PMID:22649701

Davydova, A.S.; Vorobjeva, M.A.; Venyaminova, A.G.

2011-01-01

177

Multifunctional protein nanocarriers for targeted nuclear gene delivery in nondividing cells  

Microsoft Academic Search

Compartmentalization within eukaryotic cells hinders the efficient delivery of therapeutic agents to the cell nucleus. Here we describe novel multifunc- tional DNA carriers (MDCs) that self-assemble with DNA to form structured nanoparticles that possess virus-like functions for cellular trafficking. MDCs con- tain, in fusion, the DNA-compacting sperm chromatin component protamine, -melanocyte-stimulating hor- mone for cell-targeted internalization, the endosome- translocation domain

Dominic J. Glover; S. M. Ng; A. Mechler; L. L. Martin; D. A. Jans

2009-01-01

178

87. Efficient Delivery of Small Interfering RNA Targeting Pro-Inflammatory Cytokines in Experimental Arthritis  

Microsoft Academic Search

The TNF-? is one of the most prominent central cytokines in rheumatoid arthritis (RA). We recently demonstrated that systemic non-viral delivery of a siRNA targeting the TNF-? efficiently restore the immunological balance in an experiment model of RA. However, 30% of treated patients do not respond to the anti-TNF-? biotherapies. Strong association of other pro-inflammatory cytokines with the pathogenesis of

Maroun Khoury; Virginie Escriou; Pascale Louis-Plence; Danièle Noel; Daniel Scherman; Florence Apparailly

2006-01-01

179

Magnetic Nanoparticles as Intraocular Drug Delivery System to Target Retinal Pigmented Epithelium (RPE)  

PubMed Central

One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life of drugs, especially in the anterior eye chamber, while targeting the posterior chamber is still an open issue. The retina and the retinal pigment epithelium/choroid tissues, located in the posterior eye chamber, are responsible for the majority of blindness both in childhood and adulthood. In the present study, we used magnetic nanoparticles (MNPs) as a nanotool for ocular drug delivery that is capable of specific localization in the retinal pigmented epithelium (RPE) layer. We demonstrate that, following intraocular injection in Xenopus embryos, MNPs localize specifically in RPE where they are retained for several days. The specificity of the localization did not depend on particle size and surface properties of the MNPs used in this work. Moreover, through similar experiments in zebrafish, we demonstrated that the targeting of RPE by the nanoparticles is not specific for the Xenopus species. PMID:24451140

Giannaccini, Martina; Giannini, Marianna; Calatayud, M. Pilar; Goya, Gerardo F.; Cuschieri, Alfred; Dente, Luciana; Raffa, Vittoria

2014-01-01

180

Formulation design for target delivery of iron nanoparticles to TCE zones.  

PubMed

Nanoparticles of zero-valent iron (NZVI) are effective reducing agents for some dense non-aqueous phase liquid (DNAPL) contaminants such as trichloroethylene (TCE). However, target delivery of iron nanoparticles to DNAPL zones in the aquifer remains an elusive feature for NZVI technologies. This work discusses three strategies to deliver iron nanoparticles to DNAPL zones. To this end, iron oxide nanoparticles coated with oleate (OL) ions were used as stable analogs for NZVI. The OL-coated iron oxide nanoparticles are rendered lipophilic via (a) the addition of CaCl2, (b) acidification, or (c) the addition of a cationic surfactant, benzethonium chloride (BC). Mixtures of OL and BC show promise as a target delivery strategy due to the high stability of the nanoparticles in water, and their preferential partition into TCE in batch experiments. Column tests show that while the OL-BC coated iron oxide nanoparticles remain largely mobile in TCE-free columns, a large fraction of these particles are retained in TCE-contaminated columns, confirming the effectiveness of this target delivery strategy. PMID:24096200

Wang, Ziheng; Acosta, Edgar

2013-12-01

181

Glycan-targeted drug delivery for intravesical therapy: in the footsteps of uropathogenic bacteria.  

PubMed

The human urothelium belongs to the most efficient biobarriers, and represents a highly rewarding but challenging target for local drug administration. Inadequate urothelial bioavailability is a major obstacle for successful treatment of bladder cancer and other diseases, yet little research has addressed the development of advanced delivery concepts for the intravesical route. A prominent example of how to overcome the urothelial barrier by means of specific biorecognition is the efficient cytoinvasion of UPEC bacteria, mediated by the mannose-targeted lectin domain FimH. Similar mechanisms of non-bacterial origin may be exploited for enhancing drug uptake from the bladder cavity. This review covers the current status in the development of lectin-based delivery strategies for the urinary tract. Different concepts for preparing and optimizing carbohydrate-targeted delivery systems are presented, along with important design parameters, benefits and shortcomings. Bioconjugate- and nano-/microparticle-based systems are discussed in further detail with regard to their performance in preclinical testing. PMID:24998273

Neutsch, Lukas; Gabor, Franz; Wirth, Michael

2014-05-01

182

A smart multifunctional nanocomposite for intracellular targeted drug delivery and self-release  

NASA Astrophysics Data System (ADS)

A multifunctional 'all-in-one' nanocomposite is fabricated using a colloid, template and surface-modification method. This material encompasses magnetic induced target delivery, cell uptake promotion and controlled drug release in one system. The nanocomposite is characterized by scanning electron microscopy, transmission electron microscopy, x-ray diffraction, N2 adsorption and vibrating sample magnetometry. The prepared material has a diameter of 350-400 nm, a high surface area of 420.29 m2 g - 1, a pore size of 1.91 nm and a saturation magnetization of 32 emu g - 1. Doxorubicin (DOX) is loaded in mesopores and acid-sensitive blockers are introduced onto the orifices of the mesopores by a Schiff base linker to implement pH-dependent self-release. Folate was also introduced to improve DOX targeted delivery and endocytosis. The linkers remained intact to block pores with ferrocene valves and inhibit the diffusion of DOX at neutral pH. However, in lysosomes of cancer cells, which have a weak acidic pH, hydrolysis of the Schiff base group removes the nanovalves and allows the trapped DOX to be released. These processes are demonstrated by UV-visible absorption spectra, confocal fluorescence microscopy images and methyl thiazolyl tetrazolium assays in vitro, which suggest that the smart nanocomposite successfully integrates targeted drug delivery with internal stimulus induced self-release and is a potentially useful material for nanobiomedicine.

Wang, Chan; Lv, Piping; Wei, Wei; Tao, Shengyang; Hu, Tao; Yang, Jingbang; Meng, Changgong

2011-10-01

183

A Targeting Drug Delivery System for Ovarian Carcinoma: Transferrin Modified Lipid Coated Paclitaxel-loaded Nanoparticles.  

PubMed

The transferring modified lipid coated PLGA nanoparticles, as a targetable vector, were developed for the targeting delivery of anticancer drugs with paclitaxel (PTX) as a model drug to the ovarian carcinoma, which combines the advantages and avoids disadvantages of polymeric nanoparticles and liposomes in drug delivery. A transmission electron microscopy (TEM) confirmed the lipid coating on the polymeric core. Physicochemical characterizations of TFLPs, such as particle size, zeta potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. In the cellular uptake study, the TFLPs were more efficiently endocytosed by the A2780 cells with high expression of transferrin receptors than HUVEC cells without the transferrin receptors. Furthermore, the anticancer efficacy of TFLPs on the tumor spheroids was stronger than that of lipid coated PLGA nanoparticles (LPs) and PLGA nanoparticles. In the in vivo study, the TFLPs showed the best inhibition effect of the tumor growth for the ovarian carcinoma-bearing mice. In brief, the TFLPs were proved to be an efficient targeting drug delivery system for ovarian carcinoma. PMID:24443309

Li, R; Zhang, Q; Wang, X-Y; Chen, X-G; He, Y-X; Yang, W-Y; Yang, X

2014-10-01

184

Magnetic nanoparticles as intraocular drug delivery system to target retinal pigmented epithelium (RPE).  

PubMed

One of the most challenging efforts in drug delivery is the targeting of the eye. The eye structure and barriers render this organ poorly permeable to drugs. Quite recently the entrance of nanoscience in ocular drug delivery has improved the penetration and half-life of drugs, especially in the anterior eye chamber, while targeting the posterior chamber is still an open issue. The retina and the retinal pigment epithelium/choroid tissues, located in the posterior eye chamber, are responsible for the majority of blindness both in childhood and adulthood. In the present study, we used magnetic nanoparticles (MNPs) as a nanotool for ocular drug delivery that is capable of specific localization in the retinal pigmented epithelium (RPE) layer. We demonstrate that, following intraocular injection in Xenopus embryos, MNPs localize specifically in RPE where they are retained for several days. The specificity of the localization did not depend on particle size and surface properties of the MNPs used in this work. Moreover, through similar experiments in zebrafish, we demonstrated that the targeting of RPE by the nanoparticles is not specific for the Xenopus species. PMID:24451140

Giannaccini, Martina; Giannini, Marianna; Calatayud, M Pilar; Goya, Gerardo F; Cuschieri, Alfred; Dente, Luciana; Raffa, Vittoria

2014-01-01

185

Nucleolin targeting AS1411 modified protein nanoparticle for antitumor drugs delivery.  

PubMed

Over recent years, cell surface nucleolin as an anticancer target has attracted many researchers' attentions. To improve the antitumor efficacy, we developed a nucleolin targeted protein nanoparticle (NTPN) delivery system in which human serum albumin (HSA) was used as drug carrier and a DNA aptamer named AS1411, which had high affinity to nucleolin, was used as a bullet. The HSA nanoparticles (NPs-PTX) were fabricated by a novel self-assembly method and then modified with AS1411 (Apt-NPs-PTX). The resulted Apt-NPs-PTX were spherical. Compared with NPs-PTX, the uptake of Apt-NPs-PTX displayed a significant increase in MCF-7 cells while there was a decrease in nontumor cell lines such as MCF-10A and 3T3 cells. In a cytotoxic study, Apt-NPs-PTX displayed an enhanced cytotoxicity in MCF-7 tumor cells while there was almost no cytotoxicity in MCF-10A cells. Endostatin, a nucleolin inhibitor, could significantly decrease the internalization of Apt-NPs-PTX, suggesting nucleolin mediates the transmembrane process of Apt-NPs-PTX. Therefore, the AS1411 modified NTPN delivery system might be a promising targeted drug delivery system. PMID:23679916

Wu, Jinhui; Song, Chenchen; Jiang, Chenxiao; Shen, Xin; Qiao, Qian; Hu, Yiqiao

2013-10-01

186

Realizing the Clinical Potential of Cancer Nanotechnology by Minimizing Toxicological and Targeted Delivery Concerns  

PubMed Central

Nanotechnology has the potential to make smart drugs that would be capable of targeting cancer but not normal cells and loading combinations of cooperating agents into a single nano-sized particle to more effectively treat this disease. However, to realize the full potential of this technology the negative aspects associated with these nanoparticles needs to be overcome. This review discusses concerns in the field limiting realization of the full clinical potential of this technology, which are toxicity and targeted delivery. Strategies to overcome these hurdles are also reviewed which could lead to attainment of the full clinical potential of this exciting technology. PMID:23139207

Singh, Sanjay; Sharma, Arati; Robertson, Gavin P.

2013-01-01

187

Furin Targeted Drug Delivery for Treatment of Rhabdomyosarcoma in a Mouse Model  

PubMed Central

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Improvement of treatment efficacy and decreased side effects through tumor-targeted drug delivery would be desirable. By panning with a phage-displayed cyclic random peptide library we selected a peptide with strong affinity for RMS in vitro and in vivo. The peptide minimal binding motif Arg-X-(Arg/Lys)(Arg/Lys) identified by alanine-scan, suggested the target receptor to be a proprotein convertase (PC). Expression profiling of all PCs in RMS biopsies and cell lines revealed consistent high expression levels for the membrane-bound furin and PC7. Direct binding of RMS-P3 peptide to furin was demonstrated by affinity chromatography and supported by activity and colocalization studies. Treatment of RMS in mice with doxorubicin coupled to the targeting peptide resulted in a two-fold increase in therapeutic efficacy compared to doxorubicin treatment alone. Our findings indicate surface-furin binding as novel mechanism for therapeutic cell penetration which needs to be further investigated. Furthermore, this work demonstrates that specific targeting of membrane-bound furin in tumors is possible for and suggests that RMS and other tumors might benefit from proprotein convertases targeted drug delivery. PMID:20454619

Hajdin, Katarina; D'Alessandro, Valentina; Niggli, Felix K.; Schafer, Beat W.; Bernasconi, Michele

2010-01-01

188

Dual drug encapsulated thermo-sensitive fibrinogen-graft-poly (N-isopropyl acrylamide) nanogels for breast cancer therapy.  

PubMed

5-FU/Megestrol acetate loaded fibrinogen-graft-PNIPAAm Nanogels (5-FU/Meg-fib-graft-PNIPAAm NGs) were prepared for thermo responsive drug delivery toward ?5?1-integrins expressing breast cancer cells in vitro (MCF-7 cells). The 60-100 nm sized fib-graft-PNIPAAm nanogels (LCST=35 °C) were prepared by CaCl2 cross-linker. 5-FU/Meg-fib-graft-PNIPAAm NGs showed particle size of 165-195 nm size. The drug loading efficiency with 5-FU was 60% and 70% for Meg. "Drug release was greater above the lower critical solution temperature (LCST). Above LCST, drug release system triggers apopotosis and enhance toxicity to MCF-7 cells when compared to the equivalent dose of the free drug. This effect was due to the greater uptake of the drug by MCF-7 cells". 5-FU/Meg-fib-graft-PNIPAAm NGs is portrayed here as a new combinatorial thermo-responsive drug delivery agent for breast cancer therapy. PMID:24189196

Rejinold, N Sanoj; Baby, Thejus; Chennazhi, K P; Jayakumar, R

2014-02-01

189

Enhanced Affinity Bifunctional Bisphosphonates for Targeted Delivery of Therapeutic Agents to Bone  

PubMed Central

Skeletal diseases have a major impact on the worldwide population and economy. Although several therapeutic agents and treatments are available for addressing bone diseases, they are not being fully utilized because of their uptake in non-targeted sites and related side effects. Active targeting with controlled delivery is an ideal approach for treatment of such diseases. Because bisphosphonates are known to have high affinity to bone and are being widely used in treatment of osteoporosis, they are well-suited for drug targeting to bone. In this study, a targeted delivery of therapeutic agent to resorption sites and wound healing sites of bone was explored. Towards this goal, bifunctional hydrazine-bisphosphonates (HBPs), with spacers of various lengths, were synthesized and studied for their enhanced affinity to bone. Crystal growth inhibition studies showed that these HBPs have high affinity to hydroxyapatite, and HBPs with shorter spacers bind stronger than alendronate to hydroxyapatite. The HBPs did not affect proliferation of MC3T3-E1 pre-osteoblasts, did not induce apoptosis, and were not cytotoxic at the concentration range tested (10?6 - 10?4 M). Furthermore, drugs can be linked to the HBPs through a hydrazone linkage that is cleavable at the low pH of bone resorption and wound healing sites, leading to release of the drug. This was demonstrated using hydroxyapatite as a model material of bone and 4-nitrobenzaldehyde as a model drug. This study suggests that these HBPs could be used for targeted delivery of therapeutic agents to bone. PMID:22073906

Yewle, Jivan N.; Puleo, David A.; Bachas, Leonidas G.

2011-01-01

190

Extracellularly activated nanocarriers: A new paradigm of tumor targeted drug delivery  

PubMed Central

One of the main goals of nanomedicine is to develop a nanocarrier that can selectively deliver anti-cancer drugs to the targeted tumors. Extensive efforts have resulted in several tumor-targeted nanocarriers, some of which are approved for clinical use. Most nanocarriers achieve tumor-selective accumulation through the enhanced permeability and retention effect. Targeting molecules such as antibodies, peptides, ligands, or nucleic acids attached to the nanocarriers further enhance their recognition and internalization by the target tissues. While both the stealth and targeting features are important for effective and selective drug delivery to the tumors, achieving both features simultaneously is often found to be difficult. Some of the recent targeting strategies have the potential to overcome this challenge. These strategies utilize the unique extracellular environment of tumors to change the long-circulating nanocarriers to release the drug or interact with cells in a tumor-specific manner. This review discusses the new targeting strategies with recent examples, which utilize the environmental stimuli to activate the nanocarriers. Traditional strategies for tumor-targeted nanocarriers are briefly discussed with an emphasis on their achievements and challenges. PMID:19366234

Gullotti, Emily; Yeo, Yoon

2009-01-01

191

Targeted Delivery of Vancomycin to Staphylococcus epidermidis Biofilms Using a Fibrinogen-Derived Peptide  

PubMed Central

This study reports on the use of a fibrinogen-derived peptide for the specific targeting and delivery of vancomycin to Staphylococcus epidermidis biofilms. One method by which S. epidermidis initially adheres to biomaterials uses the plasma protein fibrinogen as an intermediary, where the S. epidermidis surface protein SdrG binds to a short amino acid sequence near the amino terminus of the B? chain of fibrinogen. We mimicked this binding interaction and demonstrated the use of a synthetic fibrinogen-based ?6-20 peptide to target and deliver vancomycin to S. epidermidis in vitro. The ?6-20 peptide was synthesized and labeled with a nanogold probe, and its targeting capabilities were examined through the use of scanning electron microscopy. The Nanogold component was then replaced by vancomycin, utilizing a flexible, variable length poly(ethylene glycol) linker between the peptide and antibiotic to create the targeted vancomycin products, ?6-20-PEGx-VAN. Initial binding to surface adherent S. epidermidis was increased in a concentration-dependent manner relative to vancomycin for all equivalent concentrations ?4 ?g/ml, with targeted vancomcyin content up to 22.9 times that of vancomycin alone. Retention of the targeted antibiotics was measured after an additional 24 hour incubation period, revealing levels 1.3 times that of vancomycin. The results demonstrate the improved targeting and retention of vancomycin within a biofilm due to the incorporation of a specific targeting motif. PMID:22623343

Hofmann, Christopher M.; Anderson, James M.; Marchant, Roger E.

2012-01-01

192

Carrier-free, functionalized pure drug nanorods as a novel cancer-targeted drug delivery platform  

NASA Astrophysics Data System (ADS)

A one-dimensional drug delivery system (1D DDS) is highly attractive since it has distinct advantages such as enhanced drug efficiency and better pharmacokinetics. However, drugs in 1D DDSs are all encapsulated in inert carriers, and problems such as low drug loading content and possible undesirable side effects caused by the carriers remain a serious challenge. In this paper, a novel, carrier-free, pure drug nanorod-based, tumor-targeted 1D DDS has been developed. Drugs are first prepared as nanorods and then surface functionalized to achieve excellent water dispersity and stability. The resulting drug nanorods show enhanced internalization rates mainly through energy-dependent endocytosis, with the shape-mediated nanorod (NR) diffusion process as a secondary pathway. The multiple endocytotic mechanisms lead to significantly improved drug efficiency of functionalized NRs with nearly ten times higher cytotoxicity than those of free molecules and unfunctionalized NRs. A targeted drug delivery system can be readily achieved through surface functionalization with targeting group linked amphipathic surfactant, which exhibits significantly enhanced drug efficacy and discriminates between cell lines with high selectivity. These results clearly show that this tumor-targeting DDS demonstrates high potential toward specific cancer cell lines.

Li, Yanan; Yang, Yinlong; An, Feifei; Liu, Zhuang; Zhang, Xiujuan; Zhang, Xiaohong

2013-01-01

193

Molecularly Self-Assembled Nucleic Acid Nanoparticles for Targeted In Vivo siRNA Delivery  

PubMed Central

Nanoparticles are employed for delivering therapeutics into cells1,2. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell specific internalization, excretion, toxicity, and efficacy3-7. A variety of materials have been explored for delivering small interfering RNAs (siRNAs) - a therapeutic agent that suppresses the expression of targeted genes8,9. However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, lack of tissue specificity and potential toxicity10-12. Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer targeting ligands (such as peptides and folate) on the nanoparticle surface can be precisely controlled. We show that at least three folate molecules per nanoparticle is required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t1/2 ? 24.2 min) than the parent siRNA (t1/2 ? 6 min). PMID:22659608

Lee, Hyukjin; Lytton-Jean, Abigail K. R.; Chen, Yi; Love, Kevin T.; Park, Angela I.; Karagiannis, Emmanouil D.; Sehgal, Alfica; Querbes, William; Zurenko, Christopher S.; Jayaraman, Muthusamy; Peng, Chang G.; Charisse, Klaus; Borodovsky, Anna; Manoharan, Muthiah; Donahoe, Jessica S.; Truelove, Jessica; Nahrendorf, Matthias; Langer, Robert; Anderson, Daniel G.

2013-01-01

194

Non-Condensing Polymeric Nanoparticles for Targeted Gene and siRNA Delivery  

PubMed Central

Gene therapy has shown a tremendous potential to benefit patients in a variety of disease conditions. However, finding a safe and effective systemic delivery system is the major obstacle in this area. Although viral vectors showed promise for high transfection rate, the immunogenicity associated with these systems has hindered further development. As an alternative to viral gene delivery, this review focuses on application of novel safe and effective non-condensing polymeric systems that have shown high transgene expression when administered systemically or by the oral route. Type B gelatin-based engineered nanocarriers were evaluated for passive and active tumor-targeted delivery and transfection using both reporter and therapeutic plasmid DNA. Additionally, we have shown that nanoparticles-in-microsphere oral system (NiMOS) can efficiently deliver reporter and therapeutic gene constructs in the gastrointestinal tract. Additionally, there has been a significant recent interest in the use small interfering RNA (siRNA) as a therapeutic system for gene silencing. Both gelatin nanoparticles and NiMOS have shown activity in systemic and oral delivery of siRNA, respectively. PMID:21621597

Xu, Jing; Ganesh, Shanthi; Amiji, Mansoor

2011-01-01

195

Safety Assessment of Liver-Targeted Hydrodynamic Gene Delivery in Dogs  

PubMed Central

Evidence in support of safety of a gene delivery procedure is essential toward gene therapy. Previous studies using the hydrodynamics-based procedure primarily focus on gene delivery efficiency or gene function analysis in mice. The current study focuses on an assessment of the safety of computer-controlled and liver-targeted hydrodynamic gene delivery in dogs as the first step toward hydrodynamic gene therapy in clinic. We demonstrate that the impacts of the hydrodynamic procedure were limited in the injected region and the influences were transient. Histological examination and the hepatic microcirculation measurement using reflectance spectrophotometry reveal that the liver-specific impact of the procedure involves a transient expansion of the liver sinusoids. No systemic damage or toxicity was observed. Physiological parameters, including electrocardiogram, heart rate, blood pressure, oxygen saturation, and body temperature, remained in normal ranges during and after hydrodynamic injection. Body weight was also examined to assess the long-term effects of the procedure in animals who underwent 3 hydrodynamic injections in 6 weeks with 2-week time interval in between. Serum biochemistry analysis showed a transient increase in liver enzymes and a few cytokines upon injection. These results demonstrate that image-guided, liver-specific hydrodynamic gene delivery is safe. PMID:25251246

Kamimura, Kenya; Kanefuji, Tsutomu; Yokoo, Takeshi; Abe, Hiroyuki; Suda, Takeshi; Kobayashi, Yuji; Zhang, Guisheng; Aoyagi, Yutaka; Liu, Dexi

2014-01-01

196

Cargo-towing fuel-free magnetic nanoswimmers for targeted drug delivery.  

PubMed

Fuel-free nanomotors are essential for future in-vivo biomedical transport and drug-delivery applications. Herein, the first example of directed delivery of drug-loaded magnetic polymeric particles using magnetically driven flexible nanoswimmers is described. It is demonstrated that flexible magnetic nickel-silver nanoswimmers (5-6 ?m in length and 200 nm in diameter) are able to transport micrometer particles at high speeds of more than 10 ?m s(-1) (more than 0.2 body lengths per revolution in dimensionless speed). The fundamental mechanism of the cargo-towing ability of these magnetic (fuel-free) nanowire motors is modelled, and the hydrodynamic features of these cargo-loaded motors discussed. The effect of the cargo size on swimming performance is evaluated experimentally and compared to a theoretical model, emphasizing the interplay between hydrodynamic drag forces and boundary actuation. The latter leads to an unusual increase of the propulsion speed at an intermediate particle size. Potential applications of these cargo-towing nanoswimmers are demonstrated by using the directed delivery of drug-loaded microparticles to HeLa cancer cells in biological media. Transport of the drug carriers through a microchannel from the pick-up zone to the release microwell is further illustrated. It is expected that magnetically driven nanoswimmers will provide a new approach for the rapid delivery of target-specific drug carriers to predetermined destinations. PMID:22174121

Gao, Wei; Kagan, Daniel; Pak, On Shun; Clawson, Corbin; Campuzano, Susana; Chuluun-Erdene, Erdembileg; Shipton, Erik; Fullerton, Eric E; Zhang, Liangfang; Lauga, Eric; Wang, Joseph

2012-02-01

197

Biodegradable poly(amine-co-ester) terpolymers for targeted gene delivery  

PubMed Central

Many synthetic polycationic vectors for non-viral gene delivery show high efficiency in vitro, but their usually excessive charge density makes them toxic for in vivo applications. Here we describe the synthesis of a series of high molecular weight terpolymers with low charge density, and show that they exhibit efficient gene delivery, some surpassing the efficiency of the commercial transfection reagents Polyethylenimine and Lipofectamine 2000. The terpolymers were synthesized via enzyme-catalyzed copolymerization of lactone with dialkyl diester and amino diol, and their hydrophobicity adjusted by varying the lactone content and by selecting a lactone comonomer of specific ring size. Targeted delivery of the pro-apoptotic TRAIL gene to tumour xenografts by one of the terpolymers results in significant inhibition of tumour growth, with minimal toxicity both in vitro and in vivo. Our findings suggest that the gene delivery ability of the terpolymers stems from their high molecular weight and increased hydrophobicity, which compensates for their low charge density. PMID:22138789

Zhou, Jiangbing; Liu, Jie; Cheng, Christopher J.; Patel, Toral R.; Weller, Caroline E.; Piepmeier, Joseph M.; Jiang, Zhaozhong; Saltzman, W. Mark

2014-01-01

198

Ultrasound-enhanced delivery of targeted echogenic liposomes in a novel ex vivo mouse aorta model  

PubMed Central

The goal of this study was to determine whether targeted, Rhodamine-labeled echogenic liposomes (Rh-ELIP) containing nanobubbles could be delivered to the arterial wall, and whether 1 MHz continuous wave ultrasound would enhance this delivery profile. Aortae excised from apolipoprotein-E-deficient (n = 8) and wild-type (n = 8) mice were mounted in a pulsatile flow system through which Rh-ELIP were delivered in a stream of bovine serum albumin. Half the aortae from each group were treated with 1-MHz continuous wave ultrasound at 0.49 MPa peak-to-peak pressure, and half underwent sham exposure. Ultrasound parameters were chosen to promote stable cavitation and avoid inertial cavitation. A broadband hydrophone was used to monitor cavitation activity. After treatment, aortic sections were prepared for histology and analyzed by an individual blinded to treatment conditions. Delivery of Rh-ELIP to the vascular endothelium was observed, and subendothelial penetration of Rh-ELIP was present in five of five ultrasound-treated aortae and was absent in those not exposed to ultrasound. However, the degree of penetration in the ultrasound-exposed aortae was variable. There was no evidence of ultrasound-mediated tissue damage in any specimen. Ultrasound-enhanced delivery within the arterial wall was demonstrated in this novel model, which allows quantitative evaluation of therapeutic delivery. PMID:20202474

Hitchcock, Kathryn E.; Caudell, Danielle N.; Sutton, Jonathan T.; Klegerman, Melvin E.; Vela, Deborah; Pyne-Geithman, Gail J.; Abruzzo, Todd; Cyr, Peppar E. P.; Geng, Yong-Jian; McPherson, David D.; Holland, Christy K.

2010-01-01

199

Targeted delivery of siRNA to cell death proteins in sepsis  

PubMed Central

Immune suppression is a major cause of morbidity and mortality in the septic patient. Apoptotic loss of immune effector cells such as CD4 T and B cells is a key component in the loss immune competence in sepsis. Inhibition of lymphocyte apoptosis has led to improved survival in animal models of sepsis. Using qRT-PCR of isolated splenic CD4 T and B cells, we determined that Bim and PUMA, two key cell death proteins, are markedly up-regulated during sepsis. Lymphocytes have been notoriously difficult to transfect with siRNA. Consequently a novel, cyclodextrin polymer-based, transferrin receptor-targeted, delivery vehicle was employed to co-administer siRNA to Bim and PUMA to mice immediately after cecal ligation and puncture. Anti-apoptotic siRNA based therapy markedly decreased lymphocyte apoptosis and prevented the loss of splenic CD4 T and B cells. Flow cytometry confirmed in vivo delivery of siRNA to CD4 T and B cells and also demonstrated decreases in intracellular Bim and PUMA protein. In conclusion, Bim and PUMA are two critical mediators of immune cell death in sepsis. Use of a novel cyclodextrin polymer-based, transferrin receptor-targeted siRNA delivery vehicle enables effective administration of anti-apoptotic siRNAs to lymphocytes and reverses the immune cell depletion that is a hallmark of this highly lethal disorder. PMID:19033888

Brahmamdam, Pavan; Watanabe, Eizo; Unsinger, Jacqueline; Chang, Katherine C.; Schierding, William; Hoekzema, Andrew S.; Zhou, Tony T.; McDonough, Jacquelyn S.; Holemon, Heather; Heidel, Jeremy D.; Coopersmith, Craig M.; McDunn, Jonathan E.; Hotchkiss, Richard S.

2010-01-01

200

A novel liposomal formulation of FTY720 (Fingolimod) for promising enhanced targeted delivery  

PubMed Central

We describe here the development and characterization of the physicochemical and pharmacokinetic properties of a novel liposomal formulation for FTY720 delivery, LP-FTY720. The mean diameter of LP-FTY720 was ~157 nm, and the FTY720 entrapment efficiency was ~85%. The liposomal formulation protected FTY720 from degradation in aqueous buffer and showed toxicity in CLL patient B cells comparable to that of free FTY720. Following intravenous injection in ICR mice, LP-FTY720 had an increased elimination phase half-life (~28 vs. ~19 hr) and decreased clearance (235 vs. 778 mL/h/kg) compared to the free drug. Antibodies against CD19, CD20 and CD37 were incorporated into LP-FTY720, which provided targeted delivery to CLL patient B cells and thus achieved higher killing efficacy. The novel liposomal carrier of FTY720 demonstrated improved pharmacokinetic properties, comparable activity, and a potential platform for targeted delivery to CLL by overcoming the limited application of free FTY720 to B malignancy treatment. PMID:23969101

Mao, Yicheng; Wang, Jiang; Zhao, Yuan; Wu, Yun; Kwak, Kwang Joo; Chen, Ching-Shih; Byrd, John C.; Lee, Robert J.; Phelps, Mitch A.; Lee, L. James; Muthusamy, Natarajan

2014-01-01

201

Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells.  

PubMed

In this paper, a targeted drug delivery system has been developed based on hyaluronic acid (HA) modified mesoporous silica nanoparticles (MSNs). HA-MSNs possess a specific affinity to CD44 over-expressed on the surface of a specific cancer cell line, HCT-116 (human colon cancer cells). The cellular uptake performance of fluorescently labelled MSNs with and without HA modification has been evaluated by confocal microscopy and fluorescence-activated cell sorter (FACS) analysis. Compared to bare MSNs, HA-MSNs exhibit a higher cellular uptake via HA receptor mediated endocytosis. An anticancer drug, doxorubicin hydrochloride (Dox), has been loaded into MSNs and HA-MSNs as drug delivery vehicles. Dox loaded HA-MSNs show greater cytotoxicity to HCT-116 cells than free Dox and Dox-MSNs due to the enhanced cell internalization behavior of HA-MSNs. It is expected that HA-MSNs have a great potential in targeted delivery of anticancer drugs to CD44 over-expressing tumors. PMID:23076766

Yu, Meihua; Jambhrunkar, Siddharth; Thorn, Peter; Chen, Jiezhong; Gu, Wenyi; Yu, Chengzhong

2013-01-01

202

Focusing of photomechanical waves with an optical lens for depth-targeted molecular delivery  

NASA Astrophysics Data System (ADS)

We have been developing molecular delivery systems based on photomechanical waves (PMWs), which are generated by the irradiation of a laser absorbing material with nanosecond laser pulses. This method enables highly site-specific delivery in the horizontal plane of the tissue. However, targeting in the vertical direction is a remaining challenge. In this study, we developed a novel PMW focusing device for deeper tissue targeting. A commercial optical concave lens and black natural rubber sheet (laser absorber) were attached to the top and bottom end of a cylindrical spacer, respectively, which was filled with water. A laser pulse was transmitted through the lens and water and hit the rubber sheet to induce a plasma, generating a PMW. The PMW was propagated both downward and upward. The downward wave (1st wave) was diffused, while the upward (2nd wave) wave was reflected with the concave surface of the lens and focused at a depth determined by the geometrical parameters. To attenuate the 1st wave, a small-diameter silicon sponge rubber disk was adhered just under the rubber sheet concentrically with the laser axis. With the lens of f = -40 mm, the 2nd wave was focused to a diameter of 5.7 mm at a targeted depth of 20 mm, which was well agreed with the result of calculation by ray tracing. At a laser fluence of 5.1 J/cm2, peak pressure of the PMW reached ~40 MPa at the depth of 20 mm. Under this condition, we examined depth-targeted gene delivery to the rat skin.

