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Sample records for targeted nanogel delivery

  1. Nanogel Carrier Design for Targeted Drug Delivery

    PubMed Central

    Eckmann, D. M.; Composto, R. J.; Tsourkas, A.; Muzykantov, V. R.

    2014-01-01

    Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanogel drug carrier design. In particular, we highlight published studies of nanogel design, descriptions of nanogel functional characteristics and their behavior in biological models. These studies form a compendium of information that supports the scientific and clinical rationale for development of this carrier for targeted therapeutic interventions. PMID:25485112

  2. Internalized compartments encapsulated nanogels for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Yu, Jicheng; Zhang, Yuqi; Sun, Wujin; Wang, Chao; Ranson, Davis; Ye, Yanqi; Weng, Yuyan; Gu, Zhen

    2016-04-01

    Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The resulting nanogels loaded with doxorubicin (DOX) displayed enhanced internalization efficiency to the source cells through a specific homotypic affinity in vitro. However, when treated with the non-source cells, the EM-NGs exhibited insignificant difference in therapeutic efficiency compared to a bare HA nanogel with DOX. This study illustrates the potential of utilizing an internalized compartments encapsulated formulation for targeted cancer therapy, and offers guidelines for developing a natural particulate-inspired drug delivery system.Drug delivery systems inspired by natural particulates hold great promise for targeted cancer therapy. An endosome formed by internalization of plasma membrane has a massive amount of membrane proteins and receptors on the surface, which is able to specifically target the homotypic cells. Herein, we describe a simple method to fabricate an internalized compartments encapsulated nanogel with endosome membrane components (EM-NG) from source cancer cells. Following intracellular uptake of methacrylated hyaluronic acid (m-HA) adsorbed SiO2/Fe3O4 nanoparticles encapsulating a crosslinker and a photoinitiator, EM-NG was readily prepared through in situ crosslinking initiated under UV irradiation after internalization. The

  3. Galactose-functionalized multi-responsive nanogels for hepatoma-targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Lou, Shaofeng; Gao, Shan; Wang, Weiwei; Zhang, Mingming; Zhang, Ju; Wang, Chun; Li, Chen; Kong, Deling; Zhao, Qiang

    2015-02-01

    We report here a hepatoma-targeting multi-responsive biodegradable crosslinked nanogel, poly(6-O-vinyladipoyl-d-galactose-ss-N-vinylcaprolactam-ss-methacrylic acid) P(ODGal-VCL-MAA), using a combination of enzymatic transesterification and emulsion copolymerization for intracellular drug delivery. The nanogel exhibited redox, pH and temperature-responsive properties, which can be adjusted by varying the monomer feeding ratio. Furthermore, the volume phase transition temperature (VPTT) of the nanogels was close to body temperature and can result in rapid thermal gelation at 37 °C. Scanning electron microscopy also revealed that the P(ODGal-VCL-MAA) nanogel showed uniform spherical monodispersion. With pyrene as a probe, the fluorescence excitation spectra demonstrated nanogel degradation in response to glutathione (GSH). X-ray diffraction (XRD) showed an amorphous property of DOX within the nanogel, which was used in this study as a model anti-cancer drug. Drug-releasing characteristics of the nanogel were examined in vitro. The results showed multi-responsiveness of DOX release by the variation of environmental pH values, temperature or the availability of GSH, a biological reductase. An in vitro cytotoxicity assay showed a higher anti-tumor activity of the galactose-functionalized DOX-loaded nanogels against human hepatoma HepG2 cells, which was, at least in part, due to specific binding between the galactose segments and the asialoglycoprotein receptors (ASGP-Rs) in hepatic cells. Confocal laser scanning microscopy (CLSM) and flow cytometric profiles further confirmed elevated cellular uptake of DOX by the galactose-functionalised nanogels. Thus, we report here a multi-responsive P(ODGal-VCL-MAA) nanogel with a hepatoma-specific targeting ability for anti-cancer drug delivery.We report here a hepatoma-targeting multi-responsive biodegradable crosslinked nanogel, poly(6-O-vinyladipoyl-d-galactose-ss-N-vinylcaprolactam-ss-methacrylic acid) P(ODGal-VCL-MAA), using

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

    NASA Astrophysics Data System (ADS)

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

    2014-09-01

    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 αvβ3 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

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

    PubMed

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

    2011-06-28

    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.

  6. Synergistic Cisplatin/Doxorubicin Combination Chemotherapy for Multidrug-Resistant Cancer via Polymeric Nanogels Targeting Delivery.

    PubMed

    Wu, Haiqiu; Jin, Haojie; Wang, Cun; Zhang, Zihao; Ruan, Haoyu; Sun, Luyan; Yang, Chen; Li, Yongjing; Qin, Wenxin; Wang, Changchun

    2017-03-08

    Combination chemotherapy has been proposed to achieve synergistic effect and minimize drug dose for cancer treatment in clinic application. In this article, the stimuli-responsive polymeric nanogels (<100 nm in size) based on poly(acrylic acid) were designed as codelivery system for doxorubicin and cisplatin to overcome drug resistance. By chelation, electrostatic interaction, and π-π stacking interactions, the nanogels could encapsulate doxorubicin and cisplatin with designed ratio and high capacity. Compared with free drugs, the nanogels could deliver more drugs into MCF-7/ADR cells. Significant accumulation in tumor tissues was observed in the biodistribution experiments. The in vitro antitumor studies demonstrated the superior cell-killing activity of the nanogel drug delivery system with a combination index of 0.84, which indicated the great synergistic effect. All the antitumor experimental data revealed that the combination therapy was effective for the multidrug-resistant MCF-7/ADR tumor with reduced side effects.

  7. Nanogels for Oligonucleotide Delivery to the Brain

    PubMed Central

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

    2009-01-01

    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

  8. Triple-responsive Expansile Nanogel for Tumor and Mitochondria Targeted Photosensitizer Delivery

    PubMed Central

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

    2014-01-01

    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

  9. Polymer nanogels: a versatile nanoscopic drug delivery platform

    PubMed Central

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

    2012-01-01

    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

  10. Surface-Modified P(HEMA-co-MAA) Nanogel Carriers for Oral Vaccine Delivery: Design, Characterization, and In Vitro Targeting Evaluation

    PubMed Central

    Durán-Lobato, Matilde; Carrillo-Conde, Brenda; Khairandish, Yasmine; Peppas, Nicholas A.

    2015-01-01

    Oral drug delivery is a route of choice for vaccine administration because of its noninvasive nature and thus efforts have focused on efficient delivery of vaccine antigens to mucosal sites. An effective oral vaccine delivery system must protect the antigen from degradation upon mucosal delivery, penetrate mucosal barriers, and control the release of the antigen and costimulatory and immunomodulatory agents to specific immune cells (i.e., APCs). In this paper, mannan-modified pH-responsive P(HEMA-co-MAA) nanogels were synthesized and assessed as carriers for oral vaccination. The nanogels showed pH-sensitive properties, entrapping and protecting the loaded cargo at low pH values, and triggered protein release after switching to intestinal pH values. Surface decoration with mannan as carbohydrate moieties resulted in enhanced internalization by macrophages as well as increasing the expression of relevant costimulatory molecules. These findings indicate that mannan-modified P(HEMA-co-MAA) nanogels are a promising approach to a more efficacious oral vaccination regimen. PMID:24955658

  11. Nanocarrier-Integrated Microspheres: Nanogel Tectonic Engineering for Advanced Drug-Delivery Systems.

    PubMed

    Tahara, Yoshiro; Mukai, Sada-Atsu; Sawada, Shin-Ichi; Sasaki, Yoshihiro; Akiyoshi, Kazunari

    2015-09-09

    A nanocarrier-integrated bottom-up method is a promising strategy for advanced drug-release systems. Self-assembled nanogels, which are one of the most beneficial nanocarriers for drug-delivery systems, are tectonically integrated to prepare nanogel-crosslinked (NanoClik) microspheres. NanoClik microspheres consisting of nanogel-derived structures (observed by STED microscopy) release "drug-loaded nanogels" after hydrolysis, resulting in successful sustained drug delivery in vivo.

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

    PubMed

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

    2014-06-01

    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.

  13. Polymeric nanogel formulations of nucleoside analogs

    PubMed Central

    Vinogradov, Serguei V

    2008-01-01

    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

  14. Chitosan-based luminescent/magnetic hybrid nanogels for insulin delivery, cell imaging, and antidiabetic research of dietary supplements.

    PubMed

    Shen, Jian-Min; Xu, Luan; Lu, Yan; Cao, Hui-Ming; Xu, Zhi-Gang; Chen, Tong; Zhang, Hai-Xia

    2012-05-10

    In this work, the chitosan-based luminescent/magnetic (CLM) nanomaterials were synthesized by direct gelation of chitosan, CdTe and superparamagnetic iron oxide into the hybrid nanogels. The morphology, sizes and properties of the nanogels prepared with different chitosan/QD/MNP ratios and under different processing parameters were researched. Fluorescence microscopy, FTIR spectra and TEM images confirmed the success of the preparation of the CLM hybrid nanogels. Spherical CLM hybrid nanogels with appropriate average sizes (<160 nm) were used for insulin loading. The actual loading amount of insulin was approximately 40.1mg/g. Human normal hepatocytes L02 cell line was used to explore the effects of additives, such as mangiferin (MF), (-)-epigallocatechin gallate (EGCG), and (-)-epicatechin gallate (ECG) on the insulin-receptor-mediated cellular uptake using insulin-loaded CLM (ICLM) hybrid nanogels. Above 80% of viability of L02 cells were watched at a nanogels concentration of 500 μg/mL whatever the additives existed or not. The study discovered that the fluorescent signals of the ICLM hybrid nanogels in L02 cells were more intense in the presence of MF, EGCG and ECG in medium than in the absence of these components, respectively. These results demonstrate that MF, EGCG and ECG are potentially able to enhance targeting combination of insulin with L02 cells and improve insulin sensitivity in L02 cells. The hybrid nanogels designed as a targeting carrier can potentially offer an approach for integration of insulin delivery, cell imaging, and antidiabetic investigation of dietary supplements.

  15. Block and graft copolymers and NanoGel copolymer networks for DNA delivery into cell.

    PubMed

    Lemieux, P; Vinogradov, S V; Gebhart, C L; Guérin, N; Paradis, G; Nguyen, H K; Ochietti, B; Suzdaltseva, Y G; Bartakova, E V; Bronich, T K; St-Pierre, Y; Alakhov, V Y; Kabanov, A V

    2000-01-01

    Self-assembling complexes from nucleic acids and synthetic polymers are evaluated for plasmid and oligonucleotide (oligo) delivery. Polycations having linear, branched, dendritic. block- or graft copolymer architectures are used in these studies. All these molecules bind to nucleic acids due to formation of cooperative systems of salt bonds between the cationic groups of the polycation and phosphate groups of the DNA. To improve solubility of the DNA/polycation complexes, cationic block and graft copolymers containing segments from polycations and non-ionic soluble polymers, for example, poly(ethylene oxide) (PEO) were developed. Binding of these copolymers with short DNA chains, such as oligos, results in formation of species containing hydrophobic sites from neutralized DNA polycation complex and hydrophilic sites from PEO. These species spontaneously associate into polyion complex micelles with a hydrophobic core from neutralized polyions and a hydrophilic shell from PEO. Such complexes are very small (10-40 nm) and stable in solution despite complete neutralization of charge. They reveal significant activity with oligos in vitro and in vivo. Binding of cationic copolymers to plasmid DNA forms larger (70-200 nm) complexes. which are practically inactive in cell transfection studies. It is likely that PEO prevents binding of these complexes with the cell membranes ("stealth effect"). However attaching specific ligands to the PEO-corona can produce complexes, which are both stable in solution and bind to target cells. The most efficient complexes were obtained when PEO in the cationic copolymer was replaced with membrane-active PEO-b-poly(propylene oxide)-b-PEO molecules (Pluronic 123). Such complexes exhibited elevated levels of transgene expression in liver following systemic administration in mice. To increase stability of the complexes, NanoGel carriers were developed that represent small hydrogel particles synthesized by cross-linking of PEI with double end

  16. Soy protein/soy polysaccharide complex nanogels: folic acid loading, protection, and controlled delivery.

    PubMed

    Ding, Xuzhe; Yao, Ping

    2013-07-09

    In this study, we developed a facile approach to produce nanogels via self-assembly of folic acid, soy protein, and soy polysaccharide. High-pressure homogenization was introduced to break down the original aggregates of soy protein, which benefits the binding of soy protein with soy polysaccharide and folic acid at pH 4.0. After a heat treatment that causes the soy protein denaturation and gelation, folic acid-loaded soy protein/soy polysaccharide complex nanogels were fabricated. The nanogels have a polysaccharide surface that makes the nanogels dispersible in acidic conditions where folic acid is insoluble and soy protein forms precipitates after heating. More importantly, the protein and polysaccharide can inhibit the reactions between dissolved oxygen and folic acid during UV irradiation. After the preparation and storage of the nanogels in the presence of heat, oxygen, and light in acidic conditions, most of the folic acid molecules in the nanogels remain in their natural structure and can be released rapidly at neutral pH, that is, in the intestine. Because most food and beverages are acidic, the nanogels are a suitable delivery system of folic acid in food and beverages.

  17. Dendritic polyglycerol and N-isopropylacrylamide based thermoresponsive nanogels as smart carriers for controlled delivery of drugs through the hair follicle.

    PubMed

    Sahle, Fitsum Feleke; Giulbudagian, Michael; Bergueiro, Julian; Lademann, Jürgen; Calderón, Marcelo

    2017-01-07

    Nanoparticles with a size of several hundred nanometers can effectively penetrate into the hair follicles and may serve as depots for controlled drug delivery. However, they can neither overcome the hair follicle barrier to reach the viable cells nor release the loaded drug adequately. On the other hand, small drug molecules cannot penetrate deep into the hair follicles. Thus, the most efficient way for drug delivery through the follicular route is to employ nanoparticles that can release the drug close to the target structure upon exposure to some external or internal stimuli. Accordingly, 100-700 nm sized thermoresponsive nanogels with a phase transition temperature of 32-37 °C were synthesized by the precipitation polymerization technique using N-isopropylacrylamide as a monomer, acrylated dendritic polyglycerol as a crosslinker, VA-044 as an initiator, and sodium dodecyl sulphate as a stabilizer. The follicular penetration of the indodicarbocyanine (IDCC) labeled nanogels into the hair follicles and the release of coumarin 6, which was loaded as a model drug, in the hair follicles were assessed ex vivo using porcine ear skin. Confocal laser scanning microscopy (CLSM) enabled independent tracking of the nanogels and the loaded dye, although it is not as precise and accurate as standard analytical methods. The results showed that, unlike smaller nanogels (<100 nm), medium and larger sized nanogels (300-500 nm) penetrated effectively into the hair follicles with penetration depths proportional to the nanogel size. The release of the loaded dye in the hair follicles increased significantly when the investigation on penetration was carried out above the cloud point temperature of the nanogels. The follicular penetration of the nanogels from the colloidal dispersion and a 2.5% hydroxyethyl cellulose gel was not significantly different.

  18. Targeted Smart pH and Thermoresponsive N,O-Carboxymethyl Chitosan Conjugated Nanogels for Enhanced Therapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells.

    PubMed

    Verma, Neeraj K; Purohit, Mahaveer P; Equbal, Danish; Dhiman, Nitesh; Singh, Amrita; Kar, Aditya K; Shankar, Jai; Tehlan, Sarita; Patnaik, Satyakam

    2016-11-16

    In cancer treatment, developing ideal anticancer drug delivery systems to target tumor microenvironment by circumventing various physiological barriers still remains a daunting challenge. Here, in our work, a series of pH- and temperature-responsive nanogels based on poly(N-isopropylacrylamide-co-1-propene-2-3-dicarboxylate-co-2-acrylamido-2-methyl-1-propanesulfonate [poly(NIPAAm-IA-AMPS)] cross-linked by ethylene glycol dimethacrylate (EGDMA) were synthesized by random copolymerization. The molar ratio between monomer-comonomers-cross-linker was varied to fine-tune the optimum responsiveness of the nanogels. These optimized nanogels were further coupled to N,O-carboxymethyl chitosan (NOCC) stoichiometrically using EDC-NHS coupling chemistry to enhance the swelling behavior at lower pH. Interestingly, these NOCC-g-nanogels, when dispersed in aqueous media under sonication, attain nanosize and retain their high water-retention capacity with conspicuous pH and temperature responsiveness (viz. nanogel shrinkage in size beyond 35 °C and swelled at acidic pH) in vitro, as reflected by dynamic light scattering data. Doxorubicin (DOX), a potent anticancer drug, was loaded into these nanogels using the physical entrapment method. These drug-loaded nanogels exhibited a slow and sustained DOX release profile at physiological temperature and cytosolic pH. Furthermore, confocal and TEM results demonstrate that these nanogels were swiftly internalized by MCF-7 cells, and cell viability data showed preferential heightened cytotoxicity toward cancer cells (MCF-7 and MDA-MB231) compared to the MCF10A cells (human breast epithelial cell). Furthermore, intracellular DNA damage and cell cycle arrest assays suggest a mitochondrial mediated apoptosis in MCF-7 cells. This study substantiates our NOCC-g-nanogel platform as an excellent modality for passive diffusive loading and targeted release of entrapped drug(s) at physiological conditions in a controlled way for the improved

  19. Crosslinked duplex DNA nanogels that target specified proteins

    PubMed Central

    Iwasaki, Yasuhiko; Kondo, Jun-ichi; Kuzuya, Akinori; Moriyama, Rui

    2016-01-01

    Abstract Specific detection of protein biomarkers plays an important role in diagnostics and therapeutics. We have fabricated polymeric nanogels, which can specifically interact with the cancer biomarker thrombin to serve as a model. Two types of 2-methacryloyloxyethyl phosphorylcholine (MPC) copolymers bearing a thrombin-binding oligonucleotide aptamer and its complementary chain were independently synthesized by redox-initiated radical polymerization. These MPC polymers associate in a complimentary fashion due to double strand formation of the oligonucleotides in aqueous media, leading to the spontaneous formation of spherical nanogels. Nanogel formation was confirmed by dynamic light scattering (DLS) and transmittance microscopy. The average size of nanogel particles was 124 ± 2 nm and the nanogels were mono-dispersed (polydispersity index 0.21). Functional intercalators could be stably incorporated into nanogels through the physical interaction between the intercalators and the oligonucleotides. The ethidium bromide (EtBr)-incorporating nanogels were used as detectors for thrombin. The fluorescence intensity of solutions containing the EtBr-incorporating nanogels was decreased with an increase in the concentration of thrombin. The transformation of quadruplex–thrombin structure from complementary double-stranded structures resulted in the decrease in fluorescence intensity. In contrast, the intensity did not change when the nanogels were incubated with albumin. Thrombin is only one such model used to demonstrate this technique; oligonucleotide aptamers can be freely designed to interact with versatile bio-substances. Therefore, aptamer-crosslinked nanogels can be appropriate nanomaterials for disease diagnosis and therapy. PMID:27877881

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

    NASA Astrophysics Data System (ADS)

    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

    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.

  1. Amphiphilic cationic nanogels as brain-targeted carriers for activated nucleoside reverse transcriptase inhibitors

    PubMed Central

    Warren, G; Makarov, E; Lu, Y; Senanayake, T; Rivera, K; Gorantla, S; Poluektova, LY; Vinogradov, SV

    2015-01-01

    Progress in AIDS treatment shifted emphasis towards limiting adverse effects of antiviral drugs while improving the treatment of hard-to-reach viral reservoirs. Many therapeutic nucleoside reverse transcriptase inhibitors (NRTI) have a limited access to the central nervous system (CNS). Increased NRTI levels induced various complications during the therapy, including neurotoxicity, due to the NRTI toxicity to mitochondria. Here, we describe an innovative design of biodegradable cationic cholesterol-ε-polylysine nanogel carriers for delivery of triphosphorylated NRTIs that demonstrated high anti-HIV activity along with low neurotoxicity, warranting minimal side effects following systemic administration. Efficient CNS targeting was achieved by nanogel modification with brain-specific peptide vectors. Novel dual and triple-drug nanoformulations, analogous to therapeutic NRTI cocktails, displayed equal or higher antiviral activity in HIV-infected macrophages compared to free drugs. Our results suggest potential alternative approach to HIV-1 treatment focused on the effective nanodrug delivery to viral reservoirs in the CNS and reduced neurotoxicity. PMID:25559020

  2. Modular 'click-in-emulsion' bone-targeted nanogels.

    PubMed

    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

    2013-03-13

    A new class of nanogel demonstrates modular biodistribution and affinity for bone. Nanogels, ∼70 nm in diameter and synthesized via an astoichiometric click-chemistry in-emulsion method, controllably display residual, free clickable 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.

  3. Solvent-Responsive Molecularly Imprinted Nanogels for Targeted Protein Analysis in MALDI-TOF Mass Spectrometry.

    PubMed

    Bertolla, Maddalena; Cenci, Lucia; Anesi, Andrea; Ambrosi, Emmanuele; Tagliaro, Franco; Vanzetti, Lia; Guella, Graziano; Bossi, Alessandra Maria

    2017-03-01

    Molecular imprinted poly(acrylamido)-derivative nanogels have shown their selectivity to bind the protein human serum transferrin (HTR) and also showed their capability for instantaneous solvent-induced modification upon the addition of acetonitrile. Integrated to matrix-assisted laser desorption/ionization time-of-flight mass analysis the HTR-imprinted solvent-responsive nanogels permitted the determination of HTR straight from serum and offered novel perspectives in targeted protein analysis.

  4. Delivery of LLKKK18 loaded into self-assembling hyaluronic acid nanogel for tuberculosis treatment.

    PubMed

    Silva, João P; Gonçalves, Carine; Costa, César; Sousa, Jeremy; Silva-Gomes, Rita; Castro, António G; Pedrosa, Jorge; Appelberg, Rui; Gama, F Miguel

    2016-08-10

    Tuberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, recently joined HIV/AIDS on the top rank of deadliest infectious diseases. Low patient compliance due to the expensive, long-lasting and multi-drug standard therapies often results in treatment failure and emergence of multi-drug resistant strains. In this scope, antimicrobial peptides (AMPs) arise as promising candidates for TB treatment. Here we describe the ability of the exogenous AMP LLKKK18 to efficiently kill mycobacteria. The peptide's potential was boosted by loading into self-assembling Hyaluronic Acid (HA) nanogels. These provide increased stability, reduced cytotoxicity and degradability, while potentiating peptide targeting to main sites of infection. The nanogels were effectively internalized by macrophages and the peptide presence and co-localization with mycobacteria within host cells was confirmed. This resulted in a significant reduction of the mycobacterial load in macrophages infected in vitro with the opportunistic M. avium or the pathogenic M. tuberculosis, an effect accompanied by lowered pro-inflammatory cytokine levels (IL-6 and TNF-α). Remarkably, intra-tracheal administration of peptide-loaded nanogels significantly reduced infection levels in mice infected with M. avium or M. tuberculosis, after just 5 or 10 every other day administrations. Considering the reported low probability of resistance acquisition, these findings suggest a great potential of LLKKK18-loaded nanogels for TB therapeutics.

  5. Modulation of electrostatic interactions to improve controlled drug delivery from nanogels.

    PubMed

    Mauri, Emanuele; Chincarini, Giulia M F; Rigamonti, Riccardo; Magagnin, Luca; Sacchetti, Alessandro; Rossi, Filippo

    2017-03-01

    The synthesis of nanogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy in controlled drug delivery. However, with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small hydrophilic molecules through polymeric network pores. For these reasons research community is pointing toward the use of click strategies to reduce release rates of the linked drugs to the polymer chains. Here we propose an alternative method that considers the electrostatic interactions between polymeric chains and drugs to tune the release kinetics from nanogel network. The main advantage of these systems lies in the fact that the carried drugs are not modified and no chemical reactions take place during their loading and release. In this work we synthesized PEG-PEI based nanogels with different protonation degrees and the release kinetics with charged and uncharged drug mimetics (sodium fluorescein, SF, and rhodamine B, RhB) were studied. Moreover, also the effect of counterion used to induce protonation was taken into account in order to build a tunable drug delivery system able to provide multiple release rates with the same device.

  6. Bio-inspired pulmonary surfactant-modified nanogels: A promising siRNA delivery system.

    PubMed

    De Backer, Lynn; Braeckmans, Kevin; Stuart, Marc C A; Demeester, Jo; De Smedt, Stefaan C; Raemdonck, Koen

    2015-05-28

    Inhalation therapy with small interfering RNA (siRNA) is a promising approach in the treatment of pulmonary disorders. However, clinical translation is severely limited by the lack of suitable delivery platforms. In this study, we aim to address this limitation by designing a novel bioinspired hybrid nanoparticle with a core-shell nanoarchitecture, consisting of a siRNA-loaded dextran nanogel (siNG) core and a pulmonary surfactant (Curosurf®) outer shell. The decoration of siNGs with a surfactant shell enhances the colloidal stability and prevents siRNA release in the presence of competing polyanions, which are abundantly present in biofluids. Additionally, the impact of the surfactant shell on the biological efficacy of the siNGs is determined in lung cancer cells. The presence of the surfactants substantially reduces the cellular uptake of siNGs. Remarkably, the lowered intracellular dose does not impede the gene silencing effect, suggesting a crucial role of the pulmonary surfactant in the intracellular processing of the nanoparticles. In order to surmount the observed reduction in cellular dose, folate is incorporated as a targeting ligand in the pulmonary surfactant shell to incite receptor-mediated endocytosis. The latter substantially enhances both cellular uptake and gene silencing potential, achieving efficient knockdown at siRNA concentrations in the low nanomolar range.

  7. Targeted Nanogel Conjugate for Improved Stability and Cellular Permeability of Curcumin: Synthesis, Pharmacokinetics, and Tumor Growth Inhibition

    PubMed Central

    2015-01-01

    Curcumin (CUR) is a unique natural compound with promising anticancer and anti-inflammatory activities. However, the therapeutic efficacy of curcumin was challenged in clinical trials, mostly due to its low bioavailability, rapid metabolism, and elimination. We designed a nanodrug form of curcumin, which makes it stable and substantially enhances cellular permeability and anticancer activity at standard oral administration. Curcumin was conjugated as an ester to cholesteryl-hyaluronic acid (CHA) nanogel that is capable of targeted delivery to CD44-expressing drug-resistant cancer cells. CHA-CUR nanogels demonstrated excellent solubility and sustained drug release in physiological conditions. It induced apoptosis in cancer cells, suppressing the expression of NF-κB, TNF-α, and COX-2 cellular targets similar to free curcumin. Pharmacokinetic/pharmacodynamic (PK/PD) studies also revealed improved circulation parameters of CHA-CUR at oral, i.p. and i.v. administration routes. CHA-CUR showed targeted tumor accumulation and effective tumor growth inhibition in human pancreatic adenocarcinoma MiaPaCa-2 and aggressive orthotropic murine mammary carcinoma 4T1 animal models. CHA-CUR treatment was well-tolerated and resulted in up to 13-fold tumor suppression, making this nanodrug a potential candidate for cancer prevention and therapeutic treatment. PMID:25072100

  8. Biodistribution and Renal Clearance of Biocompatible Lung Targeted Poly(ethylene glycol) (PEG) Nanogel Aggregates

    PubMed Central

    Deshmukh, Manjeet; Kutscher, Hilliard L.; Gao, Dayuan; Sunil, Vasanthi R.; Malaviya, Rama; Vayas, Kinal; Stein, Stanley; Laskin, Jeffrey D.; Laskin, Debra L.; Sinko, Patrick J.

    2013-01-01

    A novel stabilized aggregated nanogel particle (SANP) drug delivery system was prepared for injectable passive lung targeting. Gel nanoparticles (GNPs) were synthesized by irreversibly cross-linking 8 Arm PEG thiol with 1,6-Hexane-bis-vinylsulfone (HBVS) in phosphate buffer (PB, pH 7.4) containing 0.1% v/v Tween™ 80. Aggregated nanogel particles (ANPs) were generated by aggregating GNPs to micron-size, which were then stabilized (i.e., SANPs) using a PEG thiol polymer to prevent further growth-aggregation. The size of SANPs, ANPs and GNPs was analyzed using a Coulter counter and transmission electron microscopy (TEM). Stability studies of SANPs were performed at 37 °C in rat plasma, phosphate buffered saline (PBS, pH 7.4) and PB (pH 7.4). SANPs were stable in rat plasma, PBS and PB over 7 days. SANPs were covalently labeled with HiLyteFluor™750 (DYE-SANPs) to facilitate ex vivo imaging. Biodistribution of intravenous DYE-SANPs (30 μm, 4 mg in 500 μL PBS) in male Sprague-Dawley rats was compared to free HiLyteFluor™750 DYE alone (1 mg in 500 μL PBS) and determined using a Xenogen IVIS®100 Imaging System. Biodistribution studies demonstrated that free DYE was rapidly eliminated from the body by renal filtration, whereas DYE-SANPs accumulated in the lung within 30 minutes and persisted for 48 h. DYE-SANPs were enzymatically degraded to their original principle components (i.e., DYE-PEG-thiol and PEG-VS polymer) and were then eliminated from the body by renal filtration. Histological evaluation using H & E staining and broncho alveolar lavage (BAL) confirmed that these flexible SANPs were not toxic. This suggests that because of their flexible and non-toxic nature, SANPs may be a useful alternative for treating pulmonary diseases such as asthma, pneumonia, tuberculosis and disseminated lung cancer. PMID:23041417

  9. Hyaluronic acid nanogels with enzyme-sensitive cross-linking group for drug delivery.

    PubMed

    Yang, Chenchen; Wang, Xin; Yao, Xikuang; Zhang, Yajun; Wu, Wei; Jiang, Xiqun

    2015-05-10

    A methacrylation strategy was employed to functionalize hyaluronic acid and prepare hyaluronic acid (HA) nanogels. Dynamic light scattering, zeta potential analyzer and electron microscopy were utilized to characterize the nanogels and their enzyme-degradability in vitro. It was found that these nanogels had a spherical morphology with the diameter of about 70nm, and negative surface potential. When doxorubicin (DOX) was loaded into the nanogels, the diameter decreased to approximately 50nm with a drug loading content of 16% and encapsulation efficiency of 62%. Cellular uptake examinations showed that HA nanogels could be preferentially internalized by two-dimensional (2D) cells and three-dimensional (3D) multicellular spheroids (MCs) which both overexpress CD44 receptor. Near-infrared fluorescence imaging, biodistribution and penetration examinations in tumor tissue indicated that the HA nanogels could efficiently accumulate and penetrate the tumor matrix. In vivo antitumor evaluation found that DOX-loaded HA nanogels exhibited a significantly superior antitumor effect.

  10. Preparation and evaluation of solid lipid nanoparticles based nanogel for dermal delivery of meloxicam.

    PubMed

    Khurana, S; Bedi, P M S; Jain, N K

    2013-01-01

    The aim of the current investigation was to prepare and investigate the potential of solid lipid nanoparticles based gel (SLN-gel) for the dermal delivery of meloxicam (MLX). The meloxicam loaded SLN (MLX-SLN) gel was developed and characterized by means of photon correlation spectroscopy, rheometry, and differential scanning calorimetry to determine the physicochemical properties. The behavior of SLN gel on rat skin was evaluated in vitro using Franz diffusion cells to determine the skin permeation and penetration characteristics, in vivo on mice to determine the skin tolerance by histopathological examinations. The anti-inflammatory potential of SLN gel was assessed by carrageenan induced rat paw edema test. Biophysical studies including differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were undertaken to study the interaction between the SLN gel and skin. MLX-SLN gel with nanometric particle size exhibited the controlled release abilities and simultaneously the potential to transport the drug to various skin layers. SLN gel displayed viscoelastic properties with predominantly elastic behavior and exhibited plastic flow. Biophysical studies elucidated the interaction between the SLN gel and stratum corneum (SC) lipids, and proposed the lipid bilayer fluidization as the possible mechanism for the increased penetration of meloxicam into skin. The nano-gel system showed marked anti-inflammatory activity and excellent skin tolerability. It can be concluded that SLN gel may be a promising delivery system for MLX in the treatment of inflammatory disorders.

  11. pH-Triggered Magnetic-Chitosan Nanogels (MCNs) For Doxorubicin Delivery: Physically vs. Chemically Cross Linking Approach

    PubMed Central

    Sadighian, Somayeh; Hosseini-Monfared, Hassan; Rostamizadeh, Kobra; Hamidi, Mehrdad

    2015-01-01

    Purpose: This paper evaluates the impact of cross linking strategy on the characteristics of magnetic chitosan nanogels (MCNs) as targeted drug delivery system for doxorubicin. Methods: Sodium tripolyphosphate (TPP) and glutaraldehyde were used as physical (electrostatic) and chemical (covalent binding) cross-linker agents, respectively. MCNs were characterized by means of X-ray diffraction (XRD), Scanning electron microscopy (SEM), fourier transform infrared (FT-IR) spectroscopy and vibrating sample magnetometer (VSM). Scanning electron microscopy (SEM) indicated the formation of spherical nanostructures with the final average particle size of around 35-40 nm. Results: The finding proved the superparamagnetic properties of the MCNs with relatively high-magnetization values which indicate that the MCNs were enough sensitive to external magnetic fields as a magnetic drug carrier. To understand the differences between the drug delivery properties of chemically and physically cross linked MCNs, the drug release studies were also conducted. Altogether, the results of this study clearly indicate that, however, both MCNs exhibited sustained drug release behaviour, the chemically cross linked MCNs provided enhanced controlled drug release characteristics in comparison to physically cross linked MCNs. Besides, according to the drug release behaviour of MCNs in buffer solutions in two different medium with the pH values of 5.3 and 7.4, it was clear that both nanoparticles exhibited pH sensitivity where the extent of drug release in the acidic media was significantly higher than neutral media. Conclusion: It can be concluded that chemically cross linked MCNs may serve as an ideal carrier for stimuli-triggered and controlled anticancer drug delivery. PMID:25789228

  12. Positive/negative surface charge of chitosan based nanogels and its potential influence on oral insulin delivery.

    PubMed

    Wang, Juan; Xu, Mengxue; Cheng, Xiaojie; Kong, Ming; Liu, Ya; Feng, Chao; Chen, Xiguang

    2016-01-20

    To develop insulin delivery system for the treatment of diabetes, two insulin-loaded nanogels with opposite zeta potential (-15.94 ± 0.449 mV for insulin:CMCS/CS-NGs(-) and +17.15 ± 0.492 mV for insulin:CMCS/CS-NGs(+)) were obtained. Ex vivo results showed that the nanogels with opposite surface charge exhibited different adhesion and permeation in specific intestinal segments. There was no significant differences in adhesion and permeation in rat duodenum, but in rat jejunum, insulin:CMCS/CS-NGs(-) exhibited enhanced adhesion and permeation, which were about 3 folds (adhesion) and 1.7 folds (permeation) higher than insulin:CMCS/CS-NGs(+). These results demonstrated that the surface charge property of nanogels determined the absorption sites of CMCS/CS-NGs in small intestine. In vivo study, the blood glucose level in insulin:CMCS/CS-NGs(-) group had 3 mmol/L lower than insulin:CMCS/CS-NGs(+) group during 1h to 11h after the oral administration, which demonstrated that negative insulin:CMCS/CS-NGs had a better management of blood glucose than positive ones.

  13. Smart thermo/pH responsive magnetic nanogels for the simultaneous delivery of doxorubicin and methotrexate.

    PubMed

    Salehi, Roya; Rasouli, Sepideh; Hamishehkar, Hamed

    2015-06-20

    Two novel dual temperature/pH-sensitive superparamagnetic nanogels were developed with the aim of simultaneously delivering two different anticancer drugs, doxorubicin (DOX) and methotrexate (MTX). The studied copolymers were characterized by (1)H NMR, SEM, and FTIR spectroscopy. Morphological investigations showed that both blank and drug-loaded nanogels had uniform shapes with a mean diameter of less than 30 nm. The drug storage/release behaviors were investigated. The nanogels showed an encapsulation efficiency of about 95% for both drugs. The cumulative in vitro release of the DOX/MTX-loaded nanogels exhibited an apparent thermo/pH-triggered controlled drug release in a sustained manner that was able to distinguish between tumor tissues. The cytotoxicity assay of a blank carrier to MCF7 and MDA-MB-231 cell lines indicated that the nanogels were suitable as drug carriers. Cell viability experiments further confirmed that the co-administration of DOX with MTX had a superior cytotoxicity to the mentioned cells compared with free dual drug- or single drug-loaded forms. Therefore, dual anticancer drug-loaded thermo/pH-sensitive nanogels have the potential to be used for cancer therapy, because they maintain a low premature drug release during blood circulation while having a rapid release upon reaching tumorous tissue.

  14. Investigation of dual-sensitive nanogels based on chitosan and N-isopropylacrylamide and its intelligent drug delivery of 10-hydroxycamptothecine.

    PubMed

    Wang, Yajing; Wang, Jiu; Xu, Hongjiang; Ge, Liang; Zhu, Jiabi

    2015-01-01

    The work was to prepare and characterize a responsive drug delivery system built of chitosan-g-poly (N-isopropylacrylamide) (CTS-g-PNIPAAm) nanogels and to evaluate the effects of CTS molecular weight (Mw) on the loading and in vitro release of insoluble drug 10-hydroxycamptothecine (HCPT). The CTS-g-PNIPAAm copolymers were synthesized by radical polymerization. The Mw and physical chemistry properties such as diameter, second virial coefficient of grafted PNIPAAm were investigated by dynamic and static laser light scattering method. A series of cross-linked CTS-g-PNIPAAm nanogels were prepared with N, N'-methylenebisacrylamide initially added as a cross-linker. The thermal and pH-sensitive features of cross-linked CTS-g-PNIPAAm nanogels were studied by determining the variance of transmittance, changeable size and reversed zeta potential. The critical aggregation concentrations (CAC) of resultant nanogels decreased from 0.045 to 0.036 mg/mL with CTS Mw increased from 50 kDa to 700 kDa. The loading efficiency of the HCPT encapsulated into CTS-g-PNIPAAm nanogels increased in parallel with CTS Mw, while the cumulative release percentage of HCPT-loaded nanogels decreased with CTS Mw increasing at both 25 °C and 37 °C. Fitting results of HCPT release data to different mathematical models suggested a diffusion-controlled mechanism at 25 °C. However, the release behaviors were dominated by combined effects of polymer erosion and osmotic pressure driven at 37 °C. The cytotoxicity study of the CTS-g-PNIPAAm nanogels against hepatic L02 cells indicated that the resultant nanogels did not exhibit apparent cytotoxicity.

  15. In Vivo Imaging of Glycol Chitosan-Based Nanogel Biodistribution.

    PubMed

    Pereira, Paula; Correia, Alexandra; Gama, Francisco M

    2016-03-01

    The preclinical development of nanomedicines raises several challenges and requires a comprehensive characterization. Among them is the evaluation of the biodistribution following systemic administration. In previous work, the biocompatibility and in vitro targeting ability of a glycol chitosan (GC) based nanogel have been validated. In the present study, its biodistribution in the mice is assessed, using near-infrared (NIR) fluorescence imaging as a tool to track the nanogel over time, after intravenous administration. Rapid whole body biodistribution of both Cy5.5 labeled GC nanogel and free polymer is found at early times. It remains widespreadly distributed in the body at least up to 6 h postinjection and its concentration then decreases drastically after 24 h. Nanogel blood circulation half-life lies around 2 h with the free linear GC polymer presenting lower blood clearance rate. After 24 h, the blood NIR fluorescence intensity associated with both samples decreases to insignificant values. NIR imaging of the organs shows that the nanogel had a body clearance time of ≈48 h, because at this time point a weak signal of NIR fluorescence is observed only in the kidneys. Hereupon it can be concluded that the engineered GC nanogel has a fairly long blood circulation time, suitable for biomedical applications, namely, drug delivery, simultaneously allowing efficient and quick body clearance.

  16. Basic concepts and recent advances in nanogels as carriers for medical applications.

    PubMed

    Neamtu, Iordana; Rusu, Alina Gabriela; Diaconu, Alina; Nita, Loredana Elena; Chiriac, Aurica P

    2017-11-01

    Nanogels in biomedical field are promising and innovative materials as dispersions of hydrogel nanoparticles based on crosslinked polymeric networks that have been called as next generation drug delivery systems due to their relatively high drug encapsulation capacity, uniformity, tunable size, ease of preparation, minimal toxicity, stability in the presence of serum, and stimuli responsiveness. Nanogels show a great potential in chemotherapy, diagnosis, organ targeting and delivery of bioactive substances. The main subjects reviewed in this article concentrates on: (i) Nanogel assimilation in the nanomedicine domain; (ii) Features and advantages of nanogels, the main characteristics, such as: swelling capacity, stimuli sensitivity, the great surface area, functionalization, bioconjugation and encapsulation of bioactive substances, which are taken into account in designing the structures according to the application; some data on the advantages and limitations of the preparation techniques; (iii) Recent progress in nanogels as a carrier of genetic material, protein and vaccine. The majority of the scientific literature presents the multivalency potential of bioconjugated nanogels in various conditions. Today's research focuses over the overcoming of the restrictions imposed by cost, some medical requirements and technological issues, for nanogels' commercial scale production and their integration as a new platform in biomedicine.

  17. Non-Cytotoxic Quantum Dot–Chitosan Nanogel Biosensing Probe for Potential Cancer Targeting Agent

    PubMed Central

    Maxwell, Tyler; Banu, Tahmina; Price, Edward; Tharkur, Jeremy; Campos, Maria Gabriela Nogueira; Gesquiere, Andre; Santra, Swadeshmukul

    2015-01-01

    Quantum dot (Qdot) biosensors have consistently provided valuable information to researchers about cellular activity due to their unique fluorescent properties. Many of the most popularly used Qdots contain cadmium, posing the risk of toxicity that could negate their attractive optical properties. The design of a non-cytotoxic probe usually involves multiple components and a complex synthesis process. In this paper, the design and synthesis of a non-cytotoxic Qdot-chitosan nanogel composite using straight-forward cyanogen bromide (CNBr) coupling is reported. The probe was characterized by spectroscopy (UV-Vis, fluorescence), microscopy (Fluorescence, Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM) and Dynamic Light Scattering. This activatable (“OFF”/“ON”) probe contains a core–shell Qdot (CdS:Mn/ZnS) capped with dopamine, which acts as a fluorescence quencher and a model drug. Dopamine capped “OFF” Qdots can undergo ligand exchange with intercellular glutathione, which turns the Qdots “ON” to restore fluorescence. These Qdots were then coated with chitosan (natural biocompatible polymer) functionalized with folic acid (targeting motif) and Fluorescein Isothiocyanate (FITC; fluorescent dye). To demonstrate cancer cell targetability, the interaction of the probe with cells that express different folate receptor levels was analyzed, and the cytotoxicity of the probe was evaluated on these cells and was shown to be nontoxic even at concentrations as high as 100 mg/L.

  18. Mastocarcinoma therapy synergistically promoted by lysosome dependent apoptosis specifically evoked by 5-Fu@nanogel system with passive targeting and pH activatable dual function.

    PubMed

    Zhu, Xiandi; Sun, Yn; Chen, Di; Li, Jingfeng; Dong, Xia; Wang, Jie; Chen, Huaiwen; Wang, Ying; Zhang, Fulei; Dai, Jinaxin; Pirraco, Rogério P; Guo, Shangjing; Marques, Alexandra P; Reis, Rui L; Li, Wei

    2017-03-22

    This manuscript describes a synergistic therapy for mastocarcinoma by pH and temperature dual-sensitive nanogel, and effects of microstructure, composition and properties of nanogel on the cellular response mechanism. The extracellular internalization of nanogels was obviously enhanced, due to the passive targeting function at T>VPTT. Interestingly, the increased cytotoxicity was further synergistically enhanced by an unexpected apoptosis as evoked by the 5-fluorouracil loaded nanogel (FLNG). The systemically evaluation of the effectors generated from different sub-cellular organelles including endosome, lysosome, autophagosome confirmed that it was a lysomal dependent apoptosis. Such specific apoptosis was mainly attributed to its activatable protonated PEI at low pH, which caused lysosomal membrane destruction and lysosomal enzyme cathepsin B (Cat B) leakage. This Cat B was then translocated to the mitochondria resulting in mitochondrial membrane permeability increase and mitochondrial membrane potential (MMP) decrease, followed by cytochrome c (Cyt C) release. Cyt C was the main molecule that evoked apoptosis as reflected by overexpression of caspase 9. Additionally, such lysosome dependent, apoptosis was further enhanced by the passive cellular targeting at T>VPTT. Thus, the tumor growth inhibition was synergistically enhanced by the extracellular temperature dependent passive targeting and intracellular pH activatable lysosomal dependent apoptosis.

  19. Surface charge effect on mucoadhesion of chitosan based nanogels for local anti-colorectal cancer drug delivery.

    PubMed

    Feng, Chao; Li, Jing; Kong, Ming; Liu, Ya; Cheng, Xiao Jie; Li, Yang; Park, Hyun Jin; Chen, Xi Guang

    2015-04-01

    To develop more effective anticancer mucoadhesive drug delivery system for the treatment of colorectal cancer, chitosan based nanogels (NGs) were prepared by electrostatic interaction between chitosan (CS) and carboxymethyl-chitosan (CMCS). By respectively using tripolyphosphate (TPP) and CaCl2 as ionic crosslinker, two well-characterized doxorubicin hydrochloride (DOX) loaded NGs with opposite zeta potential (DOX:CS/CMCS/TPP NGs, -32.6±1.1 mV and DOX:CS/CMCS/Ca2+ NGs, +31.8±0.9 mV) were obtained. Compared with DOX:CS/CMCS/TPP NGs, DOX:CS/CMCS/Ca2+ NGs were taken up to a greater extent by colorectal cancer cells, resulting in greater reduction in percentage of cell viability. Owing to high binding capability to mucin and inhibited paracellular transport by colon, DOX:CS/CMCS/Ca2+ NGs exhibited improved mucoadhesion and limited permeability. This is beneficial to prolong the contact time of formulation onto intestinal mucosa and improved local drug concentration. The results provided evidence DOX:CS/CMCS/Ca2+ NGs to be exciting and promising for the treatment of colorectal cancer.

  20. Magnetic and pH dual responsive core-shell hybrid nanogels: a single nano-object for pH-dependent magnetic manipulation, fluorescent pH-sensing, and drug delivery

    SciTech Connect

    Wu, Weitai; Shen, Jing; Gai, Zheng; Hong, Kunlun; Banerjeea, Probal; Zhou, Shuiqin

    2011-01-01

    Remotely optical sensing and drug delivery using an environmentally-guided magnetically-driven hybrid nanogel particle could allow for medical diagnostics and treatment. Such multifunctional hybrid nanogels (<200 nm) were prepared through the first synthesis of magnetic Ni NPs, followed by a moderate growth of fluorescent metallic Ag on the surface of Ni NPs, and then a coverage of a pH-responsive copolymer gel shell of poly(ethylene glycol-co-methacrylic acid) [p(EG-MAA)] onto the Ni-Ag bimetallic NP cores (18 {+-} 5 nm). The introduction of the pH-responsive p(EG-MAA) gel shell onto the magnetic and fluorescent Ni-Ag NPs makes the polymer-bound Ni-Ag NPs responsive to pH over the physiologically important range 5.0-7.4. The hybrid nanogels can adapt to surrounding pH and regulate the sensitivity in response to external magnetic field (such as a small magnet of 0.1 T), resulting in the accumulation of the hybrid nanogels within the duration from hours to a few seconds as the pH value decreases from 7.4 to 5.0. The pH-dependent magnetic response characteristic of the hybrid nanogels were further integrated with the pH change to fluorescent signal transduction and pH-regulated anticancer drug (a model drug 5-fluorouracil) delivery functions. The hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells. The multiple responsive hybrid nanogel that can be manipulated in tandem endogenous and exogenous activation should enhance our ability to address the complexity of biological systems.

  1. Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes.

    PubMed

    Gerecke, Christian; Edlich, Alexander; Giulbudagian, Michael; Schumacher, Fabian; Zhang, Nan; Said, Andre; Yealland, Guy; Lohan, Silke B; Neumann, Falko; Meinke, Martina C; Ma, Nan; Calderón, Marcelo; Hedtrich, Sarah; Schäfer-Korting, Monika; Kleuser, Burkhard

    2017-03-01

    Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery.

  2. Nanogels fabricated from bovine serum albumin and chitosan via self-assembly for delivery of anticancer drug.

    PubMed

    Wang, Yuntao; Xu, Shasha; Xiong, Wenfei; Pei, Yaqiong; Li, Bin; Chen, Yijie

    2016-10-01

    In this study, bovine serum albumin (BSA) and chitosan (CS) were used to prepare BSA-CS nanogels by a simple green self-assembly technique. Then the nanogels were successfully used to entrap doxorubicin hydrochloride (DOX) with an entrapment ratio of 46.3%, aiming to realize the slow-release effect and lower the cytotoxicity of DOX. The IC50 values of DOX-loaded BSA-CS (DOX-BSA-CS) and free DOX obtained by MTT assay in SGC7901 cells were 0.22 and 0.05μg/mL, respectively. The cytotoxicity of DOX significantly decreased within 24h after encapsulation by the nanogels, indicating that the loaded drug could slowly release within 24h and the BSA-CS was a good slow release system. The cellular uptake experiments indicated DOX-BSA-CS diffused faster into the cancer cell than the bare drug. The flow cytometry and TUNEL assay proved DOX-BSA-CS could induce a larger apoptosis proportion of gastric cancer cells 7901 than the bare drug and it is promising to be used for curing gastric cancer.

  3. Ex vivo skin permeation and retention studies on chitosan-ibuprofen-gellan ternary nanogel prepared by in situ ionic gelation technique--a tool for controlled transdermal delivery of ibuprofen.

    PubMed

    Abioye, Amos Olusegun; Issah, Sureya; Kola-Mustapha, Adeola Tawakalitu

    2015-07-25

    The chemical potentials of drug-polymer electrostatic interaction have been utilized to develop a novel ternary chitosan-ibuprofen-gellan nanogel as controlled transdermal delivery tool for ibuprofen. The ternary nanogels were prepared by a combination of electrostatic nanoassembly and ionic gelation techniques. The electrostatic and hydrophobic interactions as well as hydrogen bonding between ibuprofen and chitosan were confirmed with FTIR, while DSC, TGA and SEM confirmed the physical state, thermal and morphological characteristics, respectively. The ex vivo delivery of ibuprofen onto and across the skin was evaluated based on system specific drug release parameters such as steady state permeation rate, permeability coefficient, permeability enhancement ratio, skin/gel partition coefficient, diffusion coefficient, lag time and release rate constant and mechanisms of release were determined using mathematical models. Interaction between ibuprofen and chitosan produced new spherical eutectic nanoconjugates with remarkable decrease in particle size of ibuprofen from 4580 (length-to-breadth aspect ratio) to a minimum of 14.15 nm (324-times), and thermally stable amorphous characteristics. The nanogels exhibited significant elastic and pseudoplastic characteristics dictated by the concentration of chitosan with maximum swelling capacity of 775% w/w at 6.55 mM chitosan compared with 281.16 and 506.50% for plain gellan and control ibuprofen hydrogel, respectively. Chitosan enhanced the skin penetration, permeability and the rate of transdermal release of ibuprofen by a factor of 4, dictated by the extent of ibuprofen-chitosan ionic interaction and its concentration. The major mechanism of ibuprofen release through the pig skin was drug diffusion however drug partition and matrix erosion also occurred. It was evident that ternary nanogels are novel formulations with potential application in controlled transdermal delivery of ibuprofen.

  4. Biocompatibility of a self-assembled glycol chitosan nanogel.

    PubMed

    Pereira, Paula; Pedrosa, Sílvia S; Correia, Alexandra; Lima, Cristovao F; Olmedo, Mercedes Peleteiro; González-Fernández, África; Vilanova, Manuel; Gama, Francisco M

    2015-04-01

    The research of chitosan-based nanogel for biomedical applications has grown exponentially in the last years; however, its biocompatibility is still insufficiently reported. Hence, the present work provides a thorough study of the biocompatibility of a glycol chitosan (GC) nanogel. The obtained results showed that GC nanogel induced slight decrease on metabolic activity of RAW, 3T3 and HMEC cell cultures, although no effect on cell membrane integrity was verified. The nanogel does not promote cell death by apoptosis and/or necrosis, exception made for the HMEC cell line challenged with the higher GC nanogel concentration. Cell cycle arrest on G1 phase was observed only in the case of RAW cells. Remarkably, the nanogel is poorly internalized by bone marrow derived macrophages and does not trigger the activation of the complement system. GC nanogel blood compatibility was confirmed through haemolysis and whole blood clotting time assays. Overall, the results demonstrated the safety of the use of the GC nanogel as drug delivery system.

  5. 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...

  6. Surfactant-free synthesis of biodegradable, biocompatible, and stimuli-responsive cationic nanogel particles.

    PubMed

    Urakami, Hiromitsu; Hentschel, Jens; Seetho, Kellie; Zeng, Hanxiang; Chawla, Kanika; Guan, Zhibin

    2013-10-14

    Nanogels have attracted much attention lately because of their many potential applications, including as nanocarriers for drug and gene delivery. Most nanogels reported previously, however, are not biodegradable, and their synthesis often requires the use of surfactants. Herein we report a surfactant-free method for the preparation of biodegradable, biocompatible, and stimuli-responsive cationic nanogels. The nanogels were synthesized by simply coaservating linear polymer precursors in mixed solvents followed by in situ cross-linking with homobifunctional cross-linkers. The versatility of this approach has been demonstrated by employing two different polymers and various cross-linkers to prepare nanogel particles with diameters ranging from 170 to 220 nm. Specifically, disulfide-containing tetralysine (TetK)- and oligoethylenimine (OEI)-based prepolymers were prepared and the subsequent nanogels were formed by covalently cross-linking the polymer coacervate phase. Nanogel particles are responsive to pH changes, increasing in size and zeta-potential with concomitant lowering of solution pH. Furthermore, as revealed by AFM imaging, nanogel particles were degradable in the presence of glutathione at concentrations similar to those in intracellular environment (10 mM). Both the nanogel and the polymer precursors were determined to exhibit minimal cytotoxicity against fibroblast 3T3 cells by flow cytometric analyses and fluorescent imaging. This study demonstrates a new surfactant-free method for preparing biodegradable, biocompatible, and stimuli-responsive nanogels as potential nanocarriers for the delivery of drugs and genes.

  7. In-situ immobilization of quantum dots in polysaccharide-based nanogels for integration of optical pH-sensing, tumor cell imaging, and drug delivery.

    PubMed

    Wu, Weitai; Aiello, Michael; Zhou, Ting; Berliner, Alexandra; Banerjee, Probal; Zhou, Shuiqin

    2010-04-01

    We report a class of polysaccharide-based hybrid nanogels that can integrate the functional building blocks for optical pH-sensing, cancer cell imaging, and controlled drug release into a single nanoparticle system, which can offer broad opportunities for combined diagnosis and therapy. The hybrid nanogels were prepared by in-situ immobilization of CdSe quantum dots (QDs) in the interior of the pH and temperature dual responsive hydroxypropylcellulose-poly(acrylic acid) (HPC-PAA) semi-interpenetrating polymer networks. The-OH groups of the HPC chains are designed to sequester the precursor Cd(2+) ions into the nanogels as well as stabilize the in-situ formed CdSe QDs. The pH-sensitive PAA network chains are designed to induce a pH-responsive volume phase transition of the hybrid nanogels. The developed HPC-PAA-CdSe hybrid nanogels combine a strong trap emission at 741nm for sensing physicochemical environment in a pH dependent manner and a visible excitonic emission at 592nm for mouse melanoma B16F10 cell imaging. The hybrid nanogels also provide excellent stability as a drug carrier, which cannot only provide a high drug loading capacity for a model anticancer drug temozolomide, but also offer a pH-triggered sustained-release of the drug molecules in the gel network.

  8. Biocompatibility of a Self-Assembled Crosslinkable Hyaluronic Acid Nanogel.

    PubMed

    Pedrosa, Sílvia Santos; Pereira, Paula; Correia, Alexandra; Moreira, Susana; Rocha, Hugo; Gama, Francisco Miguel

    2016-11-01

    Hyaluronic acid nanogel (HyA-AT) is a redox sensitive crosslinkable nanogel, obtained through the conjugation of a thiolated hydrophobic molecule to the hyaluronic acid chain. Engineered nanogel was studied for its biocompatibility, including immunocompatibility and hemocompatability. The nanogel did not compromise the metabolic activity or cellular membrane integrity of 3T3, microvascular endothelial cells, and RAW 264.7 cell lines, as determined by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase release assays. Also, we didn't observe any apoptotic effect on these cell lines through the Annexin V-FITC test. Furthermore, the nanogel cell internalization was analyzed using murine bone marrow derived macrophages, and the in vivo and ex vivo biodistribution of the Cy5.5 labeled nanogel was monitored using a non-invasive near-infrared fluorescence imaging system. The HyA-AT nanogel exhibits fairly a long half-live in the blood stream, thus showing potential for drug delivery applications.

  9. Intracellularly Swollen Polypeptide Nanogel Assists Hepatoma Chemotherapy

    PubMed Central

    Shi, Bo; Huang, Kexin; Ding, Jianxun; Xu, Weiguo; Yang, Yu; Liu, Haiyan; Yan, Lesan; Chen, Xuesi

    2017-01-01

    Nowadays, chemotherapy is one of the principal modes of treatment for tumor patients. However, the traditional formulations of small molecule drugs show short circulation time, low tumor selectivity, and high toxicity to normal tissues. To address these problems, a facilely prepared, and pH and reduction dual-responsive polypeptide nanogel was prepared for selectively intracellular delivery of chemotherapy drug. As a model drug, doxorubicin (DOX) was loaded into the nanogel through a sequential dispersion and dialysis technique, resulting in a high drug loading efficiency (DLE) of 96.7 wt.%. The loading nanogel, defined as NG/DOX, exhibited a uniform spherical morphology with a mean hydrodynamic radius of 58.8 nm, pH and reduction dual-triggered DOX release, efficient cell uptake, and cell proliferation inhibition in vitro. Moreover, NG/DOX exhibited improved antitumor efficacy toward H22 hepatoma-bearing BALB/c mouse model compared with free DOX·HCl. Histopathological and immunohistochemical analyses were implemented to further confirm the tumor suppression activity of NG/DOX. Furthermore, the variations of body weight, histopathological morphology, bone marrow cell micronucleus rate, and white blood cell count verified that NG/DOX showed excellent safety in vivo. With these excellent properties in vitro and in vivo, the pH and reduction dual-responsive polypeptide nanogel exhibits great potential for on-demand intracellular delivery of antitumor drug, and holds good prospect for future clinical application. PMID:28255361

  10. Adenoviral vectors modified by heparin-polyethyleneimine nanogels enhance targeting to the lung and show therapeutic potential for pulmonary metastasis in vivo.