Shimada, Takuichirou; Sato, Shunichi; Kawauchi, Satoko; Ashida, Hiroshi; Terakawa, Mitsuhiro

2014-02-01

203

Targeted drug delivery by novel polymer-drug conjugates containing linkers cleavable by disease-associated enzymes  

E-print Network

We have conceptualized a new class of polymer-linker-drug conjugates to achieve targeted drug delivery for the systemic treatment of cancer and other inflammatory diseases. The physiochemical properties of the polymer allow ...

Chau, Ying

2005-01-01

204

Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging  

PubMed Central

Magnetic nanoparticles (MNPs) represent a class of non-invasive imaging agents that have been developed for magnetic resonance (MR) imaging. These MNPs have traditionally been used for disease imaging via passive targeting, but recent advances have opened the door to cellular-specific targeting, drug delivery, and multi-modal imaging by these nanoparticles. As more elaborate MNPs are envisioned, adherence to proper design criteria (e.g. size, coating, molecular functionalization) becomes even more essential. This review summarizes the design parameters that affect MNP performance in vivo, including the physicochemical properties and nanoparticle surface modifications, such as MNP coating and targeting ligand functionalizations that can enhance MNP management of biological barriers. A careful review of the chemistries used to modify the surfaces of MNPs is also given, with attention paid to optimizing the activity of bound ligands while maintaining favorable physicochemical properties. PMID:19909778

Veiseh, Omid; Gunn, Jonathan; Zhang, Miqin

2009-01-01

205

Automated modular synthesis of aptamer-drug conjugates for targeted drug delivery.  

PubMed

Aptamer-drug conjugates (ApDCs) are promising targeted drug delivery systems for reducing toxicity while increasing the efficacy of chemotherapy. However, current ApDC technologies suffer from problems caused by the complicated preparation and low controllability of drug-aptamer conjugation. To solve such problems, we have designed and synthesized a therapeutic module for solid phase synthesis, which is a phosphoramdite containing an anticancer drug moiety and a photocleavable linker. Using this module, we have realized automated and modular synthesis of ApDCs, and multiple drugs were efficiently incorporated into ApDCs at predesigned positions. The ApDCs not only recognize target cancer cells specifically, but also release drugs in a photocontrollable manner. We demonstrated the potential of automated and modular ApDC technology for applications in targeted cancer therapy. PMID:24483627

Wang, RuoWen; Zhu, Guizhi; Mei, Lei; Xie, Yan; Ma, Haibin; Ye, Mao; Qing, Feng-Ling; Tan, Weihong

2014-02-19

206

Targeted amplification of delivery to cell surface receptors by dendrimer self-assembly.  

PubMed

Nanometer-scale architectures assembled on cell surface receptors from smaller macromolecular constituents generated a large amplification of fluorescence. A targeted dendrimer was synthesized from a cystamine-core G4 PAMAM dendrimer, and contained an anti-BrE3 monoclonal antibody as the targeting group, several fluorophores and an average of 12 aldehyde moieties as complementary bio-orthogonal reactive sites for the covalent assembly. A cargo dendrimer, derived from a PAMAM G4 dendrimer, contained several fluorophores as the cargo for delivery and five hydrazine moieties as complimentary bio-orthogonal reactive sites. The system is designed to be flexible and allow for facile incorporation of a variety of targeting ligands. PMID:24513050

Isaacman, Steven; Buckley, Michael; Wang, Xiaojian; Wang, Edwin Y; Liebes, Leonard; Canary, James W

2014-03-01

207

Reversible vagal blockade in conscious rats using a targeted delivery device.  

PubMed

Reversible methods of nerve blockade greatly aid neurophysiological and behavioral studies. We have developed an implantable device for the local delivery of anesthetics to the area surrounding the vagal nerve in rats. The device consists of a thick silicone tube for insulating the nerves from the surrounding tissue, and a thin silicone tube for the infusion of anesthetics into the insulating tube. The in vivo performance of the device was tested electrophysiologically, and cardiovascular responses to vagal stimulation were measured in conscious animals. Nerve conductivity was completely blocked by injection of a small amount (<20 microl) of 1% lidocaine, with conductivity subsequently recovering gradually after 10-40 min. Electrical stimulation of the right vagus nerve in conscious rats increased arterial pressure while decreasing heart rate. The local blockade of afferent fibers abolished the arterial pressure response but preserved the bradycardic response to vagal nerve stimulation. The targeted delivery device was useful for reversible vagal blockade in conscious rats. PMID:16564094

Zheng, Can; Kawada, Toru; Li, Meihua; Sato, Takayuki; Sunagawa, Kenji; Sugimachi, Masaru

2006-09-30

208

A peptide-mediated targeting gene delivery system for malignant glioma cells  

PubMed Central

Glioblastoma multiforme (GBM) is the most common and malignant glioma. Although there has been considerable progress in treatment strategies, the prognosis of many patients with GBM remains poor. In this work, polyethylenimine (PEI) and the VTWTPQAWFQWV (VTW) peptide were modified and synthesized into GBM-targeting nanoparticles. The transfection efficiency of U-87 (human glioblastoma) cells was evaluated using fluorescence microscopy and flow cytometry. Cell internalization was investigated to verify the nanoparticle delivery into the cytoplasm. Results showed that the methods of polymer conjugation and the amount of VTW peptide were important factors to polymer synthesis and transfection. The PEI-VTW20 nanoparticles increased the transfection efficiency significantly. This report describes the use of VTW peptide-based PEI nanoparticles for intracellular gene delivery in a GBM cell-specific manner. PMID:24101872

Wang, Chuanwei; Ning, Liping; Wang, Hongwei; Lu, Zaijun; Li, Xingang; Fan, Xiaoyong; Wang, Xuping; Liu, Yuguang

2013-01-01

209

Gene Delivery System Targets Tumor Blood Vessels in Dogs with Cancer  

Cancer.gov

In a preliminary study of pet dogs with naturally occurring cancer, researchers have developed a way to target delivery of a gene to tumor blood vessels, where the gene product damages the vessels, disrupting blood flow to the tumors but not to the surrounding tissue. The delivery method was well tolerated, and in some dogs, the size of tumors decreased or remained stable. This study provides valuable information that may aid in the design of future clinical trials. These are the first results of the Comparative Oncology Trials Consortium, a novel multicenter network sponsored by NCI to integrate cancers that naturally develop in dogs into the developmental path of new therapies for cancers in humans.

210

Multifunctional disulfide-based cationic dextran conjugates for intravenous gene delivery targeting ovarian cancer cells.  

PubMed

A folate-decorated, disulfide-based cationic dextran conjugate having dextran as the main chain and disulfide-linked 1,4-bis(3-aminopropyl)piperazine (BAP) residues as the grafts was designed and successfully prepared as a multifunctional gene delivery vector for targeted gene delivery to ovarian cancer SKOV-3 cells in vitro and in vivo. Initially, a new bioreducible cationic polyamide (denoted as pSSBAP) was prepared by polycondensation reaction of bis(p-nitrophenyl)-3,3'-dithiodipropanoate, a disulfide-containing monomer, and BAP. It was found that the pSSBAP was highly efficient for in vitro gene delivery against MCF-7 and SKOV-3 cell lines. Subsequently, two cationic dextran conjugates with different amounts of BAP residues (denoted as Dex-SSBAP6 and Dex-SSBAP30, respectively) were synthesized by coupling BAP to disulfide-linked carboxylated dextran or coupling pSSBAP-oligomer to p-nitrophenyl carbonated dextran. Both two conjugates were able to bind DNA to form nanosized polyplexes with an improved colloidal stability in physiological conditions. The polyplexes, however, were rapidly dissociated to liberate DNA in a reducing environment. In vitro transfection experiments revealed that the polyplexes of Dex-SSBAP30 efficiently transfected SKOV-3 cells, yielding transfection efficiency that is comparable to that of linear polyethylenimine or lipofectamine 2000. AlamarBlue assay showed that the conjugates had low cytotoxicity in vitro at a high concentration of 100 mg/L. Further, Dex-SSBAP30 has primary amine side groups and thus allows for folate (FA) conjugation, yielding FA-coupled Dex-SSBAP30 (Dex-SSBAP30-FA). It was found that Dex-SSBAP30-FA was efficient for targeted gene delivery to SKOV-3 tumor xenografted in a nude mouse model by intravenous injection, inducing a higher level of gene expression in the tumor as compared to Dex-SSBAP30 lacking FA and comparable gene expression to linear polyethylenimine as one of the most efficient polymeric vectors for intravenous gene delivery in vivo. Disulfide-based cationic dextran system thus has a high potential for intravenous gene delivery toward cancer gene therapy. PMID:24892216

Song, Yanyan; Lou, Bo; Zhao, Peng; Lin, Chao

2014-07-01

211

Targeted liposomal drug delivery systems for the treatment of B cell malignancies.  

PubMed

Nanoparticulate systems have demonstrated significant potential for overcoming the limitations of non-specific adverse effects related to chemotherapy. The treatment of blood malignancies employing targeted particulate drug delivery systems presents unique challenges and considerable research has been focused towards the development of targeted liposomal formulations for B cell malignancies. These formulations are aimed at achieving selectivity towards the malignant cells by targeting several cell surface markers which are over-expressed in that specific malignancy. CD19, CD20, CD22 and CD74 are few of such markers of which CD19, CD22 and CD74 are internalizing and CD20 is non-internalizing. Systems which have been developed to target both types of these cell surface markers are discussed. Specifically, the efficacy and development of targeted liposomes is considered. A number of studies have demonstrated the advantages of targeted liposomal systems encapsulating doxorubicin or vincristine. However, liposomal encapsulation of newer anti-neoplastic agents such as AD 198 which are superior to doxorubicin should be considered. PMID:24433007

Mittal, Nivesh K; Bhattacharjee, Himanshu; Mandal, Bivash; Balabathula, Pavan; Thoma, Laura A; Wood, George C

2014-06-01

212

Dendrimer-based targeted delivery of an apoptotic sensor in cancer cells.  

PubMed

Our previous studies have demonstrated the applicability of poly(amidoamine) (PAMAM) dendrimers as a platform for the targeted delivery of chemotherapeutic drugs both in vitro and in vivo. To monitor the rate and extent of cell-killing caused by the delivered chemotherapeutic drug, we wished to analyze the degree of apoptosis in targeted cells on a real-time basis. As the apoptosis-regulating caspases are activated during the apoptotic process, several caspase-hydrolyzable, fluorescence resonance energy transfer (FRET)-based substrates have been marketed for the detection of apoptosis. However, the applicability of these agents is limited because of their nonspecificity and the consequent high background fluorescence in tissues. Here we show the synthesis, characterization, and in vitro targeting of an engineered PAMAM nanodevice in which folic acid (FA) is conjugated as the targeting molecule and a caspase-specific FRET-based agent (PhiPhiLux G1D2) is conjugated as the apoptosis-detecting agent. This conjugate specifically targets FA-receptor-positive, KB cells. In these cells, the apoptosis-inducing agent staurosporine caused a 5-fold increase in the cellular fluorescence. These results show, for the first time, the potential applicability of a targeted apoptosis-measuring nanodevice, which could be used for simultaneously monitoring the apoptotic potential of a delivered drug. PMID:17206782

Myc, Andrzej; Majoros, István J; Thomas, Thommey P; Baker, James R

2007-01-01

213

Ultralow protein adsorbing coatings from clickable PEG nanogel solutions: Benefits of attachment under salt-induced phase separation conditions and comparison with PEG/albumin nanogel coatings  

PubMed Central

Clickable nanogel solutions were synthesized by using the copper catalyzed azide/alkyne cycloaddition (CuAAC) to partially polymerize solutions of azide and alkyne functionalized poly(ethylene glycol) (PEG) monomers. Coatings were fabricated using a second click reaction: a UV thiol-yne attachment of the nanogel solutions to mercaptosilanated glass. Because the CuAAC reaction was effectively halted by the addition of a copper-chelator, we were able to prevent bulk gelation and limit the coating thickness to a single monolayer of nanogels in the absence of the solution reaction. This enabled the inclusion of kosmotropic salts, which caused the PEG to phase-separate and nearly double the nanogel packing density, as confirmed by Quartz Crystal Microbalance with Dissipation (QCM-D). Protein adsorption was analyzed by single molecule counting with total internal reflection fluorescence (TIRF) microscopy and cell adhesion assays. Coatings formed from the phase-separated clickable nanogel solutions attached with salt adsorbed significantly less fibrinogen than other 100% PEG coatings tested, as well as poly-L-lysine-g-PEG (PLL-g-PEG) coatings. However, PEG/albumin nanogel coatings still outperformed the best 100% PEG clickable nanogel coatings. Additional surface crosslinking of the clickable nanogel coating in the presence of copper further reduced levels of fibrinogen adsorption closer to those of PEG/albumin nanogel coatings. However, this step negatively impacted long-term resistance to cell adhesion and dramatically altered the morphology of the coating by atomic force microscopy (AFM). The main benefit of the click strategy is that the partially polymerized solutions are stable almost indefinitely, allowing attachment in the phase-separated state without danger of bulk gelation, and thus, producing the best performing 100% PEG coating that we have studied to date. PMID:23441808

Donahoe, Casey D.; Cohen, Thomas L.; Li, Wenlu; Nguyen, Peter K.; Fortner, John D.; Mitra, Robi D.; Elbert, Donald L.

2013-01-01

214

Haptic guided virtual reality simulation for targeted drug delivery using nano-containers manipulation.  

PubMed

When dealing with nano targeted drug delivery process the significant area of virtual reality application can be visualizing real time process and simulating it at nano-scale, since the effectiveness of a drug primarily depends on the affected cell and targeted doze. This paper proposes virtual reality (VR) as a tool to analyze and simulate nanoparticles (NPs) manipulation, in this paper amorphous NPs are analyzed and simulated in virtual environment. Haptic guides virtualizing the atomic force microscope (AFM) is applied in the virtual environment which allows the operators to sense and touch the NPs when evaluating its structure, drug release time, and behavioral study. Cisplatin was loaded as a modal drug to the self-assembled amorphous copolymer P(3HV-co-4HB)-b-mPEG NPs, where the efficiency and bioavailability of Cisplatin was further investigated. The prepared NPs when simulated in virtual environment proved to show good biocompatibility. Results showed that amorphous polymeric NPs could be efficient vehicles for the constant and targeted delivery of toxic anticancer drugs. PMID:23909133

Hassan, Syed; Shah, Mohsin; Yoon, Sung Chul; Ullah, Ikram; Kim, Myeong Ok; Yoon, Jungwon

2013-07-01

215

Functionalized single-walled carbon nanotubes as rationally designed vehicles for tumor-targeted drug delivery.  

PubMed

A novel single-walled carbon nanotube (SWNT)-based tumor-targeted drug delivery system (DDS) has been developed, which consists of a functionalized SWNT linked to tumor-targeting modules as well as prodrug modules. There are three key features of this nanoscale DDS: (a) use of functionalized SWNTs as a biocompatible platform for the delivery of therapeutic drugs or diagnostics, (b) conjugation of prodrug modules of an anticancer agent (taxoid with a cleavable linker) that is activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release, and (c) attachment of tumor-recognition modules (biotin and a spacer) to the nanotube surface. To prove the efficacy of this DDS, three fluorescent and fluorogenic molecular probes were designed, synthesized, characterized, and subjected to the analysis of the receptor-mediated endocytosis and drug release inside the cancer cells (L1210FR leukemia cell line) by means of confocal fluorescence microscopy. The specificity and cytotoxicity of the conjugate have also been assessed and compared with L1210 and human noncancerous cell lines. Then, it has unambiguously been proven that this tumor-targeting DDS works exactly as designed and shows high potency toward specific cancer cell lines, thereby forming a solid foundation for further development. PMID:19554734

Chen, Jingyi; Chen, Shuyi; Zhao, Xianrui; Kuznetsova, Larisa V; Wong, Stanislaus S; Ojima, Iwao

2008-12-10

216

Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.  

PubMed

To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice. PMID:21423189

Alvarez-Erviti, Lydia; Seow, Yiqi; Yin, Haifang; Betts, Corinne; Lakhal, Samira; Wood, Matthew J A

2011-04-01

217

Octa-functional PLGA nanoparticles for targeted and efficient siRNA delivery to tumors  

PubMed Central

Therapies based on RNA interference, using agents such as siRNA, are limited by the absence of safe, efficient vehicles for targeted delivery in vivo. The barriers to siRNA delivery are well known and can be individually overcome by addition of functional modules, such as conjugation of moieties for cell penetration or targeting. But, so far, it has been impossible to engineer multiple modules into a single unit. Here, we describe the synthesis of degradable nanoparticles that carry eight synergistic functions: 1) polymer matrix for stabilization/controlled release; 2) siRNA for gene knockdown; 3) agent to enhance endosomal escape; 4) agent to enhance siRNA potency; 5) surface-bound PEG for enhancing circulatory time; and surface-bound peptides for 6) cell penetration; 7) endosomal escape; and 8) tumor targeting. Further, we demonstrate that this approach can provide prolonged knockdown of PLK1 and control of tumor growth in vivo. Importantly, all elements in these octa-functional nanoparticles are known to be safe for human use and each function can be individually controlled, giving this approach to synthetic RNA-loaded nanoparticles potential in a variety of clinical applications. PMID:22014944

Zhou, Jiangbing; Patel, Toral R.; Fu, Michael; Bertram, James P.; Saltzman, W. Mark

2014-01-01

218

LFA-1 on Leukemic Cells as a Target for Therapy or Drug Delivery  

PubMed Central

Leukemia therapeutics are aiming for improved efficacy by targeting molecular markers differentially expressed on cancerous cells. Lymphocyte function-associated antigen-1 (LFA-1) expression on various types of leukemia has been well studied. Here, the role and expression of LFA-1 on leukemic cells and the possibility of using this integrin as a target for drug delivery is reviewed. To support this rationale, experimental results were also included where cIBR, a cyclic peptide derived from a binding site of LFA-1, was conjugated to the surface of polymeric nanoparticles and used as a targeting ligand. These studies revealed a correlation of LFA-1 expression level on leukemic cell lines and binding and internalization of cIBR-NPs suggesting a differential binding and internalization of cIBR-NPs to leukemic cells overexpressing LFA-1. Nanoparticles conjugated with a cyclic peptide against an accessible molecular marker of disease hold promise as a selective drug delivery system for leukemia treatment. PMID:20618153

Phongpradist, Rungsinee; Chittasupho, Chuda; Okonogi, Siriporn; Siahaan, Teruna; Anuchapreeda, Songyot; Ampasavate, Chadarat; Berkland, Cory

2014-01-01

219

Drug-loaded nano-microcapsules delivery system mediated by ultrasound-targeted microbubble destruction: A promising therapy method  

PubMed Central

The nano-microcapsules drug delivery system is currently a promising method for the treatment of many types of diseases, particularly tumors. However, the drug delivery efficiency does not reach a satisfactory level to meet treatment demands. Therefore, the effectiveness of delivery needs to be improved. Based on the alterations in the structure and modification of nano-microcapsules, ultrasound-targeted microbubble destruction (UTMD), a safe physical targeted method, may increase tissue penetration and cell membrane permeability, aiding the drug-loaded nano-microcapsules ingress the interior of targeted tissues and cells. The effectiveness and exact mechanism of action of the drug-loaded nano-microcapsules delivery system mediated by UTMD have yet to be fully elucidated. In this study, the latest advancement in UTMD-mediated drug loaded nano-microcapsules system technology was reviewed and the hindrances of UTMD-mediated drug delivery were assessed, in combination with a prospective study. The findings suggested that the drug delivery efficiency of nano-microcapsules mediated by UTMD was distinctly improved. Thus, the UTMD-mediated drug-loaded nano-microcapsules delivery system may significantly improve the efficiency of drug delivery, which may be a promising new therapeutic method. PMID:24648976

MA, JING; DU, LIAN FANG; CHEN, MING; WANG, HANG HUI; XING, LING XI; JING, LI FANG; LI, YUN HUA

2013-01-01

220

Systemic delivery of sticky siRNAs targeting the cell cycle for lung tumor metastasis inhibition.  

PubMed

RNA interference allows the design of new inhibitors that target deregulated pathways in cancer. However systemic delivery of siRNA for the treatment of solid tumors still remains an issue. In our study, in order to suppress the progression of lung cancer metastasis in mice, we developed sticky siRNA (ssiRNA) to inhibit survivin and cyclin B1, two candidates involved in cell survival and proliferation. We exploited the linear polyethylenimine (PEI) as potent non-viral carrier to efficiently deliver our inhibitors. As a proof of concept, we have chosen a very aggressive mammary adenocarcinoma model (TSA-Luc cells), which forms lung metastases upon systemic cell injection. We confirmed in vitro, that the ssiRNAs delivered with PEI are not only able to inhibit our target genes at the mRNA and protein levels, but are also able to block the cell cycle and cell proliferation through a mechanism of RNA interference. More importantly, we showed in vivo by luciferase dosage, bioimaging and tissue section, an inhibition of lung tumor metastases after systemic delivery of cyclin B1 and survivin ssiRNA complexed with PEI. Alternating treatment with cisplatin and ssiRNA/PEI showed an additive effect between the two anticancer drugs on lung tumor inhibition leading to a significant increase in animal survival. Moreover a promising window between activity (IC??) and toxicity (LD??), essential for therapeutic application, was observed. Our data show that systemic delivery of ssiRNA/PEI complexes targeting the cell cycle is a valuable strategy for the treatment of lung tumor metastasis and that it can be combined with chemotherapy. PMID:23727288

Bonnet, Marie-Elise; Gossart, Jean-Baptiste; Benoit, Elodie; Messmer, Mélanie; Zounib, Omar; Moreau, Valérie; Behr, Jean-Paul; Lenne-Samuel, Nathalie; Kedinger, Valérie; Meulle, Aline; Erbacher, Patrick; Bolcato-Bellemin, Anne-Laure

2013-09-10

221

Combinatorial-designed multifunctional polymeric nanosystems for tumor-targeted therapeutic delivery.  

PubMed

By definition, multifunctional nanosystems include several features within a single construct so that these devices can target tumors or other disease tissue, facilitate in vivo imaging, and deliver a therapeutic agent. Investigations of these nanosystems are rapidly progressing and provide new opportunities in the management of cancer. Tumor-targeted nanosystems are currently designed based primarily on the intrinsic physico-chemical properties of off-the-shelf polymers. Following fabrication, the surfaces of these nanoscale structures are functionalized for passive or active targeted delivery to the tumors. In this Account, we describe a novel approach for the construction of multifunctional polymeric nanosystems based on combinatorial design principles. Combinatorial approaches offer several advantages over conventional methods because they allow for the integration of multiple components with varied properties into a nanosystem via self-assembly or chemical conjugation. High-throughput synthesis and screening is required in polymer design because polymer composition directly affects properties including drug loading, retention in circulation, and targeting of the nanosystems. The first approach relies on the self-assembly of macromolecular building blocks with specific functionalities in aqueous media to yield a large variety of nanoparticle systems. These self-assembled nanosystems with diverse functionalities can then be rapidly screened in a high-throughput fashion for selection of ideal formulations, or hits, which are further evaluated for safety and efficacy. In another approach, a library of a large number of polymeric materials is synthesized using different monomers. Each of the formed polymers is screened for the selection of the best candidates for nanoparticle fabrication. The combinatorial design principles allow for the selection of those nanosystems with the most favorable properties based on the type of payload, route of administration, and the desired target for imaging and delivery. PMID:21761902

Abeylath, Sampath C; Ganta, Srinivas; Iyer, Arun K; Amiji, Mansoor

2011-10-18

222

Design of an integrated hardware interface for AOSLO image capture and cone-targeted stimulus delivery  

PubMed Central

We demonstrate an integrated FPGA solution to project highly stabilized, aberration-corrected stimuli directly onto the retina by means of real-time retinal image motion signals in combination with high speed modulation of a scanning laser. By reducing the latency between target location prediction and stimulus delivery, the stimulus location accuracy, in a subject with good fixation, is improved to 0.15 arcminutes from 0.26 arcminutes in our earlier solution. We also demonstrate the new FPGA solution is capable of delivering stabilized large stimulus pattern (up to 256x256 pixels) to the retina. PMID:20721171

Yang, Qiang; Arathorn, David W.; Tiruveedhula, Pavan; Vogel, Curtis R.; Roorda, Austin

2010-01-01

223

Tumor-targeted delivery of liposome-encapsulated doxorubicin by use of a peptide that selectively binds to irradiated tumors  

PubMed Central

Tumor-targeted drug delivery improves anti-tumor efficacy and reduces systemic toxicity by limiting bioavailability of cytotoxic drugs to within tumors. Targeting reagents, such as peptides or antibodies recognizing molecular targets over-expressed within tumors, have been used to improve liposome-encapsulated drug accumulation within tumors and resulted in enhanced tumor growth control. In this report, we expand the scope of targeting reagents by showing that one peptide, HVGGSSV which was isolated from an in vivo screening of phage-displayed peptide library due to its selective binding within irradiated tumors, enabled highly selective tumor-targeted delivery of liposome-encapsulated doxorubicin and resulted in enhanced cytotoxicity within tumors. Targeting liposomes (TL) and non-targeting liposomes (nTL) were labeled with Alexa Fluor 750. Biodistribution of the liposomes within tumor-bearing mice was studied with near infrared (NIR) imaging. In the single dose pharmacokinetic study, the liposomal doxorubicin has an extended circulation half life as compared to the free doxorubicin. Targeting liposomes partitioned to the irradiated tumors and improved drug deposition and retention within tumors. The tumor-targeted delivery of doxorubicin improved tumor growth control as indicated with reduced tumor growth rate and tumor cell proliferation, enhanced tumor blood vessel destruction, and increased treatment-associated apoptosis and necrosis of tumor cells. Collectively, the results demonstrated the remarkable capability of the HVGGSSV peptide in radiation-guided drug delivery to tumors. PMID:21075152

Lowery, Amanda; Onishko, Halina; Hallahan, Dennis E.; Han, Zhaozhong

2010-01-01

224

AAV-Mediated Delivery of Zinc Finger Nucleases Targeting Hepatitis B Virus Inhibits Active Replication  

PubMed Central

Despite an existing effective vaccine, hepatitis B virus (HBV) remains a major public health concern. There are effective suppressive therapies for HBV, but they remain expensive and inaccessible to many, and not all patients respond well. Furthermore, HBV can persist as genomic covalently closed circular DNA (cccDNA) that remains in hepatocytes even during otherwise effective therapy and facilitates rebound in patients after treatment has stopped. Therefore, the need for an effective treatment that targets active and persistent HBV infections remains. As a novel approach to treat HBV, we have targeted the HBV genome for disruption to prevent viral reactivation and replication. We generated 3 zinc finger nucleases (ZFNs) that target sequences within the HBV polymerase, core and X genes. Upon the formation of ZFN-induced DNA double strand breaks (DSB), imprecise repair by non-homologous end joining leads to mutations that inactivate HBV genes. We delivered HBV-specific ZFNs using self-complementary adeno-associated virus (scAAV) vectors and tested their anti-HBV activity in HepAD38 cells. HBV-ZFNs efficiently disrupted HBV target sites by inducing site-specific mutations. Cytotoxicity was seen with one of the ZFNs. scAAV-mediated delivery of a ZFN targeting HBV polymerase resulted in complete inhibition of HBV DNA replication and production of infectious HBV virions in HepAD38 cells. This effect was sustained for at least 2 weeks following only a single treatment. Furthermore, high specificity was observed for all ZFNs, as negligible off-target cleavage was seen via high-throughput sequencing of 7 closely matched potential off-target sites. These results show that HBV-targeted ZFNs can efficiently inhibit active HBV replication and suppress the cellular template for HBV persistence, making them promising candidates for eradication therapy. PMID:24827459

Weber, Nicholas D.; Stone, Daniel; Sedlak, Ruth Hall; De Silva Feelixge, Harshana S.; Roychoudhury, Pavitra; Schiffer, Joshua T.; Aubert, Martine; Jerome, Keith R.

2014-01-01

225

AAV-mediated delivery of zinc finger nucleases targeting hepatitis B virus inhibits active replication.  

PubMed

Despite an existing effective vaccine, hepatitis B virus (HBV) remains a major public health concern. There are effective suppressive therapies for HBV, but they remain expensive and inaccessible to many, and not all patients respond well. Furthermore, HBV can persist as genomic covalently closed circular DNA (cccDNA) that remains in hepatocytes even during otherwise effective therapy and facilitates rebound in patients after treatment has stopped. Therefore, the need for an effective treatment that targets active and persistent HBV infections remains. As a novel approach to treat HBV, we have targeted the HBV genome for disruption to prevent viral reactivation and replication. We generated 3 zinc finger nucleases (ZFNs) that target sequences within the HBV polymerase, core and X genes. Upon the formation of ZFN-induced DNA double strand breaks (DSB), imprecise repair by non-homologous end joining leads to mutations that inactivate HBV genes. We delivered HBV-specific ZFNs using self-complementary adeno-associated virus (scAAV) vectors and tested their anti-HBV activity in HepAD38 cells. HBV-ZFNs efficiently disrupted HBV target sites by inducing site-specific mutations. Cytotoxicity was seen with one of the ZFNs. scAAV-mediated delivery of a ZFN targeting HBV polymerase resulted in complete inhibition of HBV DNA replication and production of infectious HBV virions in HepAD38 cells. This effect was sustained for at least 2 weeks following only a single treatment. Furthermore, high specificity was observed for all ZFNs, as negligible off-target cleavage was seen via high-throughput sequencing of 7 closely matched potential off-target sites. These results show that HBV-targeted ZFNs can efficiently inhibit active HBV replication and suppress the cellular template for HBV persistence, making them promising candidates for eradication therapy. PMID:24827459

Weber, Nicholas D; Stone, Daniel; Sedlak, Ruth Hall; De Silva Feelixge, Harshana S; Roychoudhury, Pavitra; Schiffer, Joshua T; Aubert, Martine; Jerome, Keith R

2014-01-01

226

A facile approach for dual-responsive prodrug nanogels based on dendritic polyglycerols with minimal leaching.  

PubMed

A novel pH and redox dual-responsive prodrug nanogel was prepared by an inverse nanoprecipitation method, which is mild and surfactant free, and based on a thiol-disulfide exchange reaction and thiol-Michael addition reaction. Highly biocompatible hyperbranched polyglycerol (hPG) was cross-linked with disulfide bonds, to obtain biodegradable nanogels, which could be degraded under intracellular reductive conditions. Doxorubicin (DOX) was conjugated to the biodegradable nanogel matrix via an acid-labile hydrazone linker. This is the first dual-responsive prodrug nanogel system that shows very low unspecific drug leaching, but efficient intracellular release of the payload triggered by the intracellular conditions. Two different prodrug nanogels were prepared with a size of approximately 150nm, which is big enough to take the advantage of the enhanced permeation and retention (EPR) effect in tumor tissue. Cell culture analysis by microscopy and flow cytometry revealed that the prodrug nanogels were efficiently internalized by tumor cells. Distinct release profiles of DOX were achieved by adjusting the nanogel architecture, and online detection of cytotoxicity showed that, unlike free DOX, the dual-responsive prodrug nanogels exhibited a delay in the onset of toxicity, indicating the different uptake mechanism and the need for prodrug activation to induce cell death. PMID:24225227

Zhang, Xuejiao; Achazi, Katharina; Steinhilber, Dirk; Kratz, Felix; Dernedde, Jens; Haag, Rainer

2014-01-28

227

Targeted Delivery of GDNF through the Blood–Brain Barrier by MRI-Guided Focused Ultrasound  

PubMed Central

Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), are promising therapeutic agents for neurodegenerative diseases. However, the application of GDNF to treat these diseases effectively is limited because the blood–brain barrier (BBB) prevents the local delivery of macromolecular therapeutic agents from entering the central nervous system (CNS). Focused ultrasound combined with microbubbles (MBs) using appropriate parameters has been previously demonstrated to be able to open the BBB locally and noninvasively. This study investigated the targeted delivery of GDNF MBs through the BBB by magnetic resonance imaging (MRI)-guided focused ultrasound. Evans Blue extravasation and histological examination were used to determine the optimum focused ultrasound parameters. Enzyme-linked immunosorbent assay was performed to verify the effects of GDNF bound on MBs using a biotin–avidin bridging chemistry method to promote GDNF delivery into the brain. The results showed that GDNF can be delivered locally and noninvasively into the CNS through the BBB using MRI-guided focused ultrasound combined with MBs under optimum parameters. MBs that bind GDNF combined with MRI-guided focused ultrasound may be an effective way of delivering neurotrophic factors directly into the CNS. The method described herein provides a potential means of treating patients with CNS diseases. PMID:23300823

Lu, Lin; Liu, Li; Cai, Youli; Zheng, Hairong; Liu, Xin; Yan, Fei; Zou, Chao; Sun, Chengyu; Shi, Jie; Lu, Shukun; Chen, Yun

2012-01-01

228

Engineering RNA for Targeted siRNA Delivery and Medical Application  

PubMed Central

RNA engineering for nanotechnology and medical applications is an exciting emerging research field. RNA has intrinsically defined features on the nanometer scale and is a particularly interesting candidate for such applications due to its amazing diversity, flexibility and versatility in structure and function. Specifically, the current use of siRNA to silence target genes involved in disease has generated much excitement in the scientific community. The intrinsic ability to sequence-specifically down-regulate gene expression in a temporally- and spatially-controlled fashion has led to heightened interest and rapid development of siRNA-based therapeutics. Though methods for gene silencing with high efficacy and specificity have been achieved in vitro, the effective delivery of nucleic acids to specific cells in vivo has been a hurdle for RNA therapeutics. This review covers different RNA-based approaches for diagnosis, prevention and treatment of human disease, with a focus on the latest developments of nonviral carriers of siRNA for delivery in vivo. The applications and challenges of siRNA therapy, as well as potential solutions to these problems, the approaches for using phi29 pRNA-based vectors as polyvalent vehicles for specific delivery of siRNA, ribozymes, drugs or other therapeutic agents to specific cells for therapy will also be addressed. PMID:20230868

Guo, Peixuan; Coban, Oana; Snead, Nick; Trebley, Joe; Hoeprich, Steve; Guo, Songchuan; Shu, Yi

2010-01-01

229

A novel in situ gel for sustained drug delivery and targeting.  

PubMed

The objective of this study was to develop a novel chitosan-glyceryl monooleate (GMO) in situ gel system for sustained drug delivery and targeting. The delivery system consisted of 3% (w/v) chitosan and 3% (w/v) GMO in 0.33M citric acid. In situ gel was formed at a biological pH. In vitro release studies were conducted in Sorensen's phosphate buffer (pH 7.4) and drugs were analyzed either by HPLC or spectrophotometry. Characterization of the gel included the effect of cross-linker, determination of diffusion coefficient and water uptake by thermogravimetric analysis (TGA). Mucoadhesive property of the gel was evaluated in vitro using an EZ-Tester. Incorporation of a cross-linker (glutaraldehyde) retarded the rate and extent of drug release. The in vitro release can further be sustained by replacing the free drug with drug-encapsulated microspheres. Drug release from the gel followed a matrix diffusion controlled mechanism. Inclusion of GMO enhanced the mucoadhesive property of chitosan by three- to sevenfold. This novel in situ gel system can be useful in the sustained delivery of drugs via oral as well as parenteral routes. PMID:15113617

Ganguly, Sudipta; Dash, Alekha K

2004-05-19

230

Clickable Protein Nanocapsules for Targeted Delivery of Recombinant p53 Protein.  

PubMed

Encapsulating anticancer protein therapeutics in nanocarriers is an attractive option to minimize active drug destruction, increase local accumulation at the disease site, and decrease side effects to other tissues. Tumor-specific ligands can further facilitate targeting the nanocarriers to tumor cells and reduce nonspecific cellular internalization. Rationally designed non-covalent protein nanocapsules incorporating copper-free "click chemistry" moieties, polyethylene glycol (PEG) units, redox-sensitive cross-linker, and tumor-specific targeting ligands were synthesized to selectively deliver intracellular protein therapeutics into tumor cells via receptor-mediated endocytosis. These nanocapsules can be conjugated to different targeting ligands of choice, such as anti-Her2 antibody single-chain variable fragment (scFv) and luteinizing hormone releasing hormone (LHRH) peptide, resulting in specific and efficient accumulation within tumor cells overexpressing corresponding receptors. LHRH-conjugated nanocapsules selectively delivered recombinant human tumor suppressor protein p53 and its tumor-selective supervariant into targeted tumor cells, which led to reactivation of p53-mediated apoptosis. Our results validate a general approach for targeted protein delivery into tumor cells using cellular-responsive nanocarriers, opening up new opportunities for the development of intracellular protein-based anticancer treatment. PMID:25289975

Zhao, Muxun; Liu, Yarong; Hsieh, Renee S; Wang, Nova; Tai, Wanyi; Joo, Kye-Il; Wang, Pin; Gu, Zhen; Tang, Yi

2014-10-29

231

A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo  

PubMed Central

Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents.

Huang, Yifei; Yang, Tan; Zhang, Wendian; Lu, Yao; Ye, Peng; Yang, Guang; Li, Bin; Qi, Shibo; Liu, Yong; He, Xingxing; Lee, Robert J; Xu, Chuanrui; Xiang, Guangya

2014-01-01

232

Mesenchymal stem cells as a novel carrier for targeted delivery of gene in cancer therapy based on nonviral transfection.  

PubMed

The success of gene therapy relies largely on an effective targeted gene delivery system. Till recently, more and more targeted delivery carriers, such as liposome, nanoparticles, microbubbles, etc., have been developed. However, the clinical applications of these systems were limited for their several disadvantages. Therefore, design and development of novel drug/gene delivery vehicles became a hot topic. Cell-based delivery systems are emerging as an alternative for the targeted delivery system as we described previously. Mesenchymal stem cells (MSCs) are an attractive cell therapy carrier for the delivery of therapeutic agents into tumor sites mainly for their tumor-targeting capacities. In the present study, a nonviral vector, PEI(600)-Cyd, prepared by linking low molecular weight polyethylenimine (PEI) and ?-cyclodextrin (?-CD), was used to introduce the therapeutical gene, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), to MSCs. Meanwhile, the characterization, transfection efficiency, cytotoxicity, cellular internalization, and its mechanism of this nonviral vector were evaluated. The in vitro expression of TRAIL from MSCs-TRAIL was demonstrated by both enzyme-linked immunosorbent assay and Western blot analysis. The lung tumor homing ability of MSCs was further confirmed by the in vitro and in vivo model. Moreover, the therapeutic effects as well as the safety of MSCs-TRAIL on lung metastases bearing C57BL/6 mice and normal C57BL/6 mice were also demonstrated. Our results supported both the effectiveness of nonviral vectors in transferring the therapeutic gene to MSCs and the feasibility of using MSCs as a targeted gene delivery carrier, indicating that MSCs could be a promising tumor target delivery vehicle in cancer gene therapy based on nonviral gene recombination. PMID:22862421

Hu, Yu-Lan; Huang, Bin; Zhang, Tian-Yuan; Miao, Pei-Hong; Tang, Gu-Ping; Tabata, Yasuhiko; Gao, Jian-Qing

2012-09-01

233

[Characteristics of JC virus VLP-Z for targeting gene delivery].  

PubMed

The characteristics of virus-like particle (VLP) of JC virus (JCV) as a vector for targeting gene delivery was determined. The exogenous DNA (PUC19) packaged in VLP-Z was resistant to DNase I. VLP-Z was able to deliver a reporter plasmid pEGFP-N1 into HeLa cells and the green fluorescent reporter protein was expressed in these cells. VLP-Z was also able to bind IgG by interaction with the Z fragment of VLP-Z and IgG. These results suggested that VLP-Z might be used as a vector to deliver therapeutic genes to target cells with incorporating IgG antibodies. PMID:23865321

Zeng, Junyan; Qu, Qiumin

2013-06-01

234

Intracellular Delivery of a Cell-Penetrating SOCS1 that Targets IFN-? Signaling  

PubMed Central

Suppressor of cytokine signaling–1 (SOCS1) is an intracellular inhibitor of the Janus kinase–signal transducer and activator of transcription (JAK-STAT) pathway that couples interferon-? (IFN-?) signaling to the nucleus. Because several inflammatory diseases are associated with uncontrolled IFN-? signaling, we engineered a recombinant cell-penetrating SOCS1 (CP-SOCS1) to target this pathway. Here, we show that CP-SOCS1, analogous to endogenous SOCS1, interacted with components of the IFN-? signaling complex and functionally attenuated the phosphorylation of STAT1, which resulted in the subsequent inhibition of the production of proinflammatory chemokines and cytokines. Thus, controlled, intracellular delivery of recombinant CP-SOCS1 boosted the anti-inflammatory potential of the cell by restoring the homeostatic balance between pro- and anti-inflammatory signaling. This approach to controlling signal transduction has potential use for therapeutic targeting of signaling pathways associated with inflammatory diseases. PMID:19622834

DiGiandomenico, Antonio; Wylezinski, Lukasz S.; Hawiger, Jacek

2009-01-01

235

Novel thermo/pH sensitive nanogels composed from poly(N-vinylcaprolactam) for controlled release of an anticancer drug.  

PubMed

A series of novel nanogels (NGs) with both pH and thermoresponsive properties were synthesised by free radical emulsion polymerisation of N-vinyl caprolactam (VCL) and acrylamidoglycolic acid (AGA). 5-Flurouracil, an anti cancer drug, was successfully loaded into these nanogels via equilibrium swelling method. The encapsulation efficiency of 5-FU was found up to 61%. Here we present the novel potential drug delivery system showing both pH and temperature release of 5-FU. Fourier transforms infrared spectroscopy (FTIR), and differential scanning calorimetric (DSC) examined the structure and morphology of the NGs. Transmission electron microscopy (TEM) indicates the diameter of the NGs to be about 50 nm. The size distribution of NGs was investigated using dynamic light scattering (DLS), the average diameter and polydispersity is 57 nm and 0.194. Interestingly, the in vitro release studies of 5-FU demonstrated the dual nature (pH and temperature) of NGs. The cumulative release data were analysed using an emperical equation to compute the diffusion exponent (n); whose values suggest Fickian diffusion. PMID:23107966

Madhusudana Rao, K; Mallikarjuna, B; Krishna Rao, K S V; Siraj, S; Chowdoji Rao, K; Subha, M C S

2013-02-01

236

Enhanced gene transfer activity of peptide-targeted gene-delivery vectors.  

PubMed

We have evaluated the capacity of the cell-binding heptapeptide SIGYPLP to enhance transgene expression using non-viral and viral gene delivery vectors. Targeted polyplex based vectors showed good levels of DNA uptake in freshly isolated human umbilical vein endothelial cells (HUVECs) compared to untargeted controls, whilst displaying only modest increases in reporter gene activity. The targeted polyplexes showed reduced levels of DNA uptake in cells of a none endothelial origin although they mediated higher levels of transgene expression. The enhanced efficiency of transgene expression may relate to the more rapid rate of cell division. However, since in vivo application of polyplexes is compromised by instability to serum proteins, serum-resistant polyplexes (surface modified with multivalent reactive hydrophilic polymers based on poly[N-(2-hydroxypropyl)methacrylamide] (pHPMA)) were also evaluated for their ability to mediate transgene expression. Surface modification of polyplexes with pHPMA ablates non-specific cell entry, reducing levels of transgene expression, whilst the incorporation of the SIGYPLP peptide into the hydrophilic polymer resulted in restored transgene expression in all formulations tested. The technology of surface modification using pHPMA can also be applied in the context of viruses, masking receptor-binding epitopes and enabling the linkage of novel cell targeting ligands, enabling construction of a virus with receptor-specific infectivity. Retargeting of adenovirus based vectors using the same polymer-peptide construct enhanced levels of transgene expression in HUVECs to greater than 15 times that observed using parental (unmodified) virus, whilst restoring levels of transgene expression in non-endothelial cell lines tested. The use of constructs based on conjugates between hydrophilic polymers and small receptor-binding oligopeptides as agents for retargeting viral or non-viral vectors to cellular receptors represents a simple alternative to the use of antibodies as targeting ligands for cell specific gene delivery. PMID:15848953

Parker, Alan L; Fisher, Kerry D; Oupicky, David; Read, Martin L; Nicklin, Stuart A; Baker, Andrew H; Seymour, Leonard W

2005-01-01

237

Cisplatin-alginate conjugate liposomes for targeted delivery to EGFR-positive ovarian cancer cells.  

PubMed

Systemic side effects and low aqueous solubility have limited the clinical use of cisplatin (CDDP) in ovarian carcinoma and have contributed to failures in developing effective drug delivery systems. In order to develop a novel drug delivery system with enhanced efficacy and minimal adverse effects, we exploited the properties of sodium alginate (SA) to synthesize CDDP-SA conjugate (CS), which is highly soluble and readily incorporated into liposomes (CS-PEG-Lip). Epidermal growth factor receptor (EGFR) is overexpressed in many ovarian cancers, therefore we modified EGF on the liposomes (CS-EGF-Lip) to specifically target EGFR-expressing tumors, thereby increasing the bioavailability and efficacy of CDDP. In vitro experiments confirmed that EGF-Lip selectively recognized EGFR-positive SKOV3 cells and effectively penetrated tumor spheroids. We demonstrated that CS-EGF-Lip possessed satisfactory size distribution and exhibited significantly improved encapsulation and loading efficiency. Furthermore, CS-EGF-Lip sustained release of CDDP in vitro, suggesting that CS-EGF-Lip may retain the antitumor activity of CDDP. Inhibition of proliferation and migration was also greater with CS-EGF-Lip compared to CDDP. In vivo xenograft experiments revealed that administration of CS-EGF-Lip enhanced delivery of CDDP into ovarian tumor tissues and improved the antitumor efficacy of CDDP, while reducing nephrotoxicity and body weight loss in mice. These results suggest that CS-EGF-Lip may offer a promising strategy for CDDP delivery in the treatment of EGFR-positive ovarian carcinoma or similar tumors, with enhanced efficacy and fewer adverse effects. PMID:24565522

Wang, Yunfei; Zhou, Jinhua; Qiu, Lihua; Wang, Xinran; Chen, Lilan; Liu, Ting; Di, Wen

2014-05-01

238

Nanogels fabricated by lysozyme and sodium carboxymethyl cellulose for 5-fluorouracil controlled release.  

PubMed

Lysozyme (Ly) and sodium carboxymethyl cellulose (CMC) were used to fabricate nanogels by a convenient method without using any chemical treatment except simple heating to achieve the denaturation temperature of Ly. The prepared nanogels were characterized by dynamic laser scattering (DLS), rheological analysis, transmission electron microscopy (TEM), field emission scanning electron microscope (FE-SEM) and X-ray photoelectron spectroscopy (XPS). The nanogels are of spherical shape with average hydrodynamic diameter of 241 nm and the swelling ratio of nanogels is about 5. Then 5-fluorouracil was used as a model drug to investigate the entrapment efficiency and release ability in nanogels. It turned out to be that the release in simulated gastric fluid (SGF) was more slowly compared with that in simulated intestinal fluid (SIF), which could protect the 5-Fu in stomach and ensure it released in intestines. PMID:23089579

Zhu, Kunkun; Ye, Ting; Liu, Jinjin; Peng, Zheng; Xu, Shasha; Lei, Jieqiong; Deng, Hongbing; Li, Bin

2013-01-30

239

Green synthesis of pullulan stabilized gold nanoparticles for cancer targeted drug delivery  

NASA Astrophysics Data System (ADS)

The aim of this study was to synthesize green chemistry based gold nanoparticles using liver specific biopolymer and to develop a liver cancer targeted drug delivery system with enhanced efficacy and minimal side effects. Pullulan stabilized gold nanoparticles (PAuNPs) were coupled with 5-Fluorouracil (5-Fu) and folic acid (Fa) which could be used as a tool for targeted drug delivery and imaging of cancer. The toxicity of 5-Fu, 5-Fu adsorbed gold nanoparticles (5-Fu@AuNPs), Fa-coupled 5-Fu adsorbed gold nanoparticles (5-Fu@AuNPs-Fa), was studied using zebrafish embryo as an in vivo model. The in vitro cytotoxicity of free 5-Fu, 5-Fu@AuNPs, 5-Fu@AuNPs-Fa against HepG2 cells was studied and found that the amount of 5-Fu required to achieve 50% of growth of inhibition (Ic50) was much lower in 5-Fu@AuNP-Fa than in free 5-Fu, 5-Fu@AuNPs. The in vivo biodistribution of PAuNPs showed that higher amount of gold had been accumulated in liver (54.42 ± 5.96 ?g) than in other organs.

Ganeshkumar, Moorthy; Ponrasu, Thangavel; Raja, Modhugoor Devendiran; Subamekala, Muthaiya Kannappan; Suguna, Lonchin

2014-09-01

240

Targeted Delivery of PSC-RANTES for HIV-1 Prevention using Biodegradable Nanoparticles  

PubMed Central

Purpose Nanoparticles formulated from the biodegradable co-polymer poly(lactic-co-glycolic acid) (PLGA), were investigated as a drug delivery system to enhance tissue uptake, permeation, and targeting for PSC-RANTES anti-HIV-1 activity. Materials and Methods PSC-RANTES nanoparticles formulated via a double emulsion process and characterized in both in vitro and ex vivo systems to determine PSC-RANTES release rate, nanoparticle tissue permeation, and anti-HIV bioactivity. Results Spherical, monodisperse (PDI = 0.098 ± 0.054) PSC-RANTES nanoparticles (d = 256.58 ± 19.57 nm) with an encapsulation efficiency of 82.23 ± 8.35% were manufactured. In vitro release studies demonstrated a controlled release profile of PSC-RANTES (71.48 ± 5.25% release). PSC-RANTES nanoparticle maintained comparable anti-HIV activity with unformulated PSC-RANTES in a HeLa cell-based system with an IC50 of approximately 1pM. In an ex vivo cervical tissue model, PSC-RANTES nanoparticles displayed a fivefold increase in tissue uptake, enhanced tissue permeation, and significant localization at the basal layers of the epithelium over unformulated PSC-RANTES. Conclusions These results indicate that PSC-RANTES can readily be encapsulated into a PLGA nanoparticle drug delivery system, retain its anti-HIV-1 activity, and deliver PSC-RANTES to the target tissue. This is crucial for the success of this drug candidate as a topical microbicide product. PMID:19002569

Ham, Anthony S.; Cost, Marilyn R.; Sassi, Alexandra B.; Dezzutti, Charlene S.; Rohan, Lisa Cencia

2014-01-01

241

Controlled release of PEG chain from gold nanorods: targeted delivery to tumor.  

PubMed

Gold nanorods exhibit strong absorbance of light in the near infrared region, which penetrates deeply into tissues. Since the absorbed light energy is converted into heat, gold nanorods are expected to act as a contrast agent for in vivo bioimaging and as a thermal converter for photothermal therapy. To construct a gold nanorod targeted delivery system for tumor a peptide substrate for urokinase-type plasminogen activator (uPA), expressed specifically on malignant tumors, was inserted between the PEG chain and the surface of the gold nanorods. In other words, we constructed PEG-peptide-modified gold nanorods. After mixing the gold nanorods with uPA, the PEG chain was released from the surface of the gold and subsequently nanorod aggregation took place. The formation of the aggregation was monitored as a decrease in light absorption at 900 nm. Tumor homogenate induced a significant decrease in this absorption. Larger amount of the PEG-peptide-modified gold nanorods bound to cells expressing uPA in vitro compared with control gold nanorods, which had scrambled sequence of the peptide. The PEG-peptide-modified gold nanorods showed higher accumulation in tumor than the control after they were injected intravenously into tumor-bearing mice, however, the density of the peptide on the surface of the gold nanorods was a key factor of their biodistributions. This targeted delivery system, which responds to uPA activity, is expected to be a powerful tool for tumor bioimaging and photothermal tumor therapy. PMID:20472443

Niidome, Takuro; Ohga, Akira; Akiyama, Yasuyuki; Watanabe, Kazuto; Niidome, Yasuro; Mori, Takeshi; Katayama, Yoshiki

2010-06-15

242

Maximizing gene delivery efficiencies of cationic helical polypeptides via balanced membrane penetration and cellular targeting.  

PubMed

The application of non-viral gene delivery vectors is often accompanied with the poor correlation between transfection efficiency and the safety profiles of vectors. Vectors with high transfection efficiencies often suffer from high toxicities, making it unlikely to improve their efficiencies by increasing the DNA dosage. In the current study, we developed a ternary complex system which consisted of a highly membrane-active cationic helical polypeptide (PVBLG-8), a low-toxic, membrane-inactive cationic helical polypeptide (PVBLG-7) capable of mediating mannose receptor targeting, and DNA. The PVBLG-7 moiety notably enhanced the cellular uptake and transfection efficiency of PVBLG-8 in a variety of mannose receptor-expressing cell types (HeLa, COS-7, and Raw 264.7), while it did not compromise the membrane permeability of PVBLG-8 or bring additional cytotoxicities. Because of the simplicity and adjustability of the self-assembly approach, optimal formulations of the ternary complexes with a proper balance between membrane activity and targeting capability were easily identified in each specific cell type. The optimal ternary complexes displayed desired cell tolerability and markedly outperformed the PVBLG-8/DNA binary complexes as well as commercial reagent Lipofectamine™ 2000 in terms of transfection efficiency. This study therefore provides an effective and facile strategy to overcome the efficiency-toxicity poor correlation of non-viral vectors, which contributes insights into the design strategy of effective and safe non-viral gene delivery vectors. PMID:24211080

Zheng, Nan; Yin, Lichen; Song, Ziyuan; Ma, Liang; Tang, Haoyu; Gabrielson, Nathan P; Lu, Hua; Cheng, Jianjun

2014-01-01

243

Biocompatible nanoparticles intercalated with anticancer drug for target delivery: pharmacokinetic and biodistribution study.  

PubMed

We have developed new hybrid systems consisting of anticancer drugs such as methotrexate (MTX) or 5-fluorouracil (5-FU) and two-dimensional inorganic delivery carrier like layered double hydroxide (LDH). Such an inorganic vector with biocompatible metal ions can be used to overcome toxicity, immunogenecity and poor integration capacity, which are critical problems caused by conventional viral vectors, cationic liposomes and polymers. Moreover, the intercellular mechanism of LDH nanoparticles is primarily related to clathrin-mediated endocytosis, resultihg in effective delivery and eventually enhancing drug efficacy. In this report, the effect of LDH intercalated with 5-Fu (5-Fu-LDH) was evaluated in whole animal by studying pharmacokinetic behavior and tissue distribution. The results showed that 5-Fu-LDH exhibited favorable blood clearance profiles compared to free 5-Fu, such as sustained drug release, prolonged drug half-life, and increased drug accumulation in target tumor tissue. Furthermore, LDH nanoparticles were rapidly excreted from the body and not accumulated in the organs after administration as 5-Fu-LDH. Therefore, the hybrid system can be promising anticancer chemotherapy agent for tumor targeting with biocompatibility. PMID:20355523

Choi, Soo-Jin; Oh, Jae-Min; Choy, Jin-Ho

2010-04-01

244

Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration  

PubMed Central

Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically. PMID:23836972

Gu, Wenyi; Wu, Chengtie; Chen, Jiezhong; Xiao, Yin

2013-01-01

245

Targeting the neonatal fc receptor for antigen delivery using engineered fc fragments.  

PubMed

The development of approaches for Ag delivery to the appropriate subcellular compartments of APCs and the optimization of Ag persistence are both of central relevance for the induction of protective immunity or tolerance. The expression of the neonatal Fc receptor, FcRn, in APCs and its localization to the endosomal system suggest that it might serve as a target for Ag delivery using engineered Fc fragment-epitope fusions. The impact of FcRn binding characteristics of an Fc fragment on in vivo persistence allows this property to also be modulated. We have therefore generated recombinant Fc (mouse IgG1-derived) fusions containing the N-terminal epitope of myelin basic protein that is associated with experimental autoimmune encephalomyelitis in H-2(u) mice. The Fc fragments have distinct binding properties for FcRn that result in differences in intracellular trafficking and in vivo half-lives, allowing the impact of these characteristics on CD4(+) T cell responses to be evaluated. To dissect the relative roles of FcRn and the "classical" FcgammaRs in Ag delivery, analogous aglycosylated Fc-MBP fusions have been generated. We show that engineered Fc fragments with increased affinities for FcRn at pH 6.0-7.4 are more effective in delivering Ag to FcRn-expressing APCs in vitro relative to their lower affinity counterparts. However, higher affinity of the FcRn-Fc interaction at near neutral pH results in decreased in vivo persistence. The trade-off between improved FcRn targeting efficiency and lower half-life becomes apparent during analyses of T cell proliferative responses in mice, particularly when Fc-MBP fusions with both FcRn and FcgammaR binding activity are used. PMID:19017944

Mi, Wentao; Wanjie, Sylvia; Lo, Su-Tang; Gan, Zhuo; Pickl-Herk, Beatrix; Ober, Raimund J; Ward, E Sally

2008-12-01

246

Feasibility of targeted drug delivery to selective areas of the retina  

SciTech Connect

A new method was developed to deliver locally a bolus dose of a drug to the retinal vasculature. The targeted delivery system was based on encapsulating the drug in heat-sensitive liposomes, which are injected intravenously and lysed in the retinal vessels by a heat pulse generated by a laser. To test if substances delivered in the vessels could also penetrate into the surrounding tissue, 6-carboxyfluorescein was encapsulated in liposomes and used as a marker for drug penetration. Moderate argon laser pulses were applied to the retinal vessels of Dutch pigmented rabbits to induce breakdown of the blood-retinal barrier (BRB). A suspension of liposomes at a dose of 2 ml/kg body weight, corresponding to a carboxyfluorescein dose of 12 mg/kg, was injected into the ear vein. The dye was released from the liposomes proximal to the damaged portion of the vessel. Fundus fluorescein angiograms were recorded with a video camera and digitized for subsequent image analysis. The penetration of carboxyfluorescein into the retinal tissue was evaluated by comparing the fluorescence intensity of the area around the damaged vessel with that of an adjacent control area. The dye penetration increased with the numbers of laser applications (P less than 0.001). The leakage was localized distally to the released site and was restricted to areas with a disrupted BRB. The mass of carboxyfluorescein that penetrated gradually spread with time. Both veins and arteries could be used for the targeted delivery. These results indicated that this delivery system, which is fully controllable by laser through the pupil, can deliver drugs inside the vasculature and into the retinal tissue wherever the BRB is disrupted.

Ogura, Y.; Guran, T.; Shahidi, M.; Mori, M.T.; Zeimer, R.C. (Department of Ophthalmology, UIC Eye Center, University of Illinois, College of Medicine, Chicago (USA))

1991-07-01

247

Anti-HIV Double Variable Domain Immunoglobulins Binding Both gp41 and gp120 for Targeted Delivery of  

E-print Network

Anti-HIV Double Variable Domain Immunoglobulins Binding Both gp41 and gp120 for Targeted Delivery States of America Abstract Background: Anti-HIV immunoconjugates targeted to the HIV envelope protein may be used to eradicate the latent reservoir of HIV infection using activate-and-purge protocols. Previous

Summa, Christopher M.

248

Preparation of Quantum Dot/Drug Nanoparticle Formulations for Traceable Targeted Delivery and Therapy  

PubMed Central

Quantum dots (QDs) are luminescent nanocrystals with rich surface chemistry and unique optical properties that make them useful as probes or carriers for traceable targeted delivery and therapy applications. QDs can be functionalized to target specific cells or tissues by conjugating them with targeting ligands. Recent advancement in making biocompatible QD formulations has made these nanocrystals suitable for in vivo applications. This review provides an overview of the preparation of QDs and their use as probes or carriers for traceable, targeted therapy of diseases in vitro and in vivo. More specifically, recent advances in the integration of QDs with drug formulations for therapy and their potential toxicity in vitro and in vivo are highlighted. The current findings and challenges for optimizing QD/drug formulations with respect to optimal size and stability, short-term and long-term toxicity, and in vivo applications are described. Lastly, we attempt to predict key trends in QD/drug formulation development over the next few years and highlight areas of therapy where their use may provide breakthrough results in the near future. PMID:22896770

Yong, Ken-Tye; Wang, Yucheng; Roy, Indrajit; Rui, Hu; Swihart, Mark T.; Law, Wing-Cheung; Kwak, Sang Kyu; Ye, Ling; Liu, Jianwei; Mahajan, Supriya D.; Reynolds, Jessica L.

2012-01-01

249

The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers  

NASA Astrophysics Data System (ADS)

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma exhibit a 10,000-fold greater affinity for human hepatocellular carcinoma than for hepatocytes, endothelial cells or immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, small interfering RNA and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a 106-fold improvement over comparable liposomes.

Ashley, Carlee E.; Carnes, Eric C.; Phillips, Genevieve K.; Padilla, David; Durfee, Paul N.; Brown, Page A.; Hanna, Tracey N.; Liu, Juewen; Phillips, Brandy; Carter, Mark B.; Carroll, Nick J.; Jiang, Xingmao; Dunphy, Darren R.; Willman, Cheryl L.; Petsev, Dimiter N.; Evans, Deborah G.; Parikh, Atul N.; Chackerian, Bryce; Wharton, Walker; Peabody, David S.; Brinker, C. Jeffrey

2011-05-01

250

Amphiphilic dendritic derivatives as nanocarriers for the targeted delivery of antimalarial drugs.  

PubMed

It can be foreseen that in a future scenario of malaria eradication, a varied armamentarium will be required, including strategies for the targeted administration of antimalarial compounds. The development of nanovectors capable of encapsulating drugs and of delivering them to Plasmodium-infected cells with high specificity and efficacy and at an affordable cost is of particular interest. With this objective, dendritic derivatives based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) and Pluronic(®) polymers have been herein explored. Four different dendritic derivatives have been tested for their capacity to encapsulate the antimalarial drugs chloroquine (CQ) and primaquine (PQ), their specific targeting to Plasmodium-infected red blood cells (pRBCs), and their antimalarial activity in vitro against the human pathogen Plasmodium falciparum and in vivo against the rodent malaria species Plasmodium yoelii. The results obtained have allowed the identification of two dendritic derivatives exhibiting specific targeting to pRBCs vs. non-infected RBCs, which reduce the in vitro IC50 of CQ and PQ by ca. 3- and 4-fold down to 4.0 nm and 1.1 ?m, respectively. This work on the application of dendritic derivatives to antimalarial targeted drug delivery opens the way for the use of this new type of chemicals in future malaria eradication programs. PMID:24930847

Movellan, Julie; Urbán, Patricia; Moles, Ernest; de la Fuente, Jesús M; Sierra, Teresa; Serrano, José Luis; Fernàndez-Busquets, Xavier

2014-09-01

251

Preparation of irinotecan-loaded folate-targeted liposome for tumor targeting delivery and its antitumor activity.  

PubMed

The purpose of this study was to investigate the in vivo distribution and antitumor activity of irinotecan (camptothecin (CPT)-11)-loaded folate-targeted liposome (F-Lip) in tumor-bearing mice following i.v. administration. Folate-poly(ethylene glycol)-distearoylphosphatidylcholine (FA-PEG-DSPE) was synthesized by amide reaction of DSPE-PEG-NH(2) and FA. F-Lip modified by FA-PEG-DSPE was prepared by an ammonium sulfate gradient. The mean particle size and entrapment efficiency of F-Lip with negative charge were 197.8 ± 4.58 nm and 91.39 ± 2.34 %, respectively. The distributions of CPT-11 and SN-38 in the tumor after i.v. administration of F-Lip, CPT-11-loaded liposomes (C-Lip), and CPT-11 injection (C-Inj) were far greater with the F-Lip group in comparison to the C-Inj and C-Lip, which might contribute to folate-meditated targeting uptake by the folate receptor on the surface of the tumor cells. The uptake of CPT-11 in the liver and rectum for two liposome groups were all markedly increased as compared to the C-Inj. Moreover, F-Lip exhibited a dose-dependent tumor growth inhibition and superior anticancer activity to C-Lip and C-Inj after i.v. administration. It also showed no significant body weight loss and much lower toxicity on the center immune organs. Therefore, F-Lip may be presented as potential candidates for tumor targeting drug delivery. PMID:22639238

Zhang, Ziqiang; Yao, Jing

2012-09-01

252

A folate-integrated magnetic polymer micelle for MRI and dual targeted drug delivery  

NASA Astrophysics Data System (ADS)

This paper devotes a novel micellar structure for cancer theranostics by incorporating magnetic and therapeutic functionalities into a natural sourced targeting polymer vehicle. Heparin-folic acid micelles taking advantage of both excellent loading capability and cancer targeting ability have been employed to simultaneously incorporate superparamagnetic iron oxide nanoparticles (SPIONs) and doxorubicin through an ultrasonication-assisted microemulsion method. In this system, folic acids not only take the responsibility of micelle construction, but also facilitate cellular uptake due to their specific reorganization by MCF-7 cells over-expressing folate receptors. The obtained micelles exhibit good colloidal stability, a high magnetic content, considerable drug loading and sustained in vitro drug release. These clustered SPIONs exhibited high r2 relaxivity (243.65 mM-1 s-1) and further served as efficient probes for MR imaging. Notably, the transport efficiency of these micelles could be significantly improved under an external magnetic field, owing to their quick magnetic response. As a result, the as-proposed micelle shows great potential in multimodal theranostics, including active targeting, MRI diagnosis and drug delivery.This paper devotes a novel micellar structure for cancer theranostics by incorporating magnetic and therapeutic functionalities into a natural sourced targeting polymer vehicle. Heparin-folic acid micelles taking advantage of both excellent loading capability and cancer targeting ability have been employed to simultaneously incorporate superparamagnetic iron oxide nanoparticles (SPIONs) and doxorubicin through an ultrasonication-assisted microemulsion method. In this system, folic acids not only take the responsibility of micelle construction, but also facilitate cellular uptake due to their specific reorganization by MCF-7 cells over-expressing folate receptors. The obtained micelles exhibit good colloidal stability, a high magnetic content, considerable drug loading and sustained in vitro drug release. These clustered SPIONs exhibited high r2 relaxivity (243.65 mM-1 s-1) and further served as efficient probes for MR imaging. Notably, the transport efficiency of these micelles could be significantly improved under an external magnetic field, owing to their quick magnetic response. As a result, the as-proposed micelle shows great potential in multimodal theranostics, including active targeting, MRI diagnosis and drug delivery. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr02484b

Ao, Lijiao; Wang, Bi; Liu, Peng; Huang, Liang; Yue, Caixia; Gao, Duyang; Wu, Chunlei; Su, Wu

2014-08-01

253

Reversion of multidrug resistance by tumor targeted delivery of antisense oligodeoxynucleotides in hydroxypropyl-chitosan nanoparticles.  