    PubMed

    Wei, Wei; Mu, Yandong; Li, XiaoPeng; Gou, MaLing; Zhang, HaiLong; Luo, ShunTao; Men, Ke; Mao, YongQiu; Qian, ZhiYong; Yang, Li

    2011-12-01

    Polyethyleneimine (PEI) is a well-known cationic polymer that has previously been shown to have significant potential to deliver genes in vitro and in vivo. However, PEI is non-degradable and exhibits a high cytotoxicity as its molecular weight increases. The clinical application for systemic administration of adenoviral (Ad) vectors is limited, as these vectors do not efficiently penetrate solid tumor masses due to a common deficiency of Coxsackie Adenovirus Receptor (CAR) on the tumor surface. In this study, we conjugated low molecular weight PEI (Mn = 1,800) to heparin (Mn = 4,000-6,000) to create a new type of cationic degradable nanogel (HPEI) that was then used to modify Ad vectors. The resulting HPEI-Ad complexes were used to infect CT26 and HeLa cells in vitro. Additionally, the HPEI-Ad complexes were administrated in vivo via intravenous injection, and tissue distribution was assessed using luciferase assays; the therapeutic potential of HPEI-Ad complexes for pulmonary metastasis mediated by CT26 cells was also investigated. In vitro, HPEI-Ad complexes enhanced the transfection efficiency in CT26 cells, reaching 36.3% compared with 0.1% of the native adenovirus. In vivo, HPEI-Ad complexes exhibited greater affinity for lung tissue than the native adenovirus and effectively inhibited the growth of pulmonary metastases mediated by CT26 cells. Our results indicate that Ad vectors modified by HPEI nanogels to form HPEI-Ad complexes enhanced transfection efficiency in CT26 cells that lacked CAR, targeted to the lung and demostrated a potential therapy for pulmonary metastasis.

  11. Application of chitosan-based nanocarriers in tumor-targeted drug delivery.

    PubMed

    Ghaz-Jahanian, Mohammad Ali; Abbaspour-Aghdam, Farzin; Anarjan, Navideh; Berenjian, Aydin; Jafarizadeh-Malmiri, Hoda

    2015-03-01

    Cancer is one of the major malignant diseases in the world. Current anti tumor agents are restricted during the chemotherapy due to their poor solubility in aqueous media, multidrug resistance problems, cytotoxicity, and serious side effects to healthy tissues. Development of targeted drug nanocarriers would enhance the undesirable effects of anticancer drugs and also selectively deliver them to cancerous tissues. Variety of nanocarriers such as micelles, polymeric nanoparticles, liposomes nanogels, dendrimers, and carbon nanotubes have been used for targeted delivery of anticancer agents. These nanocarriers transfer loaded drugs to desired sites through passive or active efficacy mechanisms. Chitosan and its derivatives, due to their unique properties such as hydrophilicity, biocompatibility, and biodegradability, have attracted attention to be used in nanocarriers. Grafting cancer-specific ligands onto the Chitosan nanoparticles, which leads to ligand-receptor interactions, has been successfully developed as active targeting. Chitosan-conjugated components also respond to external or internal physical and chemical stimulus in targeted tumors that is called environment triggers. In this study, mechanisms of targeted tumor deliveries via nanocarriers were explained; specifically, chitosan-based nanocarriers in tumor-targeting drug delivery were also discussed.

  12. The Nanogel-Based Scaffold in Endodontics

    NASA Astrophysics Data System (ADS)

    Kheirieh, Sanam

    Aim: The purpose of this study was to evaluate a degradable nanogel-based scaffold with antibacterial content. Methods: This nanogel design consisted of the cross-linker, polyethyleneglycol (PEG 4600) with 3-dimensional network. This polymer degrades over time ( 30 days), delivering a controlled release of antibiotic. Amoxicillin was added to the scaffold with 25 wt% (n=26). Nanogel-scaffold only and amoxicillin only were used as controls. Agar diffusion test against E. faecalis was performed at eight time intervals (days 1, 3, 5, 7, 10, 14, 21, 30). One-Way ANOVA was used to compare the antibacterial properties of experimental groups at the eight different times. Results: The antibacterial properties for experimental plates, at the different times, were not significantly different (F=.624, p=.74). Based on the profile, the scaffold-only group showed a smaller inhibition zone compared to the two other groups. The antibacterial profiles for the experimental group and the antibiotic-only group were similar. Conclusion: This particular scaffold presented antibacterial properties. Findings suggest that nanogel-modified scaffolds may have potential use for drug-delivery in endodontics..

  13. Reversible Deactivation of Enzymes by Redox-Responsive Nanogel Carriers.

    PubMed

    Peng, Huan; Rübsam, Kristin; Jakob, Felix; Pazdzior, Patrizia; Schwaneberg, Ulrich; Pich, Andrij

    2016-11-01

    Novel redox-responsive polymeric nanogels that allow highly efficient enzyme encapsulation and reversible modulation of enzyme activity are developed. The nanogel synthesis and encapsulation of enzyme are performed simultaneously via in situ crosslinking of pyridyldisulfide-functionalized water-soluble reactive copolymers, which are synthesized via reversible addition-fragmentation chain transfer copolymerization. Obtained nanogels with loaded cellulase demonstrate very good colloidal stability in aqueous solutions. The enzymatic activity of cellulase is greatly reduced when encapsulated in the nanogels and rapidly recovered in 10 × 10(-3) m dithiothreitol solution. Fluorescence resonance energy transfer (FRET)-based experiments indicate that the recovered enzymatic activity is mainly ascribed to the release of the enzyme due to the degradation of the disulfide crosslinking network after addition of dithiothreitol (DTT), instead of the enhanced substrate transport rate. The developed enzyme immobilization method opens new possibilities for reversible activation/deactivation of enzymes and opens up new directions for targeted protein therapy and biotechnology applications.

  14. Smart pH/Redox Dual-Responsive Nanogels for On-Demand Intracellular Anticancer Drug Release.

    PubMed

    Yang, Hao; Wang, Qin; Huang, Shan; Xiao, Ai; Li, Fuying; Gan, Lu; Yang, Xiangliang

    2016-03-01

    Efficient accumulation and intracellular drug release in cancer cells remain a crucial challenge in developing ideal anticancer drug delivery systems. Here, poly(N-isopropylacrylamide)-ss-acrylic acid (P(NIPAM-ss-AA)) nanogels based on NIPAM and AA cross-linked by N,N'-bis(acryloyl)cystamine (BAC) were constructed by precipitation polymerization. The nanogels exhibited pH/redox dual responsive doxorubicin (DOX) release behavior in vitro and in tumor cells, in which DOX release from nanogels was accelerated in lysosomal pH (pH 4.5) and cytosolic reduction (10 mM GSH) conditions. Moreover, intracellular tracking of DOX-loaded nanogels confirmed that after the nanogels and the loaded DOX entered the cells simultaneously mainly via lipid raft/caveolae-mediated endocytosis, DOX-loaded nanogels were transported to lysosomes and then the loaded DOX was released to nucleus triggered by lysosomal pH and cytoplasmic high GSH. MTT analysis showed that DOX-loaded nanogels could efficiently inhibit the proliferation of HepG2 cells. In vivo animal studies demonstrated that DOX-loaded nanogels were accumulated and penetrated in tumor tissues more efficiently than free DOX. Meanwhile, DOX-loaded nanogels exhibited stronger tumor inhibition activity and fewer side effects. This study indicated that pH/redox dual-responsive nanogels might present a prospective platform for intracellular drug controlled release in cancer therapy.

  15. Curcumin-encapsulating Nanogels as an Effective Anticancer Formulation for Intracellular Uptake

    PubMed Central

    Reeves, Anna; Vinogradov, Serguei V.; Morrissey, Phil; Chernin, Mitchell; Ahmed, Mansoor M.

    2016-01-01

    Nanoscale drug delivery systems represent an attractive strategy to improve both the efficacy and safety of anticancer drugs. In this work, we describe nanoformulation of curcumin, a most potent natural anticancer compound capable of killing cancer cells while sparing the normal tissues. Since curcumin is a natural hydrophobic polyphenol, it has a low aqueous solubility and bioavailability, which are challenging to its therapeutic efficacy. We developed and evaluated a novel colloidal nanogel carrier for encapsulation of curcumin to increase its solubility and cytotoxicity. Amphiphilic Poloxamer-cationic network in the nanogel NG127 was designed to efficiently encapsulate curcumin. Homogenous drug complexes were obtained with 20–25% content of curcumin and the particle size of ca. 150 nm. Using ImageStream multispectral imaging flow cytometry, we demonstrated that the curcumin-nanogel formulation (C-NG) was readily internalized into MDA-231 breast cancer cells. A real-time cell growth electronic sensing assay was used to measure proliferation responses of various breast cancer cells to C-NG treatments. Our results indicated that the C-NG formulation was 70–85% more effective in inhibiting growth, at concentrations lower than IC50 of free curcumin. This was also confirmed morphologically by modified acridine orange/ethidium bromide staining and fluorescent microscopy. Importantly, nanocarrier NG127 alone displayed practically no cytotoxicity. We conclude that nanogel carriers offer an innovative way to encapsulate curcumin and to obtain more effective anticancer therapeutics than curcumin alone with a potential to specific tumor targeting, such as using antibodies against surface receptors specific to breast cancer cells. PMID:26937266

  16. Chitosan-Based Nano-Embedded Microparticles: Impact of Nanogel Composition on Physicochemical Properties

    PubMed Central

    Islam, Paromita; Water, Jorrit J.; Bohr, Adam; Rantanen, Jukka

    2016-01-01

    Chitosan-based nanogels have been widely applied as drug delivery vehicles. Spray-drying of said nanogels allows for the preparation of dry powder nano-embedded microparticles. In this work, chitosan-based nanogels composed of chitosan, alginate, and/or sodium tri-penta phosphate were investigated, particularly with respect to the impact of composition on the resulting physicochemical properties. Different compositions were obtained as nanogels with sizes ranging from 203 to 561 nm. The addition of alginate and exclusion of sodium tri-penta phosphate led to an increase in nanogel size. The nanogels were subsequently spray-dried to form nano-embedded microparticles with trehalose or mannitol as matrix excipient. The microparticles of different composition were mostly spherical with a smooth surface and a mass median aerodynamic diameter of 6–10 µm. Superior redispersibility was observed for microparticles containing amorphous trehalose. This study demonstrates the potential of nano-embedded microparticles for stabilization and delivery of nanogel-based delivery systems. PMID:28025505

  17. Chitosan-Based Nano-Embedded Microparticles: Impact of Nanogel Composition on Physicochemical Properties.

    PubMed

    Islam, Paromita; Water, Jorrit J; Bohr, Adam; Rantanen, Jukka

    2016-12-22

    Chitosan-based nanogels have been widely applied as drug delivery vehicles. Spray-drying of said nanogels allows for the preparation of dry powder nano-embedded microparticles. In this work, chitosan-based nanogels composed of chitosan, alginate, and/or sodium tri-penta phosphate were investigated, particularly with respect to the impact of composition on the resulting physicochemical properties. Different compositions were obtained as nanogels with sizes ranging from 203 to 561 nm. The addition of alginate and exclusion of sodium tri-penta phosphate led to an increase in nanogel size. The nanogels were subsequently spray-dried to form nano-embedded microparticles with trehalose or mannitol as matrix excipient. The microparticles of different composition were mostly spherical with a smooth surface and a mass median aerodynamic diameter of 6-10 µm. Superior redispersibility was observed for microparticles containing amorphous trehalose. This study demonstrates the potential of nano-embedded microparticles for stabilization and delivery of nanogel-based delivery systems.

  18. Targeted delivery of therapeutics to endothelium

    PubMed Central

    Simone, Eric; Ding, Bi-Sen

    2009-01-01

    The endothelium is a target for therapeutic and diagnostic interventions in a plethora of human disease conditions including ischemia, inflammation, edema, oxidative stress, thrombosis and hemorrhage, and metabolic and oncological diseases. Unfortunately, drugs have no affinity to the endothelium, thereby limiting the localization, timing, specificity, safety, and effectiveness of therapeutic interventions. Molecular determinants on the surface of resting and pathologically altered endothelial cells, including cell adhesion molecules, peptidases, and receptors involved in endocytosis, can be used for drug delivery to the endothelial surface and into intracellular compartments. Drug delivery platforms such as protein conjugates, recombinant fusion constructs, targeted liposomes, and stealth polymer carriers have been designed to target drugs and imaging agents to these determinants. We review endothelial target determinants and drug delivery systems, describe parameters that control the binding of drug carriers to the endothelium, and provide examples of the endothelial targeting of therapeutic enzymes designed for the treatment of acute vascular disorders including ischemia, oxidative stress, inflammation, and thrombosis. PMID:18815813

  19. [Site-specific drug delivery systems. I. Colon targeted delivery].

    PubMed

    Szente, Virág; Zelkó, Romána

    2007-01-01

    Colon specific drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon like Chron's disease, ulcerative colitis, irritable bowel syndrome, cancer or infections, but also for the potential it holds for the systemic delivery of proteins (e.g. insulin) and therapeutic peptides. These systems enable the protection of healthy tissues from the side effects of drugs and the drug intake of targeted cells, as well. The formulation of colon specific drug delivery systems is of great impact in the case of diseases having circadian rhythm (midnight gerd). Such circadian rhythm release drug delivery systems are designed to provide a plasma concentration--time profile, which varies according to physiological need at different times during the dosing period, i.e., mimicking the circadian rhythm and severity/manifestation of gastric acid secretion (and/or midnight gerd). In general four primary approaches have been proposed for colon targeted delivery namely pH-dependent systems, time dependent systems, colonic microflora activated systems and prodrugs.

  20. Janus nanogels of PEGylated Taxol and PLGA-PEG-PLGA copolymer for cancer therapy

    NASA Astrophysics Data System (ADS)

    Wei, Jun; Wang, Huaimin; Zhu, Meifeng; Ding, Dan; Li, Dongxia; Yin, Zhinan; Wang, Lianyong; Yang, Zhimou

    2013-09-01

    Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy.Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. Electronic supplementary information (ESI) available: Synthesis and characterization of compounds, dynamic time sweep, H

  1. Nanoparticles for intracellular-targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Paulo, Cristiana S. O.; Pires das Neves, Ricardo; Ferreira, Lino S.

    2011-12-01

    Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects.

  2. Radiolabeled nanogels for nuclear molecular imaging.

    PubMed

    Singh, Smriti; Bingöl, Bahar; Morgenroth, Agnieszka; Mottaghy, Felix M; Möller, Martin; Schmaljohann, Jörn

    2013-04-12

    An efficient and simple synthesis approach to form stable (68) Ga-labeled nanogels is reported and their fundamental properties investigated. Nanogels are obtained by self-assembly of amphiphilic statistical prepolymers derivatised with chelating groups for radiometals. The resulting nanogels exhibit a well-defined spherical shape with a diameter of 290 ± 50 nm. The radionuclide (68) Ga is chelated in high radiochemical yields in an aqueous medium at room temperature. The phagocytosis assay demonstrates a highly increased internalization of nanogels by activated macrophages. Access to these (68) Ga-nanogels will allow the investigation of general behavior and clearance pathways of nanogels in vivo by nuclear molecular imaging.

  3. Applications of nanosystems to anticancer drug therapy (Part I. Nanogels, nanospheres, nanocapsules).

    PubMed

    Talevi, Alan; Gantner, Melisa E; Ruiz, María E

    2014-01-01

    One of the greatest challenges in cancer drug therapy is to maximize the effectiveness of the active agent while reducing its systemic adverse effects. To add more, many widely-used chemoterapeutic agents present unfavorable physicochemical properties (e.g. low solubility, lack of chemical or biological stability) that hamper or limit their therapeutic applications. All these issues may be overcome by designing adequate drug delivery systems; nanocarriers are particularly suitable for this purpose. Nanosystems can be used for targeted-drug release, treatment, diagnostic imaging and therapy monitoring. They allow the formulation of drug delivery systems with user-defined characteristics regarding solubility, biodegradability, particle size, release kinetics and active targeting, among others. This review (Part I) focuses on recent patents published between 2008 and the present day, related to nanospheres, nanocapsules and nanogels applied to anticancer drug therapy. Other nanosystems is covered in a second article (Part II).

  4. Biomimetic synthesis of hybrid hydroxyapatite nanoparticles using nanogel template for controlled release of bovine serum albumin.

    PubMed

    Qin, Jinli; Zhong, Zhenyu; Ma, Jun

    2016-05-01

    A biomimetic method was used to prepare hybrid hydroxyapatite (HAP) nanoparticles with chitosan/polyacrylic acid (CS-PAA) nanogel. The morphology, structure, crystallinity, thermal properties and biocompatibility of the obtained hybrid nanogel-HAP nanoparticles have been characterized. In addition, bovine serum albumin (BSA) was used as a model protein to study the loading and release behaviors of the hybrid nanogel-HAP nanoparticles. The results indicated that the obtained HAP nanoparticles were agglomerated and the nanogel could regulate the formation of HAP. When the nanogel concentration decreased, different HAP crystal shapes and agglomerate structures were obtained. The loading amount of BSA reached 67.6 mg/g for the hybrid nanoparticles when the mineral content was 90.4%, which decreased when the nanogel concentration increased. The release profile of BSA was sustained in neutral buffer. Meanwhile, an initial burst release was found at pH 4.5 due to the desorption of BSA from the surface, followed by a slow release. The hemolysis percentage of the hybrid nanoparticles was close to the negative control, and these particles were non-toxic to bone marrow stromal stem cells. The results suggest that these hybrid nanogel-HAP nanoparticles are promising candidate materials for biocompatible drug delivery systems.

  5. Gamma radiation-induced synthesis and characterization of Polyvinylpyrrolidone nanogels

    NASA Astrophysics Data System (ADS)

    Ges, A. A.; Viltres, H.; Borja, R.; Rapado, M.; Aguilera, Y.

    2017-01-01

    Due to the importance of bioactive peptides, proteins and drug for pharmaceutical purpose, there is a growing interest for suitable delivery systems, able to increase their bioavailability and to target them to the desired location. Some of the most studied delivery systems involve encapsulation or entrapment of drugs into biocompatible polymeric devices. A multitude of techniques have been described for the synthesis of nanomaterials from polymers, however, the use of ionizing radiation (γ, e-), to obtain nano- and microgels polymer is characterized by the possibility of obtaining products with a high degree of purity. Although, in the world, electronic radiation is used for this purpose, gamma radiation has not been utilized for these purposes. In this paper is developed the formulation the formulation of Polyvinylpyrrolidone (PVP) nanogels synthesized by gamma radiation techniques, for their evaluation as potential system of drug delivery. Experiments were performed in absence of oxygen using aqueous solutions of PVP (0.05% -1%). Crosslinking reactions were carried out at 25° C in a gamma irradiation chamber with a 60Co source (MPX-γ 30). The Viscosimetry, Light Scattering, X-Ray Diffraction and Transmission Electron Microscopy (TEM), were used as characterization techniques.

  6. Targeted intracellular delivery of therapeutics: an overview.

    PubMed

    Rawat, A; Vaidya, B; Khatri, K; Goyal, A K; Gupta, P N; Mahor, S; Paliwal, R; Rai, S; Vyas, S P

    2007-09-01

    During the last decade, intracellular drug delivery has become an emerging area of research in the medical and pharmaceutical field. Many therapeutic agents such as drugs and DNA/oligonucleotides can be delivered not just to the cell but also to a particular compartment of that cell to achieve better activity e.g. proapoptotic drugs to the mitochondria, antibiotics and enzymes to the lysosomes and various anticancer drugs and gene to the nucleus. The lipidic nature of biological membrans is the major obstacle to the intracellular delivery of macromolecular and ionic drugs. Additionally, after endocytosis, the lysosome, the major degradation compartment, needs to be avoided for better activity. To avoid these problems, various carriers have been investigated for efficient intracellular delivery, either by direct entry to cytoplasm or by escaping the endosomal compartment. These include cell penetrating peptides, and carrier systems such as liposomes, cationic lipids and polymers, polymeric nanoparticles, etc. Various properties of these carriers, including size, surface charge, composition and the presence of cell specific ligands, alter their efficacy and specificity towards particular cells. This review summarizes various aspects of targeted intracellular delivery of therapeutics including pathways, mechanisms and approaches. Various carrier constructs having potential for targeted intracellular delivery are also been discussed.

  7. Novel lecithin-integrated liquid crystalline nanogels for enhanced cutaneous targeting of terconazole: development, in vitro and in vivo studies.

    PubMed

    Elnaggar, Yosra Sr; Talaat, Sara M; Bahey-El-Din, Mohammed; Abdallah, Ossama Y

    Terconazole (Tr) is the first marketed, most active triazole for vaginal candidiasis. Owing to poor skin permeation and challenging physicochemical properties, Tr was not employed for the treatment of cutaneous candidiasis. This is the first study to investigate the relevance of novel lecithin-integrated liquid crystalline nano-organogels (LCGs) to improve physicochemical characteristics of Tr in order to enable its dermal application in skin candidiasis. Ternary phase diagram was constructed using lecithin/capryol 90/water to identify the region of liquid crystalline organogel. The selected organogel possessed promising physicochemical characteristics based on particle size, rheological behavior, pH, loading efficiency, and in vitro antifungal activity. Microstructure of the selected organogel was confirmed by polarized light microscopy and transmission electron microscopy. Ex vivo and in vivo skin permeation studies revealed a significant 4.7- and 2.7-fold increase in the permeability of Tr-loaded LCG when compared to conventional hydrogel. Moreover, acute irritation study indicated safety and compatibility of liquid crystalline organogel to the skin. The in vivo antifungal activity confirmed the superiority of LCG over the conventional hydrogel for the eradication of Candida infection. Overall, lecithin-based liquid crystalline organogel confirmed its potential as an interesting dermal nanocarrier for skin targeting purpose.

  8. Novel lecithin-integrated liquid crystalline nanogels for enhanced cutaneous targeting of terconazole: development, in vitro and in vivo studies

    PubMed Central

    Elnaggar, Yosra SR; Talaat, Sara M; Bahey-El-Din, Mohammed; Abdallah, Ossama Y

    2016-01-01

    Terconazole (Tr) is the first marketed, most active triazole for vaginal candidiasis. Owing to poor skin permeation and challenging physicochemical properties, Tr was not employed for the treatment of cutaneous candidiasis. This is the first study to investigate the relevance of novel lecithin-integrated liquid crystalline nano-organogels (LCGs) to improve physicochemical characteristics of Tr in order to enable its dermal application in skin candidiasis. Ternary phase diagram was constructed using lecithin/capryol 90/water to identify the region of liquid crystalline organogel. The selected organogel possessed promising physicochemical characteristics based on particle size, rheological behavior, pH, loading efficiency, and in vitro antifungal activity. Microstructure of the selected organogel was confirmed by polarized light microscopy and transmission electron microscopy. Ex vivo and in vivo skin permeation studies revealed a significant 4.7- and 2.7-fold increase in the permeability of Tr-loaded LCG when compared to conventional hydrogel. Moreover, acute irritation study indicated safety and compatibility of liquid crystalline organogel to the skin. The in vivo antifungal activity confirmed the superiority of LCG over the conventional hydrogel for the eradication of Candida infection. Overall, lecithin-based liquid crystalline organogel confirmed its potential as an interesting dermal nanocarrier for skin targeting purpose. PMID:27822033

  9. Assessment of penetration potential of pH responsive double walled biodegradable nanogels coated with eucalyptus oil for the controlled delivery of 5-fluorouracil: In vitro and ex vivo studies.

    PubMed

    Sahu, Prashant; Kashaw, Sushil K; Jain, Sanyog; Sau, Samaresh; Iyer, Arun K

    2017-03-18

    Penetration enhancers coated biodegradable polymeric nanogels loaded with cytotoxic drugs applied via the topical route, can be a promising strategy for improving the chemotherapeutic efficiency of skin cancers. The major objective of proposed research was to investigate the in vitro and ex vivo chemotherapeutic potential of double walled PLGA-chitosan biodegradable nanogel entrapped with 5-fluororuacil (5-FU) coated with eucalyptus oil, topically applied onto the skin. 5-FU was first entrapped in PLGA core by solvent evaporation technique followed by coating with cationic chitosan for ionic interaction with anionic skin cancer cell membrane. A surface coating of eucalyptus oil (1%) was employed to improve the penetration efficacy of the nanogel into stratum corneum. The surface modified biodegradable double walled nanogel was characterized for particle size, charge and thermal properties followed by pH dependent in vitro analysis. Human keratinocyte (HaCaT) cell line was employed for the bio- and cyto-compatibility testing prior to the hemolysis assay and coagulation assessment. A porcine skin ex vivo screening was performed for assessing the penetration potential of the nanogels. DLS and TEM revealed a particle size about 170nm for the double walled nanogels. The nanogels also exhibited high thermal stability as analyzed by thermogravimetry (TG) and differential thermal analysis (DTA). The drug entrapment efficacy was about ~40%. The drug release showed sustained release pattern noted up to 24h. The low hemolysis of 2.39% with short prothrombin time (PT) and activated partial thromboplastin time (APTT) of 14.2 and 35.5s respectively, revealed high biocompatibility of the nanogels. The cellular uptake and localization was assessed by confocal microscopy. The cytotoxicity (MTT assay) on HaCaT cell line demonstrated high cytocompatibilty of the nanogels. An ex vivo evaluation using porcine skin displayed efficient and steady state flux of 5-FU from the biodegradable

  10. Biopolymer based nanosystem for doxorubicin targeted delivery

    PubMed Central

    Csikós, Zsuzsanna; Kerekes, Krisztina; Fazekas, Erika; Kun, Sándor; Borbély, János

    2017-01-01

    This study describes formation of an actively and passively targeted, water-soluble drug delivery system (DDS) which contains doxorubicin (DOX). The system comprises two biocompatible and biodegradable polymers: poly-γ-glutamic acid (PGA) and chitosan (CH). Self-assembly of these biopolymers in aqueous medium results stable nanoparticles (NPs) with a hydrodynamic size of 80-150 nm and slightly negative surface charge. Folic acid (FA) was used as targeting agent bonded to the polyanion (PA) and also to the surface of the NPs. The NP’s physical stability, active targeting effect, cellular toxicity, release profile and in vivo anti-tumor efficacy were investigated. It was found that the targeted, self-assembled nanoparticles are stable at 4°C for several months, cause better in vitro toxicity effect on folate receptor (FR) positive cell lines than the doxorubicin or the non-targeted nanosystem and based on its release profile it is expected, that the nanosystem will remain stable during the circulation in the body. Pharmacodynamic studies demonstrated that the DOX-loaded nanoparticles can deliver greater tumor growth inhibition than the free drug molecules and the liposomal compound, with less general toxicity. It was observed that the overall survival is the main benefit of the biopolymer based drug delivery system.

  11. Colloidal microgels in drug delivery applications

    PubMed Central

    Vinogradov, Serguei V.

    2005-01-01

    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

  12. Thermoresponsive hyaluronic acid nanogels as hydrophobic drug carrier to macrophages.

    PubMed

    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

    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 214 nm 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 13 min 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.

  13. Acitretin and aloe-emodin loaded chitin nanogel for the treatment of psoriasis.

    PubMed

    Divya, G; Panonnummal, Rajitha; Gupta, Swati; Jayakumar, R; Sabitha, M

    2016-10-01

    The present study focuses on the development of an effective topical nanogel formulation of two anti-psoriatic drugs; Acitretin (Act) and Aloe-emodin (AE) using natural polymer chitin. Simple regeneration chemistry was used to prepare Chitin Nanogel Systems (CNGs). The developed control chitin (CNGs) nanogels, acitretin loaded chitin nanogels (ActCNGs) and aloe-emodin loaded chitin nanogels (AECNGs) were characterized by DLS, SEM, FTIR, XRD and TG-DTA. The systems were found to be spherical in shape with a size range of 98±10, 138±8 and 238±6nm having zeta potential values of +28±3, +27±3 and +25±6mV for CNGs, ActCNGs and AECNGs respectively. The in vitro haemolysis assay revealed that all the nanogel systems are blood compatible. The systems exhibited higher swelling and release at acidic pH. The ex vivo skin permeation studies using porcine skin confirmed the higher deposition of the systems at epidermal and dermal layers, which was confirmed further by fluorescent imaging. The in vivo anti-psoriatic activity study using Perry's mouse tail model and skin safety studies confirmed the potential benefit of the system for topical delivery of acitretin and aloe-emodin in psoriasis.

  14. Targeted delivery of colloids by swimming bacteria

    NASA Astrophysics Data System (ADS)

    Koumakis, N.; Lepore, A.; Maggi, C.; di Leonardo, R.

    2013-10-01

    The possibility of exploiting motile microorganisms as tiny propellers represents a fascinating strategy for the transport of colloidal cargoes. However, delivery on target sites usually requires external control fields to steer propellers and trigger cargo release. The need for a constant feedback mechanism prevents the design of compact devices where biopropellers could perform their tasks autonomously. Here we show that properly designed three-dimensional (3D) microstructures can define accumulation areas where bacteria spontaneously and efficiently store colloidal beads. The process is stochastic in nature and results from the rectifying action of an asymmetric energy landscape over the fluctuating forces arising from collisions with swimming bacteria. As a result, the concentration of colloids over target areas can be strongly increased or depleted according to the topography of the underlying structures. Besides the significance to technological applications, our experiments pose some important questions regarding the structure of stationary probability distributions in non-equilibrium systems.