PubMed

Chitosan and its derivatives have shown great potential as non-viral vectors for gene delivery therapy. Folic acid receptor (FR) is an important anti-cancer therapy target that is applicable to many cancer types. In this study, we developed an efficient and targeted delivery of antisense oligodeoxynucleotides asODNs, using folic acid (FA) conjugated hydroxypropyl-chitosan (HPCS). These nanoparticles were designed to reduce production of P-gp, in order to overcome tumor drug resistance. Nanoparticles prepared were found to be 181 nm in diameter. Spectrofluorimetry was utilized to evaluate the effect of charge ratio of the nanoparticles on loading efficiency. In PBS buffer, 40% of asODNs were released from the nanoparticles at first 24 h. However, just another 15% was released between 24 and 48 h. The antitumor effect of the nanoparticles was evaluated in KB-A-1 cells implanted in Balb/c-nu/nu mice. They inhibited the growth of tumor by 35% compared to the bare asODNs. The FA-HPCS-asODNs nanoparticles demonstrated significantly inhibition of the multi drug resistance (MDR) 1 gene levels and P-gp levels in vitro and in vivo, respectively, related with bare asODNs and HPCS-asODNs ones. During in vivo studies, FA-HPCS-asODNs nanoparticles were also found to bind specifically and efficiently to FR high-expressing cancer cells. These results suggested that the use of targeted, antisense agent nanoparticles would be potential approach to overcome tumor drug resistance. PMID:20188412

Wang, Jiaqi; Tao, Xinyi; Zhang, Yufei; Wei, Dongzhi; Ren, Yuhong

2010-05-01

254

Target-specific delivery of doxorubicin to retinoblastoma using epithelial cell adhesion molecule aptamer  

PubMed Central

Purpose To study target-specific delivery of doxorubicin (Dox) using an RNA aptamer against epithelial cell adhesion molecule (EpCAM) in retinoblastoma (RB) cells. Methods The binding affinity of the EpCAM aptamer to RB primary tumor cells, Y79 and WERI-Rb1 cells, and Müller glial cell lines were evaluated with flow cytometry. Formation of physical conjugates of aptamer and Dox was monitored with spectrofluorimetry. Cellular uptake of aptamer-Dox conjugates was monitored through fluorescent microscopy. Drug efficacy was monitored with cell proliferation assay. Results The EpCAM aptamer (EpDT3) but not the scrambled aptamer (Scr-EpDT3) bound to RB tumor cells, the Y79 and WERI-Rb1 cells. However, the EpCAM aptamer and the scrambled aptamer did not bind to the noncancerous Müller glial cells. The chimeric EpCAM aptamer Dox conjugate (EpDT3-Dox) and the scrambled aptamer Dox conjugate (Scr-EpDT3-Dox) were synthesized and tested on the Y79, WERI-Rb1, and Müller glial cells. The targeted uptake of the EpDT3-Dox aptamer caused cytotoxicity in the Y79 and WERI-Rb1 cells but not in the Müller glial cells. There was no significant binding or consequent cytotoxicity by the Scr-EpDT3-Dox in either cell line. The EpCAM aptamer alone did not cause cytotoxicity in either cell line. Conclusions The results show that the EpCAM aptamer-Dox conjugate can selectively deliver the drug to the RB cells there by inhibiting cellular proliferation and not to the noncancerous Müller glial cells. As EpCAM is a cancer stem cell marker, this aptamer-based targeted drug delivery will prevent the undesired effects of non-specific drug activity and will kill cancer stem cells precisely in RB. PMID:23213278

Subramanian, Nithya; Raghunathan, Vaishnavi; Kanwar, Jagat R.; Kanwar, Rupinder K.; Elchuri, Sailaja V.; Khetan, Vikas

2012-01-01

255

Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: Crossing the blood-brain-barrier divide  

PubMed Central

Introduction Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. Areas covered This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. Expert Opinion Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes. PMID:23751126

Chacko, Ann-Marie; Li, Chunsheng; Pryma, Daniel A.; Brem, Steven; Coukos, George; Muzykantov, Vladimir R.

2014-01-01

256

Modification of Polymer Network Properties through the Addition of Functional Nanogel Particles  

NASA Astrophysics Data System (ADS)

Multifunctional acrylic and methacrylic monomers have been widely applied in many photopolymerization applications to produce crosslinked polymers with advantages such as rapid curing, broad choices of commercially available monomers and desirable physical and mechanical properties. However, there still remain critical challenges for these materials during polymerization including limited conversion and early onset of gelation as well as the generation of significant polymerization shrinkage and stress. This thesis explores the effects of network property modification through the addition of polymeric nanoparticles or nanogels. In order to understand the relationship between nanogel structure and composite material properties, nanogels with different architectures and functionalities were studied during polymerization in terms of kinetics, shrinkage and stress reduction, mechanical performance and reaction mechanisms. Nanogel composite formulations were evaluated to understand the interaction between nanogel structure with the resin matrix during polymerization through adjustment of nanogel branching densities and reactivity of polymer chain ends. It was found that both the chemical crosslinking from reactive chain ends and physical entanglements of high branching density nanogels with the resin matrix dramatically could improve final material mechanical strength. The reductions in overall volumetric shrinkage and shrinkage stress were found to follow at least proportional behavior with respect to nanogel loading concentration while maintaining similar final conversion and modulus results compared with the control resin. Nanogels containing unique functionalities were designed in order to modify reaction mechanism during secondary polymerization. A nanogel containing an integrated photoinitiator and active chain-end RAFT groups was able to initiate secondary polymerization from the nanogel phase so that localized polymerization was achieved from the beginning of the reaction process to prevent early bulk gelation. A large amount of stress was dissipated before gelation to yield materials with low residual stress. With the incorporation of a photochromic functionality, another nanogel was found to be able to change dimensions under UV irradiation due to the change of solubility parameter after isomerization. It was observed that the final conversion of the resin matrix increased significantly with the addition of only small amounts of this nanogel albeit with somewhat reduced rates of polymerization. A delay of vitrification was also noticed for these nanogel systems with dramatic stress reduction achieved with minimal nanogel additive levels. Finally, due to the non-controlled nature of nanogel synthesis from solution polymerization, whether free radical or RAFT controlled radical based processes, uniform nanogel structure formation was studied through a block copolymer self-assembly method. Core-shell micelles were formed through the assembly of an amphiphilic block copolymer in hydrophilic environment. The crosslinking in the core region generated well-controlled, internally crosslinked nanogel particles with 30 nm dimension in aqueous solution. The uniform nanogel particles were further applied to understand particle-particle interspacing by dispersing in an inert solvent at different concentrations followed by macrogel formation tests with interparticle reaction.

Liu, JianCheng

257

Localized Increase of Tissue Oxygen Tension by Magnetic Targeted Drug Delivery  

PubMed Central

Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases, without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs) synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector, L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coaded PMNPs (L35-PMNPs) were intravenously infused (10 mg/kg) to hamster instrumented with the dorsal window chamber model. Magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after L35-PMNPs administration with and without magnetic field. The tissue PO2 untreated control animals was 25.2 mmHg. L35-PMNP without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNP with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamics changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue, without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to increase O2 in tumors enhancing the efficacy of radiation therapies. PMID:24920392

Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen; Navati, Mahantesh S.; Friedman, Joel M.; Cabrales, Pedro

2014-01-01

258

Localized increase of tissue oxygen tension by magnetic targeted drug delivery  

NASA Astrophysics Data System (ADS)

Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to increase O2 in tumors, enhancing the efficacy of radiation therapies.

Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen; Navati, Mahantesh S.; Friedman, Joel M.; Cabrales, Pedro

2014-07-01

259

Epidermal growth factor (EGF) as a potential targeting agent for delivery of boron to malignant gliomas  

SciTech Connect

The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and this often is associated with an increase in cell surface receptor expression. The rapid internalization and degradation of EGF-EGFR complexes, as well as their high affinity make EGF a potential targeting agent for delivery of {sup 10}B to tumor cells with an amplified number of EGFR. Human glioma cells can expresses as many as 10{sup 5} {minus}10{sup 6} EGF receptors per cell, and if these could be saturated with boronated EGF, then > 10{sup 8} boron atoms would be delivered per cell. Since EGF has a comparatively low molecular weight ({approximately} 6 kD), this has allowed us to construct relatively small bioconjugates containing {approximately} 900 boron atoms per EGF molecule{sup 3}, which also had high affinity for EGFR on tumor cells. In the present study, the feasibility of using EGF receptors as a potential target for therapy of gliomas was investigated by in vivo scintigraphic studies using {sup 131}I{minus} or {sup 99m}{Tc}-labeled EGF in a rat brain tumor model. Our results indicate that intratumorally delivered boron- EGF conjugates might be useful for targeting EGFR on glioma cells if the boron containing moiety of the conjugates persisted intracellularly. Further studies are required, however, to determine if this approach can be used for BNCT of the rat glioma.

Capala, J.; Barth, R.F.; Adams, D.M.; Bailey, M.Q.; Soloway, A.H. [Ohio State Univ., Columbus, OH (United States); Carlsson, J. [Uppsala Univ. (Sweden). Dept. of Radiation Sciences

1994-12-31

260

Alkali reversal of psoralen cross-link for the targeted delivery of psoralen monoadduct lesion  

SciTech Connect

Psoralen intercalates into double-stranded DNA and photoreacts mainly with thymines to form monoadducts and interstrand cross-links. The authors used an oligonucleotide model to demonstrate a novel mechanism: the reversal of psoralen cross-links by base-catalyzed rearrangement at 90/sup 0/C (BCR). The BCR reaction is more efficient than the photoreversal reaction. They show that the BCR occurs predominantly on the furan side of a psoralen cross-link. The cleavage does not result in the breaking of the DNA backbone, and the thymine based freed from the cross-link by the cleavage reaction appears to be unmodified. Similarly, BCR of the furan-side monoadduct of psoralen removed the psoralen molecule and regenerated the unaltered native oligonucleotide. The pyrone-side psoralen monoadduct is relatively resistant to BCR. One can use BCR to perform efficient oligonucleotide-directed, site-specific delivery of a psoralen monoadduct. As a demonstration of this approach, they have hybridized a 19 base long oligonucleotide vehicle containing a furan-side psoralen monoadduct to a 56 base long complementary oligonucleotide target strand and formed a specific cross-link at the target site with 365-nm UV. Subsequent BCR released the oligonucleotide vehicle and deposited the psoralen at the target site.

Yeung, A.T.; Dinehart, W.J.; Jones, B.K.

1988-08-23

261

In Vivo Fluorescence Resonance Energy Transfer Imaging for Targeted Anti-Cancer Drug Delivery Kinetics  

NASA Astrophysics Data System (ADS)

We describe an approach for the evaluation of targeted anti-cancer drug delivery in vivo. The method emulates the drug release and activation process through acceptor release from a targeted donor-acceptor pair that exhibits fluorescence resonance energy transfer (FRET). In this case, folate targeting of the cancer cells is used - 40 % of all human cancers, including ovarian, lung, breast, kidney, brain and colon cancer, over-express folate receptors. We demonstrate the reconstruction of the spatially-dependent FRET parameters in a mouse model and in tissue phantoms. The FRET parameterization is incorporated into a source for a diffusion equation model for photon transport in tissue, in a variant of optical diffusion tomography (ODT) called FRET-ODT. In addition to the spatially-dependent tissue parameters in the diffusion model (absorption and diffusion coefficients), the FRET parameters (donor-acceptor distance and yield) are imaged as a function of position. Modulated light measurements are made with various laser excitation positions and a gated camera. More generally, our method provides a new vehicle for studying disease at the molecular level by imaging FRET parameters in deep tissue, and allows the nanometer FRET ruler to be utilized in deep tissue.

Webb, Kevin; Gaind, Vaibhav; Tsai, Hsiaorho; Bentz, Brian; Chelvam, Venkatesh; Low, Philip

2012-02-01

262

Galactosylated Chitosan Oligosaccharide Nanoparticles for Hepatocellular Carcinoma Cell-Targeted Delivery of Adenosine Triphosphate  

PubMed Central

Nanoparticles composed of galactosylated chitosan oligosaccharide (Gal-CSO) and adenosine triphosphate (ATP) were prepared for hepatocellular carcinoma cell-specific uptake, and the characteristics of Gal-CSO/ATP nanoparticles were evaluated. CSO/ATP nanoparticles were prepared as a control. The average diameter and zeta potential of Gal-CSO/ATP nanoparticles were 51.03 ± 3.26 nm and 30.50 ± 1.25 mV, respectively, suggesting suitable properties for a drug delivery system. Subsequently, the cytotoxicity of Gal-CSO/ATP nanoparticles were examined by the methyl tetrazolium (MTT) assay, and the half maximal inhibitory concentration (IC50) values were calculated with HepG2 (human hepatocellular carcinoma cell line) cells. The results showed that the cytotoxic effect of nanoparticles on HepG2 cells was low. In the meantime, it was also found that the Gal-CSO/ATP nanoparticles could be uptaken by HepG2 cells, due to expression of the asialoglycoprotein receptor (ASGP-R) on their surfaces. The presented results indicate that the Gal-CSO nanoparticles might be very attractive to be used as an intracellular drug delivery carrier for hepatocellular carcinoma cell targeting, thus warranting further in vivo or clinical investigations. PMID:23899789

Zhu, Xiu Liang; Du, Yong Zhong; Yu, Ri Sheng; Liu, Ping; Shi, Dan; Chen, Ying; Wang, Ying; Huang, Fang Fang

2013-01-01

263

Preparation and characterization of magnetic gene vectors for targeting gene delivery  

NASA Astrophysics Data System (ADS)

The PEI-CMD-MNPs were successfully prepared by the surface modification of magnetic Fe3O4 nanoparticles with carboxymethyl dextran (CMD) and polyethyleneimine (PEI). The PEI-CMD-MNPs polyplexes exhibited a typical superparamagnetic behavior and were well stable over the entire range of pH and NaCl concentration. These PEI-CMD-MNPs were used as magnetic gene vectors for targeting gene delivery. The prepared MNPs at different surface modification stages were characterized using Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA), field emissions canning electron microscopy (FE-SEM), powder X-ray diffraction (XRD) and dynamic laser light scattering (DLS) analysis. The magnetic properties were studied by vibrating sample magnetometer (VSM). To evaluate the performance of the magnetic nanoparticles as gene transfer vector, the PEI-CMD-MNPs were used to delivery green fluorescent protein (GFP) gene into BHK21 cells. The expression of GFP gene was detected by fluorescence microscope. DNA-PEI-CMD-MNPs polyplexes absorbed by the cells were also monitored by Magnetic resonance imaging (MRI). The transfection efficiency and gene expression efficiency of that transfected with a magnet were much higher than that of standard transfection.

Zheng, S. W.; Liu, G.; Hong, R. Y.; Li, H. Z.; Li, Y. G.; Wei, D. G.

2012-10-01

264

Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit.  

PubMed

The gut mucosal immune system is considered to play an important role in counteracting potential adverse effects of food-derived antigens including nanovesicles. Whether nanovesicles naturally released from edible fruit work in a coordinated manner with gut immune cells to maintain the gut in a noninflammatory status is not known. Here, as proof of concept, we demonstrate that grapefruit-derived nanovesicles (GDNs) are selectively taken up by intestinal macrophages and ameliorate dextran sulfate sodium (DSS)-induced mouse colitis. These effects were mediated by upregulating the expression of heme oxygenase-1 (HO-1) and inhibiting the production of IL-1? and TNF-? in intestinal macrophages. The inherent biocompatibility and biodegradability, stability at wide ranges of pH values, and targeting of intestinal macrophages led us to further develop a novel GDN-based oral delivery system. Incorporating methotrexate (MTX), an anti-inflammatory drug, into GDNs and delivering the MTX-GDNs to mice significantly lowered the MTX toxicity when compared with free MTX, and remarkably increased its therapeutic effects in DSS-induced mouse colitis. These findings demonstrate that GDNs can serve as immune modulators in the intestine, maintain intestinal macrophage homeostasis, and can be developed for oral delivery of small molecule drugs to attenuate inflammatory responses in human disease. PMID:23939022

Wang, Baomei; Zhuang, Xiaoying; Deng, Zhong-Bin; Jiang, Hong; Mu, Jingyao; Wang, Qilong; Xiang, Xiaoyu; Guo, Haixun; Zhang, Lifeng; Dryden, Gerald; Yan, Jun; Miller, Donald; Zhang, Huang-Ge

2014-03-01

265

Ultrasound-mediated targeted drug delivery generated by multifocal beam patterns: an in vitro study.  

PubMed

Ultrasound-mediated targeted drug delivery has been a subject for a dedicated research activity for several decades. Nevertheless, in vitro studies in this field of research are characterized by their inconsistencies. To improve the repeatability of such experiments, a novel approach of multifocal spot generation was investigated. A multifocal pattern of 16 spots was utilized using an iterative Gerchberg-Saxton algorithm. The pattern was applied to insonate a 96-well Petri dish plate using a clinically available planar-phased array transducer with approximately 1000 elements with a central frequency of 0.55 MHz. The pattern was acoustically characterized and applied to a monolayer of human breast cancer cell line in the 96-well plate. With the help of ultrasonic contrast agents, the intracellular drug uptake was increased by an average factor of 3.5 compared with the control group. PMID:23332815

Gourevich, Dana; Hertzberg, Yoni; Volovick, Alexander; Shafran, Yaron; Navon, Gil; Cochran, Sandy; Melzer, Andreas

2013-03-01

266

Targeted drug delivery across the blood-brain barrier using ultrasound technique  

PubMed Central

Effective delivery of therapeutic agents into the brain can greatly improve the treatments of neurological and neurodegenerative diseases. Application of focused ultrasound facilitated by microbubbles has shown the potential to deliver drugs across the blood–brain barrier into targeted sites within the brain noninvasively. This review provides a summary of the technological background and principle, highlights of recent significant developments and research progress, as well as a critical commentary on the challenges and future directions in the field. This review also outlines and discusses the tasks that researchers face in order to successfully translate the technology into a clinical reality, including obtaining improved understanding of the mechanisms, demonstration of therapeutic efficacy and safety for specific applications, and development of methodology for rational design to achieve optimized and consistent outcome. PMID:21785679

Deng, Cheri X

2011-01-01

267

Targeted Delivery of Magnetic Cobalt Nanoparticles to the Eye Following Systemic Administration  

NASA Astrophysics Data System (ADS)

The eye offers a unique environment in the body to study progression and response to treatment of various ocular, vascular, and neurologic diseases as they occur in vivo. Due to its clear optical media, we can directly view blood vessels and nerve tissue, which often reflect the health of these tissues in the rest of the body. There are limitations to topical, periocular, or intraocular drug delivery that include access of the drug to the posterior segment of the eye and complications such as local scarring, hemorrhage, retinal detachment, cataract formation, or infection. The aim of this proof-of-concept study was to determine if systemically delivered magnetic cobalt nanoparticles (Co-MNP) could be directed to the eye of C57Bl mice via a unidirectional magnetic field. Both radioactive biodistribution studies and confocal imaging confirmed the increased presence of magnetic particles in the eye following magnetic targeting.

Dengler, Mirko; Saatchi, Katayoun; Dailey, James P.; Matsubara, Joanne; Mikelberg, Frederick S.; Häfeli, Urs O.; Yeung, Sonia N.

2010-12-01

268

Recombinant human elastin-like magnetic microparticles for drug delivery and targeting.  

PubMed

Bioinspired recombinant polypeptides represent a highly promising tool in biomedical research, being protein intrinsic constituents of both cells and their natural matrices. In this regard, a very interesting model is represented by polypeptides inspired by elastin, which naturally confers rubber-like elasticity to tissues, and is able to undergo wide deformations without rupture. In this paper, a microparticle system based on a recombinant human elastin-like polypeptide (HELP) is reported for drug delivery applications. HELP microparticles are prepared through a water-in-oil emulsion of an aqueous solution of recombinant polypeptide in isoctane, followed by enzymatic cross-linking. Superparamagnetic iron oxide nanoparticles are introduced in this system with the purpose of conferring magnetic properties to the microspheres, and thus controlling their targeting and tracking as drug vectors. The obtained microparticles are characterized in terms of morphology, structure, magnetic properties, drug release, and magnetic drivability, showing interesting and promising results for further biomedical applications. PMID:24318291

Ciofani, Gianni; Genchi, Giada Graziana; Guardia, Pablo; Mazzolai, Barbara; Mattoli, Virgilio; Bandiera, Antonella

2014-05-01

269

Contrast Ultrasound Targeted Treatment of Gliomas in Mice via Drug-Bearing Nanoparticle Delivery and Microvascular Ablation  

PubMed Central

We are developing minimally-invasive contrast agent microbubble based therapeutic approaches in which the permeabilization and/or ablation of the microvasculature are controlled by varying ultrasound pulsing parameters. Specifically, we are testing whether such approaches may be used to treat malignant brain tumors through drug delivery and microvascular ablation. Preliminary studies have been performed to determine whether targeted drug-bearing nanoparticle delivery can be facilitated by the ultrasound mediated destruction of "composite" delivery agents comprised of 100nm poly(lactide-co-glycolide) (PLAGA) nanoparticles that are adhered to albumin shelled microbubbles. We denote these agents as microbubble-nanoparticle composite agents (MNCAs). When targeted to subcutaneous C6 gliomas with ultrasound, we observed an immediate 4.6-fold increase in nanoparticle delivery in MNCA treated tumors over tumors treated with microbubbles co-administered with nanoparticles and a 8.5 fold increase over non-treated tumors. Furthermore, in many cancer applications, we believe it may be desirable to perform targeted drug delivery in conjunction with ablation of the tumor microcirculation, which will lead to tumor hypoxia and apoptosis. To this end, we have tested the efficacy of non-theramal cavitation-induced microvascular ablation, showing that this approach elicits tumor perfusion reduction, apoptosis, significant growth inhibition, and necrosis. Taken together, these results indicate that our ultrasound-targeted approach has the potential to increase therapeutic efficiency by creating tumor necrosis through microvascular ablation and/or simultaneously enhancing the drug payload in gliomas. PMID:21206463

Burke, Caitlin W.; Price, Richard J.

2010-01-01

270

Cocoon-like self-degradable DNA nanoclew for anticancer drug delivery.  

PubMed

A bioinspired cocoon-like anticancer drug delivery system consisting of a deoxyribonuclease (DNase)-degradable DNA nanoclew (NCl) embedded with an acid-responsive DNase I nanocapsule (NCa) was developed for targeted cancer treatment. The NCl was assembled from a long-chain single-stranded DNA synthesized by rolling-circle amplification (RCA). Multiple GC-pair sequences were integrated into the NCl for enhanced loading capacity of the anticancer drug doxorubicin (DOX). Meanwhile, negatively charged DNase I was encapsulated in a positively charged acid-degradable polymeric nanogel to facilitate decoration of DNase I into the NCl by electrostatic interactions. In an acidic environment, the activity of DNase I was activated through the acid-triggered shedding of the polymeric shell of the NCa, resulting in the cocoon-like self-degradation of the NCl and promoting the release of DOX for enhanced therapeutic efficacy. PMID:25336272

Sun, Wujin; Jiang, Tianyue; Lu, Yue; Reiff, Margaret; Mo, Ran; Gu, Zhen

2014-10-22

271

The pH-sensitive polyampholyte nanogels: inclusion of carbon nanotubes for improved drug loading.  

PubMed

We report a simple and facile method to prepare a novel pH sensitive polyampholyte nanogel by copolymerizing vinylimidazole (VIM) with acrylic acid (AA) using functionalized single-walled carbon nanotubes (f-SWCNTs) (as reinforcing material) and cyanuric chloride via an intermolecular quaternization reaction. The polyampholyte nanogels have been characterized by various microscopic and spectroscopic methods. These studies reveal that incorporation of nanotubes in cross-linked copolymer of poly(vinylimidazole-co-acrylic acid) (PVI-co-AA) form polyampholyte nanogel with enhanced physical properties. The thermal experiments show that the introduction of f-SWCNTs into PVI-co-AA has significant impact on the thermal stability of nanogels. The rheological study showed that the nanogel is more viscoelastic than native gel. MTT assay indicates that the prepared polyampholyte gels possess biocompatibility and cell viability. The nanogel is also useful material to load water-soluble drug such as promethazine hydrochloride. The releasing profile of the drug from the nanogel clearly shows the pH-sensitive property of the material. PMID:23974001

Sankar, Rajavelu Murali; Seeni Meera, Kamal Mohamed; Samanta, Debasis; Jithendra, Panneerselvam; Mandal, Asit Baran; Jaisankar, Sellamuthu N

2013-12-01

272

Impact of targeted specific antibiotic delivery for gut microbiota modulation on high-fructose-fed rats.  

PubMed

The objective of present investigation was to study the effect of gut microbiota alteration by oral administration of targeted delivery of pH sensitive cefdinir microspheres to high-fructose-fed (HFD) rats. Rats were fed with a high-fructose diet with or without cefdinir microsphere administration for 30 days. The fecal microbiota community, oral glucose tolerance, the markers of liver injury, plasma and hepatic lipids profile, and histological evaluation were investigated. The levels of blood glucose, liver injury markers, lipid profile in plasma and liver, and fat tissue were significantly increased in high-fructose-fed rats. However, after pH-sensitive cefdinir microsphere administration, the elevation of these parameters was significantly suppressed. Cef EL significantly lowered the increased AST (p?targeted antibiotic delivery needs to be further explored for its therapeutic applications. PMID:24574250

Jena, Prasant Kumar; Singh, Shilpa; Prajapati, Bhumika; Nareshkumar, G; Mehta, Tejal; Seshadri, Sriram

2014-04-01

273

Targeting Photoreceptors via Intravitreal Delivery Using Novel, Capsid-Mutated AAV Vectors  

PubMed Central

Development of viral vectors capable of transducing photoreceptors by less invasive methods than subretinal injection would provide a major advancement in retinal gene therapy. We sought to develop novel AAV vectors optimized for photoreceptor transduction following intravitreal delivery and to develop methodology for quantifying this transduction in vivo. Surface exposed tyrosine (Y) and threonine (T) residues on the capsids of AAV2, AAV5 and AAV8 were changed to phenylalanine (F) and valine (V), respectively. Transduction efficiencies of self-complimentary, capsid-mutant and unmodified AAV vectors containing the smCBA promoter and mCherry cDNA were initially scored in vitro using a cone photoreceptor cell line. Capsid mutants exhibiting the highest transduction efficiencies relative to unmodified vectors were then injected intravitreally into transgenic mice constitutively expressing a Rhodopsin-GFP fusion protein in rod photoreceptors (Rho-GFP mice). Photoreceptor transduction was quantified by fluorescent activated cell sorting (FACS) by counting cells positive for both GFP and mCherry. To explore the utility of the capsid mutants, standard, (non-self-complementary) AAV vectors containing the human rhodopsin kinase promoter (hGRK1) were made. Vectors were intravitreally injected in wildtype mice to assess whether efficient expression exclusive to photoreceptors was achievable. To restrict off-target expression in cells of the inner and middle retina, subsequent vectors incorporated multiple target sequences for miR181, an miRNA endogenously expressed in the inner and middle retina. Results showed that AAV2 containing four Y to F mutations combined with a single T to V mutation (quadY?F+T?V) transduced photoreceptors most efficiently. Robust photoreceptor expression was mediated by AAV2(quadY?F+T?V) ?hGRK1?GFP. Observed off-target expression was reduced by incorporating target sequence for a miRNA highly expressed in inner/middle retina, miR181c. Thus we have identified a novel AAV vector capable of transducing photoreceptors following intravitreal delivery to mouse. Furthermore, we describe a robust methodology for quantifying photoreceptor transduction from intravitreally delivered AAV vectors. PMID:23637972

Aslanidi, George V.; Min, Seok Hong; Ruan, Qing; Sun, Jingfen; Dyka, Frank M.; Kasuga, Daniel; Ayala, Andrea E.; Van Vliet, Kim; Agbandje-McKenna, Mavis; Hauswirth, William W.; Boye, Sanford L.; Boye, Shannon E.

2013-01-01

274

Intelligently Targeted Drug Delivery and Enhanced Antitumor Effect by Gelatinase-Responsive Nanoparticles  

PubMed Central

Aims The matrix metalloproteinase (MMP) 2/9, also known as collagenases IV and gelatinases A/B, play a key role in cancer invasion and metastasis. However, the clinical trials of the MMP inhibitors (MMPIs) ended up with disappointing results. In this paper, we synthesized a gelatinase-responsive copolymer (mPEG-PCL) by inserting a gelatinase cleavable peptide (PVGLIG) between mPEG and PCL blocks of mPEG-PCL for anticancer drug delivery to make use of MMP2/9 as an intelligent target for drug delivery. Materials and Methods mPEG-pep-PCL copolymer was synthesized via ring-opening copolymerization and double-amidation. To evaluate whether Nanoparticles (NPs) prepared from this copolymer are superior to NPs prepared from mPEG-PCL, NPs prepared from mPEG-PCL copolymer were used as positive control. Docetaxel-loading NPs using mPEG-pep-PCL and mPEG-PCL were prepared by nano-precipitation method, mentioned as Gel-NPs and Con-NPs, respectively. The morphologic changes of the NPs after treatment with gelatinases were observed macroscopically by spectrophotometer and microscopically by transmission electron microscopy (TEM) and atomic force microscopy (AFM). The cellular uptake amount and cytotoxicity of Gel-NPs and Con-NPs, respectively, in cell lines with different levels of gelatinase expression were studied. Moreover, the cytotoxicity study on the primary cancer cells isolated from pericardial fluids from a patient with late-stage lung cancer was conducted. Results The Gel-NPs aggregated in response to gelatinases, which was confirmed macroscopically and microscopically. The cellular uptake amount of Gel-NPs was correlated with the level of gelatinases. The in vitro antitumor effect of Gel-NPs was also correlated with the level of gelatinases and was superior to Taxotere (commercially available docetaxel) as well as the Con-NPs. The cytotoxicity study on the primary lung cancer cells also confirmed the effectiveness of Gel-NPs. Conclusion The results in this study preliminarily demonstrated the effectiveness of gelatinase-responsive targeting strategy and the prospect of this intelligent nano-drug delivery system though further studies are needed. PMID:23936062

Li, Rutian; Wu, Wei; Liu, Qin; Wu, Puyuan; Xie, Li; Zhu, Zhenshu; Yang, Mi; Qian, Xiaoping; Ding, Yin; Yu, Lixia; Jiang, Xiqun; Guan, Wenxian; Liu, Baorui

2013-01-01

275

Hepatic Stellate Cell–Targeted Delivery of Hepatocyte Growth Factor Transgene via Bile Duct Infusion Enhances Its Expression at Fibrotic Foci to Regress Dimethylnitrosamine-Induced Liver Fibrosis  

E-print Network

Liver fibrosis generates fibrotic foci with abundant activated hepatic stellate cells and excessive collagen deposition juxtaposed with healthy regions. Targeted delivery of antifibrotic therapeutics to hepatic stellate ...

Narmada, Balakrishnan Chakrapani

276

Delivery.  

PubMed

Enthusiasm greeted the development of synthetic organic insecticides in the mid-twentieth century, only to see this give way to dismay and eventually scepticism and outright opposition by some. Regardless of how anyone feels about this issue, insecticides and other pesticides have become indispensable, which creates something of a dilemma. Possibly as a result of the shift in public attitude towards insecticides, genetic engineering of microbes was first met with scepticism and caution among scientists. Later, the development of genetically modified crop plants was met with an attitude that hardened into both acceptance and hard-core resistance. Transgenic insects, which came along at the dawn of the twenty-first century, encountered an entrenched opposition. Those of us responsible for studying the protection of crops have been affected more or less by these protagonist and antagonistic positions, and the experiences have often left one thoughtfully mystified as decisions are made by non-participants. Most of the issues boil down to concerns over delivery mechanisms. PMID:23852646

Miller, Thomas A

2013-11-01

277

Tuberculosis therapeutics: Engineering of nanomedicinal systems for local delivery of targeted drug cocktails  

NASA Astrophysics Data System (ADS)

In this thesis, a multifunctional nanocarrier drug delivery system was investigated and optimized to improve tuberculosis therapy by promoting the intracellular delivery of high payloads of antibiotics. To meet the needs of a patient population which continues to grow by close to 10 million people a year, innovative therapeutics must be formulated by robust and scalable processes. We use Flash NanoPrecipitation for the continuous precipitation of nanocarriers by block copolymer directed assembly, which enables the development of nanocarriers with tunable properties. Stable nanocarriers of Rifampicin and a hydrophobic Rifampicin prodrug have efficacy against tuberculosis in vitro that is equivalent to the soluble Rifampicin. To overcome poor in vivo efficacy of the recently discovered antitubercular drug SQ641, we co-encapsulate SQ641 and Cyclosporine A in a stable aqueous nanocarrier suspension, which enables drug administration and also enhances intracellular accumulation and antitubercular efficacy relative to SQ641 in solution. Since the mannose receptor is involved in the phagocytosis of tuberculosis bacilli, we modify the surface of nanocarriers with mannoside residues to target specific intracellular accumulation in macrophages. The surface density of mannoside terminated polyethylene glycol chains was controlled between 0 and 75% and in vitro cellular association reveals a 9% surface density is optimal for internalization mediated by the mannose receptor. We explore the preparation of large, porous aerosol carrier particles of with tunable deposition characteristics by spray freeze drying with ultrasonic atomization for direct dosing to the lungs. Nanocarriers are loaded at 3 - 50 wt% in mannitol particles with constant size, limited nanocarrier aggregation, and 63% dose delivered to the lungs, as determined by in vitro cascade impaction. There has been a lag in the development of new technologies to facilitate development and commercialization of therapeutic nanocarrier formulations. We present three translational technologies. (1) The intrinsic dissolution rates of drug nanocarriers are determined using a novel assay, based on high surface area lipid sink particles and magnetic separations, to improve in vitro/in vivo correlations. (2) The nanocarrier interaction with whole serum and the polymer surface conformation are correlated to in vivo clearance and general rules are proposed for the design of nanocarriers produced by Flash NanoPrecipitation with extended circulation times for targeted delivery. (3) In Hydrogen Bonding Coacervate Precipitation, polyethylene glycol coated nanocarriers are controllably flocculated with the addition of polyacids to enable rapid filtration and drying. In summary, this research outlines approaches to the customization of nanocarrier drug delivery systems to specifically improve outcomes in tuberculosis therapy. New assays and processing techniques for transitioning formulations from bench research to the clinic are developed. The methods are flexible and can be applied to target various diseases, coupled with rational design of nanocarrier payloads, surface functionality, and dosing route.

D'Addio, Suzanne M.

278

A bacteria deriving peptide modified dendrigraft poly-l-lysines (DGL) self-assembling nanoplatform for targeted gene delivery.  

PubMed

Achieving effective gene therapy for glioma depends on gene delivery systems. The gene delivery system should be able to cross the blood-brain barrier (BBB) and further target glioma at its early stage. Active brain tumor targeted delivery can be achieved using the "Trojan horse" technology, which involves either endogenous ligands or extraneous substances that can recognize and bind to specific receptors in target sites. This method facilitates receptor-mediated endocytosis to cross the BBB and enter into glioma cells. Dendrigraft poly-l-lysines (DGLs), which are novel nonviral gene vectors, are conjugated to a peptide (sequence: EPRNEEK) derived from Streptococcus pneumonia, a pathogen causing meningitis. This process yields peptide-modified nanoparticles (NPs) after DNA loading. Cellular uptake and in vivo imaging results indicate that EPRNEEK peptide-modified NPs have a better brain tumor targeted effect compared with a pentapeptide derived from endogenous laminin after intravenous injection. The mechanism of this effect is further explored in the present study. Besides, EPRNEEK peptide-modified NPs also exhibited a prolonged median survival time. In conclusion, the EPRNEEK peptide-modified DGL NPs exhibit potential as a nonviral platform for efficient, noninvasive, and safe brain glioma dual-targeted gene delivery. PMID:24964270

Liu, Yang; He, Xi; Kuang, Yuyang; An, Sai; Wang, Chenyu; Guo, Yubo; Ma, Haojun; Lou, Jinning; Jiang, Chen

2014-10-01

279

GEN | News Highlights: Scientists Develop High-Capacity Nanoparticles for Targeted Delivery of Drug Cocktails http://www.genengnews.com/gen-news-highlights/scientists-develop-high-capacity-nanoparticles-for-targeted-delivery-of-drug-cocktails/81245016/[4/  

E-print Network

to a nanocarrier surface to promote multivalent binding can boost affinity and drug delivery and help prevent-Based Assays Cell Culture Cellular Analysis Cell Signaling CGH Depression DNA Methylation Embryonic Stem Cells to induce nanocarrier internalization, while selective targeting strategies using ligands that specifically

Brinker, C. Jeffrey

280

Engineering of Bacteria for the Visualization of Targeted Delivery of a Cytolytic Anticancer Agent  

PubMed Central

A number of recent reports have demonstrated that attenuated Salmonella typhimurium are capable of targeting both primary and metastatic tumors. The use of bacteria as a vehicle for the delivery of anticancer drugs requires a mechanism that precisely regulates and visualizes gene expression to ensure the appropriate timing and location of drug production. To integrate these functions into bacteria, we used a repressor-regulated tetracycline efflux system, in which the expression of a therapeutic gene and an imaging reporter gene were controlled by divergent promoters (tetAP and tetRP) in response to extracellular tetracycline. Attenuated S. typhimurium was transformed with the expression plasmids encoding cytolysin A, a therapeutic gene, and renilla luciferase variant 8, an imaging reporter gene, and administered intravenously to tumor-bearing mice. The engineered Salmonella successfully localized to tumor tissue and gene expression was dependent on the concentration of inducer, indicating the feasibility of peripheral control of bacterial gene expression. The bioluminescence signal permitted the localization of gene expression from the bacteria. The engineered bacteria significantly suppressed both primary and metastatic tumors and prolonged survival in mice. Therefore, engineered bacteria that carry a therapeutic and an imaging reporter gene for targeted anticancer therapy can be designed as a theranostic agent. PMID:23922014

Jiang, Sheng-Nan; Park, Seung-Hwan; Lee, Hee Jung; Zheng, Jin Hai; Kim, Hyung-Seok; Bom, Hee-Seung; Hong, Yeongjin; Szardenings, Michael; Shin, Myung Geun; Kim, Sun-Chang; Ntziachristos, Vasilis; Choy, Hyon E; Min, Jung-Joon

2013-01-01

281

Biodegradable nanoparticles mimicking platelet binding as a targeted and controlled drug delivery system.  

PubMed

This research aims to develop targeted nanoparticles as drug carriers to the injured arterial wall under fluid shear stress by mimicking the natural binding ability of platelets via interactions of glycoprotein Ib-alpha (GPIb?) of platelets with P-selectin of damaged endothelial cells (ECs) and/or with von Willebrand factor (vWF) of the subendothelium. Drug-loaded poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles were formulated using a standard emulsion method and conjugated with glycocalicin, the external fraction of platelet GPIb?, via carbodiimide chemistry. Surface-coated and cellular uptake studies in ECs showed that conjugation of PLGA nanoparticles, with GPIb, significantly increased nanoparticle adhesion to P-selectin- and vWF-coated surfaces as well as nanoparticle uptake by activated ECs under fluid shear stresses. In addition, effects of nanoparticle size and shear stress on adhesion efficiency were characterized through parallel flow chamber studies. The observed decrease in bound nanoparticle density with increased particle sizes and shear stresses is also explained through a computational model. Our results demonstrate that the GPIb-conjugated PLGA nanoparticles can be used as a targeted and controlled drug delivery system under flow conditions at the site of vascular injury. PMID:22172292

Kona, Soujanya; Dong, Jing-Fei; Liu, Yaling; Tan, Jifu; Nguyen, Kytai T

2012-02-28

282

Effect of Antigen Shedding on Targeted Delivery of Immunotoxins in Solid Tumors from a Mathematical Model  

PubMed Central

Most cancer-specific antigens used as targets of antibody-drug conjugates and immunotoxins are shed from the cell surface (Zhang & Pastan (2008) Clin. Cancer Res. 14: 7981-7986), although at widely varying rates and by different mechanisms (Dello Sbarba & Rovida (2002) Biol. Chem. 383: 69–83). Why many cancer-specific antigens are shed and how the shedding affects delivery efficiency of antibody-based protein drugs are poorly understood questions at present. Before a detailed numerical study, it was assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins. However, our previous study using a comprehensive mathematical model showed that antigen shedding can significantly improve the efficacy of the mesothelin-binding immunotoxin, SS1P (anti-mesothelin-Fv-PE38), and suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules. Here, we improved this model and applied it to both SS1P and another recombinant immunotoxin, LMB-2, which targets CD25. We show that the effect of antigen shedding is influenced by a number of factors including the number of antigen molecules on the cell surface and the endocytosis rate. The high shedding rate of mesothelin is beneficial for SS1P, for which the antigen is large in number and endocytosed rapidly. On the other hand, the slow shedding of CD25 is beneficial for LMB-2, for which the antigen is small in number and endocytosed slowly. PMID:25343405

Pak, Youngshang; Pastan, Ira; Kreitman, Robert J.; Lee, Byungkook

2014-01-01

283

Reduced ischemic injury after stroke in mice by angiogenic gene delivery via ultrasound-targeted microbubble destruction.  

PubMed

Angiogenic gene therapy in patients with cerebral infarcts may have clinical benefit, but its potential is diminished by the difficulty of introducing genes into the brain. We evaluated the safety and efficacy of ultrasound-targeted microbubble destruction (UTMD) for delivery of genes to the brains of normal mice and after transient middle cerebral artery occlusion. In normal mice, disruption of the blood-brain barrier detected with trypan blue staining was reversible within 24 hours of a single UTMD administration. Expression of reporter genes in the brain after UTMD demonstrated successful targeted gene delivery and transfection. Decreased neurologic function after transient middle cerebral artery occlusion was attenuated versus controls at 7 days after UTMD delivery of vascular endothelial growth factor. Ultrasound-targeted microbubble destruction delivery of the VEGF gene resulted in decreased infarct areas, increased vessel density, and reduced apoptosis versus controls. There was no evidence of permanent brain injury throughout the study. Thus, UTMD was a safe, minimally invasive, effective technique for gene delivery to the brain. Vascular endothelial growth factor transfection of brain cells conferred beneficial effects on histopathologic parameters and neurologic function, and stimulated angiogenesis in a mouse stroke model. PMID:24806305

Wang, Han-Bing; Yang, Lei; Wu, Jun; Sun, Lu; Wu, Jiang; Tian, Hai; Weisel, Richard D; Li, Ren-Ke

2014-06-01

284

Formulation and evaluation of niosomal nasal drug delivery system of folic acid for brain targeting.  

PubMed

Nasal mucosa offers advantages to deliver drugs to brain via olfactory route thus provides rapid onset of drug action and hence faster therapeutic effect. Therefore, various strategies have been proposed to improve the delivery of different drugs to brain including liposomes, colloidal drug carriers, micelles, chimeric peptide technology and nanotechnology through nasal route. The low blood level of folates is the primary cause of depression in Alzheimer's disease. Folic acid is a water soluble vitamin showing difficulty in crossing the blood brain barrier and thus was formulated as niosomal nasal drug delivery systems to target the brain. In the present work, folic acid niosomes were prepared using different nonionic surfactants i.e., span 20, span 60, span 80, tween 20, tween 80 and cholesterol by using lipid layer hydration technique. These were evaluated for particle size, viscosity, osmotic shock, entrapment efficiency and in vitro drug release. The influence of different formulation variables such as surfactant type, surfactant concentration, and cholesterol concentration was optimized for required size distribution, viscosity, entrapment efficiency and in vitro release. The prepared niosomes were in the size range of 3.05-5.625 µm. Niosomes prepared with span 60 and cholesterol in the ratio of 1:1 (50 mg: 50 mg) shown higher entrapment efficiency of 69.42% and better in vitro drug release of 64.2% at the end of 12 hrs and therefore considered as optimized formulation. The stability studies were carried out by storing niosomes at 4±1°C and 25±1°C and showed good stability over the period of storage. The release of drug from niosomes followed anomalous diffusion and obeyed first order release kinetics. Ex-vivo perfusion studies were also performed by using rat model, about 48.15% of drug was found to be absorbed through nasal cavity at the end of 6 hrs. PMID:23863098

Ravouru, Nagaraju; Kondreddy, Pallavi; Korakanchi, Deepthy; Haritha, M

2013-12-01

285

A phage-targeting strategy for the design of spatiotemporal drug delivery from grafted matrices  

PubMed Central

Background The natural response to injury is dynamic and normally consists of complex temporal and spatial cellular changes in gene expression, which, when acting in synchrony, result in patent tissue repair and, in some instances, regeneration. However, current therapeutic regiments are static and most rely on matrices, gels and engineered skin tissue. Accordingly, there is a need to design next-generation grafting materials to enable biotherapeutic spatiotemporal targeting from clinically approved matrices. To this end, rather then focus on developing completely new grafting materials, we investigated whether phage display could be deployed onto clinically approved synthetic grafts to identify peptide motifs capable of linking pharmaceutical drugs with differential affinities and eventually, control drug delivery from matrices over both space and time. Methods To test this hypothesis, we biopanned combinatorial peptide libraries onto different formulations of a wound-healing matrix (Integra®) and eluted the bound peptides with 1) high salt, 2) collagen and glycosaminoglycan or 3) low pH. After three to six rounds of biopanning, phage recovery and phage amplification of the bound particles, any phage that had acquired a capacity to bind the matrix was sequenced. Results In this first report, we identify distinct classes of matrix-binding peptides which elute differently from the screened matrix and demonstrate that they can be applied in a spatially relevant manner. Conclusions We suggest that further applications of these combinatorial techniques to wound-healing matrices may offer a new way to improve the performance of clinically approved matrices so as to introduce temporal and spatial control over drug delivery. PMID:21329515

2011-01-01

286

Formulation and evaluation of chondroitin sulphate tablets of aceclofenac for colon targeted drug delivery.  

PubMed

The aim of the present study was to develop a single unit, site-specific matrix tablets of aceclofenac allowing targeted drug release in the colon with a microbially degradable polymeric carrier, chondroitin suphate (CS) and to coat the optimized batches with a pH dependent polymeric. The tablets were prepared by wet granulation method using starch mucilage as a binding agent and HPMC K-100 as a swellable polymer. Chondroitin Sulphate and drug and physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The tablets were tested for their in-vitro dissolution characteristics in various simulated gastric fluids for their suitability as a colon-specific drug delivery system and also the tablets were evaluated for physicochemical properties, drug content, water percentage swelling and erosion characteristics. The dissolution data demonstrates that the 10% w/w increase in coating level of the pH dependent polymer (Eudragit L-100 and Eudragit S-100 in a ratio of 1 : 4 prevented the drug release in the simulated gastric fluid (pH 1.2-SGF) and the simulated intestinal fluid (pH 7.4-SIF). The dissolution rate of the tablet is dependent upon the concentration of Chondroitin sulphate in the simulated colonic fluid (SCF). The rapid increase in release of aceclofenac in SCF was revealed as due to the degradation of the Chondroitin sulphate membrane by bacterial enzymes. The studies confirmed that, the designed system could be used potentially as a carrier for colon delivery of aceclofenac by regulating drug release in stomach and the small intestine. PMID:24250470

Ramasamy, Thiruganesh; Subbaih Khandasamy, Umadevi; Shanmugam, Suresh; Ruttala, Himabindhu

2012-01-01

287

The Electrospray: Fundamentals and Feasibility of its Application to Targeted Drug Delivery by Inhalation.  

NASA Astrophysics Data System (ADS)

A comprehensive investigation has been performed on the principal features of a particular class of electrostatic sprays. Such electrospray can be established by feeding a liquid, with sufficient electric conductivity, into a small metal capillary maintained at several kilovolts relative to a ground electrode few centimeters away. The liquid meniscus at the outlet of the capillary takes a conical shape under the action of the electric field, through the apex of which a thin ligament is ejected. The ligament then breaks into monodisperse droplets for most of the mass flow (>=97%). Droplet size measurements, using Phase Doppler Anemometry, showed that such sprays can be established in a broad size range with a typical ratio of standard deviation to mean droplet size of less than 10%. The liquid flow rate was shown to be a dominant fact for the control of the droplet size and the liquid electric conductivity a crucial parameter affecting the spray stability. Simultaneous measurements of both droplet size and charge showed that although droplet volume charge density decreases monotonically with the increase of droplet size, the larger droplets are closer to the Rayleigh limit at which they become unstable and disintegrate. Droplet coulombic fission was captured photographically. Measurements of droplet size, velocity and number density throughout the electrospray showed that both droplet velocity field and number density field are self-similar. Complementary use of these measurements and the spray momentum equation permitted the determination of the electric field in the electrospray. The calculations showed the relative importance of the space charge field and the external electric field between the two electrodes. An experimental investigation was also performed on the feasibility of a particular application of the electrospray for targeted drug delivery by inhalation. Stable and monodisperse water sprays were successfully established with droplets in the diameter range of 2-10 ?m by using a CO_2 sheath flow to raise the electric breakdown threshold of the host gas. A prototype delivery system was also developed and was shown to be in principle suitable for aerosol drug delivery.

Tang, Keqi

288

The use of poly(methacrylic acid) nanogel to control the release of amoxycillin with lower cytotoxicity.  

PubMed

In order to control the release of amoxycillin (AM) with lower cytotoxicity and higher activity, ethylene glycol dimethacrylate was used as the cross-linker, and a series of poly(methacrylic acid) (PMAA) nanogels were prepared to load the AM. Then, the morphology, size, in vitro release property, long-term antibacterial performance, cytotoxicity, stability and activity of this novel AM/PMAA nanogel were investigated. The results showed that the AM/PMAA nanogel sustainably released AM with long-term antibacterial activity. Moreover, the AM/PMAA nanogel could improve the stability of AM. More importantly, this AM/PMAA nanogel showed slighter cytotoxicity than AM alone, suggesting that the AM/PMAA nanogel was a more useful dosage form than AM for infectious diseases. PMID:25175257

Liu, Tao; Liu, Hongxi; Wu, Zhimin; Chen, Tao; Zhou, Lin; Liang, Yuanyuan; Ke, Bo; Huang, Hongxing; Jiang, Zhenyou; Xie, Mingqiang; Wu, Ting

2014-10-01

289

A chitosan-modified graphene nanogel for noninvasive controlled drug release  

PubMed Central

A near infrared (NIR) triggered drug delivery platform based on the chitosan-modified chemically reduced graphene oxide (CRGO) incorporated into a thermosensitive nanogel (CGN) was developed. CGN exhibited an NIR-induced thermal effect similar to that of CRGO, reversible thermo-responsive characteristics at 37–42 °C and high doxorubicin hydrochloride (DOX) loading capacity (48 wt%). The DOX loaded CGN (DOX-CGN) released DOX faster at 42 °C than at 37 °C. The fluorescence images revealed DOX expression in the cytoplasm of cancer cells when incubated with DOX-CGN at 37 °C but in the nucleus at 42 °C. Upon irradiation with NIR light (808 nm), a rapid, repetitive DOX release from the DOX-CGN was observed. Furthermore, the cancer cells incubated with DOX-CGN and irradiated with NIR light displayed significantly greater cytotoxicity than without irradiation owing to NIR-triggered increase in temperature leading to nuclear DOX release. These results demonstrate CGN’s promising application for on-demand drug release by NIR light. PMID:23352802

Wang, Chunyan; Mallela, Jaya; Garapati, Ujjwala Sree; Ravi, Sowndharya; Chinnasamy, Vignesh; Girard, Yvonne; Howell, Mark; Mohapatra, Subhra

2013-01-01

290

Characterization of protein and peptide binding to nanogels formed by differently charged chitosan derivatives.  

PubMed

Chitosan (Chi) is a natural biodegradable cationic polymer with remarkable potency as a vehicle for drug or vaccine delivery. Chi possesses multiple groups, which can be used both for Chi derivatization and for particle formation. The aim of this work was to produce stable nanosized range Chi gels (nanogels, NGs) with different charge and to study the driving forces of complex formation between Chi NGs and proteins or peptides. Positively charged NGs of 150 nm in diameter were prepared from hexanoyl chitosan (HC) by the ionotropic gelation method while negatively charged NGs of 190 nm were obtained from succinoyl Chi (SC) by a Ca²? coacervation approach. NGs were loaded with a panel of proteins or peptides with different weights and charges. We show that NGs preferentially formed complexes with oppositely charged molecules, especially peptides, as was demonstrated by gel-electrophoresis, confocal microscopy and HPLC. Complex formation was accompanied by a change in zeta-potential and decrease in size. We concluded that complex formation between Chi NGs and peptide/proteins is mediated mostly by electrostatic interactions. PMID:23823877

Zubareva, Anastasia; Ily'ina, Alla; Prokhorov, Aleksander; Kurek, Denis; Efremov, Mikhail; Varlamov, Valery; Senel, Sevda; Ignatyev, Pavel; Svirshchevskaya, ?lena

2013-01-01

291

Antimicrobial surface grafted thermally responsive PNIPAM-co-ALA nano-gels.  

PubMed

Thermally responsive Poly(N-isopropylacrylamide) co-allylamine (PNIPAM-co-ALA) nano-gels were synthesised and grafted onto non-woven polypropylene. Silver nitrate was incorporated into the nano-gels in their expanded state and their antimicrobial properties tested. Bacterial growth was measured before and after the Lower Critical Solution Temperature. Below the LCST, bacteria grew, above the LCST bacterial growth was prevented or retarded. PMID:22046590

James, Charlotte; Johnson, Andrew L; Jenkins, A Toby A

2011-12-28

292

Boron-containing folate receptor-targeted liposomes as potential delivery agents for neutron capture therapy.  

PubMed

Boron neutron capture therapy (BNCT) depends on the selective delivery of a sufficient number of (10)B atoms to tumor cells to sustain a lethal (10)B(n,alpha)(7)Li reaction. Expression of FR frequently is amplified among human tumors. The goal of the present study was to investigate folate receptor (FR)-targeted liposomes as potential carriers for a series of boron-containing agents. Two highly ionized boron compounds, Na(2)[B(12)H(11)SH] and Na(3) (B(20)H(17)NH(3)), were incorporated into liposomes by passive loading with encapsulation efficiencies of 6% and 15%, respectively. In addition, five weakly basic boronated polyamines were investigated. Two were the spermidine derivatives: N(5)-(4-carboranylbutyl)spermidine.3HCl (SPD-5), N(5)-[4-(2-aminoethyl-o-carboranyl)butyl]spermidine.4HCl (ASPD-5). Three were the spermine derivatives: N(5)-(4-carboranylbutyl)spermine.4HCl (SPM-5), N(5)-[4-(2-aminoethyl-o-carboranyl)butyl]spermine.5HCl (ASPM-5), and N(5),N(10)-bis(4-carboranylbutyl)spermine.4 HCl (SPM-5,10). These were incorporated into liposomes by a pH-gradient-driven remote-loading method with varying loading efficiencies, which were influenced by the specific trapping agent and the structure of the boron compound. Greater loading efficiencies were obtained with lower molecular weight boron derivatives, using ammonium sulfate as the trapping agent, compared to those obtained with sodium citrate. The in vitro uptake of folate-derivatized, boronated liposomes was investigated using human KB squamous epithelial cancer cells, which have amplified FR expression. Higher cellular boron uptake (up to 1584 microg per 10(9) cells) was observed with FR-targeted liposomes than with nontargeted control liposomes (up to 154 microg per 10(9) cells), irrespective of the chemical form of the boron and the method used for liposomal preparation. KB cell binding of the FR-targeted liposomes was saturable and could be blocked by 1 mM free folic acid. Our findings suggest that further evaluation of FR-targeted liposomes is warranted to assess their potential as boron carriers for neutron capture therapy. PMID:12009931

Pan, Xing Q; Wang, Huaqing; Shukla, Supriya; Sekido, Masaru; Adams, Dianne M; Tjarks, Werner; Barth, Rolf F; Lee, Robert J

2002-01-01

293

Characterization and Antimicrobial Property of Poly(Acrylic Acid) Nanogel Containing Silver Particle Prepared by Electron Beam  

PubMed Central

In this study, we developed a one step process to synthesize nanogel containing silver nanoparticles involving electron beam irradiation. Water-soluble silver nitrate powder is dissolved in the distilled water and then poly(acrylic acid) (PAAc) and hexane are put into this silver nitrate solution. These samples are irradiated by an electron beam to make the PAAc nanogels containing silver nanoparticles (Ag/PAAc nanogels). The nanoparticles were characterized by scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). In addition, the particle size and zeta-potential were confirmed by a particle size analyzer (PSA). The antibacterial properties of the nanogels were evaluated by paper diffusion test. The Ag/PAAc nanogels had an antibacterial effect against Escherichia coli and Staphylococcus aureus. The nanogels also demonstrated a good healing effect against diabetic ulcer. The size of the Ag/PAAc nanogels decreased with increasing irradiation doses, and the absolute value of the zeta potential increased with increasing irradiation doses. Also, the Ag/PAAc nanogels exhibited good antibacterial activity against both Gram-negative and Gram-positive bacteria. In in vivo wound healing, the Ag/PAAc nanogels have a good healing effect. PMID:23708101

Choi, Jong-Bae; Park, Jong-Seok; Khil, Myung-Seob; Gwon, Hui-Jeong; Lim, Youn-Mook; Jeong, Sung-In; Shin, Young-Min; Nho, Young-Chang

2013-01-01

294

Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system.  

PubMed

The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. This review provides insight on the current status of this unique drug delivery technique, experience in preclinical models, and potential for clinical translation. If translated to humans, this method would offer a flexible means to target therapeutics to desired points or volumes in the brain, and enable the whole arsenal of drugs in the CNS that are currently prevented by the BBB. PMID:24462453

Aryal, Muna; Arvanitis, Costas D; Alexander, Phillip M; McDannold, Nathan

2014-06-01

295

siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene.  

PubMed

The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications. PMID:24814863

Minami, Kosuke; Okamoto, Koji; Doi, Kent; Harano, Koji; Noiri, Eisei; Nakamura, Eiichi

2014-01-01

296

siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene  

PubMed Central

The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications. PMID:24814863

MINAMI, Kosuke; OKAMOTO, Koji; DOI, Kent; HARANO, Koji; NOIRI, Eisei; NAKAMURA, Eiichi

2014-01-01

297

siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene  

NASA Astrophysics Data System (ADS)

The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications.

Minami, Kosuke; Okamoto, Koji; Doi, Kent; Harano, Koji; Noiri, Eisei; Nakamura, Eiichi

2014-05-01

298

Folic acid-conjugated iron oxide porous nanorods loaded with doxorubicin for targeted drug delivery.  

PubMed

Iron oxide porous nanorods (IOPNR) with lengths ranging from 40nm to 60nm and pore diameters ranging from 5nm to 10nm were prepared, and further modified with NH2-PEG-FA (FA-PEG-IOPNR) for ligand targeting and modified with NH2-PEG-OCH3 (PEG-IOPNR) as a control. Instead of chemical bonding, doxorubicin (DOX), a low water solubility anticancer drug, was loaded in the pores of the modified IOPNR because of their porous structure and high porosity. The release of DOX in acidic PBS solution (pH 5.3) was faster than that in neutral (pH 7.4) solution. The analysis results from TEM, inductively coupled plasma emission spectroscopy, confocal laser scanning microscopy, and flow cytometry analyses indicated that the presence of FA on the surface of the nanorods increase the cellular uptake of nanorods in the case of HeLa cells, a folate receptor (FR)-positive cell line. In contrast, for COS 7 cells, a FR-negative cell line, FA ligand on the surface of the nanorods showed no effect on the cellular uptake. MTT assay indicated that the cytotoxicity of DOX loaded in FA-PEG-IOPNR to HeLa cells was higher than that of DOX in PEG-IOPNR. In the case of COS 7 cells, no significant difference between the cytotoxicity of DOX loaded in FA-PEG-IOPNR and PEG-IOPNR was found. These results suggested that FA-PEG-IOPNR had the potential for target delivery of chemotherapeutic into cancer cells. PMID:24907583

Yu, Ping; Xia, Xi-Ming; Wu, Ming; Cui, Can; Zhang, Yang; Liu, Lei; Wu, Bo; Wang, Cai-Xia; Zhang, Liu-Jie; Zhou, Xiang; Zhuo, Ren-Xi; Huang, Shi-Wen

2014-08-01

299

Nanogels with high active ?-cyclodextrin content as physical coating system with sustained release properties.  

PubMed

We present the application of nanogels with high functional ?-cyclodextrin (?-CD) content as new and versatile method for the modification and protection of textiles. The complexation potential of covalently embedded ?-CD in nanogels is demonstrated for the common insecticide permethrin in aqueous environment. It is shown that permethrin containing ?-CD nanogels can be applied easily, homogeneously and safely on keratin fibers like wool fabrics and human hairs. The permethrin concentration on fibers is directly controlled by the permethrin content in nanogels. We tested the permanence of permethrin on treated fibers with regard to washing and UV fastness. Our results show that permethrin complexed in nanogels is removed from the textile during washing, but that the complexation of permethrin by ?-CD domains in the nanogels protects the active ingredient from UV degradation. Bioassay tests against the larvae of Tineola bisselliella and Anthrenocerus australis show that the activity of the ingredients does not decrease after complexation in ?-CD gels and it results in protection of the wool fibers against degradation by the insect larvae. PMID:24533699

Kettel, Markus J; Schaefer, Karola; Groll, Juergen; Moeller, Martin

2014-02-26

300

Temporal Multiscale Approach for Nanocarrier Motion with Simultaneous Adhesion and Hydrodynamic Interactions in Targeted Drug Delivery  

PubMed Central

We present a fluctuating hydrodynamics approach and a hybrid approach combining fluctuating hydrodynamics with generalized Langevin dynamics to resolve the motion of a nanocarrier when subject to both hydrodynamic interactions and adhesive interactions. Specifically, using these approaches, we compute equilibrium probability distributions at constant temperature as well as velocity autocorrelation functions of the nanocarrier subject to thermal motion in a quiescent Newtonian fluid medium, when tethered by a harmonic spring force mimicking a tether due to a single receptor-ligand bond. We demonstrate that the thermal equipartition of translation, rotation, and spring degrees of freedom are preserved by our formalism while simultaneously resolving the nature of the hydrodynamic correlations. Additionally, we evaluate the potential of mean force (or free energy density) along a specified reaction coordinate to faciltate extensive conformational sampling of the nanocarrier motion. We show that our results are in excellent agreement with analytical results and Monte Carlo simulations, thereby validating our methodologies. The frameworks we have presented provide a comprehensive platform for temporal multiscale modeling of hydrodynamic and microscopic interactions mediating nanocarrier motion and adhesion in vascular targeted drug delivery. PMID:23853388

Radhakrishnan, R.; Uma, B.; Liu, J.; Ayyaswamy, P. S.; Eckmann, D. M.

2012-01-01

301

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery  

PubMed Central

The sodium iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic (99mTc, 125I, 124I) and therapeutic (131I, 186Re, 188Re, 211At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy. PMID:20201784

Hingorani, M.; Spitzweg, C.; Vassaux, G.; Newbold, K.; Melcher, A.; Pandha, H.; Vile, R.; Harrington, K.

2013-01-01

302

Multifunctional, self-assembling anionic peptide-lipid nanocomplexes for targeted siRNA delivery.  

PubMed

Formulations of cationic liposomes and polymers readily self-assemble by electrostatic interactions with siRNA to form cationic nanoparticles which achieve efficient transfection and silencing in vitro. However, the utility of cationic formulations in vivo is limited due to rapid clearance from the circulation, due to their association with serum proteins, as well as systemic and cellular toxicity. These problems may be overcome with anionic formulations but they provide challenges of self-assembly and transfection efficiency. We have developed anionic, siRNA nanocomplexes utilizing anionic PEGylated liposomes and cationic targeting peptides that overcome these problems. Biophysical measurements indicated that at optimal ratios of components, anionic PEGylated nanocomplexes formed spherical particles and that, unlike cationic nanocomplexes, were resistant to aggregation in the presence of serum, and achieved significant gene silencing although their non-PEGylated anionic counterparts were less efficient. We have evaluated the utility of anionic nanoparticles for the treatment of neuronal diseases by administration to rat brains of siRNA to BACE1, a key enzyme involved in the formation of amyloid plaques. Silencing of BACE1 was achieved in vivo following a single injection of anionic nanoparticles by convection enhanced delivery and specificity of RNA interference verified by 5' RACE-PCR and Western blot analysis of protein. PMID:24985735

Tagalakis, Aristides D; Lee, Do Hyang D; Bienemann, Alison S; Zhou, Haiyan; Munye, Mustafa M; Saraiva, Luisa; McCarthy, David; Du, Zixiu; Vink, Conrad A; Maeshima, Ruhina; White, Edward A; Gustafsson, Kenth; Hart, Stephen L

2014-09-01

303

Plasma synthesis of carbon-iron magnetic nanoparticles and immobilization of doxorubicin for targeted drug delivery  

NASA Astrophysics Data System (ADS)

A novel dense-medium plasma technology (submerged arc discharge) was used to synthesize carbon/iron-based magnetic nanoparticles (CMNP) from benzene or acetonitrile at room temperature and atmospheric pressure. Scanning electron microscopy shows that the nanoparticles are spherical and 40-50 nm in diameter. Results from x-ray photoelectron spectroscopy and other analytical techniques demonstrated that the CMNP consist of iron/iron oxide clusters that are evenly dispersed in a carbon-based host-structure. After synthesis, CMNP samples were activated in three steps: argon plasma treatment, in-situ reactions with ethylene diamine, and substrate activation by glutaric dialdehyde. Free doxorubicin (DOX) molecules were then immobilized onto the activated CMNP surfaces to form CMNP-DOX conjugates. The loading efficiency of doxorubicin was determined. In vitro anti-proliferative activity of CMNP-DOX conjugates was confirmed in tumor-cell cytotoxicity assays. It is therefore suggested that CMNP may be used as a magnetic carrier for targeted drug-delivery applications.