  15. Injected nanocrystals for targeted drug delivery

    PubMed Central

    Lu, Yi; Li, Ye; Wu, Wei

    2016-01-01

    Nanocrystals are pure drug crystals with sizes in the nanometer range. Due to the advantages of high drug loading, platform stability, and ease of scaling-up, nanocrystals have been widely used to deliver poorly water-soluble drugs. Nanocrystals in the blood stream can be recognized and sequestered as exogenous materials by mononuclear phagocytic system (MPS) cells, leading to passive accumulation in MPS-rich organs, such as liver, spleen and lung. Particle size, morphology and surface modification affect the biodistribution of nanocrystals. Ligand conjugation and stimuli-responsive polymers can also be used to target nanocrystals to specific pathogenic sites. In this review, the progress on injected nanocrystals for targeted drug delivery is discussed following a brief introduction to nanocrystal preparation methods, i.e., top-down and bottom-up technologies. PMID:27006893

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

    PubMed Central

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

    2014-01-01

    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

  17. Nanogel-based pneumococcal surface protein A nasal vaccine induces microRNA-associated Th17 cell responses with neutralizing antibodies against Streptococcus pneumoniae in macaques

    PubMed Central

    Fukuyama, Y; Yuki, Y; Katakai, Y; Harada, N; Takahashi, H; Takeda, S; Mejima, M; Joo, S; Kurokawa, S; Sawada, S; Shibata, H; Park, E J; Fujihashi, K; Briles, D E; Yasutomi, Y; Tsukada, H; Akiyoshi, K; Kiyono, H

    2015-01-01

    We previously established a nanosized nasal vaccine delivery system by using a cationic cholesteryl group-bearing pullulan nanogel (cCHP nanogel), which is a universal protein-based antigen-delivery vehicle for adjuvant-free nasal vaccination. In the present study, we examined the central nervous system safety and efficacy of nasal vaccination with our developed cCHP nanogel containing pneumococcal surface protein A (PspA-nanogel) against pneumococcal infection in nonhuman primates. When [18F]-labeled PspA-nanogel was nasally administered to a rhesus macaque (Macaca mulatta), longer-term retention of PspA was noted in the nasal cavity when compared with administration of PspA alone. Of importance, no deposition of [18F]-PspA was seen in the olfactory bulbs or brain. Nasal PspA-nanogel vaccination effectively induced PspA-specific serum IgG with protective activity and mucosal secretory IgA (SIgA) Ab responses in cynomolgus macaques (Macaca fascicularis). Nasal PspA-nanogel-induced immune responses were mediated through T-helper (Th) 2 and Th17 cytokine responses concomitantly with marked increases in the levels of miR-181a and miR-326 in the serum and respiratory tract tissues, respectively, of the macaques. These results demonstrate that nasal PspA-nanogel vaccination is a safe and effective strategy for the development of a nasal vaccine for the prevention of pneumonia in humans. PMID:25669148

  18. Efficient inhibition of C-26 colon carcinoma by VSVMP gene delivered by biodegradable cationic nanogel derived from polyethyleneimine.

    PubMed

    Gou, MaLing; Men, Ke; Zhang, Juan; Li, YuHua; Song, Jia; Luo, Shan; Shi, HuaShan; Wen, YanJun; Guo, Gang; Huang, MeiJuan; Zhao, Xia; Qian, ZhiYong; Wei, YuQuan

    2010-10-26

    Biodegradable cationic nanoparticles have promising application as a gene delivery system. In this article, heparin-polyethyleneimine (HPEI) nanogels were prepared, and these nanogels were developed as a nonviral gene vector. The transfection efficiency of HPEI nanogels was comparable with that of PEI25K, while the cytotoxicity was lower than that of PEI2K and much lower than that of PEI25K in vitro. These HPEI nanogels also had better blood compatibility than PEI25K. After intravenous administration, HPEI nanogels degraded, and the degradation products were excreted through urine. The plasmid expressing vesicular stomatitis virus matrix protein (pVSVMP) could be efficiently transfected into C-26 colon carcinoma cells by HPEI nanogels in vitro, inhibiting the cell proliferation through apoptosis induction. Intraperitoneal injection of pVSVMP/HPEI complexes efficiently inhibited the abdominal metastases of C-26 colon carcinoma through apoptosis induction (mean tumor weight in mice treated with pVSVMP/HPEI complex = 0.93 g and in control mice = 3.28 g, difference = 2.35 g, 95% confidence interval [CI] = 1.75-2.95 g, P < 0.001) and prolonged the survival of treated mice. Moreover, intravenous application of pVSVMP/HPEI complexes also inhibited the growth of pulmonary metastases of C-26 colon carcinoma through apoptosis induction. The HPEI nanogels delivering pVSVMP have promising application in treating colon carcinoma.

  19. Thiol-ene clickable hyaluronans: from macro-to nanogels.

    PubMed

    Hachet, Emilie; Sereni, Nicolas; Pignot-Paintrand, Isabelle; Ravaine, Valérie; Szarpak-Jankowska, Anna; Auzély-Velty, Rachel

    2014-04-01

    The fabrication of hyaluronic acid (HA) nanogels using a thiol-ene reaction has been demonstrated. HA was modified with pentenoate groups and then cross-linked with poly(ethylene glycol)-bis(thiol) by exposure to UV light. The cross-linking density and thereby the rigidity of the obtained gels were precisely controlled by the degree of substitution of pentenoate-modified HA. Their swelling properties also depended on cross-linking density. To produce hydrogels at the nanoscale, hyaluronic acid precursors were solely confined inside liposomes before cross-linking and purified after cross-linking. The size of the resulting nanogels followed their swelling properties and was also affected by their cross-linking density. Such bionanogels with tunable mechanical and swelling properties have potential in drug delivery.

  20. Nanogels: An overview of properties, biomedical applications and obstacles to clinical translation.

    PubMed

    Soni, Kruti S; Desale, Swapnil S; Bronich, Tatiana K

    2016-10-28

    Nanogels have emerged as a versatile hydrophilic platform for encapsulation of guest molecules with a capability to respond to external stimuli that can be used for a multitude of applications. These are soft materials capable of holding small molecular therapeutics, biomacromolecules, and inorganic nanoparticles within their crosslinked networks, which allows them to find applications for therapy as well as imaging of a variety of disease conditions. Their stimuli-responsive behavior can be easily controlled by selection of constituent polymer and crosslinker components to achieve a desired response at the site of action, which imparts nanogels the ability to participate actively in the intended function of the carrier system rather than being passive carriers of their cargo. These properties not only enhance the functionality of the carrier system but also help in overcoming many of the challenges associated with the delivery of cargo molecules, and this review aims to highlight the distinct and unique capabilities of nanogels as carrier systems for the delivery of an array of cargo molecules over other nanomaterials. Despite their obvious usefulness, nanogels are still not a commonplace occurrence in clinical practice. We have also made an attempt to highlight some of the major challenges that need to be overcome to advance nanogels further in the field of biomedical applications.

  1. Preparation and characterization of tri-block poly(lactide)-poly(ethylene glycol)-poly(lactide) nanogels for controlled release of naltrexone.

    PubMed

    Asadi, H; Rostamizadeh, K; Salari, D; Hamidi, M

    2011-09-15

    Tri-block poly(lactide)-poly(ethylene glycol)-poly(lactide) (PLA-PEG-PLA) copolymers and related acrylated derivative were synthesized and used to prepare micelles and nanogels for controlled release of naltrexone. The resulting copolymers, micelles and nanogels were characterized by various techniques such as proton nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, gel permeation chromatography, fluorescence spectrometry, differential scanning calorimetry, photon correlation spectroscopy and scanning electron microscopy. The nanogels exhibited high encapsulation efficiency around 60% and excellent stability for long periods of time. The drug release profiles of micelles and nanogels were compared and it was found that the naltrexone loaded nanogels offered a steady and long-term release pattern for different periods of time up to 35 days, depending on the crosslinker concentration, compared to the micelles. The size of nanogels could be manipulated easily in the range of 128-200nm by variations in polymer concentration used in the nanogels preparation step. From the results obtained it can be concluded that PLA-PEG-PLA nanogels can be considered as a promising carrier for drug delivery purpose.

  2. Toward Intracellular Targeted Delivery of Cancer Therapeutics

    PubMed Central

    Pandya, Hetal; Debinski, Waldemar

    2013-01-01

    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

  3. Nanoparticle-based targeted drug delivery

    PubMed Central

    Singh, Rajesh; Lillard, James W.

    2009-01-01

    Nanotechnology could be defined as the technology that has allowed for the control, manipulation, study, and manufacture of structures and devices in the “nanometer” size range. These nano-sized objects, e.g., “nanoparticles”, take on novel properties and functions that differ markedly from those seen from items made of identical materials. The small size, customized surface, improved solubility, and multi-functionality of nanoparticles will continue to open many doors and create new biomedical applications. Indeed, the novel properties of nanoparticles offer the ability to interact with complex cellular functions in new ways. This rapidly growing field requires cross-disciplinary research and provides opportunities to design and develop multifunctional devices that can target, diagnose, and treat devastating diseases such as cancer. This article presents an overview of nanotechnology for the biologist and discusses the attributes of our novel XPclad© nanoparticle formulation that has shown efficacy in treating solid tumors, for single dose vaccination, and oral delivery of therapeutic proteins. PMID:19186176

  4. Antiproliferative Activity of Fucan Nanogel

    PubMed Central

    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

    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

  5. Positively charged polypeptide nanogel enhances mucoadhesion and penetrability of 10-hydroxycamptothecin in orthotopic bladder carcinoma.

    PubMed

    Guo, Hui; Xu, Weiguo; Chen, Jinjin; Yan, Lesan; Ding, Jianxun; Hou, Yuchuan; Chen, Xuesi

    2017-01-03

    Bladder cancer (BC) has become a serious public health problem due to its continuously rising incidence, high recurrence rate, and poor quality of life. Intravesical instillation of chemotherapy, one of common and important treatment strategy for BC, is restricted partially due to the short residence time and the low penetration ability of current antineoplastic agent formulations in clinic. Herein, a positively charged disulfide-core-crosslinked polypeptide nanogel of poly(l-lysine)-poly(l-phenylalanine-co-l-cystine) (PLL-P(LP-co-LC)) was synthesized. 10-Hydroxycamptothecin (HCPT) was loaded into the core via a facile diffusion to obtain loading nanogel (i.e., NG/HCPT). The reduction-responsive cationic polypeptide nanogel not only showed a high drug-loading efficiency, a prolonged residence time, and an improved tissue penetration capability, but also demonstrated an ability to accurately and rapidly release HCPT in bladder cancer cells. NG/HCPT exhibited superior cytotoxicity against human T24 bladder cancer cells compared to that of free HCPT in vitro. Moreover, the positively charged loading nanogel exhibited significantly enhanced antitumor efficacy and reduced side effects toward orthotopic bladder cancer model in vivo. Overall, the smart polypeptide nanogel with enhanced residence and permeability provides a promising drug delivery platform for local chemotherapy of BC.

  6. Near Infrared Dye Conjugated Nanogels for Combined Photodynamic and Photothermal Therapies.

    PubMed

    Asadian-Birjand, Mazdak; Bergueiro, Julian; Wedepohl, Stefanie; Calderón, Marcelo

    2016-10-01

    There is a need for new and smart formulations that will help overcome the limitations of organic dyes used in photodynamic (PDT) and photothermal (PTT) therapy and significantly accelerate their clinical translation. Therefore the aim of this work was to create a responsive nanogel scaffold as a smart vehicle for dye administration. We developed a methodology that enables the conjugation of organic dyes to thermoresponsive nanogels and yields biocompatible, nanometer-sized products with low polydispersity. The potential of the dye-nanogel conjugate as a photothermal and photodynamic agent has been demonstrated by an in vitro evaluation with a model human carcinoma cell line. Additionally, confocal cell images showed their cellular uptake profile and their potential for bioimaging and intracellular drug delivery. These conjugates are a promising scaffold as a theranostic agents and will enable further applications in combination with controlled drug release.

  7. Targeted Delivery Systems for Molecular Therapy in Skeletal Disorders

    PubMed Central

    Dang, Lei; Liu, Jin; Li, Fangfei; Wang, Luyao; Li, Defang; Guo, Baosheng; He, Xiaojuan; Jiang, Feng; Liang, Chao; Liu, Biao; Badshah, Shaikh Atik; He, Bing; Lu, Jun; Lu, Cheng; Lu, Aiping; Zhang, Ge

    2016-01-01

    Abnormalities in the integral components of bone, including bone matrix, bone mineral and bone cells, give rise to complex disturbances of skeletal development, growth and homeostasis. Non-specific drug delivery using high-dose systemic administration may decrease therapeutic efficacy of drugs and increase the risk of toxic effects in non-skeletal tissues, which remain clinical challenges in the treatment of skeletal disorders. Thus, targeted delivery systems are urgently needed to achieve higher drug delivery efficiency, improve therapeutic efficacy in the targeted cells/tissues, and minimize toxicities in non-targeted cells/tissues. In this review, we summarize recent progress in the application of different targeting moieties and nanoparticles for targeted drug delivery in skeletal disorders, and also discuss the advantages, challenges and perspectives in their clinical translation. PMID:27011176

  8. Polysaccharide-based Noncovalent Assembly for Targeted Delivery of Taxol

    NASA Astrophysics Data System (ADS)

    Yang, Yang; Zhang, Ying-Ming; Chen, Yong; Chen, Jia-Tong; Liu, Yu

    2016-01-01

    The construction of synthetic straightforward, biocompatible and biodegradable targeted drug delivery system with fluorescent tracking abilities, high anticancer activities and low side effects is still a challenge in the field of biochemistry and material chemistry. In this work, we constructed targeted paclitaxel (Taxol) delivery nanoparticles composed of permethyl-β-cyclodextrin modified hyaluronic acid (HApCD) and porphyrin modified paclitaxel prodrug (PorTaxol), through host-guest and amphiphilic interactions. The obtained nanoparticles (HATXP) were biocompatible and enzymatic biodegradable due to their hydrophilic hyaluronic acid (HA) shell and hydrophobic Taxol core, and exhibited specific targeting internalization into cancer cells via HA receptor mediated endocytosis effects. The cytotoxicity experiments showed that the HATXP exhibited similar anticancer activities to, but much lower side effects than commercial anticancer drug Taxol. The present work would provide a platform for targeted paclitaxel drug delivery and a general protocol for the design of advanced multifunctional nanoscale biomaterials for targeted drug/gene delivery.

  9. Targeted delivery of magnetic aerosol droplets to the lung.

    PubMed

    Dames, Petra; Gleich, Bernhard; Flemmer, Andreas; Hajek, Kerstin; Seidl, Nicole; Wiekhorst, Frank; Eberbeck, Dietmar; Bittmann, Iris; Bergemann, Christian; Weyh, Thomas; Trahms, Lutz; Rosenecker, Joseph; Rudolph, Carsten

    2007-08-01

    The inhalation of medical aerosols is widely used for the treatment of lung disorders such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, respiratory infection and, more recently, lung cancer. Targeted aerosol delivery to the affected lung tissue may improve therapeutic efficiency and minimize unwanted side effects. Despite enormous progress in optimizing aerosol delivery to the lung, targeted aerosol delivery to specific lung regions other than the airways or the lung periphery has not been adequately achieved to date. Here, we show theoretically by computer-aided simulation, and for the first time experimentally in mice, that targeted aerosol delivery to the lung can be achieved with aerosol droplets comprising superparamagnetic iron oxide nanoparticles--so-called nanomagnetosols--in combination with a target-directed magnetic gradient field. We suggest that nanomagnetosols may be useful for treating localized lung disease, by targeting foci of bacterial infection or tumour nodules.

  10. Perspectives on Dual Targeting Delivery Systems for Brain Tumors.

    PubMed

    Gao, Huile

    2017-03-01

    Brain tumor remains one of the most serious threats to human beings. Different from peripheral tumors, drug delivery to brain tumor is largely restricted by the blood brain barrier (BBB). To fully conquer this barrier and specifically deliver drugs to brain tumor, dual targeting delivery systems were explored, which are functionalized with two active targeting ligands: one to the BBB and the other to the brain tumor. The development of dual targeting delivery system is still in its early stage, and attentions need to be paid to issues and concerns that remain unresolved in future studies.

  11. Dendrimeric micelles for controlled drug release and targeted delivery

    PubMed Central

    Ambade, Ashootosh V.; Savariar, Elamprakash N.; Thayumanavan, S.

    2008-01-01

    This review highlights the developments in dendrimer-based micelles for drug delivery. Dendrimers, the perfectly branched monodisperse macromolecules, have certain structural advantages that make them attractive candidates as drug carriers for controlled release or targeted delivery. As polymeric micelle-based approaches precede the work in dendrimers, these are also discussed briefly. The review concludes with a perspective on possible applications of biaryl-based dendrimeric micelles that exhibit environment-dependent conformations, in drug delivery. PMID:16053329

  12. Shell-crosslinked hyaluronic acid nanogels for live monitoring of hyaluronidase activity in vivo.

    PubMed

    Kim, Jihyun; Chong, Youhoon; Mok, Hyejung

    2014-06-01

    A hyaluronidase (HAdase) has been noticed as a potential drug target as well as prognostic marker because of its close associations with tumor invasion, metastasis, and angiogenesis. Accordingly, precise monitoring of HAdase activity in vivo seems to be crucial not only for the evaluation of HAdase activity but also for non-invasive molecular imaging. In our study, we propose a new organic, near-infrared fluorescence imaging probe, indocyanine green (ICG)-based stimuli-responsive fluorescence probe for selective imaging of HAdases with appreciable signal-to-noise (S/N) ratios in serum and in vivo. Shell-crosslinked hyaluronic acid (HA) nanogels (sc-nanogels) are generated via a reducible covalent linkage which incorporate ICG derivatives. The ICG-embeded HA nanogels via shell-crosslinking have preferable properties for ideal selective imaging and detection of HAdase activity in vivo. The sc-nanogels exhibit prominent chemical stability against external light, greatly control background signals in serum, and small size compared to use of self-assembled ICG-based carriers. Collapsed ICG in the hydrogel core is selectively disentangled by HAdase treatment for selective near-infrared imaging without unwanted background signal. The newly designed sc-nanogels may have great potential to serve as probes for improved selective imaging of HAdase-associated diseases in clinics as well as HAdase-activity screening in vivo.

  13. Development of a nanogel formulation for transdermal delivery of tenoxicam: a pharmacokinetic-pharmacodynamic modeling approach for quantitative prediction of skin absorption.

    PubMed

    Elkomy, Mohammed H; El Menshawe, Shahira F; Eid, Hussein M; Ali, Ahmed M A

    2017-04-01

    This study investigates potentials of solid lipid nanoparticles (SLN)-based gel for transdermal delivery of tenoxicam (TNX) and describes a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach for predicting concentration-time profile in skin. A 2(3) factorial design was adopted to study the effect of formulation factors on SLN properties and determine the optimal formulation. SLN-gel tolerability was investigated using rabbit skin irritation test. Its anti-inflammatory activity was assessed by carrageenan-induced rat paw edema test. A published Hill model for in vitro inhibition of COX-2 enzyme was fitted to edema inhibition data. Concentration in skin was represented as a linear spline function and coefficients were estimated using non-linear regression. Uncertainty in predicted concentrations was assessed using Monte Carlo simulations. The optimized SLN was spherical vesicles (58.1 ± 3.1 nm) with adequate entrapment efficiency (69.6 ± 2.6%). The SLN-gel formulation was well-tolerated. It increased TNX activity and skin level by 40 ± 13.5, and 227 ± 116%, respectively. Average Cmax and AUC0-24 predicted by the model were 2- and 3.6-folds higher than the corresponding values computed using in vitro permeability data. SLN-gel is a safe and efficient carrier for TNX across skin in the treatment of inflammatory disorders. PK-PD modeling is a promising approach for indirect quantitation of skin deposition from PD activity data.

  14. 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)

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

    2014-06-01

    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

  15. Fabrication and characterization of sol-gel based nanoparticles for drug delivery

    NASA Astrophysics Data System (ADS)

    Yadav, Reeta

    Nanogels are cross linked polymeric sol-gel based nanoparticles that offer an interior network for incorporation and protection of biomolecules, exhibiting unique advantages for polymer based delivery systems. We have successfully synthesized stable sol-gel nanoparticles by means of [a] silicification reactions using cationic peptides like polylysine as gelating agents, and [b] lyophilization of sol-gels. Macromolecules such as Hemoglobin and Glucose Oxidase and small molecules such as Sodium Nitroprusside (SNP) and antibiotics were encapsulated within the nanogels. We have used transmission electron microscopy, dynamic light scattering, zeta potential analysis, and spectroscopy to perform a physicochemical characterization of the nanogels resulting from the two approaches. Our studies have indicated that the nanogel encapsulated proteins and small molecules remain intact, stable and functional. A Hydrogen Peroxide (H2O2) and Nitric Oxide (NO) generating drug carrier was synthesized using these nanogels and the effect of generation of H2O2 from Glucose Oxidase encapsulated nanogels and NO from SNP encapsulated nanogels was tested on E.coli. The results show that the nanoparticles exert antimicrobial activity against E.Coli, in addition NO generating nanogels potentiated H2O2 generating nanogels induced killing. These data suggest that these NO and H2O2 releasing nanogels have the potential to serve as a novel class of antimicrobials for the treatment of multidrug resistant bacteria. The unique properties of these protein/drug incorporated nanogels raise the prospect of fine tailoring to specific applications such as drug delivery and bio imaging.

  16. Design of Nanoparticle-Based Carriers for Targeted Drug Delivery

    PubMed Central

    Ren, Muqing; Duval, Kayla; Guo, Xing; Chen, Zi

    2016-01-01

    Nanoparticles have shown promise as both drug delivery vehicles and direct antitumor systems, but they must be properly designed in order to maximize efficacy. Computational modeling is often used both to design new nanoparticles and to better understand existing ones. Modeled processes include the release of drugs at the tumor site and the physical interaction between the nanoparticle and cancer cells. In this article, we provide an overview of three different targeted drug delivery methods (passive targeting, active targeting and physical targeting), compare methods of action, advantages, limitations, and the current stage of research. For the most commonly used nanoparticle carriers, fabrication methods are also reviewed. This is followed by a review of computational simulations and models on nanoparticle-based drug delivery. PMID:27398083

  17. Synthetic LDL as targeted drug delivery vehicle

    SciTech Connect

    Forte, Trudy M; Nikanjam, Mina

    2012-08-28

    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.

  18. RAFT-mediated Control of Nanogel Structure and Reactivity: Chemical, Physical and Mechanical Properties of Monomer-dispersed Nanogel Compositions

    PubMed Central

    Liu, JianCheng; Stansbury, Jeffrey W.

    2014-01-01

    Objectives This study examines how nanogel structure correlates with photopolymerization and key polymer properties upon addition of nanogels with latent reactivity into a monomer dispersant to produce polymer/polymer composites. Methods Two nanogels that retained RAFT functionality based on the synthetic approach were prepared to have different branching densities. These reactive nanogels were dispersed in triethylene glycol dimethacrylate at 0–40 wt%. Reaction kinetics, volumetric shrinkage and shrinkage stress associated with the photopolymerization of nanogel-modified formulations were measured in real time with mechanical properties of the polymers also evaluated. The basic structure of RAFT-derived nanogel particles was examined by the preparation of a separate nanogel constructed with degradable disulfide crosslinking groups. The model nanogel molecular weight and polydispersity were compared before and after degradation. Results Despite the controlled radical synthetic approach, the nanogels, which are composed of multiple interconnected, short primary chains presented relatively high polydispersity. Through addition of the reactive nanogels to a monomer that both infiltrates and disperses the nanogels, the photopolymerization rate was moderately reduced with the increase of nanogel loading levels. Volumetric shrinkage decreased proportionally with nanogel concentration; however, a greater than proportional reduction of polymerization-induced stress was observed. Mechanical properties, such as flexural strength, storage modulus were maintained at the same levels as the control resin for nanogel systems up to 40 wt%. Significance This study demonstrated that beyond the use of RAFT functionality to produce discrete nano-polymeric structures, the residual chain end groups are important to maintain reactivity and mechanical properties of nanogel-modified resin materials. PMID:25205366

  19. Mechanism-Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast Cancer Therapy

    DTIC Science & Technology

    2014-02-01

    polymerization of the PEG segment and PMA or PGA segment, respectively. Nanogels were synthesized using the general procedure as was described...aqueous ammonia in the presence of ethylenediaminetetraacetic acid (EDTA), and (5) distilled water. The resulting nanogels were of ca. 130 nm in...such as Al3+ or Gd3+. The synthesized PEG-b-PGA nanogels were of 100-300 nm in diameter and were readily degradable in the presence of proteases

  20. Mechanism-Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast Cancer Therapy

    DTIC Science & Technology

    2014-02-01

    polymerization of the PEG segment and PMA or PGA segment, respectively. Nanogels were synthesized using the general procedure as was described earlier (6...aqueous ammonia in the presence of ethylenediaminetetraacetic acid (EDTA), and (5) distilled water. The resulting nanogels were of ca. 130 nm in diameter...as Al3+ or Gd3+. The synthesized PEG-b-PGA nanogels were of 100-300 nm in diameter and were readily degradable in the presence of proteases. For

  1. Membrane-targeting liquid crystal nanoparticles (LCNPs) for drug delivery

    NASA Astrophysics Data System (ADS)

    Nag, Okhil K.; Naciri, Jawad; Spillmann, Christopher M.; Delehanty, James B.

    2016-03-01

    In addition to maintaining the structural integrity of the cell, the plasma membrane regulates multiple important cellular processes, such as endocytosis and trafficking, apoptotic pathways and drug transport. The modulation or tracking of such cellular processes by means of controlled delivery of drugs or imaging agents via nanoscale delivery systems is very attractive. Nanoparticle-mediated delivery systems that mediate long-term residence (e.g., days) and controlled release of the cargoes in the plasma membrane while simultaneously not interfering with regular cellular physiology would be ideal for this purpose. Our laboratory has developed a plasma membrane-targeted liquid crystal nanoparticle (LCNP) formulation that can be loaded with dyes or drugs which can be slowly released from the particle over time. Here we highlight the utility of these nanopreparations for membrane delivery and imaging.

  2. Strategies on the nuclear-targeted delivery of genes

    PubMed Central

    Yao, Jing; Fan, Ying; Li, Yuanke; Huang, Leaf

    2016-01-01

    To improve the nuclear-targeted delivery of non-viral vectors, extensive effort has been carried out on the development of smart vectors which could overcome multiple barriers. The nuclear envelope presents a major barrier to transgene delivery. Viruses are capable of crossing the nuclear envelope to efficiently deliver their genome into the nucleus through the specialized protein components. However, non-viral vectors are preferred over viral ones because of the safety concerns associated with the latter. Non-viral delivery systems have been designed to include various types of components to enable nuclear translocation at the periphery of the nucleus. This review summarizes the progress of research regarding nuclear transport mechanisms. “Smart” non-viral vectors that have been modified by peptides and other small molecules are able to facilitate the nuclear translocation and enhance the efficacy of gene expression. The resulting technology may also enhance delivery of other macromolecules to the nucleus. PMID:23964565

  3. Delivery of Therapeutic RNAs Into Target Cells IN VIVO

    NASA Astrophysics Data System (ADS)

    Ng, Mei Ying; Hagen, Thilo

    2014-02-01

    RNA-based therapy is one of the most promising approaches to treat human diseases. Specifically, the use of short interfering RNA (siRNA) siRNA and microRNA (miRNA) mimics for in vivo RNA interference has immense potential as it directly lowers the expression of the therapeutic target protein. However, there are a number of major roadblocks to the successful implementation of siRNA and other RNA based therapies in the clinic. These include the instability of RNAs in vivo and the difficulty to efficiently deliver the RNA into the target cells. Hence, various innovative approaches have been taken over the years to develop effective RNA delivery methods. These methods include liposome-, polymeric nanoparticle- and peptide-mediated cellular delivery. In a recent innovative study, bioengineered bacterial outer membrane vesicles were used as vehicles for effective delivery of siRNA into cells in vivo.

  4. Bioengineered Silk Gene Delivery System for Nuclear Targeting

    PubMed Central

    Yigit, Sezin; Tokareva, Olena; Varone, Antonio; Georgakoudi, Irene

    2015-01-01

    Gene delivery research has gained momentum with the use of lipophilic vectors that mimic viral systems to increase transfection efficiency. However, maintaining cell viability with these systems remains a major challenge. Therefore biocompatible and nontoxic biopolymers that are designed by combining non-immunological viral mimicking components with suitable carriers have been explored to address these limitations. In the present study recombinant DNA technology was used to design a multi-functional gene delivery system for nuclear targeting, while also supporting cell viability. Spider dragline silk recombinant proteins were modified with DNA condensing units and the proton sponge endosomal escape pathway was utilized for enhanced delivery. Short-term transfection efficiency in a COS-7 cell line (adherent kidney cells isolated from African green monkey) was enhanced compared to lipofectamine and polyethyleneimine (PEI), as was cell viability with these recombinant bio-polyplexes. Endosomal escape and consequent nuclear targeting were shown with fluorescence microscopy. PMID:24889658

  5. 'Smart' non-viral delivery systems for targeted delivery of RNAi to the lungs.

    PubMed

    Ramsey, Joanne M; Hibbitts, Alan; Barlow, James; Kelly, Ciara; Sivadas, Neeraj; Cryan, Sally-Ann

    2013-01-01

    The emergence of RNAi offers a potentially exciting new therapeutic paradigm for respiratory diseases. However, effective delivery remains a key requirement for their translation into the clinic and has been a major factor in the limited clinical success seen to date. Inhalation offers tissue-specific targeting of the RNAi to treat respiratory diseases and a diminished risk of off-target effects. In order to deliver RNAi directly to the respiratory tract via inhalation, 'smart' non-viral carriers are required to protect the RNAi during delivery/aerosolization and enhance cell-specific uptake to target cells. Here, we review the state-of-the-art in therapeutic aerosol bioengineering, and specifically non-viral siRNA delivery platforms, for delivery via inhalation. This includes developments in inhaler device engineering and particle engineering, including manufacturing methods and excipients used in therapeutic aerosol bioengineering that underpin the development of smart, cell type-specific delivery systems to target siRNA to respiratory epithelial cells and/or alveolar macrophages.