Ma, Y.; Manolache, S.; Denes, F.; Vail, D.; Thamm, D.; Kurzman, I.

2006-06-01

304

PEGylated fullerene/iron oxide nanocomposites for photodynamic therapy, targeted drug delivery and MR imaging.  

PubMed

Recently, fullerene and fullerene derivatives owning to their highly enriched physical and chemical properties have been widely explored for applications in many different fields including biomedicine. In this study, iron oxide nanoparticles (IONPs) were decorated onto the surface of fullerene (C60), and then PEGylation was performed to improve the solubility and biocompatibility of C60-IONP, obtaining a multi-functional C60-IONP-PEG nanocomposite with strong superparamagnetism and powerful photodynamic therapy capacity. Hematoporphyrin monomethyl ether (HMME), a new photodynamic anti-cancer drug, was conjugated to C60-IONP-PEG, forming a C60-IONP-PEG/HMME drug delivery system, which demonstrated an excellent magnetic targeting ability in cancer therapy. Compared with free HMME, remarkably enhanced photodynamic cancer cell killing effect using C60-IONP-PEG/HMME was realized not only in a cultured B16-F10 cells in vitro but also in an in vivo murine tumor model due to 23-fold higher HMME uptake of tumor and strong photodynamic activity of C60-IONP-PEG. Moreover, C60-IONP-PEG could be further used as a T2-contrast agent for in vivo magnetic resonance imaging. Our work showed C60-IONP-PEG/HMME had a great potential for cancer theranostic applications. PMID:24034498

Shi, Jinjin; Yu, Xiaoyuan; Wang, Lei; Liu, Yan; Gao, Jun; Zhang, Jing; Ma, Rou; Liu, Ruiyuan; Zhang, Zhenzhong

2013-12-01

305

Targeted delivery of pharmacological chaperones for Gaucher disease to macrophages by a mannosylated cyclodextrin carrier.  

PubMed

Gaucher disease (GD) is a rare monogenetic disorder leading to dysfunction of acid ?-glucosidase (?-glucocerebrosidase; GCase) and accumulation of glucosylceramide in lysosomes, especially in macrophages (Gaucher cells). Many of the mutations at the origin of GD do not impair the catalytic activity of GCase, but cause misfolding and subsequent degradation by the quality control system at the endoplasmic reticulum. Pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the endogenous mutant enzyme represent promising alternatives to the currently available enzyme replacement and substrate reduction therapies (ERT and SRT, respectively), but unfavorable biodistribution and potential side-effects remain important issues. We have now designed a strategy to enhance the controlled delivery of PCs to macrophages that exploit the formation of ternary complexes between the PC, a trivalent mannosylated ?-cyclodextrin (?CD) conjugate and the macrophage mannose receptor (MMR). First, PC candidates with appropriate relative avidities towards the ?CD cavity and the GCase active site were selected to ensure efficient transfer of the PC cargo from the host to the GCase active site. Control experiments confirmed that the ?CD carrier was selectively recognized by mannose-specific lectins and that the corresponding PC:mannosylated ?CD supramolecular complex retained both the chaperoning activity, as confirmed in human GD fibroblasts, and the MMR binding ability. Finally, fluorescence microscopy techniques proved targeting and cellular uptake of the PC-loaded system in macrophages. Altogether, the results support that combined cyclodextrin encapsulation and glycotargeting may improve the efficacy of PCs for GD. PMID:24589885

Rodríguez-Lavado, Julio; de la Mata, Mario; Jiménez-Blanco, José L; García-Moreno, M Isabel; Benito, Juan M; Díaz-Quintana, Antonio; Sánchez-Alcázar, José A; Higaki, Katsumi; Nanba, Eiji; Ohno, Kousaku; Suzuki, Yoshiyuki; Ortiz Mellet, Carmen; García Fernández, José M

2014-04-14

306

Functionalized nanoscale oil bodies for targeted delivery of a hydrophobic drug  

NASA Astrophysics Data System (ADS)

Effective formulations of hydrophobic drugs for cancer therapies are challenging. To address this issue, we have sought to nanoscale artificial oil bodies (NOBs) as an alternative. NOBs are lipid-based particles which consist of a central oil space surrounded by a monolayer of oleosin (Ole)-embedded phospholipids (PLs). Ole was first fused with the anti-HER2/neu affibody (Ole-ZH2), and the resulting hybrid protein was overproduced in Escherichia coli. ZH2-displayed NOBs were then assembled by sonicating the mixture containing plant oil, PLs, and isolated Ole-ZH2 in one step. To illustrate their usefulness, functionalized NOBs were employed to encapsulate a hydrophobic anticancer drug, Camptothecin (CPT). As a result, these CPT-loaded NOBs remained stable in serum and the release of CPT at the non-permissive condition exhibited a sustained and prolonged profile. Moreover, plain NOBs were biocompatible whereas CPT-loaded NOBs exerted a strong cytotoxic effect on HER2/neu-positive cells in vitro. Administration of xenograft nude mice with CPT-loaded NOBs also led to the regression of solid tumors in an effective way. Overall, the result indicates the potential of NOBs for targeted delivery of hydrophobic drugs.

Chiang, Chung-Jen; Lin, Che-Chin; Lu, Tzu-Li; Wang, Hesin-Fu

2011-10-01

307

Hyaluronate tethered, "smart" multiwalled carbon nanotubes for tumor-targeted delivery of doxorubicin.  

PubMed

The present study reports the optimized synthesis, physicochemical characterization, and biological evaluation of a novel, multiwalled carbon nanotube-hyaluronic acid (MWCNT-HA) conjugate, complexed with an anticancer agent, Doxorubicin (DOX) via ?-? stacking interaction. The therapeutic conjugate was concomitantly labeled with a near-infrared fluorescent dye, Alexa-Flour-647 (AF-647), and radiotracer Technetium-99m ((99m)Tc) to track its whereabouts both in vitro and in vivo via optical and scintigraphic imaging techniques. Covalent functionalization of MWCNTs with HA facilitated their internalization into human lung adenocarcinoma, A549 cells via hyaluronan receptors (HR) mediated endocytosis. Internalized nanotubes showed lysosomal trafficking, followed by low pH-triggered DOX release under endolysosomal conditions. Consequently, DOX-loaded HA-MWCNTs exhibited 3.2 times higher cytotoxicity and increased apoptotic activity than free DOX in equivalent concentrations. Organ distribution studies in Ehlrich ascites tumor (EAT) bearing mice model indicated that tumor specific localization of (99m)Tc-MWCNT-HA-DOX is significantly higher than both free drug and nontargeted MWCNTs. Pharmacodynamic studies in chemically breast-cancer-induced rats showed that the tumor-growth inhibitory effect of HA-MWCNT-DOX was 5 times higher than free DOX in equivalent concentration. DOX delivered through HA-MWCNTs was devoid of any detectable cardiotoxity, hepatotoxicity, or nephrotoxicity. All these promising attributes make HA-MWCNTs a "smart" platform for tumor-targeted delivery of anticancer agents. PMID:23039830

Datir, Satyajit R; Das, Manasmita; Singh, Raman Preet; Jain, Sanyog

2012-11-21

308

Selective occlusion of tumor blood vessels by targeted delivery of an antibody-photosensitizer conjugate.  

PubMed

The irregular vasculature and high interstitial pressure of solid tumors hinder the delivery of cytotoxic agents to cancer cells. As a consequence, the doses of chemotherapy necessary to achieve complete tumor eradication are associated with unacceptably high toxicities. The selective thrombosis of tumor blood vessels has been postulated as an alternative avenue for combating cancer, depriving tumors of nutrients and oxygen and causing an avalanche of tumor cell deaths. The human antibody L19, specific to the EDB domain of fibronectin, a marker of angiogenesis, is capable of selective in vivo localization around tumor blood vessels and is thus a suitable agent for delivering toxic payloads to the tumor neovasculature. Here we show that a chemical conjugate of the L19 antibody with the photosensitizer bis(triethanolamine)Sn(IV) chlorin e(6), after intravenous injection and irradiation with red light, caused an arrest of tumor growth in mice with subcutaneous tumors. By contrast, a photosensitizer conjugate obtained with an antibody of identical pharmacokinetic properties but irrelevant specificity did not exhibit a significant therapeutic effect. These results confirm that vascular targeting strategies, aimed at the selective occlusion/disruption of tumor blood vessels, have a significant anticancer therapeutic potential and encourage the use of antibody-photosensitizer conjugates for the therapy of superficial tumors and possibly other angiogenesis-related pathologies. PMID:16217760

Fabbrini, Monica; Trachsel, Eveline; Soldani, Patrizia; Bindi, Stefano; Alessi, Patrizia; Bracci, Luisa; Kosmehl, Hartwig; Zardi, Luciano; Neri, Dario; Neri, Paolo

2006-04-01

309

Targeted drug delivery: binding and uptake of plant lectins using human 5637 bladder cancer cells.  

PubMed

In an effort to detect novel strategies in bladder cancer therapy, the potential and the applicability of different plant lectins was investigated using 5637 cells as a model for human urinary carcinoma. The cell-lectin interaction studies were performed with single cells as well as monolayers using flow cytometry and fluorimetry. As a result, wheat germ agglutinin (WGA) and Ulex europaeus agglutinin (UEA) revealed strongest interaction with single cells demonstrating a high presence of N-acetyl-d-glucosamine, sialic acid and alpha-l-fucose residues on the membrane surface. Considering monolayers, binding of most lectins depended on the culturing period pointing to a change in the glycocalyx composition during cultivation. However, constant binding capacities combined with a high specificity were detected for WGA. Cytoinvasion studies were performed with WGA and revealed a decreased fluorescence intensity at 37 degrees C as compared to 4 degrees C, which points to internalisation of the lectin and accumulation in acidic compartments. Intracellular localization was confirmed by addition of monensin that compensates the pH-gradient between acidic compartments and cytoplasm leading to a full reversal of the decline in fluorescence. According to these findings, some lectins, especially WGA, offer promising features for targeting drugs to bladder cancer cells. This might be interesting for the development of functionalized drug delivery systems for site specific antitumor therapy leading to reduced toxicity, prolonged exposition, and improved efficacy. PMID:18602465

Plattner, Verena E; Wagner, Maria; Ratzinger, Gerda; Gabor, Franz; Wirth, Michael

2008-10-01

310

Brain-Targeted Delivery of Trans-Activating Transcriptor-Conjugated Magnetic PLGA/Lipid Nanoparticles  

PubMed Central

Magnetic poly (D,L-lactide-co-glycolide) (PLGA)/lipid nanoparticles (MPLs) were fabricated from PLGA, L-?-phosphatidylethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-amino (polyethylene glycol) (DSPE-PEG-NH2), and magnetic nanoparticles (NPs), and then conjugated to trans-activating transcriptor (TAT) peptide. The TAT-MPLs were designed to target the brain by magnetic guidance and TAT conjugation. The drugs hesperidin (HES), naringin (NAR), and glutathione (GSH) were encapsulated in MPLs with drug loading capacity (>10%) and drug encapsulation efficiency (>90%). The therapeutic efficacy of the drug-loaded TAT-MPLs in bEnd.3 cells was compared with that of drug-loaded MPLs. The cells accumulated higher levels of TAT-MPLs than MPLs. In addition, the accumulation of QD-loaded fluorescein isothiocyanate (FITC)-labeled TAT-MPLs in bEnd.3 cells was dose and time dependent. Our results show that TAT-conjugated MPLs may function as an effective drug delivery system that crosses the blood brain barrier to the brain. PMID:25187980

Zhang, Yifang; Sun, Tingting; Zhang, Fang; Wu, Jian; Fu, Yanyan; Du, Yang; Zhang, Lei; Sun, Ying; Liu, YongHai; Ma, Kai; Liu, Hongzhi; Song, Yuanjian

2014-01-01

311

Effective Targeted Gene Delivery to Dendritic Cells via Synergetic Interaction of Mannosylated Lipid with DOPE and BCAT  

PubMed Central

The efficient delivery of plasmids encoding antigenic determinants into dendritic cells (DCs) that control immune response is a promising strategy for rapid development of new vaccines. In this study, we prepared a series of targeted cationic lipoplex based on two synthetic lipid components, mannose-poly(ethylene glycol, MW3000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (Mannose-PEG3000-DSPE) and O-(2R-1,2-di-O-(1'Z,9'Z-octadecadienyl)-glycerol)-3-N-(bis-2-aminoethyl)-carbamate (BCAT), that were formulated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) for evaluation as non-viral vectors for transgene expression in DCs. First, we optimized the N:P ratio for maximum transfection and then screened the effects of mannose targeting for further enhancement of transfection levels. Our results indicate that efficient delivery of gWIZ GFP plasmid into DCs was observed for mannose compositions of ~10%, whereas low transfection efficiencies were observed with non-targeted formulations. Mannose-targeted lipofectamine complexes also showed high GFP expression levels in DCs relative to non-targeted lipofectamine controls. The best transfection performance was observed using 10 mol % Mannose-PEG3000-DSPE, 60 mol% BCAT, and 30 mol % DOPE, indicating that the most efficient delivery into DCs occurs via synergistic interaction between mannose targeting and acid-labile, fusogenic BCAT:DOPE formulations. Our data suggest that mannose-PEG3000-DSPE:BCAT:DOPE formulations may be effective gene delivery vehicles for the development of DC-based vaccines. PMID:22229467

Kim, Hee-Kwon; Wei, Huiling; Kulkarni, Aditya; Pogranichniy, Roman M.; Thompson, David H.

2012-01-01

312

Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death  

PubMed Central

Background Stimulation of CD40 can augment anti-cancer T cell immune responses by triggering effective activation and maturation of antigen-presenting cells (APCs). Although CD40 agonists have clinical activity in humans, the associated systemic activation of the immune system triggers dose-limiting side-effects. Methods To increase the tumor selectivity of CD40 agonist-based therapies, we developed an approach in which soluble trimeric CD40L (sCD40L) is genetically fused to tumor targeting antibody fragments, yielding scFv:CD40L fusion proteins. We hypothesized that scFv:CD40L fusion proteins would have reduced CD40 agonist activity similar to sCD40L but will be converted to a highly agonistic membrane CD40L-like form of CD40L upon anchoring to cell surface exposed antigen via the scFv domain. Results Targeted delivery of CD40L to the carcinoma marker EpCAM on carcinoma cells induced dose-dependent paracrine maturation of DCs ~20-fold more effective than a non-targeted control scFv:CD40L fusion protein. Similarly, targeted delivery of CD40L to the B cell leukemia marker CD20 induced effective paracrine maturation of DCs. Of note, the CD20-selective delivery of CD40L also triggered loss of cell viability in certain B cell leukemic cell lines as a result of CD20-induced apoptosis. Conclusions Targeted delivery of CD40L to cancer cells is a promising strategy that may help to trigger cancer-localized activation of CD40 and can be modified to exert additional anti-cancer activity via the targeting domain. PMID:24741998

2014-01-01

313

Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging.  

PubMed

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered. PMID:20199661

Bhaskar, Sonu; Tian, Furong; Stoeger, Tobias; Kreyling, Wolfgang; de la Fuente, Jesús M; Grazú, Valeria; Borm, Paul; Estrada, Giovani; Ntziachristos, Vasilis; Razansky, Daniel

2010-01-01

314

Development of Viral Capsid DNA Aptamer Conjugates as Cell-Targeted Delivery Vehicles  

NASA Astrophysics Data System (ADS)

The ability to generate semi-synthetic DNA-protein conjugates has become increasingly important in the fields of chemical biology and nanobiotechnology. As applications in these fields become more complex, there is also an increased need for methods of attaching synthetic DNA to protein substrates in a well-defined manner. This work outlines the development of new methods for site-specific DNA-protein bioconjugation, as well as the development of novel viral capsid DNA aptamer conjugates for cell-targeting purposes. In order to generate DNA-protein conjugates in a site-specific manner, chemistries orthogonal to native functional groups present on DNA and proteins were exploited. In one method, the attachment of DNA to proteins was achieved via oxime formation. This strategy involved the in situ deprotection of an allyloxycarbonyl-protected alkoxyamine-bearing DNA in the presence of a protein containing a single ketone group. The utility of this approach was demonstrated in the synthesis of a DNA-GFP conjugate. In addition to the oxime formation route, two oxidative coupling methods were also developed for DNA-protein bioconjugation. The first reaction coupled phenylenediamine-containing DNA to anilines, which had been site-specifically incorporated into proteins, in the presence of NaIO4. These reaction conditions were demonstrated on the proteins bacteriophage MS2 and GFP, and were mild enough for the components to retain both protein structure and DNA base-pairing capabilities. The second oxidative coupling reaction conjugated aniline-containing proteins to DNA bearing an o-aminophenol moiety. This reaction occurred under similarly mild conditions; however, higher coupling yields were achieved on MS2 at shorter reaction times by using this strategy. In all three of these methods, the generation of a singly-modified product was achieved. Using one of our oxidative coupling strategies, MS2-DNA aptamer conjugates were synthesized for the development of multivalent cell-targeting delivery vehicles. These agents were generated by selectively functionalizing the interior and exterior surfaces of MS2 with functional molecules and DNA aptamers, respectively, using orthogonal bioconjugation reactions. Interior surface modification was achieved through the incorporation of a uniquely-reactive cysteine residue, while exterior modification occurred via the introduction of the non-natural amino acid p-aminophenylalanine. MS2 capsids possessing interior fluorophores and exterior DNA aptamers targeted to a Jurkat T cell surface receptor were synthesized using this strategy. In cell-binding experiments, these dual-surface modified capsids were shown to bind target cells in an aptamer-dependent manner. In addition, colocalization experiments using confocal microscopy elucidated their cellular internalization pathway. Following validation of the cell-targeting capabilities of aptamer-MS2 conjugates, a multivalent photodynamic agent was developed for targeted photodynamic therapy. This agent was synthesized by installing singlet oxygen-generating porphyrins on the interior of MS2 capsids possessing DNA aptamers on the exterior. Upon illumination with 415 nm light, these dual-modified capsids were shown to generate cytotoxic singlet oxygen. In cell experiments, these agents were shown to selectively kill Jurkat cells in a heterogeneous cell mixture.

Tong, Gary Jen-Wei

315

Targeted delivery of Doxorubicin by folic Acid-decorated dual functional nanocarrier.  

PubMed

Doxorubicin (DOX) is one of the most commonly used antineoplastic agents, but its clinical application is oftentimes coupled with severe side effects. Selective delivery of DOX to tumors via nanosized drug carrier represents an attractive approach to this problem. Previously, we developed a dual functional nanomicellar carrier, PEG5K-embelin2 (PEG5K-EB2), which was able to deliver paclitaxel (PTX) selectively to tumors and to achieve an enhanced therapeutic effect. In the present study, we examined the utility of PEG5K-EB2 to deliver DOX to tumors. In addition, folic acid (FA) was coupled to the surface of the PEG5K-EB2 micelles (FA-PEG5K-EB2) to further improve the selective targetability of the system. DOX-loaded PEG5K-EB2 micelles were uniformly spherical particles with a diameter of approximately 20 nm. Incorporation of FA had minimal effect on the size of the particles. The DOX loading efficiency was as high as 91.7% and 93.5% for PEG5K-EB2 and FA-PEG5K-EB2, respectively. DOX formulated in PEG5K-EB2 micelles (with or without FA decoration) demonstrated sustained kinetics of DOX release compared to free DOX. FA-PEG5K-EB2 significantly facilitated the intracellular uptake of DOX over free DOX and PEGylated liposomal DOX (Doxil) in breast cancer cells, 4T1.2, and drug resistant cells, NCI/ADR-RES. P-gp ATPase assay showed that PEG5K-EB2 significantly inhibited the function of the P-gp efflux pump. The maximum tolerated dose of DOX-loaded PEG5K-EB2 micelles was 15 mg/kg in mice, which was 1.5-fold greater than that for free DOX. Pharmacokinetics (PK) and biodistribution studies showed that both types of DOX-loaded micelles, especially FA-PEG5K-EB2, were able to significantly prolong the blood circulation time of DOX and facilitate its preferential accumulation at the tumor tissue. Finally, DOX/PEG5K-EB2 mixed micelles demonstrated significantly enhanced tumor growth inhibitory effect with minimal toxicity in comparison to free DOX and Doxil and the antitumor activity was further enhanced after the decoration by folic acid. Our data suggest that FA-PEG5K-EB2 micelles represent a promising DOX delivery system that warrants more study in the future. PMID:25265550

Lu, Jianqin; Zhao, Wenchen; Huang, Yixian; Liu, Hao; Marquez, Rebecca; Gibbs, Robert B; Li, Jiang; Venkataramanan, Raman; Xu, Liang; Li, Shulin; Li, Song

2014-11-01

316

Magnetically Targeted Delivery of Therapeutic Agents to Injured Blood Vessels for Prevention of In-Stent Stenosis  

PubMed Central

Magnetic guidance is a physical targeting strategy with the potential to improve the safety and efficacy of a variety of therapeutic agents — including small-molecule pharmaceuticals, proteins, gene vectors, and cells — by enabling their site-specific delivery. The application of magnetic targeting for in-stent restenosis can address the need for safer and more efficient treatment strategies. However, its translation to humans may not be possible without revising the traditional magnetic targeting scheme, which is limited by its inability to selectively guide therapeutic agents to deep localized targets. An alternative two-source strategy can be realized through the use of uniform, deep-penetrating magnetic fields in conjunction with vascular stents included as part of the magnetic setup and the platform for targeted delivery to injured arteries. Studies showing the feasibility of this novel targeting strategy in in-stent restenosis models and considerations in the design of carrier formulations for magnetically guided antirestenotic therapy are discussed in this review. PMID:22891107

Fishbein, Ilia; Adamo, Richard F.; Forbes, Scott P.; Folchman-Wagner, Zoë; Alferiev, Ivan S.

2012-01-01

317

MUC1 aptamer conjugated to chitosan nanoparticles, an efficient targeted carrier designed for anticancer SN38 delivery.  

PubMed

Molecularly targeted therapy is of great interest for diagnosis and treatment of cancerous cells due to its low toxicity for normal cells. In this study, chitosan was utilized as a promising carrier for delivery, and aptamer (Apt) was employed for active targeting of SN38 to colon cancer. SN38 cannot be used clinically due to its poor solubility and high toxicity. Developing nanoparticles (NPs) of drug-polymer conjugates can be a good candidate for overcoming such problems. N-Carboxyethyl chitosan ester (CS-EA) was synthesized as an intermediate for conjugation of SN38 to chitosan. MUC1 DNA aptamer with 5'-NH2 functional group was conjugated to the self-assembled conjugate as a targeting agent. Prepared NPs had smooth and spherical morphology with 200 nm particle size. Conjugation of aptamer was confirmed by gel electrophoresis. In vitro cytotoxicity of NPs was assessed by HT-29 as MUC1 positive cell line through MTT assay. Aptamer conjugated NPs (Apt NPs) were more toxic than non-targeted NPs, however they were as toxic as free drug. Cellular uptake and targeting ability of prepared NPs were also confirmed via confocal microscopy. As a conclusion, prepared CS-SN38-Apt NPs can increase efficacy of drug SN38 through increasing solubility and specific delivery to the target tissue. PMID:24905777

Sayari, E; Dinarvand, M; Amini, M; Azhdarzadeh, M; Mollarazi, E; Ghasemi, Z; Atyabi, F

2014-10-01

318

Maximizing gene delivery efficiencies of cationic helical polypeptides via balanced membrane penetration and cellular targeting  

E-print Network

of the self-assembly approach, optimal formulations of the ternary complexes with a proper balance between delivery efficiency could be maxi- mized. One promising approach towards this goal is the combina- torialMaximizing gene delivery efficiencies of cationic helical polypeptides via balanced membrane

Cheng, Jianjun

319

Novel intravaginal nanomedicine for the targeted delivery of saquinavir to CD4+ immune cells  

PubMed Central

The goal of this study was to develop and characterize an intravaginal nanomedicine for the active targeted delivery of saquinavir (SQV) to CD4+ immune cells as a potential strategy to prevent or reduce HIV infection. The nanomedicine was formulated into a vaginal gel to provide ease in self-administration and to enhance retention within the vaginal tract. SQV-encapsulated nanoparticles (SQV-NPs) were prepared from poly(lactic-co-glycolic acid) (PLGA) and conjugated to antihuman anti-CD4 antibody. Antibody-conjugated SQV-NPs (Ab-SQV-NPs) had an encapsulation efficiency (EE%) of 74.4% + 3.7% and an antibody conjugation efficiency (ACE%) of 80.95% + 1.10%. Over 50% of total loaded SQV was released from NPs over 3 days. NPs were rapidly taken up by Sup-T1 cells, with more than a twofold increase in the intracellular levels of SQV when delivered by Ab-SQV-NPs in comparison to controls 1 hour post-treatment. No cytotoxicity was observed when vaginal epithelial cells were treated for 24 hours with drug-free Ab-NPs (1,000 ?g/mL), 1% HEC placebo gel (200 mg/mL), or 1% HEC gel loaded with drug-free Ab-NPs (5 mg NPs/g gel, 200 mg/mL of gel mixture). Overall, we described an intravaginal nanomedicine that is nontoxic and can specifically deliver SQV into CD4+ immune cells. This platform may demonstrate potential utility in its application as postexposure prophylaxis for the treatment or reduction of HIV infection, but further studies are required. PMID:23966779

Yang, Sidi; Chen, Yufei; Gu, Kaien; Dash, Alicia; Sayre, Casey L; Davies, Neal M; Ho, Emmanuel A

2013-01-01

320

Formulation and evaluation of chitosan microspheres of aceclofenac for colon-targeted drug delivery.  

PubMed

The objective of this investigation was to develop novel colon specific drug delivery. Aceclofenac, a NSAID, was successfully encapsulated into chitosan microspheres. Various formulations were prepared by varying the ratio of chitosan, span-85 and stirring speed and the amount of glutaraldehyde. The SEM study showed that microspheres have smooth surfaces. Microspheres were characterised by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) to confirm the absence of chemical interactions between drug and polymer and to know the formation of microspheres structure. The microspheres were evaluated for particle size, encapsulation efficiency, drug loading capacity, mucoadhesion studies, stability studies, in vitro and in vivo drug release studies. Particle sizes, as measured by the laser light scattering technique, were of an average size in the range 41-80?µm. The swelling index was in the range 0.37-0.82 and the entrapment efficiency range was 51-75% for all the formulations. The optimised batch ACM(13) released 83.6% at 8?h and 104% at 24?h in SCF containing rat caecal content. Eudragit coated chitosan microspheres prevented the release of the aceclofenac in the physiological environment of the stomach and small intestine and released 95.9±0.34% in the colon. With regard to release kinetics, the data were best fitted with the Higuchi model and showed zero order release with non-Fickian diffusion mechanism. The in vivo findings suggest that aceclofenac microspheres exhibit a prolonged effect of aceclofenac in rats and produce a significant anti-inflammatory effect. The findings of the present study conclusively state that chitosan microspheres are promising for colon targeting of aceclofenac to synchronise with chronobiological symptoms of rheumatoid arthritis. PMID:20848388

Umadevi, S K; Thiruganesh, R; Suresh, S; Reddy, K Bhaskar

2010-10-01

321

Development and characterization of gelatin based nanoparticles for targeted delivery of zidovudine  

PubMed Central

Introduction: The present work was aimed at development and evaluation of zidovudin (AZT) loaded gelatin nanoparticles (GNPs) by simple desolvation method and further couple it with mannose. Material and Methods: Total seven batches of GNPs (A1-A7) were formulated by changing the concentration of polymer gelatin. Various parameters such as particle size, polydispersity index, zeta potential, % entrapment efficiency and in-vitro drug release of plain and mannosylated gelatin nanoparticles (M-GNPs) were studied. Results: Scanning electron microscopy (SEM) studies revealed that the average particle size of GNPs and M-GNPs were found to be 394 ± 3.21 and 797.2 ± 2.89 nm respectively (optimised batch A3). It was interesting to note that the average particle size of M-GNPs was more due to anchored mannose, whereas drug entrapment was lesser compared to plain GNPs. Studies have showed drug loading for GNPs and M-GNPs to be 66.56% and 58.85% respectively. Zeta potential studies demonstrated little reduction in solution stability of M-GNPs compared to GNPs. In-vitro drug release studies showed almost 80% release (bimodal) up to 24 h, following Korsmeyer-Peppas release kinetics model (GNPs, r = 0.9760; M-GNPs, r = 0.9712). Conclusions: Hence, it can be concluded that, development of GNPs and M-GNPs will pave the way for reticuloendothelial system uptake of AZT; thus, achieving targeted delivery, selectivity and reduction in associated side effect reduction in acquired immuno defficiency syndrome. PMID:24167784

Jadhav, Namdeo R; Tone, Jadhav S; Irny, Preeti V; Nadaf, Sameer J

2013-01-01

322

Multifaceted chitin/poly(lactic-co-glycolic) acid composite nanogels.  

PubMed

Cyto-compatible, 80nm sized chitin/PLGA composite nanogels (chit/PLGA-comp NGs) were prepared by regeneration method and characterized. The multifaceted chit/PLGA-comp NGs were surface modified with Au, Fe3O4, CdTe/ZnTe-QDs and umbelliferone, respectively. 185nm sized Au-chit/PLGA-comp NGs, 170nm sized QD-chit/PLGA-comp-NGs and 160nm sized Fe3O4-chit/PLGA-comp-NGs showed RF heating. The QD-chit/PLGA-comp-NGs and 180nm sized umb-chit/PLGA-comp-NGs were well uptaken by Escherichia coli, Staphylococcus aureus and Candida albicans. The chit/PLGA-comp NGs could be useful for microbial monitoring and RF application for cancer therapy. The preliminary data showed that multifaceted chit/PLGA-comp-NGs could be useful for hyperthermia for cancer treatment and microbial labelling and imaging. PMID:24685461

Rejinold, N Sanoj; Biswas, Raja; Chellan, Gopi; Jayakumar, R

2014-06-01

323

Targeted cytosolic delivery of hydrogel nanoparticles into HepG2 cells through engineered Sendai viral envelopes  

Microsoft Academic Search

Hydrogel nanoparticles of cross-linked polyvinylpyrrolidone (PVP-NP) (35–50 nm in diameter) containing fluoresceinated dextran (FITC-Dx) were encapsulated in reconstituted Sendai viral envelopes containing only the fusion (F) protein (F-virosomes11Process for Producing a Targeted Gene (1997) US Patent 5, 683, 866).). Incubation of these loaded F-virosomes with human hepatoblastoma cells (HepG2) in culture resulted in membrane-fusion-mediated delivery of NPs to the cell

Siddhartha S. Jana; Dhruba J. Bharali; Prashant Mania; Amarnath Maitra; Chhitar M Gupta; Debi P Sarkar

2002-01-01

324

Effective Targeted Gene Knockdown in Mammalian Cells Using the piggyBac Transposase-based Delivery System  

PubMed Central

Nonviral gene delivery systems are rapidly becoming a desirable and applicable method to overexpress genes in various types of cells. We have recently developed a piggyBac transposase-based, helper-independent and self-inactivating delivery system (pmGENIE-3) capable of high-efficiency transfection of mammalian cells including human cells. In the following study, we have assessed the potential of this delivery system to drive the expression of short hairpin RNAs to knock down genes in human cells. Two independent pmGENIE-3 vectors were developed to specifically target knockdown of an endogenous gene, telomerase reverse transcriptase (TERT), in telomerase-positive human immortalized cell lines. As compared with a transposase-deficient vector, pmGENIE-3 showed significantly improved short-term transfection efficiency (~4-fold enhancement, 48 hours posttransfection) and long-term integration efficiency (~5-fold enhancement) following antibiotic selection. We detected a significant reduction of both TERT expression and telomerase activity in both HEK293 and MCF-7 breast carcinoma cells transfected with two pmGENIE-3 construct targeting distinct regions of TERT. Importantly, this knockdown of expression was sufficient to abrogate telomerase function since telomeres were significantly shortened (3–4 Kb, P < 0.001) in both TERT-targeted cell lines following antibiotic selection of stable integrants. Together, these data show the capacity of the piggyBac nonviral delivery system to stably knockdown gene expression in mammalian cells and indicate the potential to develop novel tumor-targeting therapies. PMID:24326734

Owens, Jesse B; Mathews, Juanita; Davy, Philip; Stoytchev, Ilko; Moisyadi, Stefan; Allsopp, Rich

2013-01-01

325

Anti-Her2 single-chain antibody mediated DNMTs-siRNA delivery for targeted breast cancer therapy.  