  6. Self-Assembling Peptide Amphiphiles for Targeted Drug Delivery

    NASA Astrophysics Data System (ADS)

    Moyer, Tyson

    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

  7. Systems approaches to design of targeted therapeutic delivery.

    PubMed

    Myerson, Jacob W; Brenner, Jacob S; Greineder, Colin F; Muzykantov, Vladimir R

    2015-01-01

    Targeted drug delivery aims to improve therapeutic effects and enable mechanisms that are not feasible for untargeted agents (e.g., due to impermeable biological barriers). To achieve targeting, a drug or its carrier should possess properties providing specific accumulation from circulation at the desired site. There are several examples of systems-inspired approaches that have been applied to achieve this goal. First, proteomics analysis of plasma membrane fraction of the vascular endothelium has identified a series of target molecules and their ligands (e.g., antibodies) that deliver conjugated cargoes to well-defined vascular cells and subcellular compartments. Second, selection of ligands binding to cells of interest using phage display libraries in vitro and in vivo has provided peptides and polypeptides that bind to normal and pathologically altered cells. Finally, large-scale high-throughput combinatorial synthesis and selection of lipid- and polymer-based nanocarriers varying their chemical components has yielded a series of carriers accumulating in diverse organs and delivering RNA interference agents to diverse cells. Together, these approaches offer a basis for systems-based design and selection of targets, targeting molecules, and targeting vehicles. Current studies focus on expanding the arsenal of these and alternative targeting strategies, devising drug delivery systems capitalizing on these strategies and evaluation of their benefit/risk ratio in adequate animal models of human diseases. These efforts, combined with better understanding of mechanisms and unintended consequences of these targeted interventions, need to be ultimately translated into industrial development and the clinical domain.

  8. Colon targeting: an emerging frontier for oral insulin delivery.

    PubMed

    Patel, Mayur Mahendrakumar

    2013-06-01

    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.

  9. Prostate Cancer Relevant Antigens and Enzymes for Targeted Drug Delivery

    PubMed Central

    Barve, Ashutosh; Jin, Wei; Cheng, Kun

    2014-01-01

    Chemotherapy is one of the most widely used approaches in combating advanced prostate cancer, but its therapeutic efficacy is usually insufficient due to lack of 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-specific 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

  10. Delivery of Polymeric Nanoparticles to Target Vascular Diseases

    PubMed Central

    Agyare, Edward; Kandimalla, Karunyna

    2015-01-01

    Current advances in nanotechnology have paved the way for the early detection, prevention and treatment of various diseases such as vascular disorders and cancer. These advances have provided novel approaches or modalities of incorporating or adsorbing therapeutic, biosensor and targeting agents into/on nanoparticles. With significant progress, nanomedicine for vascular therapy has shown significant advantages over traditional medicine because of its ability to selectively target the disease site and reduce adverse side effects. Targeted delivery of nanoparticles to vascular endothelial cells or the vascular wall provides an effective and more efficient way for early detection and/or treatment of vascular diseases such as atherosclerosis, thrombosis and Cerebrovascular Amyloid Angiopathy (CAA). Clinical applications of biocompatible and biodegradable polymers in areas such as vascular graft, implantable drug delivery, stent devices and tissue engineering scaffolds have advanced the candidature of polymers as potential nano-carriers for vascular-targeted delivery of diagnostic agents and drugs. This review focuses on the basic aspects of the vasculature and its associated diseases and relates them to polymeric nanoparticle-based strategies for targeting therapeutic agents to diseased vascular site. PMID:26069867

  11. Ex vivo investigation of magnetically targeted drug delivery system

    NASA Astrophysics Data System (ADS)

    Yoshida, Y.; Fukui, S.; Fujimoto, S.; Mishima, F.; Takeda, S.; Izumi, Y.; Ohtani, S.; Fujitani, Y.; Nishijima, S.

    2007-03-01

    In conventional systemic drug delivery the drug is administered by intravenous injection; it then travels to the heart from where it is pumped to all regions of the body. When the drug is aimed at a small target region, this method is extremely inefficient and leads to require much larger doses than those being necessary. In order to overcome this problem a number of targeted drug delivery methods are developed. One of these, magnetically targeted drug delivery system (MT-DDS) will be a promising way, which involves binding a drug to small biocompatible magnetic particles, injecting these into the blood stream and using a high gradient magnetic field to pull them out of suspension in the target region. In the present paper, we describe an ex vivo experimental work. It is also reported that navigation and accumulation test of the magnetic particles in the Y-shaped glass tube was performed in order to examine the threshold of the magnetic force for accumulation. It is found that accumulation of the magnetic particles was succeeded in the blood vessel when a permanent magnet was placed at the vicinity of the blood vessel. This result indicates the feasibility of the magnetically drug targeting in the blood vessel.

  12. Targeted drug delivery using genetically engineered diatom biosilica.

    PubMed

    Delalat, Bahman; Sheppard, Vonda C; Rasi Ghaemi, Soraya; Rao, Shasha; Prestidge, Clive A; McPhee, Gordon; Rogers, Mary-Louise; Donoghue, Jacqueline F; Pillay, Vinochani; Johns, Terrance G; Kröger, Nils; Voelcker, Nicolas H

    2015-11-10

    The ability to selectively kill cancerous cell populations while leaving healthy cells unaffected is a key goal in anticancer therapeutics. The use of nanoporous silica-based materials as drug-delivery vehicles has recently proven successful, yet production of these materials requires costly and toxic chemicals. Here we use diatom microalgae-derived nanoporous biosilica to deliver chemotherapeutic drugs to cancer cells. The diatom Thalassiosira pseudonana is genetically engineered to display an IgG-binding domain of protein G on the biosilica surface, enabling attachment of cell-targeting antibodies. Neuroblastoma and B-lymphoma cells are selectively targeted and killed by biosilica displaying specific antibodies sorbed with drug-loaded nanoparticles. Treatment with the same biosilica leads to tumour growth regression in a subcutaneous mouse xenograft model of neuroblastoma. These data indicate that genetically engineered biosilica frustules may be used as versatile 'backpacks' for the targeted delivery of poorly water-soluble anticancer drugs to tumour sites.

  13. The role of acoustofluidics in targeted drug delivery

    PubMed Central

    Bose, Nilanjana; Zhang, Xunli; Maiti, Tapas K.; Chakraborty, Suman

    2015-01-01

    With the fast development of acoustic systems in clinical and therapeutic applications, acoustically driven microbubbles have gained a prominent role as powerful tools to carry, transfer, direct, and target drug molecules in cells, tissues, and tumors in the expanding fields of targeted drug delivery and gene therapy. The aim of the present study is to establish a biocompatible acoustic microfluidic system and to demonstrate the generation of an acoustic field and its effects on microbubbles and biological cells in the microfluidic system. The acoustic field creates non-linear oscillations of the microbubble-clusters, which results in generation of shear stress on cells in such microsystems. This effectively helps in delivering extracellular probes in living cells by sonoporation. The sonoporation is investigated under the combined effects of acoustic stress and hydrodynamic stress during targeted drug and gene delivery. PMID:26339329

  14. Non-Spherical Particles for Targeted Drug Delivery

    PubMed Central

    Chen, Jinrong; Clay, Nicholas; Kong, Hyunjoon

    2015-01-01

    Nano- and microparticles loaded with various bioimaging contrast agents or therapeutic molecules have been increasingly used for the diagnosis and treatment of diseases and tissue defects. These particles, often a filled or hollow sphere, can extend the lifetime of encapsulated biomedical modalities in circulation and in target tissue. However, there is a great need to improve the drug loading and targeting efficiency of these particles. Recently, several simulation and in vitro experimental studies reported that particle shape plays a pivotal role in the targeted delivery of molecules. To better understand these findings and subsequently expedite the use of particles in biomedical applications, this review paper summarizes the methods to prepare non-spherical nano- and micro-scaled particles. In addition, this review covers studies reporting the effects of particle shape on the loading, delivery and release of encapsulated bioactive cargos. Finally, it discusses future directions to further improve the properties of non-spherical particles. PMID:25838583

  15. Active Targeted Drug Delivery for Microbes Using Nano-Carriers

    PubMed Central

    Lin, Yung-Sheng; Lee, Ming-Yuan; Yang, Chih-Hui; Huang, Keng-Shiang

    2015-01-01

    Although vaccines and antibiotics could kill or inhibit microbes, many infectious diseases remain difficult to treat because of acquired resistance and adverse side effects. Nano-carriers-based technology has made significant progress for a long time and is introducing a new paradigm in drug delivery. However, it still has some challenges like lack of specificity toward targeting the infectious site. Nano-carriers utilized targeting ligands on their surface called ‘active target’ provide the promising way to solve the problems like accelerating drug delivery to infectious areas and preventing toxicity or side-effects. In this mini review, we demonstrate the recent studies using the active targeted strategy to kill or inhibit microbes. The four common nano-carriers (e.g. liposomes, nanoparticles, dendrimers and carbon nanotubes) delivering encapsulated drugs are introduced. PMID:25877093

  16. Polymeric Nanomaterials for Islet Targeting and Immunotherapeutic Delivery

    PubMed Central

    Ghosh, Kaustabh; Kanapathipillai, Mathumai; Korin, Netanel; McCarthy, Jason R.; Ingber, Donald E.

    2012-01-01

    Here we report a proof-of-concept for development of pancreatic islet-targeting nanoparticles for immunomodulatory therapy of autoimmune Type 1 Diabetes. Modified with a unique islet-homing peptide, these polymeric nanomaterials exhibit 3-fold greater binding to islet endothelial cells and a 200-fold greater anti-inflammatory effect through targeted islet endothelial cell delivery of an immunosuppressant drug. Our findings also underscore the need to carefully tailor drug loading and nanoparticle dosage to achieve maximal vascular targeting and immunosuppression. PMID:22196766

  17. Pharmacytes: an ideal vehicle for targeted drug delivery.

    PubMed

    Freitas, Robert A

    2006-01-01

    An ideal nanotechnology-based drug delivery system is a pharmacyte--a self-powered, computer-controlled medical nanorobot system capable of digitally precise transport, timing, and targeted delivery of pharmaceutical agents to specific cellular and intracellular destinations within the human body. Pharmacytes may be constructed using future molecular manufacturing technologies such as diamond mechanosynthesis which are currently being investigated theoretically using quantum ab initio and density-functional computational methods. Pharmacytes will have many applications in nanomedicine such as initiation of apoptosis in cancer cells and direct control of cell signaling processes.

  18. Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice.

    PubMed

    Otomo, Kotaro; Koga, Tomohiro; Mizui, Masayuki; Yoshida, Nobuya; Kriegel, Christina; Bickerton, Sean; Fahmy, Tarek M; Tsokos, George C

    2015-12-15

    Treatment of autoimmune diseases is still largely based on the use of systemically acting immunosuppressive drugs, which invariably cause severe side effects. Calcium/calmodulin-dependent protein kinase IV is involved in the suppression of IL-2 and the production of IL-17. Its pharmacologic or genetic inhibition limits autoimmune disease in mice. In this study, we demonstrate that KN93, a small-molecule inhibitor of calcium/calmodulin-dependent protein kinase IV, targeted to CD4(+) T cells via a nanolipogel delivery system, markedly reduced experimental autoimmune encephalomyelitis and was 10-fold more potent than the free systemically delivered drug in the lupus mouse models. The targeted delivery of KN93 did not deplete T cells but effectively blocked Th17 cell differentiation and expansion as measured in the spinal cords and kidneys of mice developing experimental autoimmune encephalomyelitis or lupus, respectively. These results highlight the promise of cell-targeted inhibition of molecules involved in the pathogenesis of autoimmunity as a means of advancing the treatment of autoimmune diseases.

  19. Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia

    PubMed Central

    Davis, Thomas P.

    2013-01-01

    Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion–transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia. PMID:23343976

  20. Targeted Cellular Drug Delivery using Tailored Dendritic Nanostructures

    NASA Astrophysics Data System (ADS)

    Kannan, Rangaramanujam; Kolhe, Parag; Kannan, Sujatha; Lieh-Lai, Mary

    2002-03-01

    Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorble, ‘peripheral’ functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug and gene delivery. The large number of end groups can also be tailored to create special affinity to targeted cells, and can also encapsulate drugs and deliver them in a controlled manner. We are developing tailor-modified dendritic systems for drug delivery. Synthesis, in-vitro drug loading, in-vitro drug delivery, and the targeting efficiency to the cell are being studied systematically using a wide variety of experimental tools. Polyamidoamine and Polyol dendrimers, with different generations and end-groups are studied, with drugs such as Ibuprofen and Methotrexate. Our results indicate that a large number of drug molecules can be encapsulated/attached to the dendrimers, depending on the end groups. The drug-encapsulated dendrimer is able to enter the cells rapidly and deliver the drug. Targeting strategies being explored

  1. Multi-Shell Hollow Nanogels with Responsive Shell Permeability

    PubMed Central

    Schmid, Andreas J.; Dubbert, Janine; Rudov, Andrey A.; Pedersen, Jan Skov; Lindner, Peter; Karg, Matthias; Potemkin, Igor I.; Richtering, Walter

    2016-01-01

    We report on hollow shell-shell nanogels with two polymer shells that have different volume phase transition temperatures. By means of small angle neutron scattering (SANS) employing contrast variation and molecular dynamics (MD) simulations we show that hollow shell-shell nanocontainers are ideal systems for controlled drug delivery: The temperature responsive swelling of the inner shell controls the uptake and release, while the thermoresponsive swelling of the outer shell controls the size of the void and the colloidal stability. At temperatures between 32 °C < T < 42 °C, the hollow nanocontainers provide a significant void, which is even larger than the initial core size of the template, and they possess a high colloidal stability due to the steric stabilization of the swollen outer shell. Computer simulations showed, that temperature induced switching of the permeability of the inner shell allows for the encapsulation in and release of molecules from the cavity. PMID:26984478

  2. A smart multifunctional drug delivery nanoplatform for targeting cancer cells

    NASA Astrophysics Data System (ADS)

    Hoop, M.; Mushtaq, F.; Hurter, C.; Chen, X.-Z.; Nelson, B. J.; Pané, S.

    2016-06-01

    Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of most tumors. Approximately a 2.5 times higher drug release from Ni nanotubes at pH = 6 is achieved compared to that at pH = 7.4. The outside of the Ni tube is coated with gold. A fluorescein isothiocyanate (FITC) labeled thiol-ssDNA, a biological marker, was conjugated on its surface by thiol-gold click chemistry, which enables traceability. The Ni nanotube allows the propulsion of the device by means of external magnetic fields. As the proposed nanoarchitecture integrates different functional building blocks, our drug delivery nanoplatform can be employed for carrying molecular drug conjugates and for performing targeted combinatorial therapies, which can provide an alternative and supplementary solution to current drug delivery technologies.Wirelessly guided magnetic nanomachines are promising vectors for targeted drug delivery, which have the potential to minimize the interaction between anticancer agents and healthy tissues. In this work, we propose a smart multifunctional drug delivery nanomachine for targeted drug delivery that incorporates a stimuli-responsive building block. The nanomachine consists of a magnetic nickel (Ni) nanotube that contains a pH-responsive chitosan hydrogel in its inner cavity. The chitosan inside the nanotube serves as a matrix that can selectively release drugs in acidic environments, such as the extracellular space of

  3. Aptamer-Mediated Targeted Delivery of Therapeutics: An Update

    PubMed Central

    Catuogno, Silvia; Esposito, Carla L.; de Franciscis, Vittorio

    2016-01-01

    The selective delivery of drugs in a cell- or tissue-specific manner represents the main challenge for medical research; in order to reduce the occurrence of unwanted off-target effects. In this regard, nucleic acid aptamers have emerged as an attractive class of carrier molecules due to their ability to bind with high affinity to specific ligands; their high chemical flexibility; as well as tissue penetration capability. To date, different aptamer-drug systems and aptamer–nanoparticles systems, in which nanoparticles function together with aptamers for the targeted delivery, have been successfully developed for a wide range of therapeutics, including toxins; peptides; chemotherapeutics and oligonucleotides. Therefore, aptamer-mediated drug delivery represents a powerful tool for the safe and effective treatment of different human pathologies, including cancer; neurological diseases; immunological diseases and so on. In this review, we will summarize recent progress in the field of aptamer-mediated drug delivery and we will discuss the advantages, the achieved objectives and the challenges to be still addressed in the near future, in order to improve the effectiveness of therapies. PMID:27827876

  4. Nanostructured lipid carriers (NLCs) for drug delivery and targeting.

    PubMed

    Fang, Chia-Lang; Al-Suwayeh, Saleh A; Fang, Jia-You

    2013-01-01

    Nanostructured lipid carriers (NLCs) are drug-delivery systems composed of both solid and liquid lipids as a core matrix. It was shown that NLCs reveal some advantages for drug therapy over conventional carriers, including increased solubility, the ability to enhance storage stability, improved permeability and bioavailability, reduced adverse effect, prolonged half-life, and tissue-targeted delivery. NLCs have attracted increasing attention in recent years. This review describes recent developments in drug delivery using NLCs strategies. The structures, preparation techniques, and physicochemical characterization of NLCs are systematically elucidated in this review. The potential of NLCs to be used for different administration routes is highlighted. Special attention is paid to parenteral injection and topical delivery since these are the most common routes for investigating NLCs. Relevant issues for the introduction of NLCs to market, including pharmaceutical and cosmetic applications, are discussed. The related patents of NLCs for drug delivery are also reviewed. Finally, the future development and current obstacles needing to be resolved are elucidated.

  5. Plasmid DNA nanogels as photoresponsive materials for multifunctional bio-applications.

    PubMed

    Costa, Diana; Valente, Artur J M; Queiroz, João

    2015-05-20

    This study provides a detailed description on the synthesis and characterization of novel polyamine plasmid DNA nanogels. Ethylene glycol diglycidyl ether was used as cross-linker, in conjugation with polyamines to promote pDNA condensation. The biocompatible nanovectors exhibit a unique swelling behavior in water and salt solutions. These systems are light photodegradable allowing their use in a broad range of biotechnological applications. Different plasmids, pVAX1-LacZ and pcDNA3-FLAG-p53, and anticancer drugs were, thus, efficiently loaded in the nanogels and their controlled release was demonstrated. Furthermore, the dual delivery of pcDNA3-FLAG-p53 gene and anticancer drugs illustrates the possibility of the combination of chemical and gene therapies. This new versatile and easy method of nanohydrogels preparation provides a potential synthetic approach for the design of tunable systems which can display multiple functions, sensitivity to different stimuli and exhibit programmed responses as well.

  6. Prodrugs - an efficient way to breach delivery and targeting barriers.

    PubMed

    Huttunen, Kristiina M; Rautio, Jarkko

    2011-01-01

    The study of prodrugs that are chemically modified bioreversible derivatives of active drug compounds to alter their undesired properties has been expanded widely during the last decades. Despite the commercial success the prodrugs have afforded, the concept is still quite unknown among many scientist. Furthermore, many scientists regard prodrugs as a pure interest of academic research groups and not as a feasible solution to improve the delivery or targeting properties of new chemical entities, drug candidates failed in clinical trials, or drugs withdrawn from the market. Although there are still unmet needs that require addressing, prodrugs should be seen as fine-tuning tools for the successful drug research and development. This review represents the potential of prodrugs to improve the drug delivery by enhanced aqueous solubility or permeability as well as describes several targeted prodrug strategies.

  7. Receptor-Mediated Drug Delivery Systems Targeting to Glioma

    PubMed Central

    Wang, Shanshan; Meng, Ying; Li, Chengyi; Qian, Min; Huang, Rongqin

    2015-01-01

    Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications.

  8. Breakable mesoporous silica nanoparticles for targeted drug delivery.

    PubMed

    Maggini, Laura; Cabrera, Ingrid; Ruiz-Carretero, Amparo; Prasetyanto, Eko A; Robinet, Eric; De Cola, Luisa

    2016-04-07

    "Pop goes the particle". Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery.

  9. Hydrophilic fluorescent nanogel thermometer for intracellular thermometry.

    PubMed

    Gota, Chie; Okabe, Kohki; Funatsu, Takashi; Harada, Yoshie; Uchiyama, Seiichi

    2009-03-04

    The first methodology to measure intracellular temperature is described. A highly hydrophilic fluorescent nanogel thermometer developed for this purpose stays in the cytoplasm and emits stronger fluorescence at a higher temperature. Thus, intracellular temperature variations associated with biological processes can be monitored by this novel thermometer with a temperature resolution of better than 0.5 degrees C.

  10. Breakable mesoporous silica nanoparticles for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Maggini, Laura; Cabrera, Ingrid; Ruiz-Carretero, Amparo; Prasetyanto, Eko A.; Robinet, Eric; de Cola, Luisa

    2016-03-01

    ``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery.``Pop goes the particle''. Here we report on the preparation of redox responsive mesoporous organo-silica nanoparticles containing disulfide (S-S) bridges (ss-NPs) that, even upon the exohedral grafting of targeting ligands, retained their ability to undergo structural degradation, and increase their local release activity when exposed to a reducing agent. This degradation could be observed also inside glioma C6 cancer cells. Moreover, when anticancer drug-loaded pristine and derivatized ss-NPs were fed to glioma C6 cells, the responsive hybrids were more effective in their cytotoxic action compared to non-breakable particles. The possibility of tailoring the surface functionalization of this hybrid, yet preserving its self-destructive behavior and enhanced drug delivery properties, paves the way for the development of effective biodegradable materials for in vivo targeted drug delivery. Electronic supplementary information (ESI) available: Full experimental procedures, additional SEM and TEM images of particles, complete UV-Vis and PL-monitored characterization of the breakdown of

  11. Magnetically Targeted Stem Cell Delivery for Regenerative Medicine

    PubMed Central

    Cores, Jhon; Caranasos, Thomas G.; Cheng, Ke

    2015-01-01

    Stem cells play a special role in the body as agents of self-renewal and auto-reparation for tissues and organs. Stem cell therapies represent a promising alternative strategy to regenerate damaged tissue when natural repairing and conventional pharmacological intervention fail to do so. A fundamental impediment for the evolution of stem cell therapies has been the difficulty of effectively targeting administered stem cells to the disease foci. Biocompatible magnetically responsive nanoparticles are being utilized for the targeted delivery of stem cells in order to enhance their retention in the desired treatment site. This noninvasive treatment-localization strategy has shown promising results and has the potential to mitigate the problem of poor long-term stem cell engraftment in a number of organ systems post-delivery. In addition, these same nanoparticles can be used to track and monitor the cells in vivo, using magnetic resonance imaging. In the present review we underline the principles of magnetic targeting for stem cell delivery, with a look at the logic behind magnetic nanoparticle systems, their manufacturing and design variants, and their applications in various pathological models. PMID:26133387

  12. New targets and delivery systems for antifungal therapy.

    PubMed

    Walsh, T J; Viviani, M A; Arathoon, E; Chiou, C; Ghannoum, M; Groll, A H; Odds, F C

    2000-01-01

    Development of new approaches for treatment of invasive fungal infections encompasses new delivery systems for approved and investigational compounds, as well as exploiting the cell membrane, cell wall and virulence factors as putative antifungal targets. Novel delivery systems consisting of cyclodextrins, cochleates, nanoparticles/nanospheres and long circulating ('stealth') liposomes, substantially modulate the pharmacokinetics of existing compounds, and may also be useful to enhance the delivery of antifungal agents to sites of infection. Further insights into the structure-activity relationship of the antifungal triazoles that target the biosynthesis of ergosterol in the fungal cell membrane have led to the development of highly potent broad spectrum agents, including posaconazole, ravuconazole and voriconazole. Similarly, a novel generation of cell-wall active semisynthetic echinocandin 1,3 beta-glucan inhibitors (caspofungin, FK463, and VER-002) has entered clinical development. These agents have potent and broad-spectrum activity against Candida spp, and potentially useful activity against Aspergillus spp. and Pneumocystis carinii. The ongoing convergence of the fields of molecular pathogenesis, antifungal pharmacology and vaccine development will afford the opportunity to develop novel targets to complement the existing antifungal armamentarium.

  13. Exploiting EPR in polymer drug conjugate delivery for tumor targeting.

    PubMed

    Modi, Sweta; Prakash Jain, Jay; Domb, A J; Kumar, Neeraj

    2006-01-01

    Treatment of tumor tissue without affecting normal cells has always been formidable task for drug delivery scientists and this task is effectively executed by polymer drug conjugate (PDC) delivery. The novelty of this concept lies in the utilization of a physical mechanism called enhanced permeability and retention (EPR) for targeting tumors. EPR is a physiological phenomenon that is customary for fast growing tumor and solves the problem of targeting the miscreant tissue. PDCs offer added advantages of reduced deleterious effects of anticancer drugs and augmentation of its formulation capability (e.g. Solubility). There are now at least eleven PDCs that have entered phase I/II/III clinical trial as anticancer drugs. PDCs once entered into the tumor tissue, taking advantage of EPR, are endocytosed into the cell either by simple or receptor mediated endocytosis. Various polymeric carriers have been used with hydrolyzable linker arm for conjugation with bioactive moiety. The hydrolyzable linkages of PDC are broken down by acid hydrolyses of lysosomes and releases the drug. High concentrations of the chemotherapeutic agent are maintained near the nucleus, the target site. Passive targeting by PDCs is due to the physiological event of EPR, which is becoming one of the major thrust areas for targeting solid tumors.

  14. Systems approaches to design of targeted therapeutic delivery

    PubMed Central

    Myerson, Jacob W.; Brenner, Jacob S.; Greineder, Colin F.; Muzykantov, Vladimir R.

    2016-01-01

    Targeted drug delivery aims to improve therapeutic effects and enable mechanisms that are not feasible for untargeted agents (e.g., due to impermeable biological barriers). To achieve targeting, a drug or its carrier should possess properties providing specific accumulation from circulation at the desired site. There are several examples of systems-inspired approaches that have been applied to achieve this goal. First, proteomics analysis of plasma membrane fraction of the vascular endothelium has identified a series of target molecules and their ligands (e.g., antibodies) that deliver conjugated cargoes to well-defined vascular cells and subcellular compartments. Second, selection of ligands binding to cells of interest using phage display libraries in vitro and in vivo has provided peptides and polypeptides that bind to normal and pathologically altered cells. Finally, large-scale high-throughput combinatorial synthesis and selection of lipid- and polymer-based nanocarriers varying their chemical components has yielded a series of carriers accumulating in diverse organs and delivering RNA interference agents to diverse cells. Together, these approaches offer a basis for systems-based design and selection of targets, targeting molecules, and targeting vehicles. Current studies focus on expanding the arsenal of these and alternative targeting strategies, devising drug delivery systems capitalizing on these strategies and evaluation of their benefit/risk ratio in adequate animal models of human diseases. These efforts, combined with better understanding of mechanisms and unintended consequences of these targeted interventions, need to be ultimately translated into industrial development and the clinical domain. PMID:25946066

  15. Targeted multidrug delivery system to overcome chemoresistance in breast cancer

    PubMed Central

    Tang, Yuan; Soroush, Fariborz; Tong, Zhaohui; Kiani, Mohammad F; Wang, Bin

    2017-01-01

    Chemotherapy has been widely used in breast cancer patients to reduce tumor size. However, most anticancer agents cannot differentiate between cancerous and normal cells, resulting in severe systemic toxicity. In addition, acquired drug resistance during the chemotherapy treatment further decreases treatment efficacy. With the proper treatment strategy, nanodrug carriers, such as liposomes/immunoliposomes, may be able to reduce undesired side effects of chemotherapy, to overcome the acquired multidrug resistance, and to further improve the treatment efficacy. In this study, a novel combinational targeted drug delivery system was developed by encapsulating antiangiogenesis drug bevacizumab into liposomes and encapsulating chemotherapy drug doxorubicin (DOX) into immunoliposomes where the human epidermal growth factor receptor 2 (HER2) antibody was used as a targeting ligand. This novel combinational system was tested in vitro using a HER2 positive and multidrug resistant breast cancer cell line (BT-474/MDR), and in vivo using a xenograft mouse tumor model. In vitro cell culture experiments show that immunoliposome delivery led to a high cell nucleus accumulation of DOX, whereas free DOX was observed mostly near the cell membrane and in cytoplasm due to the action of P-gp. Combining liposomal bevacizumab with immunoliposomal DOX achieved the best tumor growth inhibition and the lowest toxicity. Tumor size decreased steadily within a 60-day observation period indicating a potential synergistic effect between DOX and bevacizumab through the targeted delivery. Our findings clearly indicate that tumor growth was significantly delayed in the combinational liposomal drug delivery group. This novel combinational therapy has great potential for the treatment of patients with HER2/MDR double positive breast cancer. PMID:28176940

  16. Magnetic nanoparticles as targeted delivery systems in oncology

    PubMed Central

    Prijic, Sara; Sersa, Gregor

    2011-01-01

    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

  17. Tumor Targeting and Drug Delivery by Anthrax Toxin

    PubMed Central

    Bachran, Christopher; Leppla, Stephen H.

    2016-01-01

    Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery. PMID:27376328

  18. Nano-enhanced optical delivery into targeted cells (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Wright, Weldon; Pradhan, Sanjay

    2016-03-01

    Nano-enhanced optical field of gold nanoparticles allowed the use of a continuous wave (cw) laser beam for efficient delivery of exogenous impermeable materials into targeted cells. Using this Nano-enhanced Optical Delivery (NOD) method, we show that large molecules could be delivered with low power cw laser with exposure time ~ 1sec. At such low power (and exposure), the non-targeted cells (not bound to gold nanoparticles) were not adversely affected by the laser beam. Further, by varying the size of the gold nanoparticles, cells could be exclusively sensitized to selective wavelengths of laser beam. In contrast other nanoparticles, gold nanoparticles were found to have lower cytotoxicity, making it better suited for clinical NOD. Further, as compared with pulsed lasers, cw (diode) lasers are compact, easy-to-use and therefore, NOD using cw laser beam has significant translational potential for delivery of impermeable bio-molecules to tissues in different organs. We will present optimization of NOD parameters for delivering different molecules to different cells. Success of this NOD method may lead to a new clinical approach for treating AMD and RP patients with geographic atrophy in retina.

  19. Design and Application of Nanogel-Based Polymer Networks

    NASA Astrophysics Data System (ADS)

    Dailing, Eric Alan

    Crosslinked polymer networks have wide application in biomaterials, from soft hydrogel scaffolds for cell culture and tissue engineering to glassy, high modulus dental restoratives. Composite materials formed with nanogels as a means for tuning network structure on the nanoscale have been reported, but no investigation into nanogels as the primary network component has been explored to this point. This thesis was dedicated to studying network formation from the direct polymerization of nanogels and investigating applications for these unique materials. Covalently crosslinked polymer networks were synthesized from polymerizable nanogels without the use of reactive small monomers or oligomers. Network properties were controlled by the chemical and physical properties of the nanogel, allowing for materials to be designed from nanostructured macromolecular precursors. Nanogels were synthesized from a thermally initiated solution free radical polymerization of a monomethacrylate, a dimethacrylate, and a thiol-based chain transfer agent. Monomers with a range of hydrophilic and hydrophobic character were copolymerized, and polymerizable groups were introduced through an alcohol-isocyanate click reaction. Nanogels were dispersible in water up to 75 wt%, including nanogels that contained a relatively high fraction of a conventionally water-insoluble component. Nanogels with molecular weights that ranged from 10's to 100's of kDa and hydrodynamic radii between 4 and 10 nm were obtained. Macroscopic crosslinked polymer networks were synthesized from the photopolymerization of methacrylate-functionalized nanogels in inert solvent, which was typically water. The nanogel composition and internal branching density affected both covalent and non-covalent interparticle interactions, which dictated the final mechanical properties of the networks. Nanogels with progressively disparate hydrophilic and hydrophobic character were synthesized to explore the potential for creating

  20. Cartilage-targeting drug delivery: can electrostatic interactions help?

    PubMed

    Bajpayee, Ambika G; Grodzinsky, Alan J

    2017-03-01

    Current intra-articular drug delivery methods do not guarantee sufficient drug penetration into cartilage tissue to reach cell and matrix targets at the concentrations necessary to elicit the desired biological response. Here, we provide our perspective on the utilization of charge-charge (electrostatic) interactions to enhance drug penetration and transport into cartilage, and to enable sustained binding of drugs within the tissue's highly negatively charged extracellular matrix. By coupling drugs to positively charged nanocarriers that have optimal size and charge, cartilage can be converted from a drug barrier into a drug reservoir for sustained intra-tissue delivery. Alternatively, a wide variety of drugs themselves can be made cartilage-penetrating by functionalizing them with specialized positively charged protein domains. Finally, we emphasize that appropriate animal models, with cartilage thickness similar to that of humans, must be used for the study of drug transport and retention in cartilage.

  1. Delivery and targeting of nanoparticles into hair follicles.

    PubMed

    Fang, Chia-Lang; Aljuffali, Ibrahim A; Li, Yi-Ching; Fang, Jia-You

    2014-01-01

    It has been demonstrated that nanoparticles used for follicular delivery provide some advantages over conventional pathways, including improved skin bioavailability, enhanced penetration depth, prolonged residence duration, fast transport into the skin and tissue targeting. This review describes recent developments using nanotechnology approaches for drug delivery into the follicles. Different types of nanosystems may be employed for management of follicular permeation, such as polymeric nanoparticles, metallic nanocrystals, liposomes, and lipid nanoparticles. This review systematically introduces the mechanisms of follicles for nanoparticulate penetration, highlighting the therapeutic potential of drug-loaded nanoparticles for treating skin diseases. Special attention is paid to the use of nanoparticles in treating appendage-related disorders, in particular, nanomedical strategies for treating alopecia, acne, and transcutaneous immunization.

  2. Mesoporous silica nanoparticles in target drug delivery system: A review

    PubMed Central

    Bharti, Charu; Nagaich, Upendra; Pal, Ashok Kumar; Gulati, Neha

    2015-01-01

    Due to lack of specification and solubility of drug molecules, patients have to take high doses of the drug to achieve the desired therapeutic effects for the treatment of diseases. To solve these problems, there are various drug carriers present in the pharmaceuticals, which can used to deliver therapeutic agents to the target site in the body. Mesoporous silica materials become known as a promising candidate that can overcome above problems and produce effects in a controllable and sustainable manner. In particular, mesoporous silica nanoparticles (MSNs) are widely used as a delivery reagent because silica possesses favorable chemical properties, thermal stability, and biocompatibility. The unique mesoporous structure of silica facilitates effective loading of drugs and their subsequent controlled release of the target site. The properties of mesoporous, including pore size, high drug loading, and porosity as well as the surface properties, can be altered depending on additives used to prepare MSNs. Active surface enables functionalization to changed surface properties and link therapeutic molecules. They are used as widely in the field of diagnosis, target drug delivery, bio-sensing, cellular uptake, etc., in the bio-medical field. This review aims to present the state of knowledge of silica containing mesoporous nanoparticles and specific application in various biomedical fields. PMID:26258053

  3. Nanogel formation from dilute solutions of clickable elastin-like recombinamers and its dependence on temperature: two fractal gelation modes.

    PubMed

    González de Torre, Israel; Quintanilla, Luis; Pinedo-Martín, Guillermo; Alonso, Matilde; Rodríguez-Cabello, José Carlos

    2014-08-27

    Diluted, complementary, click-reactive elastin-like recombinamer (ELR) solutions have been prepared and mixed at two different temperatures, one below and one above the characteristic transition temperature (Tt) of these chemically modified ELRs. FTIR measurements, size, aspect ratio, zeta potential, and microrheological measurements have been carried out on the nanostructures formed under these dilute conditions as a way to better understand the relationship between the final macroscopic properties of ELR-based hydrogels and the molecular conditions governing the initial stages of the chemical cross-linking process that occurs, especially its dependence on the preparation temperature relative to Tt. As a result, two different fractal modes of gel formation have been found at the two temperatures studied (above and below Tt). Thus, when the reaction mixture is prepared below Tt, essentially one-dimensional linear nanogels with a high aspect ratio are obtained. In contrast, 3D nanogels are formed above Tt, with spherical shapes predominating. These different structures seem to reflect the two molecular organizations of the single components of the mixture under these conditions, namely extended chains below Tt and a spherical arrangement above Tt. In addition to the interest in these nanogels as models for understanding the formation of microscopic structures and differential macroscopic properties under more conventional hydrogel-formation conditions, these nanogels are of interest because of their thermoresponsiveness and biocompatibility, which provide them with potential uses for drug delivery and other biomedical applications in living systems.

  4. An Efficient Targeted Drug Delivery through Apotransferrin Loaded Nanoparticles

    PubMed Central

    Kishore, Golla; Kondapi, Anand Kumar

    2009-01-01

    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 ηm, which increase to 60–80 ηm upon direct loading of drug (direct-nano), and showed further increase in dimension (75–95 ηm) 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

  5. Cancer nanomedicine: from targeted delivery to combination therapy.

    PubMed

    Xu, Xiaoyang; Ho, William; Zhang, Xueqing; Bertrand, Nicolas; Farokhzad, Omid

    2015-04-01

    The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of various diseases, including cancer. The unique properties of nanoparticles (NPs), such as large surface-to-volume ratio, small size, the ability to encapsulate various drugs, and tunable surface chemistry, give them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make NPs a mode of treatment potentially superior to conventional cancer therapies. This review highlights the most recent developments in cancer treatment using NPs as drug delivery vehicles, including promising opportunities in targeted and combination therapy.

  6. Modular Nanotransporters for Targeted Intracellular Delivery of Drugs: Folate Receptors as Potential Targets

    PubMed Central

    Slastnikova, Tatiana A.; Rosenkranz, Andrey A.; Zalutsky, Michael R.; Sobolev, Alexander S.

    2015-01-01

    The review is devoted to a subcellular drug delivery system, modular nanotransporters (MNT) that can penetrate into target cells and deliver a therapeutic into their subcellular compartments, particularly into the nucleus. The therapeutics which need such type of delivery belong to two groups: (i) those that exert their effect only when delivered into a certain cell compartment (like DNA delivered into the nucleus); and (ii) those drugs that are capable of exerting their effect in different parts of the cells, however there can be found a cell compartment that is the most sensitive to their effect. A particular interest attract such cytotoxic agents as Auger electron emitters which are known to be ineffective outside the cell nucleus, whereas they possess high cytotoxicity in the vicinity of nuclear DNA through the induction of non-reparable double-strand DNA breaks. The review discusses main approaches permitting to choose internalizable receptors permitting both recognition of target cells and penetration into them. Special interest attract folate receptors which become accessible to blood circulating therapeutics after malignant transformation or on activated macrophages which makes them an attractive target for both several oncological and inflammatory diseases, like atherosclerosis. In vitro and in vivo experiments demonstrated that MNT is a promising platform for targeted delivery of different therapeutics into the nuclei of target cells. PMID:25312738

  7. Efficient delivery of therapeutic agents by using targeted albumin nanoparticles.

    PubMed

    Kouchakzadeh, Hasan; Safavi, Maryam Sadat; Shojaosadati, Seyed Abbas

    2015-01-01

    Albumin nanoparticles are one of the most important drug carriers for the delivery of therapeutic drugs, especially for the treatment of malignancies. This potential is due to their high binding capacity for both hydrophobic and hydrophilic drugs and the possibility of surface modification. Accumulation of albumin-bound drugs in the tumor interstitium occurs by the enhanced permeability and retention effect, which is also facilitated by the 60-kDa glycoprotein transcytosis pathway and binding to secreted protein, acidic and rich in cysteine located in the tumor extracellular matrix. In addition, specific ligands such as monoclonal antibodies, folic acid, transferrin, and peptides can be conjugated to the surface of albumin nanoparticles to actively target the drug to its site of action. The albumin-bound paclitaxel, Abraxane, is one of the several therapeutic nanocarriers that have been approved for clinical use. By the development of Abraxane that demonstrates a higher response rate and improved tolerability and therapeutic efficiency in comparison with solvent-based formulation, and with consideration of its commercial success, albumin is attracting the interest of many biotechnological and pharmaceutical companies. This chapter explores the current targeted and nontargeted albumin-based nanoparticles that are in various stages of development for the delivery of therapeutic agents in order to enhance the efficacy of cancer treatment.

  8. Targeted Intracellular Delivery of Proteins with Spatial and Temporal Control

    PubMed Central

    2015-01-01

    While a host of methods exist to deliver genetic materials or small molecules to cells, very few are available for protein delivery to the cytosol. We describe a modular, light-activated nanocarrier that transports proteins into cells by receptor-mediated endocytosis and delivers the cargo to the cytosol by light triggered endosomal escape. The platform is based on hollow gold nanoshells (HGN) with polyhistidine tagged proteins attached through an avidity-enhanced, nickel chelation linking layer; here, we used green fluorescent protein (GFP) as a model deliverable cargo. Endosomal uptake of the GFP loaded nanocarrier was mediated by a C-end Rule (CendR) internalizing peptide fused to the GFP. Focused femtosecond pulsed-laser excitation triggered protein release from the nanocarrier and endosome disruption, and the released protein was capable of targeting the nucleoli, a model intracellular organelle. We further demonstrate the generality of the approach by loading and releasing Sox2 and p53. This method for targeting of individual cells, with resolution similar to microinjection, provides spatial and temporal control over protein delivery. PMID:25490248

  9. Functionalized mesoporous silicon for targeted-drug-delivery.

    PubMed

    Tabasi, Ozra; Falamaki, Cavus; Khalaj, Zahra

    2012-10-01

    The present work concerns a preliminary step in the production of anticancer drug loaded porous silicon (PSi) for targeted-drug-delivery applications. A successful procedure for the covalent attachment of folic acid, polyethylene glycol (PEG) and doxorubicin to hydrophilic mesoporous silicon layers is presented. A systematic approach has been followed to obtain the optimal composition of the N,N'-dicyclohexylcarbodiimide (DCC)/N-hydroxysuccimide (NHS) in dimethylsulfoxide (DMSO) solution for the surface activation process of the undecylenic acid (UD) grafted molecules to take place with minimal undesired byproduct formation. The effect of reactant concentration and kind of solvent (aqueous or DMSO) on the attachment of folic acid to the activated PSi layer has been investigated. The covalent attachment of the doxorubicin molecules to the PSi layer functionalized with folic acid and PEG is discussed. The drug release kinetics as a function of pH has been studied. The functionalized PSi particles show a high cytotoxicity compared to the equivalent amount of free drug. Cell toxicity tests show clearly that the incorporation of folate molecules increases substantially the toxicity of the loaded PSi particles. Accordingly this new functionalized PSi may be considered a proper candidate for targeted drug delivery.

  10. Targeted drug delivery and enhanced intracellular release using functionalized liposomes

    NASA Astrophysics Data System (ADS)

    Garg, Ashish

    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

  11. Advanced drug delivery and targeting technologies for the ocular diseases

    PubMed Central

    Barar, Jaleh; Aghanejad, Ayuob; Fathi, Marziyeh; Omidi, Yadollah

    2016-01-01

    Introduction: Ocular targeted therapy has enormously been advanced by implementation of new methods of drug delivery and targeting using implantable drug delivery systems (DDSs) or devices (DDDs), stimuli-responsive advanced biomaterials, multimodal nanomedicines, cell therapy modalities and medical bioMEMs. These technologies tackle several ocular diseases such as inflammation-based diseases (e.g., scleritis, keratitis, uveitis, iritis, conjunctivitis, chorioretinitis, choroiditis, retinitis, retinochoroiditis), ocular hypertension and neuropathy, age-related macular degeneration and mucopolysaccharidosis (MPS) due to accumulation of glycosaminoglycans (GAGs). Such therapies appear to provide ultimate treatments, even though much more effective, yet biocompatible, noninvasive therapies are needed to control some disabling ocular diseases/disorders. Methods: In the current study, we have reviewed and discussed recent advancements on ocular targeted therapies. Results: On the ground that the pharmacokinetic and pharmacodynamic analyses of ophthalmic drugs need special techniques, most of ocular DDSs/devices developments have been designed to localized therapy within the eye. Application of advanced DDSs such as Subconjunctival insert/implants (e.g., latanoprost implant, Gamunex-C), episcleral implant (e.g., LX201), cationic emulsions (e.g., Cationorm™, Vekacia™, Cyclokat™), intac/punctal plug DDSs (latanoprost punctal plug delivery system, L-PPDS), and intravitreal implants (I-vitaion™, NT-501, NT- 503, MicroPump, Thethadur, IB-20089 Verisome™, Cortiject, DE-102, Retisert™, Iluvein™ and Ozurdex™) have significantly improved the treatment of ocular diseases. However, most of these DDSs/devices are applied invasively and even need surgical procedures. Of these, use of de novo technologies such as advanced stimuli-responsive nanomaterials, multimodal nanosystems (NSs)/nanoconjugates (NCs), biomacromolecualr scaffolds, and bioengineered cell therapies

  12. Nanosized Drug Delivery Systems in Gastrointestinal Targeting: Interactions with Microbiota

    PubMed Central

    Karavolos, Michail; Holban, Alina

    2016-01-01

    The new age of nanotechnology has signaled a stream of entrepreneurial possibilities in various areas, form industry to medicine. Drug delivery has benefited the most by introducing nanostructured systems in the transport and controlled release of therapeutic molecules at targeted sites associated with a particular disease. As many nanosized particles reach the gastrointestinal tract by various means, their interactions with the molecular components of this highly active niche are intensively investigated. The well-characterized antimicrobial activities of numerous nanoparticles are currently being considered as a reliable and efficient alternative to the eminent world crisis in antimicrobial drug discovery. The interactions of nanosystems present in the gastrointestinal route with host microbiota is unavoidable; hence, a major research initiative is needed to explore the mechanisms and effects of these nanomaterials on microbiota and the impact that microbiota may have in the outcome of therapies entailing drug delivery nanosystems through the gastrointestinal route. These coordinated studies will provide novel techniques to replace or act synergistically with current technologies and help develop new treatments for major diseases via the discovery of unique antimicrobial molecules. PMID:27690060

  13. Possibilities of acoustic thermometry for controlling targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Anosov, A. A.; Nemchenko, O. Yu.; Less, Yu. A.; Kazanskii, A. S.; Mansfel'd, A. D.

    2015-07-01

    Model acoustic thermometry experiments were conducted during heating of an aqueous liposome suspension. Heating was done to achieve the liposome phase transition temperature. At the moment of the phase transition, the thermal acoustic signal achieved a maximum and decreased, despite continued heating. During subsequent cooling of the suspension, when lipids again passed through the phase transition point, the thermal acoustic signal again increased, despite a reduction in temperature. This effect is related to an increase in ultrasound absorption by the liposome suspension at the moment of the lipid phase transition. The result shows that acoustic thermography can be used to control targeted delivery of drugs mixed in thermally sensitive liposomes, the integrity of which is violated during heating to the phase transition temperature.

  14. A hyaluronic acid nanogel for photo-chemo theranostics of lung cancer with simultaneous light-responsive controlled release of doxorubicin

    NASA Astrophysics Data System (ADS)

    Khatun, Zehedina; Nurunnabi, Md; Nafiujjaman, Md; Reeck, Gerald R.; Khan, Haseeb A.; Cho, Kwang Jae; Lee, Yong-Kyu

    2015-06-01

    The combined delivery of photo- and chemo-therapeutic agents is an emerging strategy to overcome drug resistance in treating cancer, and controlled light-responsive drug release is a proven tactic to produce a continuous therapeutic effect for a prolonged duration. Here, a combination of light-responsive graphene, chemo-agent doxorubicin and pH-sensitive disulfide-bond linked hyaluronic acid form a nanogel (called a graphene-doxorubicin conjugate in a hyaluronic acid nanogel) that exerts an activity with multiple effects: thermo and chemotherapeutic, real-time noninvasive imaging, and light-glutathione-responsive controlled drug release. The nanogel is mono-dispersed with an average diameter of 120 nm as observed by using TEM and a hydrodynamic size analyzer. It has excellent photo-luminescence properties and good stability in buffer and serum solutions. Graphene itself, being photoluminescent, can be considered an optical imaging contrast agent as well as a heat source when excited by laser irradiation. Thus the nanogel shows simultaneous thermo-chemotherapeutic effects on noninvasive optical imaging. We have also found that irradiation enhances the release of doxorubicin in a controlled manner. This release synergizes therapeutic activity of the nanogel in killing tumor cells. Our findings demonstrate that the graphene-doxorubicin conjugate in the hyaluronic acid nanogel is very effective in killing the human lung cancer cell line (A549) with limited toxicity in the non-cancerous cell line (MDCK).The combined delivery of photo- and chemo-therapeutic agents is an emerging strategy to overcome drug resistance in treating cancer, and controlled light-responsive drug release is a proven tactic to produce a continuous therapeutic effect for a prolonged duration. Here, a combination of light-responsive graphene, chemo-agent doxorubicin and pH-sensitive disulfide-bond linked hyaluronic acid form a nanogel (called a graphene-doxorubicin conjugate in a hyaluronic acid

  15. Competition between excluded-volume and electrostatic interactions for nanogel swelling: effects of the counterion valence and nanogel charge.

    PubMed

    Adroher-Benítez, Irene; Martín-Molina, Alberto; Ahualli, Silvia; Quesada-Pérez, Manuel; Odriozola, Gerardo; Moncho-Jordá, Arturo

    2017-03-01

    In this work the equilibrium distribution of ions around a thermo-responsive charged nanogel particle in an electrolyte aqueous suspension is explored using coarse-grained Monte Carlo computer simulations and the Ornstein-Zernike integral equation theory. We explicitly consider the ionic size in both methods and study the interplay between electrostatic and excluded-volume effects for swollen and shrunken nanogels, monovalent and trivalent counterions, and for two different nanogel charges. We find good quantitative agreement between the ionic density profiles obtained using both methods when the excluded repulsive force exerted by the cross-linked polymer network is taken into account. For the shrunken conformation, the electrostatic repulsion between the charged groups provokes a heterogeneous polymer density profile, leading to a nanogel structure with an internal low density hole surrounded by a dense corona. The results show that the excluded-volume repulsion strongly hinders the ion permeation for shrunken nanogels, where volume exclusion is able to significantly reduce the concentration of counterions in the more dense regions of the nanogel. In general, we demonstrate that the thermosensitive behaviour of nanogels, as well as their internal structure, is strongly influenced by the valence of the counterions and also by the charge of the particles. On the one hand, an increase of the counterion valence moves the swelling transition to lower temperatures, and induces a major structuring of the charged monomers into internal and external layers around the crown for shrunken nanogels. On the other hand, increasing the particle charge shifts the swelling curve to larger values of the effective radius of the nanogel.

  16. Electrospun Nanofibers of Guar Galactomannan for Targeted Drug Delivery

    NASA Astrophysics Data System (ADS)

    Chu, Hsiao Mei Annie

    2011-12-01

    Guar galactomannan is a biodegradable polysaccharide used widely in the food industry but also in the cosmetics, pharmaceutical, oil drilling, textile and paper industries. Guar consists of a mannose backbone and galactose side groups that are both susceptible to enzyme degradation, a unique property that can be explored for targeted drug delivery especially since those enzymes are naturally secreted by the microflora in human colon. The present study can be divided into three parts. In the first part, we discuss ways to modify guar to produce nanofibers by electrospinning, a process that involves the application of an electric field to a polymer solution or melt to facilitate production of fibers in the sub-micron range. Nanofibers are currently being explored as the next generation of drug carriers due to its many advantages, none more important than the fact that nanofibers are on a size scale that is a fraction of a hair's width and have large surface-to-volume ratio. The incorporation and controlled release of nano-sized drugs is one way in which nanofibers are being utilized in drug delivery. In the second part of the study, we explore various methods to crosslink guar nanofibers as a means to promote water-resistance in a potential drug carrier. The scope and utility of water-resistant guar nanofibers can only be fully appreciated when subsequent drug release studies are carried out. To that end, the third part of our study focuses on understanding the kinetics and diffusion mechanisms of a model drug, Rhodamine B, through moderately-swelling (crosslinked) hydrogel nanofibers in comparison to rapidly-swelling (non-crosslinked) nanofibers. Along the way, our investigations led us to a novel electrospinning set-up that has a unique collector designed to capture aligned nanofibers. These aligned nanofiber bundles can then be twisted to hold them together like yarn. From a practical standpoint, these yarns are advantageous because they come freely suspended and

  17. A novel double-targeted nondrug delivery system for targeting cancer stem cells

    PubMed Central

    Qiao, Shupei; Zhao, Yufang; Geng, Shuai; Li, Yong; Hou, Xiaolu; Liu, Yi; Lin, Feng-Huei; Yao, Lifen; Tian, Weiming

    2016-01-01

    Instead of killing cancer stem cells (CSCs), the conventional chemotherapy used for cancer treatment promotes the enrichment of CSCs, which are responsible for tumor growth, metastasis, and recurrence. However, most therapeutic agents are only able to kill a small proportion of CSCs by targeting one or two cell surface markers or dysregulated CSC pathways, which are usually shared with normal stem cells (NSCs). In this study, we developed a novel nondrug delivery system for the dual targeting of CSCs by conjugating hyaluronic acid (HA) and grafting the doublecortin-like kinase 1 (DCLK1) monoclonal antibody to the surface of poly(ethylene glycol) (PEG)–poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs), which can specifically target CD44 receptors and the DCLK1 surface marker – the latter was shown to possess the capacity to distinguish between CSCSs and NSCs. The size and morphology of these NPs were characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). This was followed by studies of NP encapsulation efficiency and in vitro drug release properties. Then, the cytotoxicity of the NPs was tested via Cell Counting Kit-8 assay. Finally, the 4T1 CSCs were obtained from the alginate-based platform, which we developed as an in vitro tumor model. Tumor-bearing nude mice were used as in vivo models to systematically detect the ability of NPs to target CSCs. Our results showed that the DCLK1–HA–PEG–PLGA NPs exhibited a targeting effect toward CSCs both in vitro and in vivo. These findings have important implications for the rational design of drug delivery systems that target CSCs with high efficacy. PMID:27994463

  18. Buparvaquone loaded solid lipid nanoparticles for targeted delivery in theleriosis

    PubMed Central

    Soni, Maheshkumar P.; Shelkar, Nilakash; Gaikwad, Rajiv V.; Vanage, Geeta R.; Samad, Abdul; Devarajan, Padma V.

    2014-01-01

    Background: Buparvaquone (BPQ), a hydroxynaphthoquinone derivative, has been investigated for the treatment of many infections and is recommended as the gold standard for the treatment of theileriosis. Theileriosis, an intramacrophage infection is localized mainly in reticuloendotheileial system (RES) organs. The present study investigates development of solid lipid nanoparticles (SLN) of BPQ for targeted delivery to the RES. Materials and Methods: BPQ SLN was prepared using melt method by adding a molten mixture into aqueous Lutrol F68 solution (80°C). Larger batches were prepared up to 6 g of BPQ with GMS: BPQ, 2:1. SLN of designed size were obtained using ultraturrax and high pressure homogenizer. A freeze and thaw study was used to optimize type and concentration of cryoprotectant with Sf: Mean particle size, Si: Initial particle size <1.3. Differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and scanning electron microscope (SEM) study was performed on optimized formulation. Formulation was investigated for in vitro serum stability, hemolysis and cell uptake study. Pharmacokinetic and biodistribution study was performed in Holtzman rat. Results: Based on solubility in lipid; glyceryl monostearate (GMS) was selected for preparation of BPQ SLN. Batches of BPQ SLN were optimized for average particle size and entrapment efficiency at <100 mg solid content. A combination of Solutol HS-15 and Lutrol F68 at 2% w/v and greater enabled the desired Sf/Si < 1.3. Differential scanning calorimetry and powder X-ray diffraction revealed decrease in crystallinity of BPQ in BPQ SLN while, scanning electron microscope revealed spherical morphology. BPQ SLN revealed good stability at 4°C and 25°C. Low hemolytic potential (<8%) and in vitro serum stability up to 5 h was observed. Cytotoxicity of SLN to the U937 cell was low. The macrophage cell line revealed high (52%) uptake of BPQ SLN in 1 h suggesting the potential to RES uptake. SLN revealed longer

  19. Chitosan coatings to control release and target tissues for therapeutic delivery.

    PubMed

    Jennings, Jessica Amber; Wells, Carlos Montez; McGraw, Gregory S; Velasquez Pulgarin, Diego A; Whitaker, Marsalas D; Pruitt, Reginald L; Bumgardner, Joel David

    2015-07-01

    The natural biopolymer chitosan has versatile applications in therapeutic delivery. Coating drug delivery matrices or biomaterials with chitosan offers several advantages in drug delivery, including control of drug release, slowing degradation rate and improving biocompatibility. Advanced uses of chitosan in coating form include targeting drug delivery vehicles to specific tissue as well as providing a stimulus-controlled release response. The present review summarizes the current applications of chitosan coatings in the context of different biomaterial delivery technologies, as well as future directions of chitosan coatings for drug delivery technologies under development.

  20. Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability.

    PubMed

    Lux, Jacques; Chan, Minnie; Elst, Luce Vander; Schopf, Eric; Mahmoud, Enas; Laurent, Sophie; Almutairi, Adah

    2013-12-14

    We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd(3+) within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd(3+). This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy.

  1. Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability

    PubMed Central

    Elst, Luce Vander; Schopf, Eric; Mahmoud, Enas; Laurent, Sophie; Almutairi, Adah

    2013-01-01

    We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd3+ within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd3+. This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy. PMID:24505553

  2. Universal conformational properties of polymers in ionic nanogels

    PubMed Central

    Kobayashi, Hideki; Winkler, Roland G.

    2016-01-01

    Polyelectrolyte gels are known to undergo significant conformational changes in response to external stimuli such as pH, temperature, or the dielectric constant. Specifically, an increase of the degree of ionization associated with an increasing number of counterions leads to swelling of the network. For a macroscopically large gel, which is electrostatically neutral in its interior, swelling is no longer governed by electrostatic interactions, but rather by the osmotic pressure of counterions. However, this electrostatic neutrality is typically violated for nanogels, because counterions are free to leave a gel particle. Although nanogel-swelling exhibits similar features as swelling of micro- and macrogels, another mechanism has to be relevant. Here, we use molecular dynamics simulations and scaling theory to unravel the structural properties of nanogels upon changing the electrostatic interactions. We demonstrate that the swelling of nanogels is governed by screened electrostatic interactions without a relevant contribution by the counterion osmotic pressure. PMID:26830457

  3. Transporter targeted gatifloxacin prodrugs: synthesis, permeability, and topical ocular delivery.

    PubMed

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

    2012-11-05

    In this work, we aim to design and synthesize prodrugs of gatifloxacin targeting organic cation transporter (OCT), monocarboxylate transporter (MCT), and ATB (0, +) transporters and to identify a prodrug with enhanced delivery to the back of the eye. 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. An 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. The permeability of the prodrugs was determined in the cornea, conjunctiva, and sclera-choroid-retinal pigment epitheluim (SCRPE) and compared with gatifloxacin using an 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 α-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. 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 the cornea, conjunctiva, and 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 the cornea, conjunctiva, and SCRPE, respectively. In the presence of nicotinic acid (competitive inhibitor of MCT), the

  4. Stimuli responsive magnetic nanogels for biomedical application

    SciTech Connect

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

    2013-11-13

    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 Fe{sub 3}O{sub 4} 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.

  5. Mucoadhesive platforms for targeted delivery to the colon.

    PubMed

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

    2011-11-25

    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.

  6. Modern prodrug design for targeted oral drug delivery.

    PubMed

    Dahan, Arik; Zimmermann, Ellen M; Ben-Shabat, Shimon

    2014-10-14

    The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

  7. Improved dental adhesive formulations based on reactive nanogel additives.

    PubMed

    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

    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.