PubMed

The targeted delivery of small interfering RNA (siRNA) to specific tumor tissues and tumor cells remains as one of the key challenges in the development of RNA interference as a therapeutic application. To target breast cancer, we developed a therapeutic delivery system using a fusion protein of an anti-Her2 single-chain antibody fragment with a positively charged protamine, namely F5-P, as the carrier to specifically deliver siRNA-targeting DNA methyltransferases 1 and/or 3b genes (siDNMTs) into Her2-expressing breast tumor cells. The carrier F5-P, expressed by the Escherichia coli system, was able to bind siRNA molecules and specifically deliver the siRNA to Her2-expressing BT474 breast cancer cells but not Her2-nonexpressing MDA-MB-231 breast cancer cells, while delivery of siDNMTs to BT474 cells successfully silenced the expression of targeted DNA methyltransferases (DNMTs) and facilitated the de-methylation of the RASSF1A tumor suppressor gene promoter, leading to the suppression of tumor cell proliferation. Moreover, as demonstrated in the BT474 xenograft murine model, F5-P successfully delivered siRNA into a Her2-expressing breast tumor, and tumor growth inhibition was mediated by an intravenous injection of F5-P/siDNMTs complex by down-regulating the expression of DNMTs and restoring tumor suppressor gene expression. These data suggest that the delivery of siDNMTs by F5-P could be used to treat Her2-expressing breast cancer. PMID:22762887

Dou, Shuang; Yao, Yan-Dan; Yang, Xian-Zhu; Sun, Tian-Meng; Mao, Cheng-Qiong; Song, Er-Wei; Wang, Jun

2012-08-10

326

Nanoplex delivery of siRNA and Prodrug Enzyme for Multimodality Image-Guided Molecular Pathway Targeted Cancer Therapy  

PubMed Central

The ability to destroy cancer cells while sparing normal tissue is highly sought after in cancer therapy. Small interfering RNA (siRNA)-mediated silencing of cancer-cell specific targets, or the use of a prodrug enzyme delivered to the tumor to convert a non-toxic prodrug to an active drug are two promising approaches in achieving this goal. Combining both approaches into a single treatment strategy can amplify selective targeting of cancer cells while sparing normal tissue. Noninvasive imaging can assist in optimizing such a strategy, by determining effective tumor delivery of the siRNA and prodrug enzyme to time prodrug administration, and detecting target downregulation by siRNA, and prodrug conversion by the enzyme. In proof-of-principle studies, we synthesized a nanoplex carrying magnetic resonance imaging (MRI) reporters for in vivo detection, and optical reporters for microscopy, to image the delivery of siRNA and a functional prodrug enzyme in breast tumors, and achieve image-guided molecular targeted cancer therapy. siRNA targeting of choline kinase-? (Chk-?), an enzyme significantly up regulated in aggressive breast cancer cells, was combined with the prodrug enzyme bacterial cytosine deaminase (bCD) that converts the non-toxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU). In vivo MRI and optical imaging showed efficient intratumoral nanoplex delivery. siRNA-mediated downregulation of Chk-? and the conversion of 5-FC to 5-FU by bCD were detected noninvasively with 1H MR spectroscopic imaging and 19F MR spectroscopy. Combined siRNA and prodrug enzyme activated treatment achieved higher growth delay than either treatment alone. The strategy can be expanded to target multiple pathways with siRNA. PMID:20958072

Li, Cong; Penet, Marie-France; Wildes, Flonne; Takagi, Tomoyo; Chen, Zhihang; Winnard, Paul T.; Artemov, Dmitri; Bhujwalla, Zaver M.

2010-01-01

327

The application of high-content analysis in the study of targeted particulate delivery systems for intracellular drug delivery to alveolar macrophages.  

PubMed

With an ever increasing number of particulate drug delivery systems being developed for the intracellular delivery of therapeutics a robust high-throughput method for studying particle-cell interactions is urgently required. Current methods used for analyzing particle-cell interaction include spectrofluorimetry, flow cytometry, and fluorescence/confocal microscopy, but these methods are not high throughput and provide only limited data on the specific number of particles delivered intracellularly to the target cell. The work herein presents an automated high-throughput method to analyze microparticulate drug delivery system (DDS) uptake byalveolar macrophages. Poly(lactic-co-glycolic acid) (PLGA) microparticles were prepared in a range of sizes using a solvent evaporation method. A human monocyte cell line (THP-1) was differentiated into macrophage like cells using phorbol 12-myristate 13-acetate (PMA), and cells were treated with microparticles for 1 h and studied using confocal laser scanning microscopy (CLSM), spectrofluorimetry and a high-content analysis (HCA). PLGA microparticles within the size range of 0.8-2.1 ?m were found to be optimal for macrophage targeting (p < 0.05). Uptake studies carried out at 37 °C and 4 °C indicated that microparticles were internalized in an energy dependent manner. To improve particle uptake, a range of opsonic coatings were assessed. Coating PLGA particles with gelatin and ovalbumin was found to significantly increase particle uptake from 2.75 ± 0.98 particles per cell for particles coated with gelatin. Opsonic coating also significantly increased particle internalization into primary human alveolar macrophages (p < 0.01) with a 1.7-fold increase in uptake from 4.19 ± 0.48 for uncoated to 7.53 ± 0.88 particles per cell for coated particles. In comparison to techniques such as spectrofluorimetry and CLSM, HCA provides both qualitative and quantitative data on the influence of carrier design on cell targeting that can be gathered in a high-throughput format and therefore has great potential in the screening of intracellularly targeted DDS. PMID:21591762

Lawlor, Ciaran; O'Sullivan, Mary P; Sivadas, Neera; O'Leary, Seonadh; Gallagher, Paul J; Keane, Joseph; Cryan, Sally-Ann

2011-08-01

328

Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders  

PubMed Central

Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood–brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations. PMID:21811247

Bevan, Adam K; Duque, Sandra; Foust, Kevin D; Morales, Pablo R; Braun, Lyndsey; Schmelzer, Leah; Chan, Curtis M; McCrate, Mary; Chicoine, Louis G; Coley, Brian D; Porensky, Paul N; Kolb, Stephen J; Mendell, Jerry R; Burghes, Arthur HM; Kaspar, Brian K

2011-01-01

329

Non-ionic, thermo-responsive DEA/DMA nanogels: Synthesis, characterization, and use for DNA separations by microchip electrophoresis  

E-print Network

) copolymers, made by free-radical, surfactant-free dispersion polymerization. The volume-phase transition, and attenuates and broadens it as well. We find that concentrated DEA/DMA nanogel dispersions are optically clear­17]. NIPA-based nanogels are typically synthesized by emulsion precipitation polymerization at 70 °C [2

Barron, Annelise E.

330

Stable and pH-Sensitive Protein Nanogels Made by Self-Assembly of Heat Denatured Soy Protein.  

PubMed

In this study, we examined the possibility of preparing stable soy protein nanogels by simply heating homogeneous soy protein dispersion. The protein nanogels formed were characterized by z-average hydrodynamic diameter, polydispersity index, turbidity, ?-potential, morphology, and their stability to pH and ionic strength change. Soy protein dispersion (1% w/v) was homogeneous around pH 5.9 where it had the lowest polydispersity index (?0.1). Stable and spherical nanogels were formed by heating soy protein dispersion at pH 5.9 under 95 °C. They sustained constantly low polydispersity index (?0.1) in the investigated pH range of 6.06-7.0 and 2.6-3.0. The nanogels were pH-sensitive and would swell with pH change. They were stable at 0-200 mM NaCl concentration. Denaturation of soy glycinin was the prerequisite for the formation of stable nanogels. Soy protein nanogels had a core-shell structure with basic polypeptides and ? subunits interacting together as the hydrophobic core; and acid polypeptides, ?', and ? subunits locating outside the core as hydrophilic shell. The inner structure of soy protein nanogels was mainly stabilized by disulfide bonds cross-linked network and hydrophobic interaction. Soy protein nanogels made in this study would be useful as functional ingredients in biotechnological, pharmaceutical, and food industries. PMID:25180907

Chen, Nannan; Lin, Lianzhu; Sun, Weizheng; Zhao, Mouming

2014-10-01

331

Drug-Loaded Sickle Cells Programmed ex vivo for Delayed Hemolysis Target Hypoxic Tumor Microvessels and Augment Tumor Drug Delivery  

PubMed Central

Selective drug delivery to hypoxic tumor niches remains a significant therapeutic challenge that calls for new conceptual approaches. Sickle red blood cells (SSRBCs) have shown an ability to target such hypoxic niches and induce tumoricidal properties when used together with exogenous pro-oxidants. Here we determine whether the delivery of a model therapeutic encapsulated in murine SSRBCs can be enhanced by ex vivo photosensitization under conditions that delay autohemolysis to a time that coincides with maximal localization of SSRBCs in a hypoxic tumor. Hyperspectral imaging of 4T1 carcinomas shows oxygen saturation levels <10% in a large fraction (commonly 50% or more) of the tumor. Using video microscopy of dorsal skin window chambers implanted with 4T1 tumors, we demonstrate that allogeneic SSRBCs, but not normal RBCs (nRBCs), selectively accumulate in hypoxic 4T1 tumors between 12-24 hours after systemic administration. We further show that ex vivo photo-oxidation can program SSRBCs to postpone hemolysis/release of a model therapeutic to a point that coincides with their maximum sequestration in hypoxic tumor microvessels. Under these conditions, drug-loaded photosensitized SSRBCs show a 3-4 fold greater drug delivery to tumors compared to non-photosensitized SSRBCs, drug-loaded photosensitized nRBCs, and free drug. These results demonstrate that photo-oxidized SSRBCs, but not photo-oxidized nRBCs, sequester and hemolyze in hypoxic tumors and release substantially more drug than photo-oxidized nRBCs and non-photo-oxidized SSRBCs. Photo-oxidation of drug-loaded SSRBCs thus appears to exploit the unique tumor targeting and carrier properties of SSRBCs to optimize drug delivery to hypoxic tumors. Such programmed and drug-loaded SSRBCs therefore represent a novel and useful tool for augmenting drug delivery to hypoxic solid tumors. PMID:23871960

Choe, Se-woon; Terman, David S.; Rivers, Angela E.; Rivera, Jose; Lottenberg, Richard; Sorg, Brian S.

2014-01-01

332

Hyaluronic acid and alginate covalent nanogels by template cross-linking in polyion complex micelle nanoreactors.  

PubMed

Hyaluronic acid (HA) and alginate (AL) covalent nanogels cross-linked with l-lysine ethyl ester were prepared by template chemical cross-linking of the polysaccharide in polyion complex micelle (PIC) nanoreactors. By using this method we were able to prepare HA and AL nanogels without organic solvents. PICs were prepared by using poly(ethylene oxide)-block-poly[(3-acrylamidopropyl)-trimethylammonium chloride] (PEO-b-PAMPTMA) or poly[(N-isopropylacrylamide)-block-PAMPTMA] (PNIPAAM-b-PAMPTMA). Only PNIPAAM-b-PAMPTMA block copolymers allowed to prepare PIC with small and controlled size. Short polysaccharide chains (Xn=50 and 63 for AL and HA, respectively, where Xn is the number of monosaccharidic units present in the polysaccharide) where used to optimize PIC formation. The remarkable difference in charge density and rigidity of HA and AL did not have a significant influence on the formation of PICs. PICs with small size (diameter of about 50-80 nm) and low polydispersity were obtained up to 5mg/mL of polymer. After cross-linking with l-lysine ethyl ester, the nanoreactors were dissociated by adding NaCl. The nanogels were easily purified and isolated by dialysis. The dissociation of the nanoreactors and the formation of the nanogels were confirmed by (1)H NMR, DLS, TEM and ?-potential measurements. The size of the smallest nanogels in solution in the swollen state was 50-70 nm in presence of salt and 80-100 nm in water. PMID:24299754

De Santis, Serena; Diociaiuti, Marco; Cametti, Cesare; Masci, Giancarlo

2014-01-30

333

Novel chitosan-based pH-sensitive and disintegrable polyelectrolyte nanogels.  

PubMed

A novel approach to design pH-sensitive and disintegrable polyelectrolyte nanogels composed of citraconic-based N-(carboxyacyl) chitosan (polyanion) and quaternary chitosan (polycation) was reported. Firstly, the hydrolysis of citraconic-modified chitosan was monitored using fluorescamine assay and it could selectively dissociate in acidic media (e.g., pH ?5.0) due to the isomerization during the addition of citraconic anhydride to chitosan. Secondly, the self-assembly behaviors of different polyelectrolyte pairs between citraconic-based chitosan and quaternary chitosan were investigated via colloidal titration assay. It was indicated that the difference in molecular weight (MW) of opposite charged polyelectrolytes played an important role on the formation of polyelectrolyte nanogels. Results showed that polyelectrolyte nanogels (ca. 300nm in size) only formed when polyanion and polycation had a very large difference in MW. The pH-sensitive behavior of polyelectrolyte nanogels was comprehensively investigated by dynamic light scattering (DLS) and transmission electron microscope (TEM). The incorporation of charge-conversional citraconic-based chitosan into polyelectrolyte complexes has provided an effective approach to prepare polyelectrolyte nanogels which were very stable at neutral pH but disintegrated quickly in acidic media. PMID:25042598

Yuan, Fang; Wang, Shasha; Chen, Gaojian; Tu, Kehua; Jiang, Hongliang; Wang, Li-Qun

2014-10-01

334

THE USE OF NANOPARTICLE-MEDIATED TARGETED GENE SILENCING AND DRUG DELIVERY TO OVERCOME TUMOR DRUG RESISTANCE  

PubMed Central

Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) enables cancer cells to develop resistance to multiple anticancer drugs. Functional inhibitors of P-gp have shown promising efficacy in early clinical trials, but their long-term safety is yet to be established. A novel approach to overcome drug resistance is to use siRNA-mediated RNA interference to silence the expression of the efflux transporter. Because P-gp plays an important role in the physiological regulation of endogenous and xenobiotic compounds in the body, it is important to deliver P-gp targeted siRNA and anticancer drug specifically to tumor cells. Further, for optimal synergy, both the drug and siRNA may need to be temporally colocalized in the tumor cells. In the current study, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel, along with P-gp targeted siRNA, using poly(D,L-lactide-co-glycolide) nanoparticles to overcome tumor drug resistance. Nanoparticles were surface functionalized with biotin for active tumor targeting. Dual agent nanoparticles encapsulating the combination of paclitaxel and P-gp targeted siRNA showed significantly higher cytotoxicity in vitro than nanoparticles loaded with paclitaxel alone. Enhanced therapeutic efficacy of dual agent nanoparticles could be correlated with effective silencing of the MDR1 gene that encodes for P-gp and with increased accumulation of paclitaxel in drug-resistant tumor cells. In vivo studies in a mouse model of drug-resistant tumor demonstrated significantly greater inhibition of tumor growth following treatment with biotin-functionalized nanoparticles encapsulating both paclitaxel and P-gp targeted siRNA at a paclitaxel dose that was ineffective in the absence of gene silencing. These results suggest that that the combination of P-gp gene silencing and cytotoxic drug delivery using targeted nanoparticles can overcome tumor drug resistance. PMID:19800114

Patil, Yogesh; Swaminathan, Suresh; Sadhukha, Tanmoy; Ma, Linan; Panyam, Jayanth

2009-01-01

335

Targeted delivery of ?-galactosylceramide to CD8?+ dendritic cells optimizes type I NKT cell-based antitumor responses.  

PubMed

Immunotherapy aiming at enhancing innate and acquired host immunity is a promising approach for cancer treatment. The invariant NKT (iNKT) cell ligand ?-galactosylceramide (?-GalCer) holds great promise in cancer therapy, although several concerns limit its use in clinics, including the uncontrolled response it promotes when delivered in a nonvectorized form. Therefore, development of delivery systems to in vivo target immune cells might be a valuable option to optimize iNKT cell-based antitumor responses. Using dendritic cell (DC)-depleted mice, DC transfer experiments, and in vivo active cell targeting, we show that presentation of ?-GalCer by DCs not only triggers optimal primary iNKT cell stimulation, but also maintains secondary iNKT cell activation after challenge. Furthermore, targeted delivery of ?-GalCer to CD8?(+) DCs, by means of anti-DEC205 decorated nanoparticles, enhances iNKT cell-based transactivation of NK cells, DCs, and ?? T cells. We report that codelivery of ?-GalCer and protein Ag to CD8?(+) DCs triggers optimal Ag-specific Ab and cytotoxic CD8(+) T cell responses. Finally, we show that targeting nanoparticles containing ?-GalCer and Ag to CD8?(+) DCs promotes potent antitumor responses, both in prophylactic and in therapeutic settings. Our data may have important implications in tumor immunotherapy and vaccine development. PMID:24913977

Macho-Fernandez, Elodie; Cruz, Luis Javier; Ghinnagow, Reem; Fontaine, Josette; Bialecki, Emilie; Frisch, Benoit; Trottein, François; Faveeuw, Christelle

2014-07-15

336

Mechanism-based tumor-targeting drug delivery system. Validation of efficient vitamin receptor-mediated endocytosis and drug release.  

PubMed

An efficient mechanism-based tumor-targeting drug delivery system, based on tumor-specific vitamin-receptor mediated endocytosis, has been developed. The tumor-targeting drug delivery system is a conjugate of a tumor-targeting molecule (biotin: vitamin H or vitamin B-7), a mechanism-based self-immolative linker and a second-generation taxoid (SB-T-1214) as the cytotoxic agent. This conjugate (1) is designed to be (i) specific to the vitamin receptors overexpressed on tumor cell surface and (ii) internalized efficiently through receptor-mediated endocytosis, followed by smooth drug release via glutathione-triggered self-immolation of the linker. In order to monitor and validate the sequence of events hypothesized, i.e., receptor-mediated endocytosis of the conjugate, drug release, and drug-binding to the target protein (microtubules), three fluorescent/fluorogenic molecular probes (2, 3, and 4) were designed and synthesized. The actual occurrence of these processes was unambiguously confirmed by means of confocal fluorescence microscopy (CFM) and flow cytometry using L1210FR leukemia cells, overexpressing biotin receptors. The molecular probe 4, bearing the taxoid linked to fluorescein, was also used to examine the cell specificity (i.e., efficacy of receptor-based cell targeting) for three cell lines, L1210FR (biotin receptors overexpressed), L1210 (biotin receptors not overexpressed), and WI38 (normal human lung fibroblast, biotin receptor negative). As anticipated, the molecular probe 4 exhibited high specificity only to L1210FR. To confirm the direct correlation between the cell-specific drug delivery and anticancer activity of the probe 4, its cytotoxicity against these three cell lines was also examined. The results clearly showed a good correlation between the two methods. In the same manner, excellent cell-specific cytotoxicity of the conjugate 1 (without fluorescein attachment to the taxoid) against the same three cell lines was confirmed. This mechanism-based tumor-targeting drug delivery system will find a range of applications. PMID:20429547

Chen, Shuyi; Zhao, Xianrui; Chen, Jingyi; Chen, Jin; Kuznetsova, Larisa; Wong, Stanislaus S; Ojima, Iwao

2010-05-19

337

A new targeted drug delivery method using ultrasound and acoustically active lipospheres  

NASA Astrophysics Data System (ADS)

The goal is to create a strategy for localized drug delivery using engineered delivery vehicles and ultrasound energy. These drug delivery vehicles, referred to as acoustically active lipospheres (AALs), consist of small gas bubbles surrounded by thick oil shells (where drugs can be carried) and are enclosed by an outermost lipid layer. Ultrasound radiation force can be used to displace these vehicles near the blood vessel wall, after which a higher intensity pulse can fragment the vehicle and transfer its contents to the endothelium. Blood velocity ranges from 1 to 10 mm/s in the microvasculature. Therefore, agents in capillaries insonified by a transducer with a 1 mm focal beam width for 0.1 to 1 seconds can be displaced of 1 to 2 mm. Delivery vehicles containing various fluorescent dyes within the oil layer are exposed to ultrasound in cell chambers or flowing vessels. Fluorescence intensity increases more than 10-fold with application of radiation force and fragmentation, both over no exposure and over fragmentation pulses alone (both P<0.001). This implies radiation force is necessary to bring AALs into proximity of the cell monolayer before their destruction in order for drug delivery to occur.

Shortencarier, Michaelann; Bloch, Susannah; Dayton, Paul; Ferrara, Kathy; Matsunaga, Terry; Labell, Rachel; Schumann, Patricia

2005-04-01

338

Development and Testing of Simulation (Game) to Illustrate Basic Principles of Integrated Project Delivery and Target Value Design: A First Run Study  

E-print Network

This research is focused on developing a simulation (game) that will help explain the basic principles of Integrated Project Delivery (IPD) and Target Value Design (TVD). The transfer of knowledge about Lean principles is currently limited...

Munankami, Manish 1972-

2012-12-07

339

Lambert targeting for on-orbit delivery of debris remediation dust  

NASA Astrophysics Data System (ADS)

An idea proposed for the elimination of some small debris calls for the deployment of a dust that decreases the energy of the debris, in effect de-orbiting it partway. The delivery of that dust on-orbit is possible by pre-positioning on orbit a vehicle with the intended cargo. If the goal is to reach a specified point in inertial space to precede the return of another vehicle to that point using Lambert targeting, and there is a limit to the amount of delta v available, then some orbits are better choices than others. In the context of dispensing a dust to enhance drag for elimination of debris, I examine the combination of vehicles which gives the most coverage to treat the most populous altitude band of satellites. An idea proposed by Ganguli and coworkers for remediation of on-orbit small debris is to place in orbit a dusty plasma which acts as an artificial atmosphere, bringing down the debris, not immediately, but over months or years. The region of space that should be filled with dust is smaller if it can be applied as soon as possible after the fragmentation event that creates the debris (explosion or collision). It is very time consuming to prepare, launch and deliver a dust-bearing, or ``cleanup'' vehicle, and in that time, the initial delta v from the impact or explosion will spread the fragments over a large volume. If such a vehicle or vehicles are prepared and launched ahead of time, they will need a much shorter time to reach a region filled with debris fragments than a ground launch. The purpose of this study is to determine whether it is practical from an astrodynamics perspective to put a small number of cleanup vehicles on orbit in the most heavily populated neighborhood of low-earth orbit (500-1200 km altitude and 95°-105° inclination) such that if notified a short time after a fragmentation, at least one could reach a significant fraction of the compact debris field before it disperses. Each of the possible sources for orbital debris is assumed to be in this orbital parameter range. For each set of source and cleanup vehicle orbits, maximum delta v, and delay between fragmentation and cleanup vehicle dispatch, we can compute whether the debris is reachable by the cleanup vehicle at the first return of the debris one orbit of the source vehicle after the fragmentation event. Then by sampling over many source vehicle orbits and delays, we can determine for each cleanup vehicle the reachable fraction of source vehicles, with a higher fraction being more desirable. I assume that once a cleanup vehicle reaches its target, it is able to deliver the dust in an appropriate pattern without regard to the relative velocity of the vehicle (in other words, no maneuver is performed at the target point; all the available delta v may be consumed at the departure from original orbit). The next step is to sample many cleanup orbits to find those with the highest reachable fraction. Those orbits may be combined into pairs, triples, etc., corresponding to fleets of cleanup vehicles of two or three or more. The potential advantage of doing so is that much more of the target orbital neighborhood is reachable, at the cost of adding more cleanup vehicles. I use low-discrepancy, or quasi-random, sequences to evenly fill the space of parameters for both source and cleanup vehicles, and find through stepwise increase in the density of the sample, find a limiting value of the number of samples (about 500 for source and 2000 for single cleanup vehicle). The results show that, for example, a fleet of two vehicles with a capacity of 4 km/s could cover 69% of the potential debris sources with a minimum delay of 30 minutes between event and dispatch. While there are other technological problems that must be overcome for this approach to the debris problem to be feasible, this is a plausible number of spacecraft to consider for such a cleanup task.

Healy, Liam

2012-07-01

340

Surface engineering of macrophages with nanoparticles to generate a cell-nanoparticle hybrid vehicle for hypoxia-targeted drug delivery.  

PubMed

Tumors frequently contain hypoxic regions that result from a shortage of oxygen due to poorly organized tumor vasculature. Cancer cells in these areas are resistant to radiation- and chemotherapy, limiting the treatment efficacy. Macrophages have inherent hypoxia-targeting ability and hold great advantages for targeted delivery of anticancer therapeutics to cancer cells in hypoxic areas. However, most anticancer drugs cannot be directly loaded into macrophages because of their toxicity. In this work, we designed a novel drug delivery vehicle by hybridizing macrophages with nanoparticles through cell surface modification. Nanoparticles immobilized on the cell surface provide numerous new sites for anticancer drug loading, hence potentially minimizing the toxic effect of anticancer drugs on the viability and hypoxia-targeting ability of the macrophage vehicles. In particular, quantum dots and 5-(aminoacetamido) fluorescein-labeled polyamidoamine dendrimer G4.5, both of which were coated with amine-derivatized polyethylene glycol, were immobilized to the sodium periodate-treated surface of RAW264.7 macrophages through a transient Schiff base linkage. Further, a reducing agent, sodium cyanoborohydride, was applied to reduce Schiff bases to stable secondary amine linkages. The distribution of nanoparticles on the cell surface was confirmed by fluorescence imaging, and it was found to be dependent on the stability of the linkages coupling nanoparticles to the cell surface. PMID:20161985

Holden, Christopher A; Yuan, Quan; Yeudall, W Andrew; Lebman, Deborah A; Yang, Hu

2010-01-01

341

mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation  

PubMed Central

Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapy to treat several diseases and are compelling to consider as vehicles for delivery of biological agents. However, MSCs appear to act through a seemingly limited “hit-and-run” mode to quickly exert their therapeutic impact, mediated by several mechanisms, including a potent immunomodulatory secretome. Furthermore, MSC immunomodulatory properties are highly variable and the secretome composition following infusion is uncertain. To determine whether a transiently controlled antiinflammatory MSC secretome could be achieved at target sites of inflammation, we harnessed mRNA transfection to generate MSCs that simultaneously express functional rolling machinery (P-selectin glycoprotein ligand-1 [PSGL-1] and Sialyl-Lewisx [SLeX]) to rapidly target inflamed tissues and that express the potent immunosuppressive cytokine interleukin-10 (IL-10), which is not inherently produced by MSCs. Indeed, triple-transfected PSGL-1/SLeX/IL-10 MSCs transiently increased levels of IL-10 in the inflamed ear and showed a superior antiinflammatory effect in vivo, significantly reducing local inflammation following systemic administration. This was dependent on rapid localization of MSCs to the inflamed site. Overall, this study demonstrates that despite the rapid clearance of MSCs in vivo, engineered MSCs can be harnessed via a “hit-and-run” action for the targeted delivery of potent immunomodulatory factors to treat distant sites of inflammation. PMID:23980067

Levy, Oren; Zhao, Weian; Mortensen, Luke J.; LeBlanc, Sarah; Tsang, Kyle; Fu, Moyu; Phillips, Joseph A.; Sagar, Vinay; Anandakumaran, Priya; Ngai, Jessica; Cui, Cheryl H.; Eimon, Peter; Angel, Matthew; Lin, Charles P.

2013-01-01

342

Hyaluronan microspheres for sustained gene delivery and site-specific targeting  

Microsoft Academic Search

Hyaluronan is a naturally occurring polymer that has enjoyed wide successes in biomedical and cosmetic applications as coatings, matrices, and hydrogels. For controlled delivery applications, formulating native hyaluronan into microspheres could be advantageous but has been difficult to process unless organic solvents are used or hyaluronan has been modified by etherification. Therefore, we present a novel method of preparing hyaluronan

Yang H. Yun; Douglas J. Goetz; Paige Yellen; Weiliam Chen

2004-01-01

343

Antheraea pernyi silk fibroin for targeted gene delivery of VEGF165-Ang-1 with PEI.  

PubMed

Vascularization is a crucial challenge in tissue engineering. One solution for this problem is to implant scaffolds that contain functional genes that promote vascularization by providing angiogenic growth factors via a gene delivery carrier. Poly(ethylenimine) (PEI) is a gene delivery carrier with high transfection efficiency but with cytotoxicity. To solve this problem, we utilized Antheraea pernyi silk fibroin (ASF), which has favorable cytocompatibility and biodegradability, RGD sequences and a negative charge, in conjunction with PEI, as the delivery vector for vascular endothelial growth factor (VEGF) 165-angiopoietin-1 (Ang-1) dual gene simultaneous expression plasmid, creating an ASF/PEI/pDNA complex. The results suggested that the zeta potential of the ASF/PEI/pDNA complex was significantly lower than that of the PEI/pDNA complex. Decreased nitrogen and increased oxygen on the surface of the complex demonstrated that the ASF had successfully combined with the surface of the PEI/pDNA. Furthermore, the complexes resisted digestion by nucleic acid enzymes and degradation by serum. L929 cells were cultured and transfected in vitro and improved cytotoxicity was found when the cells were transfected with ASF/PEI/pDNA compared with PEI/pDNA. In addition, the transfection efficiency and VEGF secretion increased. In general, this study provides a novel method for decreasing the cytotoxicity of PEI gene delivery vectors and increasing transfection efficiency of angiogenesis-related genes. PMID:24867887

Ma, Caili; Lv, Linlin; Liu, Yu; Yu, Yanni; You, Renchuan; Yang, Jicheng; Li, Mingzhong

2014-06-01

344

Retro-Inverso Isomer of Angiopep-2: A Stable d-Peptide Ligand Inspires Brain-Targeted Drug Delivery.  

PubMed

The blood-brain barrier (BBB) prevents most drugs from reaching the site of central nervous system (CNS) diseases, intensively confining the therapeutic efficiency. Angiopep-2 (here termed (L)Angiopep), which is a 19-mer peptide derived from human Kunitz domain, can trigger transcytosis and traverse the BBB by recognizing low density lipoprotein-related protein 1 (LRP-1) expressed on the brain capillary endothelial cells. Various enzymes in the blood and the BBB, however, present multiple metabolic barriers to peptide-inspired brain-targeted drug delivery. Here we designed a retro-inverso isomer of (L)Angiopep, termed (D)Angiopep, to inspire brain-targeted drug delivery. Both (D)Angiopep and (L)Angiopep displayed high uptake capacity in LRP-1 overexpressed cells, including bEnd.3 and U87 cells. (D)Angiopep demonstrated lower uptake efficiency in both cell lines than did (L)Angiopep, suggestive of lower binding affinity to LRP-1 of the d-peptide. (D)Angiopep was resistant to proteolysis in fresh rat blood serum, while more than 85% of (L)Angiopep disappeared within 2 h. Endocytosed (D)Angiopep and (L)Angiopep were found to be colocalized with lysosomal compartments of bEnd.3 cells, indicating that susceptibility to proteolysis of (L)Angiopep in the BBB may further attenuate its transcytosis efficiency. In vivo, (D)Angiopep modified PEG-DSPE micelles displayed high distribution in normal brain and intracranial glioblastoma. Due to the expression of LRP-1 on the BBB and glioblastoma cells, proteolytically stable (D)Angiopep holds much potential for designing two-order brain tumor targeted delivery systems. PMID:24673510

Wei, Xiaoli; Zhan, Changyou; Chen, Xishan; Hou, Jiapeng; Xie, Cao; Lu, Weiyue

2014-10-01

345

Long-Term Reduction of Jaundice in Gunn Rats by Nonviral Liver-Targeted Delivery of Sleeping Beauty Transposon  

PubMed Central

Asialoglycoprotein receptor (ASGPR)-mediated endocytosis has been used to target genes to hepatocytes in vivo. However, the level and duration of transgene expression have been low because of lysosomal translocation and degradation of the DNA and lack of its integration into the host genome. In this study we packaged the DNA of interest in proteoliposomes containing the fusogenic galactose-terminated F-glycoprotein of the Sendai virus (FPL) for targeted delivery to hepatocytes. After the FPL binds to ASGPR on the hepatocyte surface, fusogenic activity of the F-protein delivers the DNA into the cytosol, bypassing the endosomal pathway. For transgene integration we designed plasmids containing one transcription unit expressing the Sleeping Beauty transposase (SB) and another expressing human uridinediphosphoglucuronate glucuronosyltransferase-1A1 (pSB-hUGT1A1). The latter was flanked by inverted/direct repeats that are substrates of SB. In cell culture, FPL-mediated delivery of the E. coli ?-galactosidase gene (LacZ) resulted in transduction of ASGPR-positive cells (rat hepatocytes or Hepa1 cell line), but not of ASGPR-negative 293 cells. Intravenous injection of the FPL-entrapped pSB-hUGT1A1 (4–8 ?g/day, 1–4 doses) into UGT1A1-deficient hyperbilirubinemic Gunn rats (model of Crigler-Najjar syndrome type 1) resulted in hUGT1A1 expression in 5%–10% of hepatocytes, but not in other cell types. Serum bilirubin levels declined by 30% ± 4% in 2 weeks and remained at that level throughout the 7-month study duration. With histidine containing FPL, serum bilirubin was reduced by 40% ± 5%, and bilirubin glucuronides were excreted into bile. No antibodies were detectable in the recipient rats against the F-protein or human UGT1A1. Conclusion FPL is an efficient hepatocyte-targeted gene delivery platform in vivo that warrants further exploration toward clinical application. PMID:19585550

Wang, Xia; Sarkar, Debi P.; Mani, Prashant; Steer, Clifford J.; Chen, Yong; Guha, Chandan; Chandrasekhar, Voshavar; Chaudhuri, Arabinda; Roy-Chowdhury, Namita; Kren, Betsy T.; Roy-Chowdhury, Jayanta

2014-01-01

346

Non-ionic, thermo-responsive DEA/DMA nanogels: synthesis, characterization, and use for DNA separations by microchip electrophoresis.  

PubMed

Thermo-responsive polymer "nanogels" (crosslinked hydrogel particles with sub-100 nm diameters) are intriguing for many potential applications in biotechnology and medicine. There have been relatively few reports of electrostatically neutral, thermosensitive nanogels comprising a high fraction of hydrophilic co-monomer. Here we demonstrate the syntheses and characterization of novel, non-ionic nanogels based on random N,N-diethylacrylamide (DEA)/N,N-dimethylacrylamide (DMA) copolymers, made by free-radical, surfactant-free dispersion polymerization. The volume-phase transition temperatures of these DEA/DMA nanogels are strongly affected by co-monomer composition, providing a way to "tune" the phase transition temperature of these non-ionic nanogels. While DEA nanogels (comprising no DMA) can be obtained at 70 °C by standard emulsion precipitation, DEA/DMA random co-polymer nanogels can be obtained only in a particular range of temperatures, above the initial phase transition temperature and below the critical precipitation temperature of the DEA/DMA copolymer, controlled by co-monomer composition. Increasing percentages of DMA in the nanogels raises the phase transition temperature, and attenuates and broadens it as well. We find that concentrated DEA/DMA nanogel dispersions are optically clear at room temperature. This good optical clarity was exploited for their use in a novel DNA sieving matrix for microfluidic chip electrophoresis. An ultrafast, high-efficiency dsDNA separation was achieved in less than 120 s for dsDNA ranging from 75 bp to 15,000 bp. PMID:21392778

Lu, Xihua; Sun, Mingyun; Barron, Annelise E

2011-05-15

347

Pectin-coated chitosan-LDH bionanocomposite beads as potential systems for colon-targeted drug delivery.  

PubMed

This work introduces results on a new drug delivery system (DDS) based on the use of chitosan/layered double hydroxide (LDH) biohybrid beads coated with pectin for controlled release in the treatment of colon diseases. Thus, the 5-aminosalicylic acid (5ASA), the most used non-steroid-anti-inflammatory drug (NSAID) in the treatment of ulcerative colitis and Crohn's disease, was chosen as model drug aiming to a controlled and selective delivery in the colon. The pure 5ASA drug and the hybrid material prepared by intercalation in a layered double hydroxide of Mg2Al using the co-precipitation method, were incorporated in a chitosan matrix in order to profit from its mucoadhesiveness. These compounds processed as beads were further treated with the polysaccharide pectin to create a protective coating that ensures the stability of both chitosan and layered double hydroxide at the acid pH of the gastric fluid. The resulting composite beads presenting the pectin coating are stable to water swelling and procure a controlled release of the drug along their passage through the simulated gastrointestinal tract in in vitro experiments, due to their resistance to pH changes. Based on these results, the pectin@chitosan/LDH-5ASA bionanocomposite beads could be proposed as promising candidates for the colon-targeted delivery of 5ASA, with the aim of acting only in the focus of the disease and minimizing side effects. PMID:24374607

Ribeiro, Lígia N M; Alcântara, Ana C S; Darder, Margarita; Aranda, Pilar; Araújo-Moreira, Fernando M; Ruiz-Hitzky, Eduardo

2014-03-10

348

A novel target-specific gene delivery system combining baculovirus and sequence-specific long interspersed nuclear elements.  

PubMed

Transposable elements are valuable for somatic and germ-line transformation. However, long interspersed nuclear elements (LINEs) have not been used because of poor information on the transposition mechanism. We have developed a novel gene delivery system combining baculovirus AcNPV and two silkworm LINEs, SART1 and R1, which integrate into specific sequences of telomeric repeats and 28S ribosomal DNA, respectively. When two LINEs containing the enhanced green fluorescent protein gene recombined into AcNPV were infected into fifth instar larvae of the silkworm, we observed target-specific retrotransposition of LINEs at 72h post-infection, using polymerase chain reaction amplification and sequencing. Telomere- and 28S rDNA-specific transposition occurred in all nine tissues tested, including the ovary and testis. This is the first demonstration of site-specific gene delivery in living larvae. Insertion efficiencies were dependent on the virus titer for injection and the host strains of Bombyx mori. Using this system, we successfully detected the intergeneration transmission of retrotransposed sequences. In addition, AcNPV-mediated SART1 also transposed into telomere of another lepidopteran, Orgyia recens, suggesting that this system is useful for a wide variety of AcNPV-infectious insects. Site-specific gene delivery by virus-mediated LINE will be a potential gene therapy tool to avoid harmful unexpected insertions. PMID:17498830

Kawashima, Tomoko; Osanai, Mizuko; Futahashi, Ryo; Kojima, Tetsuya; Fujiwara, Haruhiko

2007-07-01

349

Encapsulated microbubbles and echogenic liposomes for contrast ultrasound imaging and targeted drug delivery  

NASA Astrophysics Data System (ADS)

Micron- to nanometer-sized ultrasound agents, like encapsulated microbubbles and echogenic liposomes, are being developed for diagnostic imaging and ultrasound mediated drug/gene delivery. This review provides an overview of the current state of the art of the mathematical models of the acoustic behavior of ultrasound contrast microbubbles. We also present a review of the in vitro experimental characterization of the acoustic properties of microbubble based contrast agents undertaken in our laboratory. The hierarchical two-pronged approach of modeling contrast agents we developed is demonstrated for a lipid coated (Sonazoid and a polymer shelled (poly D-L-lactic acid) contrast microbubbles. The acoustic and drug release properties of the newly developed echogenic liposomes are discussed for their use as simultaneous imaging and drug/gene delivery agents. Although echogenicity is conclusively demonstrated in experiments, its physical mechanisms remain uncertain. Addressing questions raised here will accelerate further development and eventual clinical approval of these novel technologies.

Paul, Shirshendu; Nahire, Rahul; Mallik, Sanku; Sarkar, Kausik

2014-03-01

350

Delivery of Membrane Impermeable Cargo into CHO Cells by Peptide Nanoparticles Targeted by a Protein Corona  

PubMed Central

Nanocarriers can fulfill essential functions in the stabilization and delivery of drugs: they prevent solubility issues and degradation, reduce side effects and modify the pharmacokinetic profile. However, particle based pharmaceuticals are very complex and thus challenging to scale up. As formulation routines account for a large fraction of production costs, reducing complexity in the process of assembly, loading and functionalization of nanoparticles is very desirable. Unlike existing approaches with similar goals, our protocol is designed to minimize usage of material and time. Prerequisite to this elegant one-step procedure is the controlled phase-separation of a hydrophobic peptide to nanoparticles, inducing concurrent cargo-entrapment and association of a protein corona. We demonstrate the process by assembling Flutax-2 containing peptide nanoparticles functionalized with transferrin. Cellular uptake of the particles and cargo release depend on specific particle-cell interactions via transferrin receptor. These data indicate corona-mediated delivery of membrane impermeable cargo in vitro by a particulate delivery system entirely composed of amino acids. PMID:22226586

Dittrich, Christian; Burckhardt, Christoph J.; Danuser, Gaudenz

2012-01-01

351

Screening siRNAs targeting a novel gene (HA117) and the development of a derivative recombinant adenovirus delivery system.  

PubMed

A novel gene, HA117, was discovered in our previous work. Using the pSOS-HUS vector method which we designed at previous study, we screened for small interfering RNAs (siRNAs) that targeted HA117. The pSOS-HUS siRNA screening results were verified and a delivery system was developed that contained a recombinant adenovirus carrying DNA templates for the transcription of the HA117 siRNAs. Of five pairs of DNA templates, siRNA transcribed from HAi5 produced the strongest effect against HA117. A recombinant adenovirus containing HAi5 (Ad-HAi5) was successfully constructed and evaluated. This work has laid the foundation for further study of HA117 gene function using RNA interference technology and has showed the pSOS-HUS vector method was successfully utilized as a rapid and effective screen of siRNAs for a target gene. PMID:21720420

Zheng, G H; Luo, Q; Jin, X Q; Guo, Y X; Xu, Y H

2011-09-01

352

Enhanced noscapine delivery using uPAR-targeted optical-MR imaging trackable nanoparticles for prostate cancer therapy.  

PubMed

The tubulin-binding anticancer activity of noscapine, an orally available plant-derived anti-tussive alkaloid, has been recently identified. Noscapine inhibits tumor growth in nude mice bearing human xenografts of hematopoietic, breast, lung, ovarian, brain and prostate origin. Despite its nontoxic attributes, significant elimination of the disease has not been achieved, perhaps since the bioavailability of noscapine to tumors saturates at an oral dose of 300 mg/kg body weight. To enable the selective and specific delivery of noscapine to prostate cancer cells, we have engineered a multifunctional nanoscale delivery vehicle that takes advantage of urokinase plasminogen activator receptor (uPAR) overexpression in prostate cancer compared to normal prostate epithelia and can be tracked by magnetic resonance imaging (MRI) and near-infrared (NIR) imaging. Specifically, we employed the human-type 135 amino-acid amino-terminal fragment (hATF) of urokinase plasminogen activator (uPA), a high-affinity natural ligand for uPAR. Noscapine (Nos) was efficiently adsorbed onto the amphiphilic polymer coating of uPAR-targeted nanoparticles (NPs). Nos-loaded NPs were uniformly compact-sized, stable at physiological pH and efficiently released the drug at pH 4 to 5 within a span of 4h. Our results demonstrate that these uPAR-targeted NPs were capable of binding to the receptor and were internalized by PC-3 cells. uPAR-targeted Nos-loaded NPs enhanced intracellular noscapine accumulation as evident by the ~6-fold stronger inhibitory effect on PC-3 growth compared to free noscapine. In addition, Nos-loaded iron oxide NPs maintained their T2 MRI contrast effect upon internalization into tumor cells owing to their significant susceptibility effect in cells. Thus, our data provide compelling evidence that these optically and magnetic resonance imaging (MRI)-trackable uPAR-targeted NPs may offer a great potential for image-directed targeted delivery of noscapine for the management of prostate cancer. PMID:21047537

Abdalla, Mohamed O; Karna, Prasanthi; Sajja, Hari Krishna; Mao, Hui; Yates, Clayton; Turner, Timothy; Aneja, Ritu

2011-02-10

353

A brain-targeted rabies virus glycoprotein-disulfide linked PEI nanocarrier for delivery of neurogenic microRNA.  

PubMed

Recent advances in efficient microRNA (miRNA) delivery techniques using brain-targeted nanoparticles offer critical information for understanding the functional role of miRNAs in vivo, and for supporting targeted gene therapy in terms of treating miRNA-associated neurological diseases. Here, we report the rabies virus glycoprotein (RVG)-labeled non-toxic SSPEI nanomaterials capable of neuron-specific miR-124a delivery to neuron in vivo. The RVG-labeled BPEI-SS (RVG-SSPEI) nanocarrier showed less toxicity in acetylcholine receptor-positive Neuro2a cells, and electrostatic interaction of RVG-SSPEI with miR-124a exhibited optimal transfection efficacy. The RVG-SSPEI polymer specifically targeted Neuro2a using cy5.5-miR-124a mixed with RVG-SSPEI. The functional action of miR-124a oligomers released from polyplexes in the cytoplasmic region was evaluated by a reporter vector containing a miR-124a -binding sequence, and showed a significantly reduced reporter signal in a dose-dependent manner. Cy5.5-miR-124a/RVG-SSPEI- injected into mice via tail veins displayed the enhanced accumulation of miR-124a in the isolated brain. Hindrance of the efficient penetration of neuronal cells by size limitation of the miR-124a/RVG-SSPEI improved with the help of mannitol through blood-brain barrier disruption. These findings indicated that the RVG peptide combined with mannitol infusion using SSPEI polymer for neuron-specific targeting in vivo is sufficient to deliver neurogenic microRNA into the brain. PMID:21489620

Hwang, Do Won; Son, Sejin; Jang, Jaeho; Youn, Hyewon; Lee, Song; Lee, Duhwan; Lee, Yun-Sang; Jeong, Jae Min; Kim, Won Jong; Lee, Dong Soo

2011-07-01

354

CD44-targeting for antitumor drug delivery: a new SN-38-hyaluronan bioconjugate for locoregional treatment of peritoneal carcinomatosis.  

PubMed

An innovative approach for cancer therapy implies the use of drugs covalently conjugated to macromolecular carriers that specifically target molecules over-expressed on tumor cells. This drug delivery strategy may allow a controlled release of the drug and a high targeting selectivity on tumor cells, increasing drug cytotoxicity and decreasing its undesirable side effects. We provide in vitro and in vivo preclinical data on the antitumor efficacy of ONCOFID™-S, a new bioconjugate of hyaluronic acid (HA) with SN-38 (the CPT11 active metabolite), that support the validity of the drug delivery strategy implying the use of HA as macromolecular carrier of antineoplastic drugs, an approach based on the over-expression of its target CD44 (the receptor for HA-mediated motility) in a wide variety of cancers. We show that ONCOFID™-S exerts a strong in vitro anti-proliferative activity on CD44 over-expressing rat DHD/K12/trb colon adenocarcinoma cells, as well as on gastric, breast, oesophageal, ovarian and lung human cancer cells, higher than that exerted by unconjugated SN-38. We also demonstrated the in vivo anti-tumor efficacy of locoregional treatment with ONCOFID™-S on two pre-clinical models of colorectal cancer (CRC) in BDIX rats: a) syngeneic model of subcutaneous tumor; b) syngeneic model of metastatic tumor induced by injection of cells into the peritoneal cavity, mimicking the clinical situation of peritoneal carcinomatosis. Specifically, in the latter model ONCOFID™-S is able to dramatically reduce all parameters indicative of a poor prognosis in peritoneal metastatization of CRC without any myelotoxicity or mesothelial inflammation. We propose this CD44-targeted therapeutic strategy for locoregional treatment of peritoneal carcinomatosis from CRC, against which systemic chemotherapy results almost inefficient. PMID:21486216

Serafino, Annalucia; Zonfrillo, Manuela; Andreola, Federica; Psaila, Rossana; Mercuri, Luana; Moroni, Noemi; Renier, Davide; Campisi, Monica; Secchieri, Cynthia; Pierimarchi, Pasquale

2011-06-01

355

Application of Collagen-Model Triple-Helical Peptide-Amphiphiles for CD44-Targeted Drug Delivery Systems  

PubMed Central

Cancer treatment by chemotherapy is typically accompanied by deleterious side effects, attributed to the toxic action of chemotherapeutics on proliferating cells from nontumor tissues. The cell surface proteoglycan CD44 has been recognized as a cancer stem cell marker. The present study has examined CD44 targeting as a way to selectively deliver therapeutic agents encapsulated inside colloidal delivery systems. CD44/chondroitin sulfate proteoglycan binds to a triple-helical sequence derived from type IV collagen, ?1(IV)1263–1277. We have assembled a peptide-amphiphile (PA) in which ?1(IV)1263–1277 was sandwiched between 4 repeats of Gly-Pro-4-hydroxyproline and conjugated to palmitic acid. The PA was incorporated into liposomes composed of DSPG, DSPC, cholesterol, and DSPE-PEG-2000 (1?:?4?:?5?:?0.5). Doxorubicin-(DOX-)loaded liposomes with and without 10%??1(IV)1263–1277 PA were found to exhibit similar stability profiles. Incubation of DOX-loaded targeted liposomes with metastatic melanoma M14#5 and M15#11 cells and BJ fibroblasts resulted in IC50 values of 9.8, 9.3, and >100??M, respectively. Nontargeted liposomes were considerably less efficacious for M14#5 cells. In the CD44+ B16F10 mouse melanoma model, CD44-targeted liposomes reduced the tumor size to 60% of that of the untreated control, whereas nontargeted liposomes were ineffective. These results suggest that PA targeted liposomes may represent a new class of nanotechnology-based drug delivery systems. PMID:23213537

Ndinguri, Margaret W.; Zheleznyak, Alexander; Lauer, Janelle L.; Anderson, Carolyn J.; Fields, Gregg B.

2012-01-01

356

Polymeric micelle nanocarriers for the cutaneous delivery of tacrolimus: a targeted approach for the treatment of psoriasis.  

PubMed

Tacrolimus (TAC) suffers from poor cutaneous bioavailability when administered topically using conventional vehicles with the consequence that although it is indicated for the treatment of atopic dermatitis, it has poor efficacy against psoriasis. The aim of this work was to formulate TAC loaded polymeric micelles using the biodegradable and biocompatible methoxy-poly(ethylene glycol)-dihexyl substituted polylactide (MPEG-dihexPLA) diblock copolymer and to investigate their potential for targeted delivery of TAC into the epidermis and upper dermis. Micelle formulations were characterized with respect to drug content, stability, and size. An optimal 0.1% micelle formulation was developed and shown to be stable over a period of 7 months at 4 °C; micelle diameters ranged from 10 to 50 nm. Delivery experiments using human skin and involving quantification by UHPLC-MS/MS demonstrated that this formulation resulted in significantly greater TAC deposition in skin than that with Protopic (0.1% w/w; TAC ointment), (1.50 ± 0.59 and 0.47 ± 0.20 ?g/cm(2), respectively). The cutaneous biodistribution profile of TAC in the upper 400 ?m of tissue (at a resolution of 20 ?m) demonstrated that the increase in cutaneous drug levels was due to improved TAC deposition in the stratum corneum, viable epidermis, and upper dermis. Given that there was no increase in the amount of TAC in deeper skin layers or any transdermal permeation, the results suggested that it would be possible to increase TAC levels selectively in the target tissue without increasing systemic absorption and the risk of side effects in vivo. Micelle distribution and molecular penetration pathways were subsequently visualized with confocal laser scanning microscopy (CLSM) using a fluorescently labeled copolymer and fluorescent dyes. The CLSM study indicated that the copolymer was unable to cross the stratum corneum and that release of the micelle "payload" was dependent on the molecular properties of the "cargo" as evidenced by the different behaviors of DiO and fluorescein. A preferential deposition of micelles into the hair follicle was also confirmed by CLSM. Overall, the results indicate that MPEG-dihexPLA micelles are highly efficient nanocarriers for the selective cutaneous delivery of tacrolimus, superior to the marketed formulation (Protopic). Furthermore, they may also have significant potential for targeted delivery to the hair follicle. PMID:25057896

Lapteva, Maria; Mondon, Karine; Möller, Michael; Gurny, Robert; Kalia, Yogeshvar N

2014-09-01

357

171. PEG-b-PPA\\/DNA Micelles for Liver Targeted-Gene Delivery  

Microsoft Academic Search

Liver is a critically important target for gene medicine applications because of the access of the transgene product to systemic circulation, and because it is the site of many metabolic genetic disorders, viral infection and malignancies. At present, the full potential of liver- targeted gene transfer is hindered by a lack of safe and efficient gene carriers. Recently, we have

Xuan Jiang; Hui Dai; Kam W. Leong; Hai-Quan Mao

2006-01-01

358

A Targetable, Injectable Adenoviral Vector for Selective Gene Delivery to Pulmonary Endothelium in Vivo  

Microsoft Academic Search

Adenoviral (Ad) vectors are promising gene therapy vehicles due to their in vivo stability and effi- ciency, but their potential utility is compromised by their restricted tropism. Targeting strategies have been devised to improve the efficacy of these agents, but specific targeting following in vivo systemic administration of vector has not previously been demonstrated. The distinct aim of the current

Paul N. Reynolds; Kurt R. Zinn; Vitaliy D. Gavrilyuk; Irina V. Balyasnikova; Buck E. Rogers; Donald J. Buchsbaum; Ming H. Wang; David J. Miletich; William E. Grizzle; Joanne T. Douglas; Sergei M. Danilov; David T. Curiel

2000-01-01

359

Targeted Delivery of Plasmid DNA to Myogenic Cells via Transferrin-Conjugated Peptide Nucleic Acid  

Microsoft Academic Search

We describe a novel approach to conjugate a targeting ligand to plasmid DNA without affecting either its supercoiled conformation or its ability to be efficiently transcribed. A 14-mer peptide nucleic acid (PNA) containing lysine and cysteine on each end was designed to target to a unique sequence located at the antibiotic resistance gene of the plasmid. The binding of PNA

Kenneth W. Liang; Eric P. Hoffman; Leaf Huang

2000-01-01

360

Pulsed-High Intensity Focused Ultrasound and Low Temperature- Sensitive Liposomes for Enhanced Targeted Drug Delivery and Antitumor Effect  

PubMed Central

Purpose To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors. Experimental Design Comparisons in vitro and in vivo were carried out between non - thermosensitive liposomes (NTSL) and low temperature - sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors. Results In vitro incubations simulating the pulsed-HIFU thermal dose (42°C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups. Conclusions Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases. PMID:17473205

Dromi, Sergio; Frenkel, Victor; Luk, Alfred; Traughber, Bryan; Angstadt, Mary; Bur, Monica; Poff, Jason; Xie, Jianwu; Libutti, Steven K.; Li, King C.P.; Wood, Bradford J.

2008-01-01

361

Co-delivery of Doxorubicin and Bmi1 siRNA by Folate Receptor Targeted Liposomes Exhibits Enhanced Anti-Tumor Effects in vitro and in vivo  

PubMed Central

Bmi1 gene overexpression is found in various human tumors and has been shown as a potential target for gene treatment. However, siRNA-based treatments targeting Bmi1 gene have been restricted to limited delivery, low bioavailability and hence relatively reduced efficacy. To overcome these barriers, we developed a folate receptor targeted co-delivery system folate-doxorubicin/Bmi1 siRNA liposome (FA-DOX/siRNA-L). The FA-DOX/siRNA-L was prepared through electrostatic interaction between folate doxorubicin liposome (FA-DOX-L) and Bmi1 siRNA. In vitro and in vivo studies showed that FA-DOX/siRNA-L inhibited tumor growth by combinatory role of Bmi1 siRNA and doxorubicin (DOX). Co-delivery of Bmi1 siRNA and DOX by FA-DOX/siRNA-L showed significantly higher efficacy than sole delivery of either DOX or Bmi1 siRNA. Real-time PCR and western blot analysis showed that FA-DOX/siRNA-L silenced the expression of Bmi1 gene. In addition, higher accumulation of the siRNA and DOX in tumor cells indicated that folate ligand displayed tumor targeting effect. These results suggest that Bmi1 is an effective therapeutic target for siRNA based cancer treatment that can be further improved by co-delivery of DOX through targeted liposomes.

Yang, Tan; Li, Bin; Qi, Shibo; Liu, Yong; Gai, Yongkang; Ye, Peng; Yang, Guang; Zhang, Wendian; Zhang, Peng; He, Xingxing; Li, Weijie; Zhang, Zhiping; Xiang, Guangya; Xu, Chuanrui

2014-01-01

362

Fabrication of Fe@mSiO2 nanowires with large remanence and low cytotoxicity for targeted drug delivery  

NASA Astrophysics Data System (ADS)

Core-shell structured Fe@mSiO2 nanowires for targeted drug delivery have been prepared through electrodeposition followed by a CTAB-template sol-gel process. The magnetic Fe nanowire core has a diameter of ˜40 nm and the mesoporous silica shell has a uniform thickness of ˜40 nm with an average pore size of ˜2.45 nm. The drug loading experiment indicates Fe@mSiO2 nanowires have a good capability for loading drug molecules due to the large surface area of the mesoporous silica shell. Furthermore, MDA-MB-231 human breast cancer cells were chosen as model cells to investigate cyototoxicity of the nanowires by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and lactate dehydrogenase (LDH) assays. MTT results show low cytotoxicity of the nanowires, which is concentration-dependent and the cell viability is still nearly 80% while the concentration reaches as high as 250 ?g/mL. Moreover, LDH assay has demonstrated that the nanowires have no influence on the integrity of the cell membrane. All results indicate that the as-prepared Fe@mSiO2 nanowires have a potential application as a drug nanocarrier for magnetic-targeted drug delivery.

Song, Meng-Meng; Bi, Hong; Zhang, Ye

2012-04-01

363

Genetically modified Tomato aspermy virus 2b protein as a tumor-targeting siRNA delivery carrier.  

PubMed

In nature, there exist a wide range of dsRNA-binding proteins that have different binding modes for small interfering RNA (siRNA) as well as structural differences, and some of these proteins have potential as effective siRNA delivery carriers. In order to deliver siRNA into cancer cells, a dsRNA-binding 2b protein derived from Tomato aspermy virus was genetically modified by fusing the integrin-targeting RGD peptide to its C-terminus, and biosynthesized. The resulting 2b-RGD protein possesses distinct characteristics favorable for biomedical applications of siRNA: (i) high affinity for siRNA, (ii) siRNA protection against RNases in serum, (iii) low cytotoxicity compared to the polycationic polymers often employed in conventional siRNA carriers, (iv) specific binding to integrins on cancer cells, and the ability to pass through the cell membrane via endocytosis, and (v) the ability to facilitate cytosolic release of siRNA. Here, we demonstrate that the 2b-RGD/siRNA complexes have great potential as a tumor-targeting siRNA delivery carrier and suggest their possible therapeutic applications for cancer treatment. PMID:25050774

Park, Eun Young; Jang, Mihue; Kim, Jong Hwan; Ahn, Hyung Jun

2014-11-01

364

Polysaccharide-Gold Nanocluster Supramolecular Conjugates as a Versatile Platform for the Targeted Delivery of Anticancer Drugs  

NASA Astrophysics Data System (ADS)

Through the high affinity of the ?-cyclodextrin (?-CD) cavity for adamantane moieties, novel polysaccharide-gold nanocluster supramolecular conjugates (HACD-AuNPs) were successfully constructed from gold nanoparticles (AuNPs) bearing adamantane moieties and cyclodextrin-grafted hyaluronic acid (HACD). Due to their porous structure, the supramolecular conjugates could serve as a versatile and biocompatible platform for the loading and delivery of various anticancer drugs, such as doxorubicin hydrochloride (DOX), paclitaxel (PTX), camptothecin (CPT), irinotecan hydrochloride (CPT-11), and topotecan hydrochloride (TPT), by taking advantage of the controlled association/dissociation of drug molecules from the cavities formed by the HACD skeletons and AuNPs cores as well as by harnessing the efficient targeting of cancer cells by hyaluronic acid. Significantly, the release of anticancer drugs from the drug@HACD-AuNPs system was pH-responsive, with more efficient release occurring under a mildly acidic environment, such as that in a cancer cell. Taking the anticancer drug DOX as an example, cell viability experiments revealed that the DOX@HACD-AuNPs system exhibited similar tumor cell inhibition abilities but lower toxicity than free DOX due to the hyaluronic acid reporter-mediated endocytosis. Therefore, the HACD-AuNPs supramolecular conjugates may possess great potential for the targeted delivery of anticancer drugs.

Li, Nan; Chen, Yong; Zhang, Ying-Ming; Yang, Yang; Su, Yue; Chen, Jia-Tong; Liu, Yu

2014-02-01

365

Self-assembled silk sericin/poloxamer nanoparticles as nanocarriers of hydrophobic and hydrophilic drugs for targeted delivery  

NASA Astrophysics Data System (ADS)

In recent times self-assembled micellar nanoparticles have been successfully employed in tissue engineering for targeted drug delivery applications. In this review, silk sericin protein from non-mulberry Antheraea mylitta tropical tasar silk cocoons was blended with pluronic F-127 and F-87 in the presence of solvents to achieve self-assembled micellar nanostructures capable of carrying both hydrophilic (FITC-inulin) and hydrophobic (anticancer drug paclitaxel) drugs. The fabricated nanoparticles were subsequently characterized for their size distribution, drug loading capability, cellular uptake and cytotoxicity. Nanoparticle sizes ranged between 100 and 110 nm in diameter as confirmed by dynamic light scattering. Rapid uptake of these particles into cells was observed in in vitro cellular uptake studies using breast cancer MCF-7 cells. In vitro cytotoxicity assay using paclitaxel-loaded nanoparticles against breast cancer cells showed promising results comparable to free paclitaxel drugs. Drug-encapsulated nanoparticle-induced apoptosis in MCF-7 cells was confirmed by FACS and confocal microscopic studies using Annexin V staining. Up-regulation of pro-apoptotic protein Bax, down-regulation of anti-apoptotic protein Bcl-2 and cleavage of regulatory protein PARP through Western blot analysis suggested further drug-induced apoptosis in cells. This study projects silk sericin protein as an alternative natural biomaterial for fabrication of self-assembled nanoparticles in the presence of poloxamer for successful delivery of both hydrophobic and hydrophilic drugs to target sites.

Mandal, Biman B.; Kundu, S. C.

2009-09-01

366

Preparation, Characterization and Pharmacokinetics of Folate Receptor-Targeted Liposomes for Docetaxel Delivery  

PubMed Central

A novel liposomal formulation of docetaxel targeting the folate receptor (FR) was synthesized and characterized. Liposomal formulations are less toxic and can provide longer systemic circulation time than the Tween 80 and ethanol based clinical formulation of docetaxel. Folate receptor-? (FR) is frequently over-expressed on epithelial cancer cells. Therefore, FR targeted liposomes can potentially enhance tumor cell uptake and antitumor efficacy of encapsulated drugs. The formulation studied had the compositions of egg phosphatidylcholine/cholesterol/methoxy-polyethylene glycol (PEG)2,000-distesroylphnosphatidylethanolamine/folate-PEG3,350-cholesteryl hemisuccinate (ePC/Chol/mPEG-DSPE/folate-PEG-CHEMS) at ratios of (80:15:4.5:0.5, mol/mol) and a drug-to-lipid ratio of 1:20, wt/wt. Sucrose was used as a lyoprotectant. The liposomes were prepared by thin-film hydration, polycarbonate membrane extrusion, followed by lyophilization. They remained stable for more than 5 months when stored as lyophilized powder and for 72 h at 4 °C following rehydration. The mean particle size of reconstituted liposomes ranged from 110 to 120 nm. FR-targeted liposomes of the same lipid composition entrapping calcein were shown to be efficiently taken up by FR + KB oral carcinoma cells. FR-targeted liposomes containing docetaxel showed 4.4-fold greater cytotoxicity compared to non-targeted liposomes in KB cells. Plasma clearance profiles of FR-targeted and non-targeted liposomeal docetaxel were evaluated and compared with that of docetaxel in Tween 80/ethanol formulation. The liposomal formulations showed much longer terminal half lives (4.92 h and 6.75 h for FR-targeted and non-targeted, respectively) than docetaxel in Tween 80/ethanol solution (1.09 h). FR-targeted liposomes are promising tumor cell-selective nanocarriers for docetaxel with potential for therapeutic applications. PMID:19435095

Zhai, Guangxi; Wu, Jun; Xiang, Guangya; Mao, Wenxue; Yu, Bo; Li, Hong; Piao, Longzhu; Lee, L. James

2013-01-01

367

Alginate-whey protein dry powder optimized for target delivery of essential oils to the intestine of chickens.  

PubMed

In poultry production, there is a lack of effective and convenient approaches to deliver bioactive compounds such as some essential oils, which have been proposed as alternatives to antibiotic growth promoters. The objective of this research was to develop a method for target delivery of essential oils in feed to the lower intestines of chickens. Carvacrol was used as a model essential oil, and 2 food-grade biopolymers, alginate and whey protein, were selected to encapsulate carvacrol in microparticles. The effects of a medium molecular weight alginate, a low molecular weight alginate (LBA), and whey protein concentrations on the properties of carvacrol-loaded microparticles were investigated using response surface methodology. The encapsulation efficiencies for all the tested formulations were ?98% and carvacrol content in the dry microparticles was 72 ± 2% (wt/wt). The microparticles showed good gastric resistance and rapid intestinal release under simulated gastrointestinal conditions. Alginate concentrations had the strongest influence on the gastric resistance of microparticles, whereas whey protein was the dominant parameter in controlling the intestinal release. The concentration of LBA was found to be the critical factor affecting the mechanical strength of the microparticles. A predicted optimum formulation from in vitro optimization was tested in chickens. It was found that a negligible amount of carvacrol was detected in the intestines of chickens fed with unencapsulated carvacrol. Microparticles of predicted optimum formulation delivered a remarkably higher concentration of carvacrol to the jejunum and ileum regions. The high concentration was sustained for more than 3 h after oral administration. The in vivo release of carvacrol from the microparticles appeared faster than release from in vitro simulation. Nonetheless, the in vitro simulation provided good indications of the in vivo performance, and thus may serve as a useful tool for formula optimization. In conclusion, the current study indicates that alginate-whey protein microparticles could be used as a target delivery carrier in the feed to enhance the intestinal delivery of essential oils in poultry production. PMID:25085933

Zhang, Y; Gong, J; Yu, H; Guo, Q; Defelice, C; Hernandez, M; Yin, Y; Wang, Q

2014-10-01

368

Delivery of acid sphingomyelinase in normal and niemann-pick disease mice using intercellular adhesion molecule-1-targeted polymer nanocarriers.  

PubMed

Type B Niemann-Pick disease (NPD) is a multiorgan system disorder caused by a genetic deficiency of acid sphingomyelinase (ASM), for which lung is an important and challenging therapeutic target. In this study, we designed and evaluated new delivery vehicles for enzyme replacement therapy of type B NPD, consisting of polystyrene and poly(lactic-coglycolic) acid polymer nanocarriers targeted to intercellular adhesion molecule (ICAM)-1, an endothelial surface