  8. Hybrid micro-/nanogels for optical sensing and intracellular imaging

    PubMed Central

    Wu, Weitai; Zhou, Shuiqin

    2010-01-01

    Hybrid micro-/nanogels are playing an increasing important part in a diverse range of applications, due to their tunable dimensions, large surface area, stable interior network structure, and a very short response time. We review recent advances and challenges in the developments of hybrid micro-/nanogels toward applications for optical sensing of pH, temperature, glucose, ions, and other species as well as for intracellular imaging. Due to their unique advantages, hybrid micro-/nanogels as optical probes are attracting substantial interests for continuous monitoring of chemical parameters in complex samples such as blood and bioreactor fluids, in chemical research and industry, and in food quality control. In particular, their intracellular probing ability enables the monitoring of the biochemistry and biophysics of live cells over time and space, thus contributing to the explanation of intricate biological processes and the development of novel diagnoses. Unlike most other probes, hybrid micro-/nanogels could also combine other multiple functions into a single probe. The rational design of hybrid micro-/nanogels will not only improve the probing applications as desirable, but also implement their applications in new arenas. With ongoing rapid advances in bionanotechnology, the well-designed hybrid micro-/nanogel probes will be able to provide simultaneous sensing, imaging diagnosis, and therapy toward clinical applications. PMID:22110866

  9. One-pot synthesis of doxorubicin-loaded multiresponsive nanogels based on hyperbranched polyglycerol.

    PubMed

    Sousa-Herves, Ana; Wedepohl, Stefanie; Calderón, Marcelo

    2015-03-28

    Doxorubicin-loaded nanogels with multiresponsive properties are prepared using hyperbranched polyglycerol as a biocompatible scaffold. The nanogels are synthesized in a single step combining free-radical polymerization and a mild nanoprecipitation technique. The nanogels respond to different biological stimuli such as low pH and reductive environments, resulting in a more efficient cell proliferation inhibition in A549 cells.

  10. Correlation between the chemical composition of thermoresponsive nanogels and their interaction with the skin barrier.

    PubMed

    Giulbudagian, Michael; Rancan, Fiorenza; Klossek, André; Yamamoto, Kenji; Jurisch, Jana; Neto, Victor Colombo; Schrade, Petra; Bachmann, Sebastian; Rühl, Eckart; Blume-Peytavi, Ulrike; Vogt, Annika; Calderón, Marcelo

    2016-12-10

    In this paper we present a comprehensive study for the ability of thermoresponsive nanogels (tNG) to act as cutaneous penetration enhancers. Given the unique properties of such molecular architectures with regard to their chemical composition and thermoresponsive properties, we propose a particular mode of penetration enhancement mechanism, i.e. hydration of the stratum corneum. Different tNG were fabricated using dendritic polyglycerol as a multifunctional crosslinker and three different kinds of thermoresponsive polymers as linear counterpart: poly(N-isopropylacrylamide) (pNIPAM), p(di(ethylene glycol) methyl ether methacrylate - co - oligo ethylene glycol methacrylate) (DEGMA-co-OEGMA475), and poly(glycidyl methyl ether - co - ethyl glycidyl ether) (tPG). Excised human skin was investigated by means of fluorescence microscopy, which enabled the detection of significant increment in the penetration of tNG as well as the encapsulated fluorescein. The morphology of the treated skin samples was thoroughly investigated by transmission electron microscopy and stimulated Raman spectromicroscopy. We found that tNG can perturbate the organization of both proteins and lipids in the skin barrier, which was attributed to tNG hydration effects. Interestingly, different drug delivery properties were detected and the ability of each investigated tNG to enhance skin penetration correlated well with the degree of induced stratum corneum hydration. The differences in the penetration enhancements could be attributed to the chemical structures of the nanogels used in this study. The most effective stratum corneum hydration was detected for nanogels having additional or more exposed polyether structure in their chemical composition.

  11. Microemulsion-based drug delivery system for transnasal delivery of Carbamazepine: preliminary brain-targeting study.

    PubMed

    Patel, Rashmin Bharatbhai; Patel, Mrunali Rashmin; Bhatt, Kashyap K; Patel, Bharat G; Gaikwad, Rajiv V

    2016-01-01

    This study reports the development and evaluation of Carbamazepine (CMP)-loaded microemulsions (CMPME) for intranasal delivery in the treatment of epilepsy. The CMPME was prepared by the spontaneous emulsification method and characterized for physicochemical parameters. All formulations were radiolabeled with (99m)Tc (technetium) and biodistribution of CMP in the brain was investigated using Swiss albino rats. Brain scintigraphy imaging in rats was also performed to determine the uptake of the CMP into the brain. CMPME were found crystal clear and stable with average globule size of 34.11 ± 1.41 nm. (99m)Tc-labeled CMP solution (CMPS)/CMPME/CMP mucoadhesive microemulsion (CMPMME) were found to be stable and suitable for in vivo studies. Brain/blood ratio at all sampling points up to 8 h following intranasal administration of CMPMME compared to intravenous CMPME was found to be 2- to 3-fold higher signifying larger extent of distribution of the CMP in brain. Drug targeting efficiency and direct drug transport were found to be highest for CMPMME post-intranasal administration compared to intravenous CMP. Rat brain scintigraphy also demonstrated higher intranasal uptake of the CMP into the brain. This investigation demonstrates a prompt and larger extent of transport of CMP into the brain through intranasal CMPMME, which may prove beneficial for treatment of epilepsy.

  12. Development of a successive targeting liposome with multi-ligand for efficient targeting gene delivery

    PubMed Central

    Ma, Kun; Shen, Haijun; Shen, Song; Xie, Men; Mao, Chuanbin; Qiu, Liyan; Jin, Yi

    2012-01-01

    Background A successful gene delivery system needs to breakthrough several barriers to allow efficient transgenic expression. In the present study, successive targeting liposomes (STL) were constructed by integrating various targeting groups into a nanoparticle to address this issue. Methods Polyethylenimine (PEI) 1800-triamcinolone acetonide (TA) with nuclear targeting capability was synthesized by a two-step reaction. Lactobionic acid was connected with cholesterol to obtain a compound of [(2-lactoylamido) ethylamino]formic acid cholesterol ester (CHEDLA) with hepatocyte-targeting capability. The liposome was modified with PEI 1800-TA and CHEDLA to prepare successive targeting liposome (STL). Its physicochemical properties and transfection efficiency were investigated both in vitro and in vivo. Results The diameter of STL was approximately 100 nm with 20 mV of potential. The confocal microscopy observation and potential assay verified that lipid bilayer of STL was decorated with PEI 1800-TA. Cytotoxicity of STL was significantly lower than that of PEI 1800-TA and PEI 25K. The transfection efficiency of 10% CHEDLA STL in HepG2 cells was the higher than of the latter two with serum. Its transfection efficiency was greatly reduced with excessive free galactose, indicating that STL was absorbed via galactose receptor-mediated endocytosis. The in vivo study in mice showed that 10% CHEDLA STL had better transgenic expression in liver than the other carriers. Conclusions STL with multi-ligand was able to overcome the various barriers to target nucleus and special cells and present distinctive transgenic expression. Therefore, it has a great potential for gene therapy as a nonviral carrier. PMID:21574214

  13. A stabilized peptide ligand for multifunctional glioma targeted drug delivery.

    PubMed

    Ying, Man; Shen, Qing; Zhan, Changyou; Wei, Xiaoli; Gao, Jie; Xie, Cao; Yao, Bingxin; Lu, Weiyue

    2016-12-10

    Peptide ligands consisting of l-amino acids are subject to proteolysis in vivo. When modified on the surface of nanocarriers, those peptide ligands would readily degrade and the targeting efficacy is significantly attenuated. It has received increasing scrutiny to design stable peptide ligands for targeted drug delivery. Here, we present the design of a stable peptide ligand by the formation of a head-to-tail amide bond as an example. Even though the linear l-peptide A7R (termed (L)A7R) can bind specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) that are overexpressed on glioma cells, neovasculature and glioma vasculogenic mimicry (VM), the tumor-homing capacity of (L)A7R is greatly impaired in vivo due to proteolysis (e.g. in the serum). A cyclic A7R (cA7R) peptide was identified by computer-aided peptide design and synthesized with high yield by combining solid phase peptide synthesis and native chemical ligation. The binding of cA7R to both receptors was theoretically and experimentally assessed. In our simulated model hydrophobic and ionic interactions dominated the binding of (L)A7R to receptors. It is very interesting that cA7R adopting a different structure from (L)A7R retained high binding affinities to receptors without affecting the hydrophobic and ionic interactions. After head-to-tail cyclization by the formation of an amide bond, cA7R exhibited exceptional stability in mouse serum. Either cA7R or (L)A7R was conjugated on the surface of doxorubicin (DOX) loaded liposomes (cA7R-LS/DOX or (L)A7R-LS/DOX). The results of in vitro cellular assays indicated that cA7R-LS/DOX not only displayed stronger anti-proliferative effect against glioma cells, but also demonstrated to be more efficient in destruction of VM and HUVEC tubes in comparison to (L)A7R-LS/DOX and plain liposomes (LS/DOX, without peptide conjugation). cA7R conjugation could achieve significantly higher accumulation of liposomes in glioma than did (L

  14. Dual responsive PNIPAM-chitosan targeted magnetic nanopolymers for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Yadavalli, Tejabhiram; Ramasamy, Shivaraman; Chandrasekaran, Gopalakrishnan; Michael, Isaac; Therese, Helen Annal; Chennakesavulu, Ramasamy

    2015-04-01

    A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation.

  15. Contact-facilitated drug delivery with Sn2 lipase labile prodrugs optimize targeted lipid nanoparticle drug delivery

    PubMed Central

    Pan, Dipanjan; Pham, Christine TN; Weilbaecher, Katherine N; Tomasson, Michael H; Wickline, Samuel A; Lanza, Gregory M

    2016-01-01

    Sn2 lipase labile phospholipid prodrugs in conjunction with contact-facilitated drug delivery offer an important advancement in Nanomedicine. Many drugs incorporated into nanosystems, targeted or not, are substantially lost during circulation to the target. However, favorably altering the pharmacokinetics and volume of distribution of systemic drug delivery can offer greater efficacy with lower toxicity, leading to new prolonged-release nanoexcipients. However, the concept of achieving Paul Erhlich's inspired vision of a ‘magic bullet’ to treat disease has been largely unrealized due to unstable nanomedicines, nanosystems achieving low drug delivery to target cells, poor intracellular bioavailability of endocytosed nanoparticle payloads, and the substantial biological barriers of extravascular particle penetration into pathological sites. As shown here, Sn2 phospholipid prodrugs in conjunction with contact-facilitated drug delivery prevent premature drug diffusional loss during circulation and increase target cell bioavailability. The Sn2 phospholipid prodrug approach applies equally well for vascular constrained lipid-encapsulated particles and micelles the size of proteins that penetrate through naturally fenestrated endothelium in the bone marrow or thin-walled venules of an inflamed microcirculation. At one time Nanomedicine was considered a ‘Grail Quest’ by its loyal opposition and even many in the field adsorbing the pains of a long-learning curve about human biology and particles. However, Nanomedicine with innovations like Sn2 phospholipid prodrugs has finally made ‘made the turn’ toward meaningful translational success. PMID:26296541

  16. Synthesis and evaluation of airway targeted PLGA nanoparticles for drug delivery in obstructive lung diseases.

    PubMed

    Vij, Neeraj

    2012-01-01

    Chronic airway inflammation is a hallmark of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease), and CF (cystic fibrosis). It is also a major challenge in delivery and therapeutic efficacy of nano-based delivery systems in these chronic airway conditions as nanoparticle (NP) need to bypass airways defense mechanisms as we recently discussed. NPs which are capable of overcoming airways defense mechanisms should allow targeted drug delivery to disease cells. Over the last decade there has been increasing interest in development of targeted NPs for cancer but relatively little effort on designing novel systems for treating chronic inflammatory and obstructive airway conditions. Here we describe methods for preparing drug loaded multifunctional nanoparticles for targeted delivery to specific cell types in airways. The formulations and methods for selective drug delivery, discussed here are currently under preclinical development in our laboratory for treating chronic airway conditions such as COPD, CF, and asthma.

  17. Photo-Reactive Nanogel as a Means to Tune Properties during Polymer Network Formation

    PubMed Central

    Liu, JianCheng; Rad, Ima Y.; Sun, Fang; Stansbury, Jeffrey W.

    2013-01-01

    Photo-reactive nanogels with an integrated photoinitiator-based functionality were synthesized via a Reversible Addition-Fragmentation Chain Transfer (RAFT) process. Without additional free initiators, this nanogel is capable of radical generation and initiating polymerization of a secondary monomer (i.e. dimethacrylate) that infiltrates and disperses the nanogel particles. Due to the presence of RAFT functionality and the fact that all initiating sites are initially located within the nanogel structure, gelation can be delayed by sequencing the polymerization from the nanogel to the bulk matrix. During polymerization of a nanogel-filled resin system, a progressive delay of gelation conversion from about 2 % for conventional chain growth polymerization to 18 % for the same monomer containing 20 wt% nanogel additive was achieved. A significant delay of stress development was also observed with much lower final stress achieved with the nanogel-modified systems due to the change of network formation mechanics. Compared with the nanogel-free dimethacrylate control, which contained uniformly distributed free initiator, the flexural modulus and mechanical strength results were maintained for the photopolymers with nanogel contents greater than 10 wt%. There appears to be a critical interparticle spacing of the photo-reactive nanogel that provides effective photopolymerization while providing delayed gelation and substantial stress reduction. PMID:24348753

  18. Control of polymerization shrinkage and stress in nanogel-modified monomer and composite materials

    PubMed Central

    Moraes, Rafael R.; Garcia, Jeffrey W.; Barros, Matthew D.; Lewis, Steven H.; Pfeifer, Carmem S.; Liu, JianCheng; Stansbury, Jeffrey W.

    2011-01-01

    Objectives This study demonstrates the effects of nano-scale prepolymer particles as additives to model dental monomer and composite formulations. Methods Discrete nanogel particles were prepared by solution photopolymerization of isobornyl methacrylate and urethane dimethacrylate in the presence of a chain transfer agent, which also provided a means to attach reactive groups to the prepolymer. Nanogel was added to triethylene glycol dimethacrylate (TEGDMA) in increments between 5 and 40 wt% with resin viscosity, reaction kinetics, shrinkage, mechanical properties, stress and optical properties evaluated. Maximum loading of barium glass filler was determined as a function of nanogel content and composites with varied nanogel content but uniform filler loading were compared in terms of consistency, conversion, shrinkage and mechanical properties. Results High conversion, high molecular weight internally crosslinked and cyclized nanogel prepolymer was efficiently prepared and redispersed into TEGDMA with an exponential rise in viscosity accompanying nanogel content. Nanogel addition at any level produced no deleterious effects on reaction kinetics, conversion or mechanical properties, as long as reactive nanogels were used. A reduction in polymerization shrinkage and stress was achieved in proportion to nanogel content. Even at high nanogel concentrations, the maximum loading of glass filler was only marginally reduced relative to the control and high strength composite materials with low shrinkage were obtained. Significance The use of reactive nanogels offers a versatile platform from which resin and composite handling properties can be adjusted while the polymerization shrinkage and stress development that challenge the adhesive bonding of dental restoratives are controllably reduced. PMID:21388669

  19. Multifunctional magnetic silica nanotubes for MR imaging and targeted drug delivery.

    PubMed

    Huang, Liang; Ao, Lijiao; Wang, Wei; Hu, Dehong; Sheng, Zonghai; Su, Wu

    2015-03-04

    A multifunctional drug delivery vehicle consisting of a tubular shaped silica host, a compact superparamagnetic iron oxide nanoparticle layer and a hyaluronic acid surface coating was developed as a theranostic platform, for in vivo MR imaging and magnetically guided/cancer targeted drug delivery.

  20. Cell-mediated Delivery and Targeted Erosion of Noncovalently Crosslinked Hydrogels

    NASA Technical Reports Server (NTRS)

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

    2013-01-01

    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.

  1. [Targeted Delivery of Quantum Dots to HER2-Expressing Tumor Using Recombinant Antibodies].

    PubMed

    Balalaeva, I V; Zdobnova, T A; Sokolova, E A; Deyev, S M

    2015-01-01

    Targeted delivery of semiconductor quantum dots (Q Ds) to tumors overexpressing HER2 cancer marker has been. demonstrated on immunocompromised mice bearing human breast cancer xenografts. To obtain targeted QDs complexes we applied the approach based on the use of protein adaptor system, RNAase barnase and its inhibitor barstar. Specific binding to target cancer marker was achieved through bivalent fusion protein containing two fragments of4D5scFv recombinant antibody and a fragment of barnase. QDs were conjugated to barstar, and final assembly of targeted complexes was obtained through non-covalent specific interaction of barstar, attached to QD, and barnase, that is part of the recombinant targeting protein. The efficient delivery of QDs to HER2-expressing tumor demonstrates the possibilities and prospects of the approach for targeted delivery of nanoparticles to cancer cells in vivo as the way to improve the efficiency of diagnosis and promote development of therapies based on the use of nanoparticles.

  2. A Partnership Training Program: Studying Targeted Drug Delivery Using Nanoparticles in Breast Cancer Diagnosis and Therapy

    DTIC Science & Technology

    2013-10-01

    TITLE: A Partnership Training Program: Studying Targeted Drug Delivery Using Nanoparticles in Breast Cancer Diagnosis and Therapy PRINCIPAL...Drug Delivery Using Nanoparticles in Breast Cancer Diagnostics and Therapy 5a. CONTRACT NUMBER W81XWH-10-1-0767 5b. GRANT NUMBER 5c. PROGRAM...graduate and 3 undergraduate students from 7 departments at the Howard University have been trained in the use of nanoparticles as targeted drug

  3. Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis

    DTIC Science & Technology

    2015-12-01

    AWARD NUMBER: W81XWH-13-1-0495 TITLE: Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis PRINCIPAL...TITLE AND SUBTITLE 5a. CONTRACT NUMBER Platelets as Contractile Nanomachines for Targeting Drug Delivery in Hemostasis and Thrombosis 5b. GRANT...flow and thrombin concentration affect drug release. The proposed proof-of-concept experiments will validate our concept of platelet contraction

  4. Coupled Particulate and Continuum Model for Nanoparticle Targeted Delivery

    PubMed Central

    Tan, Jifu; Wang, Shunqiang; Yang, Jie; Liu, Yaling

    2013-01-01

    Prediction of nanoparticle (NP) distribution in a vasculature involves transport phenomena at various scales and is crucial for the evaluation of NP delivery efficiency. A combined particulate and continuum model is developed to model NP transport and delivery processes. In the particulate model ligand-receptor binding kinetics is coupled with Brownian dynamics to study NP binding on a microscale. An analytical formula is derived to link molecular level binding parameters to particulate level adhesion and detachment rates. The obtained NP adhesion rates are then coupled with a convection-diffusion-reaction model to study NP transport and delivery at macroscale. The binding results of the continuum model agree well with those from the particulate model. The effects of shear rate, particle size and vascular geometry on NP adhesion are investigated. Attachment rates predicted by the analytical formula also agree reasonably well with the experimental data reported in literature. The developed coupled model that links ligand-receptor binding dynamics to NP adhesion rate along with macroscale transport and delivery processes may serve as a faster evaluation and prediction tool to determine NP distribution in complex vascular networks. PMID:23729869

  5. Nanostructured lipid carriers and their current application in targeted drug delivery.

    PubMed

    Jaiswal, Piyush; Gidwani, Bina; Vyas, Amber

    2016-01-01

    In the last few decades, various drug-delivery technologies have emerged and a fascinating part of this has been the development of nanoscale drug delivery devices. Nanoparticles (NPs) and other colloidal drug-delivery systems modify the kinetics, drug distribution in the body and release profile of an associated drug. Nanostructured lipid carriers (NLCs) have been reported to be an alternative system to emulsions, liposomes, microparticles, solid lipid nanoparticles (SLNs) and their polymeric counterparts due to their numerous advantages. This paper basically reviews the types of NLCs, mechanism of skin penetration, stability related issues along with their production techniques, characterisation and applications towards targeted drug delivery.

  6. Targeted Drug Delivery in Covalent Organic Nanosheets (CONs) via Sequential Postsynthetic Modification.

    PubMed

    Mitra, Shouvik; Sasmal, Himadri Sekhar; Kundu, Tanay; Kandambeth, Sharath; Illath, Kavya; Díaz Díaz, David; Banerjee, Rahul

    2017-03-29

    Covalent organic nanosheets (CONs) have emerged as a new class of functional two-dimensional (2D) porous organic polymeric materials with a high accessible surface, diverse functionality, and chemical stability. They could become versatile candidates for targeted drug delivery. Despite their many advantages, there are limitations to their use for target specific drug delivery. We anticipated that these drawbacks could be overturned by judicious postsynthetic modification steps to use CONs for targeted drug delivery. The postsynthetic modification would not only produce the desired functionality, it would also help to exfoliate to CONs as well. In order to meet this requirement, we have developed a facile, salt-mediated synthesis of covalent organic frameworks (COFs) in the presence of p-toluenesulfonic acid (PTSA). The COFs were subjected to sequential postsynthetic modifications to yield functionalized targeted CONs for targeted delivery of 5-fluorouracil to breast cancer cells. This postsynthetic modification resulted in simultaneous chemical delamination and functionalization to targeted CONs. Targeted CONs showed sustained release of the drug to the cancer cells through receptor-mediated endocytosis, which led to cancer cell death via apoptosis. Considering the easy and facile COF synthesis, functionality based postsynthetic modifications, and chemical delamination to CONs for potential advantageous targeted drug delivery, this process can have a significant impact in biomedical applications.

  7. Protocells and their use for targeted delivery of multicomponent cargos to cancer cells

    DOEpatents

    Brinker, C Jeffrey; Ashley, Carlee Erin; Jiang, Xingmao; Liu, Juewen; Peabody, David S; Wharton, Walker Richard; Carnes, Eric; Chackerian, Bryce; Willman, Cheryl L

    2015-03-31

    Various embodiments provide materials and methods for synthesizing protocells for use in targeted delivery of cargo components to cancer cells. In one embodiment, the lipid bilayer can be fused to the porous particle core to form a protocell. The lipid bilayer can be modified with targeting ligands or other ligands to achieve targeted delivery of cargo components that are loaded within the protocell to a target cell, e.g., a type of cancer. Shielding materials can be conjugated to the surface of the lipid bilayer to reduce undesired non-specific binding.

  8. Protocells and their use for targeted delivery of multicomponent cargos to cancer cells

    DOEpatents

    Brinker, Jeffrey C.; Ashley, Carlee Erin; Jiang, Xingmao; Liu, Juewen; Peabody, David S.; Wharton, Walker Richard; Carnes, Eric; Chackerian, Bryce; Willman, Cheryl L.

    2016-11-01

    Various embodiments provide materials and methods for synthesizing protocells for use in targeted delivery of cargo components to cancer cells. In one embodiment, the lipid bilayer can be fused to the porous particle core to form a protocell. The lipid bilayer can be modified with targeting ligands or other ligands to achieve targeted delivery of cargo components that are loaded within the protocell to a target cell, e.g., a type of cancer. Shielding materials can be conjugated to the surface of the lipid bilayer to reduce undesired non-specific binding.

  9. Targeted delivery of a poorly water-soluble compound to hair follicles using polymeric nanoparticle suspensions.

    PubMed

    Morgen, Michael; Lu, Guang Wei; Du, Daniel; Stehle, Randall; Lembke, Franz; Cervantes, Jessica; Ciotti, Susan; Haskell, Roy; Smithey, Dan; Haley, Kevin; Fan, Conglin

    2011-09-15

    This study explored the utility of topically applied polymeric nanoparticle suspensions to target delivery of poorly water-soluble drugs to hair follicles. Several formulations of amorphous drug/polymer nanoparticles were prepared from ethyl cellulose and UK-157,147 (systematic name (3S,4R)-[6-(3-hydroxyphenyl)sulfonyl]-2,2,3-trimethyl-4-(2-methyl-3-oxo-2,3-dihydropyridazin-6-yloxy)-3-chromanol), a potassium channel opener, using sodium glycocholate (NaGC) as a surface stabilizer. Nanoparticle suspensions were evaluated to determine if targeted drug delivery to sebaceous glands and hair follicles could be achieved. In in vitro testing with rabbit ear tissue, delivery of UK-157,147 to the follicles was demonstrated with limited distribution to the surrounding dermis. Delivery to hair follicles was also demonstrated in vivo, based on stimulation of hair growth in tests of 100-nm nanoparticles with a C3H mouse model. The nanoparticles were well-tolerated, with no visible skin irritation. In vivo tests of smaller nanoparticles with a hamster ear model also indicated targeted delivery to sebaceous glands. The nanoparticles released drug rapidly in in vitro nonsink dissolution tests and were stable in suspension for 3 months. The present results show selective drug delivery to the follicle by follicular transport of nanoparticles and rapid release of a poorly water-soluble drug. Thus, nanoparticles represent a promising approach for targeted topical delivery of low-solubility compounds to hair follicles.

  10. Preparation, characterization and in vitro release of Zein-pectin capsules for target delivery.

    PubMed

    Tang, Wai-Wa; Dong, Fangyuan; Wong, Ka-Hing; Wang, Yi

    2015-01-01

    Targeted drug delivery has been the interest of many researchers to improve drug efficiency and reduce side effects. Because of the potential toxicity and contamination problems of the current gelatin capsules, plant derived materials are selected for the developments of capsules for drug delivery systems. The objective of this work is to develop a target drug delivery system using zein and pectin. Different ratios of zein and pectin were used to achieve target delivery in stomach and small intestine. Zein-pectin capsule for colon-specific delivery was also developed. In vitro performance of zeinpectin capsules was examined and their structural morphology was characterized using scanning electron microscopy (SEM). Chemical interactions between zein and pectin were analyzed using Fourier transform infrared spectroscopy equipped with attenuated total reflectance (FTIR-ATR). Zein and pectin formed complex by hydrogen bonding. The swelling behavior of pectin was suppressed by zein in the zein-pectin interacted complex. By adjusting the ratio of zein to pectin, the drug release from the capsule in simulated gastric solution for 2 hours can be controlled in the range of 0% to 38%. Zein-pectin capsule for colon-specific delivery had no release in gastric and intestinal solutions while gradual release from zein-pectin capsule was observed in colonic solution, finally reaching about 80% release. Zein-pectin capsule has a potential in developing targeted drug delivery system.

  11. Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition

    PubMed Central

    Mohapatra, Bhopal; Luan, Haitao; Soni, Kruti; Zhang, Jinjin; Storck, Matthew A.; Feng, Dan; Bielecki, Timothy A.; Band, Vimla; Cohen, Samuel M.; Bronich, Tatiana K.; Band, Hamid

    2016-01-01

    Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla®; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance

  12. Marked enhancement of lysosomal targeting and efficacy of ErbB2-targeted drug delivery by HSP90 inhibition.

    PubMed

    Raja, Srikumar M; Desale, Swapnil S; Mohapatra, Bhopal; Luan, Haitao; Soni, Kruti; Zhang, Jinjin; Storck, Matthew A; Feng, Dan; Bielecki, Timothy A; Band, Vimla; Cohen, Samuel M; Bronich, Tatiana K; Band, Hamid

    2016-03-01

    Targeted delivery of anticancer drugs to tumor cells using monoclonal antibodies against oncogenic cell surface receptors is an emerging therapeutic strategy. These strategies include drugs directly conjugated to monoclonal antibodies through chemical linkers (Antibody-Drug Conjugates, ADCs) or those encapsulated within nanoparticles that in turn are conjugated to targeting antibodies (Antibody-Nanoparticle Conjugates, ANPs). The recent FDA approval of the ADC Trastuzumab-TDM1 (Kadcyla; Genentech; San Francisco) for the treatment of ErbB2-overexpressing metastatic breast cancer patients has validated the strong potential of these strategies. Even though the activity of ANPs and ADCs is dependent on lysosomal traffic, the roles of the endocytic route traversed by the targeted receptor and of cancer cell-specific alterations in receptor dynamics on the efficiency of drug delivery have not been considered in these new targeted therapies. For example, constitutive association with the molecular chaperone HSP90 is thought to either retard ErbB2 endocytosis or to promote its recycling, traits undesirable for targeted therapy with ANPs and ADCs. HSP90 inhibitors are known to promote ErbB2 ubiquitination, targeting to lysosome and degradation. We therefore hypothesized that ErbB2-targeted drug delivery using Trastuzumab-conjugated nanoparticles could be significantly improved by HSP90 inhibitor-promoted lysosomal traffic of ErbB2. Studies reported here validate this hypothesis and demonstrate, both in vitro and in vivo, that HSP90 inhibition facilitates the intracellular delivery of Trastuzumab-conjugated ANPs carrying a model chemotherapeutic agent, Doxorubicin, specifically into ErbB2-overexpressing breast cancer cells, resulting in improved antitumor activity. These novel findings highlight the need to consider oncogene-specific alterations in receptor traffic in the design of targeted drug delivery strategies. We suggest that combination of agents that enhance receptor

  13. Exosomes for targeted siRNA delivery across biological barriers.

    PubMed

    El Andaloussi, Samir; Lakhal, Samira; Mäger, Imre; Wood, Matthew J A

    2013-03-01

    Using oligonucleotide-based drugs to modulate gene expression has opened a new avenue for drug discovery. In particular small interfering RNAs (siRNAs) are being rapidly recognized as promising therapeutic tools, but their poor bioavailability limits the full realization of their clinical potential. In recent years, cumulating evidence has emerged for the role of membrane vesicles, secreted by most cells and found in all body fluids, as key mediators of information transmission between cells. Importantly, a sub-group of these termed exosomes, have recently been shown to contain various RNA species and to mediate their horizontal transfer to neighbouring- or distant recipient cells. Here, we provide a brief overview on membrane vesicles and their role in exchange of genetic information. We also describe how these natural carriers of genetic material can be harnessed to overcome the obstacle of poor delivery and allow efficient systemic delivery of exogenous siRNA across biological barriers such as the blood-brain barrier.

  14. Nanomicellar carriers for targeted delivery of anticancer agents

    PubMed Central

    Zhang, Xiaolan; Huang, Yixian; Li, Song

    2014-01-01

    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

  15. Time-controlled oral delivery systems for colon targeting.

    PubMed

    Gazzaniga, Andrea; Maroni, Alessandra; Sangalli, Maria Edvige; Zema, Lucia

    2006-09-01

    In recent years, many research efforts have been spent in the achievement of selective delivery of drugs into the colon following oral administration. Indeed, colonic release is regarded as a beneficial approach to the pharmacological treatment or prevention of widespread large bowel pathologies, such as inflammatory bowel disease and adenocarcinoma. In addition, it is extensively explored as a potential means of enhancing the oral bioavailability of peptides, proteins and other biotechnological molecules, which are known to be less prone to enzymatic degradation in the large, rather than in the small, intestine. Based on these premises, several formulation strategies have been attempted in pursuit of colonic release, chiefly including microflora-, pH-, pressure- and time-dependent delivery technologies. In particular, this review is focused on the main design features and release performances of time-controlled devices, which rely on the relative constancy that is observed in the small intestinal transit time of dosage forms.

  16. Ultrasound-targeted HSVtk and Timp3 gene delivery for synergistically enhanced antitumor effects in hepatoma.

    PubMed

    Yu, B-F; Wu, J; Zhang, Y; Sung, H-W; Xie, J; Li, R-K

    2013-05-01

    Cancer gene therapy has great potential for decreasing tumor-induced mortality but has been clinically limited by non-targeted and insufficient gene transfer. We evaluated gene therapy targeting hepatocellular carcinoma (HCC) using the herpes simplex virus thymidine kinase/ganciclovir (HSVtk/GCV) suicide gene system and the tissue inhibitor of metalloproteinase 3 (Timp3) gene. Ultrasound-targeted microbubble destruction (UTMD) targeted gene delivery to the tumor tissue, and the α-fetoprotein promoter targeted HSVtk expression to the HCC cells. Human HepG2 cells transfected with the HSVtk or Timp3 gene demonstrated a reduction in cell viability by >40% compared with the vector control. Cell viability was further inhibited by over 50% with co-transfection of the genes. HepG2 cells were inoculated subcutaneously into athymic mice to induce tumors. UTMD-mediated delivery of HSVtk or Timp3 suppressed tumor growth by >45% and increased survival of tumor-bearing animals (P<0.01 vs vector control). Co-delivery of the genes resulted in a further 30% improvement in tumor suppression and significant extension of animal survival (P<0.01 vs vector control). Targeted gene delivery increased the number of apoptotic cells and decreased the vascular density of the tumors. Targeted co-delivery of the genes synergistically improved the antitumor effects and may provide an effective therapy for HCC.

  17. Novel targeted bladder drug-delivery systems: a review

    PubMed Central

    Zacchè, Martino Maria; Srikrishna, Sushma; Cardozo, Linda

    2015-01-01

    The objective of pharmaceutics is the development of drugs with increased efficacy and reduced side effects. Prolonged exposure of the diseased tissue to the drug is of crucial importance. Drug-delivery systems (DDSs) have been introduced to control rate, time, and place of release. Drugs can easily reach the bladder through a catheter, while systemically administered agents may undergo extensive metabolism. Continuous urine filling and subsequent washout hinder intravesical drug delivery (IDD). Moreover, the low permeability of the urothelium, also described as the bladder permeability barrier, poses a major challenge in the development of the IDD. DDSs increase bioavailability of drugs, therefore improving therapeutic effect and patient compliance. This review focuses on novel DDSs to treat bladder conditions such as overactive bladder, interstitial cystitis, bladder cancer, and recurrent urinary tract infections. The rationale and strategies for both systemic and local delivery methods are discussed, with emphasis on new formulations of well-known drugs (oxybutynin), nanocarriers, polymeric hydrogels, intravesical devices, encapsulated DDSs, and gene therapy. We give an overview of current and future prospects of DDSs for bladder disorders, including nanotechnology and gene therapy. PMID:26649286

  18. Novel targeted bladder drug-delivery systems: a review.

    PubMed

    Zacchè, Martino Maria; Srikrishna, Sushma; Cardozo, Linda

    2015-01-01

    The objective of pharmaceutics is the development of drugs with increased efficacy and reduced side effects. Prolonged exposure of the diseased tissue to the drug is of crucial importance. Drug-delivery systems (DDSs) have been introduced to control rate, time, and place of release. Drugs can easily reach the bladder through a catheter, while systemically administered agents may undergo extensive metabolism. Continuous urine filling and subsequent washout hinder intravesical drug delivery (IDD). Moreover, the low permeability of the urothelium, also described as the bladder permeability barrier, poses a major challenge in the development of the IDD. DDSs increase bioavailability of drugs, therefore improving therapeutic effect and patient compliance. This review focuses on novel DDSs to treat bladder conditions such as overactive bladder, interstitial cystitis, bladder cancer, and recurrent urinary tract infections. The rationale and strategies for both systemic and local delivery methods are discussed, with emphasis on new formulations of well-known drugs (oxybutynin), nanocarriers, polymeric hydrogels, intravesical devices, encapsulated DDSs, and gene therapy. We give an overview of current and future prospects of DDSs for bladder disorders, including nanotechnology and gene therapy.

  19. Molecularly imprinted polymeric micro- and nano-particles for the targeted delivery of active molecules.

    PubMed

    Gagliardi, Mariacristina; Mazzolai, Barbara

    2015-01-01

    Molecular imprinting (MI) represents a strategy to introduce a 'molecular memory' in a polymeric system obtaining materials with specific recognition properties. MI particles can be used as drug delivery systems providing a targeted release and thus reducing the side effects. The introduction of molecular recognition properties on a polymeric drug carrier represents a challenge in the development of targeted delivery systems to increase their efficiency. This review will summarize the limited number of drug delivery MI particles described in the literature along with an overview of potential solutions for a larger exploitation of MI particles as targeted drug delivery carriers. Molecularly imprinted drug carriers can be considered interesting candidates to significantly improve the efficiency of a controlled drug treatment.

  20. Progress and Challenges in Developing Aptamer-Functionalized Targeted Drug Delivery Systems

    PubMed Central

    Jiang, Feng; Liu, Biao; Lu, Jun; Li, Fangfei; Li, Defang; Liang, Chao; Dang, Lei; Liu, Jin; He, Bing; Atik Badshah, Shaikh; Lu, Cheng; He, Xiaojuan; Guo, Baosheng; Zhang, Xiao-Bing; Tan, Weihong; Lu, Aiping; Zhang, Ge

    2015-01-01

    Aptamers, which can be screened via systematic evolution of ligands by exponential enrichment (SELEX), are superior ligands for molecular recognition due to their high selectivity and affinity. The interest in the use of aptamers as ligands for targeted drug delivery has been increasing due to their unique advantages. Based on their different compositions and preparation methods, aptamer-functionalized targeted drug delivery systems can be divided into two main categories: aptamer-small molecule conjugated systems and aptamer-nanomaterial conjugated systems. In this review, we not only summarize recent progress in aptamer selection and the application of aptamers in these targeted drug delivery systems but also discuss the advantages, challenges and new perspectives associated with these delivery systems. PMID:26473828

  1. Computational design of nanoparticle drug delivery systems for selective targeting

    NASA Astrophysics Data System (ADS)

    Duncan, Gregg A.; Bevan, Michael A.

    2015-09-01

    Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues.Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting

  2. Local delivery of nitric oxide: targeted delivery of therapeutics to bone and connective tissues

    PubMed Central

    Nichols, Scott P.; Storm, Wesley L.; Koh, Ahyeon; Schoenfisch, Mark H.

    2012-01-01

    Non-invasive treatment of injuries and disorders affecting bones and connective tissue is a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair. PMID:22433782

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

    PubMed

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

    2012-12-01

    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 β-cyclodextrin (β-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 μPAR-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.

  4. Claudin 4-targeted protein incorporated into PLGA nanoparticles can mediate M cell targeted delivery

    PubMed Central

    Rajapaksa, Thejani E.; Stover-Hamer, Mary; Fernandez, Xiomara; Eckelhoefer, Holly A.; Lo, David D.

    2009-01-01

    Polymer-based microparticles are in clinical use mainly for their ability to provide controlled release of peptides and compounds, but they are also being explored for their potential to deliver vaccines and drugs as suspensions directly into mucosal sites. It is generally assumed that uptake is mediated by epithelial M cells, but this is often not directly measured. To study the potential for optimizing M cell uptake of polymer microparticles in vivo, we produced sub-micron size PLGA particles incorporating a recombinant protein. This recombinant protein was produced with or without a c-terminal peptide previously shown to have high affinity binding to Claudin 4, a protein associated with M cell endocytosis. While the PLGA nanoparticles incorporate the protein throughout the matrix, much of the protein was also displayed on the surface, allowing us to take advantage of the binding activity of the targeting peptide. Accordingly, we found that instillation of these nanoparticles into the nasal passages or stomach of mice was found to significantly enhance their uptake by upper airway and intestinal M cells. Our results suggest that a reasonably simple nanoparticle manufacture method can provide insight into developing an effective needle-free delivery system. PMID:19896996

  5. Targeting metastatic cancer from the inside: a new generation of targeted gene delivery vectors enables personalized cancer vaccination in situ.

    PubMed

    Gordon, Erlinda M; Levy, John P; Reed, Rebecca A; Petchpud, W Nina; Liu, Liqiong; Wendler, Carlan B; Hall, Frederick L

    2008-10-01

    The advent of pathotropic (disease-seeking) targeting technologies, combined with advanced gene delivery vectors, provides a unique opportunity for the systemic delivery of immunomodulatory cytokine genes to remote sites of cancer metastasis. When injected intravenously, such pathotropic nanoparticles seek out and accumulate selectively at sites of tumor invasion and neo-angiogenesis, resulting in enhanced gene delivery, and thus cytokine production, within the tumor nodules. Used in conjunction with a primary tumoricidal agent (e.g., Rexin-G) that exposes tumor neoantigens, the tumor-targeted immunotherapy vector is intended to promote the recruitment and activation of host immune cells into the metastastic site(s), thereby initiating cancer immunization in situ. In this study, we examine the feasibility of cytokine gene delivery to cancerous lesions in vivo using intravenously administered pathotropically targeted nanoparticles bearing the gene encoding granulocyte/macrophage colony-stimulating factor (GM-CSF; i.e., Reximmune-C). In vitro, transduction of target cancer cells with Reximmune-C resulted in the quantitative production of bioactive and immunoreactive GM-CSF protein. In tumor-bearing nude mice, intravenous infusions of Reximmune-C-induced GM-CSF production by transduced cancer cells and paracrine secretion of the cytokine within the tumor nodules, which promoted the recruitment of host mononuclear cells, including CD40+ B cells and CD86+ dendritic cells, into the tumors. With the first proofs of principle established in preclinical studies, we generated an optimized vector configuration for use in advanced clinical trial designs, and extended the feasibility studies to the clinic. Targeted delivery and localized expression of the GM-CSF transgene was confirmed in a patient with metastatic cancer, as was the recruitment of significant tumor-infiltrating lymphocytes (TILs). Taken together, these studies provide the first demonstrations of cytokine gene

  6. Naltrexone: a review of existing sustained drug delivery systems and emerging nano-based systems.

    PubMed

    Goonoo, Nowsheen; Bhaw-Luximon, Archana; Ujoodha, Reetesh; Jhugroo, Anil; Hulse, Gary K; Jhurry, Dhanjay

    2014-06-10

    Narcotic antagonists such as naltrexone (NTX) have shown some efficiency in the treatment of both opiate addiction and alcohol dependence. A few review articles have focused on clinical findings and pharmacogenetics of NTX, advantages and limitations of sustained release systems as well as pharmacological studies of NTX depot formulations for the treatment of alcohol and opioid dependency. To date, three NTX implant systems have been developed and tested in humans. In this review, we summarize the latest clinical data on commercially available injectable and implantable NTX-sustained release systems and discuss their safety and tolerability aspects. Emphasis is also laid on recent developments in the area of nanodrug delivery such as NTX-loaded micelles and nanogels as well as related research avenues. Due to their ability to increase the therapeutic index and to improve the selectivity of drugs (targeted delivery), nanodrug delivery systems are considered as promising sustainable drug carriers for NTX in addressing opiate and alcohol dependence.

  7. Nanovectors for Targeting and Delivery of Therapeutics to HER-2 NEU Positive Breast Cancer Cells

    DTIC Science & Technology

    2008-10-01

    targeted nanoparticles. The bivalent cyclic antibody mimic against Her-2 neu, (i.e. a peptide derived from the antigen-binding site of anti-Her-2...Guccione, S., Reisfeld, R. A., et al., Tumor regression by targeted gene delivery to the neovasculature. Science 296 (2002) 2404-2407. [14] Arap, W

  8. Advances toward More Efficient Targeted Delivery of Nanoparticles in Vivo: Understanding Interactions between Nanoparticles and Cells.

    PubMed

    Polo, Ester; Collado, Manuel; Pelaz, Beatriz; Del Pino, Pablo

    2017-03-07

    In this Perspective, we describe current challenges and recent advances in efficient delivery and targeting of nanoparticles in vivo. We discuss cancer therapy, nanoparticle-biomolecule interactions, nanoparticle trafficking in cells, and triggers and responses to nanoparticle-cell interactions. No matter which functionalization strategy to target cancer is chosen, passive or active targeting, more than 99% of the nanoparticles administered in vivo end up in the mononuclear phagocytic system, mainly sequestered by macrophages. Comprehensive studies, such as the one reported by MacParland et al. in this issue of ACS Nano, will help to close the gap between nanotechnology-based drug-delivery solutions and advanced medicinal products.

  9. Synthesis of folate-functionalized RAFT polymers for targeted siRNA delivery.

    PubMed

    Benoit, Danielle S W; Srinivasan, Selvi; Shubin, Andrew D; Stayton, Patrick S

    2011-07-11

    Receptor-mediated, cell-specific delivery of siRNA enables silencing of target genes in specific tissues, opening the door to powerful therapeutic options for a multitude of diseases. However, the development of delivery systems capable of targeted and effective siRNA delivery typically requires multiple steps and the use of sophisticated, orthogonal chemistries. Previously, we developed diblock copolymers consisting of dimethaminoethyl methacrylate-b-dimethylaminoethyl methacrylate-co-butyl methacrylate-co-propylacrylic acid as potent siRNA delivery systems that protect siRNA from enzymatic degradation and enable its cytosolic delivery through pH-responsive, endosomolytic behavior. (1, 2) These architectures were polymerized using a living radical polymerization method, specifically reversible addition-fragmentation chain transfer (RAFT) polymerization, which employs a chain transfer agent (CTA) to modulate the rate of reaction, resulting in polymers with low polydispersity and telechelic chain ends reflecting the chemistry of the CTA. Here we describe the straightforward, facile synthesis of a folate receptor-targeted diblock copolymer siRNA delivery system because the folate receptor is an attractive target for tumor-selective therapies as a result of its overexpression in a number of cancers. Specifically, we detail the de novo synthesis of a folate-functionalized CTA, use the folate-CTA for controlled polymerizations of diblock copolymers, and demonstrate efficient, specific cellular folate receptor interaction and in vitro gene knockdown using the folate-functionalized polymer.

  10. Dendritic polymer-based nanodevices for targeted drug delivery applications

    NASA Astrophysics Data System (ADS)

    Kannan, R. M.; Kolhe, Parag; Gurdag, Sezen; Khandare, Jayant; Lieh-Lai, Mary

    2004-03-01

    Dendrimers and hyperbranched polymers are unimolecular micellar nanostructures, characterized by globular shape ( ˜ 20 nm) and large density of functional groups at periphery. The tailorable end groups make them ideal for conjugation with drugs, ligands, and imagining agents, making them an attractive molecular nanodevices for drug delivery. Compared to linear polymers and nanoparticles, these nanodevices enter cells rapidly, carrying drugs and delivering them inside cells. Performance of nanodevices prepared for asthma and cancer drug delivery will be discussed. Our conjugation procedure produced very high drug payloads. Dendritic polymer-drug conjugates were very effective in transporting methotrexate (a chemotherapy drug) into both sensitive (CCRF-CEM cell line) and resistant cell line (CEM-MTX). The conjugate nanodevice was 3 times more effective than free drug in the sensitive line, and 9 times more effective in the resistant cell line (based on IC50). The physics of cell entry and drug release from these nanodevices are being investigated. The conjugates appear to enter cells through endocytosis, with the rate of entry dependent on end-group, molecular weight, the pH of the medium, and the cancerous nature of the cells.

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

    NASA Astrophysics Data System (ADS)

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

    2014-10-01

    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

  12. Direct Cytoplasmic Delivery and Nuclear Targeting Delivery of HPMA-MT Conjugates in a Microtubules Dependent Fashion.

    PubMed

    Zhong, Jiaju; Zhu, Xi; Luo, Kui; Li, Lian; Tang, Manlin; Liu, Yanxi; Zhou, Zhou; Huang, Yuan

    2016-09-06

    As the hearts of tumor cells, the nucleus is the ultimate target of many chemotherapeutic agents and genes. However, nuclear drug delivery is always hampered by multiple intracellular obstacles, such as low efficiency of lysosome escape and insufficient nuclear trafficking. Herein, an N-(2-hydroxypropyl) methacrylamide (HPMA) polymer-based drug delivery system was designed, which could achieve direct cytoplasmic delivery by a nonendocytic pathway and transport into the nucleus in a microtubules dependent fashion. A special targeting peptide (MT), derived from an endogenic parathyroid hormone-related protein, was conjugated to the polymer backbone, which could accumulate into the nucleus a by microtubule-mediated pathway. The in vitro studies found that low temperature and NaN3 could not influence the cell internalization of the conjugates. Besides, no obvious overlay of the conjugates with lysosome demonstrated that the polymer conjugates could enter the tumor cell cytoplasm by a nonendocytic pathway, thus avoiding the drug degradation in the lysosome. Furthermore, after suppression of the microtubule dynamics with microtubule stabilizing docetaxel (DTX) and destabilizing nocodazole (Noc), the nuclear accumulation of polymeric conjugates was significantly inhibited. Living cells fluorescence recovery after photobleaching study found that the nuclear import rate of conjugates was 2-fold faster compared with the DTX and Noc treated groups. These results demonstrated that the conjugates transported into the nucleus in a microtubules dependent way. Therefore, in addition to direct cytoplasmic delivery, our peptide conjugated polymeric platform could simultaneously mediate nuclear drug accumulation, which may open a new path for further intracellular genes/peptides delivery.

  13. Targeted blood-to-brain drug delivery --10 key development criteria.

    PubMed

    Gaillard, Pieter J; Visser, Corine C; Appeldoorn, Chantal C M; Rip, Jaap

    2012-09-01

    Drug delivery to the brain remains challenging due to the presence of the blood-brain barrier. In this review, 10 key development criteria are presented that are important for successful drug development to treat CNS diseases by targeted drug delivery systems. Although several routes of delivery are being investigated, such as intranasal delivery, direct injections into the brain or CSF, and transient opening of the blood-brain barrier, the focus of this review is on physiological strategies aiming to target endogenous transport mechanisms. Examples from literature, focusing on targeted drug delivery systems that are being commercially developed, will be discussed to illustrate the 10 key development criteria. The first four criteria apply to the targeting of the blood-brain barrier: (1) a proven inherently safe receptor biology, (2) a safe and human applicable ligand, (3) receptor specific binding, and (4) applicable for acute and chronic indications. Next to an efficient and safe targeting strategy, as captured in key criteria 1 to 4, a favorable pharmacokinetic profile is also important (key criterion 5). With regard to the drug carriers, two criteria are important: (6) no modification of active ingredient and (7) able to carry various classes of molecules. The final three criteria apply to the development of a drug from lab to clinic: (8) low costs and straightforward manufacturing, (9) activity in all animal models, and (10) strong intellectual property (IP) protection. Adhering to these 10 key development criteria will allow for a successful brain drug development.

  14. Conceptual design report for the University of Rochester cryogenic target delivery system

    SciTech Connect

    Fagaly, R.L.; Alexander, N.B.; Bourque, R.F.; Dahms, C.F.; Lindgren, J.R.; Miller, W.J. ); Bittner, D.N.; Hendricks, C.D. )

    1993-05-01

    The upgrade of the Omega laser at the University of Rochester's Laboratory for Laser Energetics (UR/LLE) will result in a need for large targets filled with D[sub 2] or Dt and maintained at cryogenic temperatures. This mandates a cryogenic target delivery system capable of filling, layering, characterizing and delivering cryogenic targets to the Omega Upgrade target chamber. The program goal is to design, construct, and test the entire target delivery system by June 1996. When completed (including an operational demonstration), the system will be shipped to Rochester for reassembly and commissioning in time for the Omega Upgrade cryogenic campaign, scheduled to start in 1998. General Atomics has been assigned the task of developing the conceptual design for the cryogenic target delivery system. Design and fabrication activities will be closely coordinated with the University of Rochester, Lawrence Livermore National laboratory (LLNL) and Los Alamos National Laboratory (LANL), drawing upon their knowledge base in fuel layering and cryogenic characterization. The development of a target delivery system for Omega could also benefit experiments at Lawrence Livermore National Laboratory and the other ICF Laboratories in that the same technologies could be applied to NOVA, the National Ignition Facility or the future Laboratory Microfusion Facility.

  15. Conceptual design report for the University of Rochester cryogenic target delivery system

    SciTech Connect

    Fagaly, R.L.; Alexander, N.B.; Bourque, R.F.; Dahms, C.F.; Lindgren, J.R.; Miller, W.J.; Bittner, D.N.; Hendricks, C.D.

    1993-05-01

    The upgrade of the Omega laser at the University of Rochester`s Laboratory for Laser Energetics (UR/LLE) will result in a need for large targets filled with D{sub 2} or Dt and maintained at cryogenic temperatures. This mandates a cryogenic target delivery system capable of filling, layering, characterizing and delivering cryogenic targets to the Omega Upgrade target chamber. The program goal is to design, construct, and test the entire target delivery system by June 1996. When completed (including an operational demonstration), the system will be shipped to Rochester for reassembly and commissioning in time for the Omega Upgrade cryogenic campaign, scheduled to start in 1998. General Atomics has been assigned the task of developing the conceptual design for the cryogenic target delivery system. Design and fabrication activities will be closely coordinated with the University of Rochester, Lawrence Livermore National laboratory (LLNL) and Los Alamos National Laboratory (LANL), drawing upon their knowledge base in fuel layering and cryogenic characterization. The development of a target delivery system for Omega could also benefit experiments at Lawrence Livermore National Laboratory and the other ICF Laboratories in that the same technologies could be applied to NOVA, the National Ignition Facility or the future Laboratory Microfusion Facility.

  16. ICS-283: a system for targeted intravenous delivery of siRNA.

    PubMed

    Schiffelers, Raymond M; Storm, Gert

    2006-05-01

    ICS-283 was developed within Intradigm Corporation as a system that is designed for the systemic delivery of therapeutic small interfering (siRNA) to sites of pathological angiogenesis. The non-viral siRNA delivery system is based on synthetic nanoparticles, known as Targe (Intradigm Corporation), which functions as a broad-platform technology to deliver siRNA to specific target cells in diseased tissues. The system is constructed to incorporate different functionalities that address critical needs for successful nucleic acid delivery. The TargeTran synthetic vector is a self-assembling, layered nanoparticle that protects and targets siRNA to specific cell types in pathological tissues. At present, ICS-283 is the only antiangiogenic siRNA delivery system that is designed for intravenous administration to treat angiogenesis-driven diseases.

  17. Mitochondrion: A Promising Target for Nanoparticle-Based Vaccine Delivery Systems

    PubMed Central

    Wen, Ru; Umeano, Afoma C.; Francis, Lily; Sharma, Nivita; Tundup, Smanla; Dhar, Shanta

    2016-01-01

    Vaccination is one of the most popular technologies in disease prevention and eradication. It is promising to improve immunization efficiency by using vectors and/or adjuvant delivery systems. Nanoparticle (NP)-based delivery systems have attracted increasing interest due to enhancement of antigen uptake via prevention of vaccine degradation in the biological environment and the intrinsic immune-stimulatory properties of the materials. Mitochondria play paramount roles in cell life and death and are promising targets for vaccine delivery systems to effectively induce immune responses. In this review, we focus on NPs-based delivery systems with surfaces that can be manipulated by using mitochondria targeting moieties for intervention in health and disease. PMID:27258316

  18. Self-assembled peptide-based nanostructures: Smart nanomaterials toward targeted drug delivery.

    PubMed

    Habibi, Neda; Kamaly, Nazila; Memic, Adnan; Shafiee, Hadi

    2016-02-01

    Self-assembly of peptides can yield an array of well-defined nanostructures that are highly attractive nanomaterials for many biomedical applications such as drug delivery. Some of the advantages of self-assembled peptide nanostructures over other delivery platforms include their chemical diversity, biocompatibility, high loading capacity for both hydrophobic and hydrophilic drugs, and their ability to target molecular recognition sites. Furthermore, these self-assembled nanostructures could be designed with novel peptide motifs, making them stimuli-responsive and achieving triggered drug delivery at disease sites. The goal of this work is to present a comprehensive review of the most recent studies on self-assembled peptides with a focus on their "smart" activity for formation of targeted and responsive drug-delivery carriers.

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

    PubMed Central

    Philip, Anil K.; Philip, Betty

    2010-01-01

    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

  20. Cell-Mediated Delivery of Nanoparticles: Taking Advantage of Circulatory Cells to Target Nanoparticles

    PubMed Central

    Anselmo, Aaron C.; Mitragotri, Samir

    2014-01-01

    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

  1. Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles.

    PubMed

    Zhen, Zipeng; Tang, Wei; Chuang, Yen-Jun; Todd, Trever; Zhang, Weizhong; Lin, Xin; Niu, Gang; Liu, Gang; Wang, Lianchun; Pan, Zhengwei; Chen, Xiaoyuan; Xie, Jin

    2014-06-24

    Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors' origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as "smart" carriers that site-specifically deliver (1)O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine.

  2. A Partnership Training Program: Studying Targeted Drug Delivery Using Nanoparticles in Breast Cancer Diagnosis and Therapy

    DTIC Science & Technology

    2012-10-01

    Yuan H, He R, Gao X, Jing L, Zhao F, et al. The strong MRI relaxivity of paramagnetic nanoparticles . J Phys Chem B 2008;112: 6288-91. 10. Shu CY...Delivery Using Nanoparticles In Breast Cancer Diagnosis and Therapy Paul C. Wang, Ph.D. Howard University Washington, DC 20059 15 September...undergraduate students from 6 departments at the Howard University have been trained in the use of nanoparticles as targeted drug delivery vehicles for

  3. A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery

    PubMed Central

    Leach, John C.; Wang, Andrew; Ye, Kaiming; Jin, Sha

    2016-01-01

    The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox) was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA+ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells. PMID:26985893

  4. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: A review.

    PubMed

    Kanamala, Manju; Wilson, William R; Yang, Mimi; Palmer, Brian D; Wu, Zimei

    2016-04-01

    As the mainstay in the treatment of various cancers, chemotherapy plays a vital role, but still faces many challenges, such as poor tumour selectivity and multidrug resistance (MDR). Targeted drug delivery using nanotechnology has provided a new strategy for addressing the limitations of the conventional chemotherapy. In the last decade, the volume of research published in this area has increased tremendously, especially with functional nano drug delivery systems (nanocarriers). Coupling a specific stimuli-triggered drug release mechanism with these delivery systems is one of the most prevalent approaches for improving therapeutic outcomes. Among the various stimuli, pH triggered delivery is regarded as the most general strategy, targeting the acidic extracellular microenvironment and intracellular organelles of solid tumours. In this review, we discuss recent advances in the development of pH-sensitive nanocarriers for tumour-targeted drug delivery. The review focuses on the chemical design of pH-sensitive biomaterials, which are used to fabricate nanocarriers for extracellular and/or intracellular tumour site-specific drug release. The pH-responsive biomaterials bring forth conformational changes in these nanocarriers through various mechanisms such as protonation, charge reversal or cleavage of a chemical bond, facilitating tumour specific cell uptake or drug release. A greater understanding of these mechanisms will help to design more efficient drug delivery systems to address the challenges encountered in conventional chemotherapy.

  5. Use of Single-Chain Antibody Derivatives for Targeted Drug Delivery

    PubMed Central

    Safdari, Yaghoub; Ahmadzadeh, Vahideh; Khalili, Masoumeh; Jaliani, Hossein Zarei; Zarei, Vahid; Erfani-Moghadam, Vahid

    2016-01-01

    Single-chain antibodies (scFvs), which contain only the variable domains of full-length antibodies, are relatively small molecules that can be used for selective drug delivery. In this review, we discuss how scFvs help improve the specificity and efficiency of drugs. Small interfering RNA (siRNA) delivery using scFv-drug fusion peptides, siRNA delivery using scFv-conjugated nanoparticles, targeted delivery using scFv-viral peptide-fusion proteins, use of scFv in fusion with cell-penetrating peptides for effective targeted drug delivery, scFv-mediated targeted delivery of inorganic nanoparticles, scFv-mediated increase of tumor killing activity of granulocytes, use of scFv for tumor imaging, site-directed conjugation of scFv molecules to drug carrier systems, use of scFv to relieve pain and use of scFv for increasing drug loading efficiency are among the topics that are discussed here. PMID:27249008

  6. Targeted Delivery System of Nanobiomaterials in Anticancer Therapy: From Cells to Clinics

    PubMed Central

    Jin, Su-Eon; Jin, Hyo-Eon; Hong, Soon-Sun

    2014-01-01

    Targeted delivery systems of nanobiomaterials are necessary to be developed for the diagnosis and treatment of cancer. Nanobiomaterials can be engineered to recognize cancer-specific receptors at the cellular levels and to deliver anticancer drugs into the diseased sites. In particular, nanobiomaterial-based nanocarriers, so-called nanoplatforms, are the design of the targeted delivery systems such as liposomes, polymeric nanoparticles/micelles, nanoconjugates, norganic materials, carbon-based nanobiomaterials, and bioinspired phage system, which are based on the nanosize of 1–100 nm in diameter. In this review, the design and the application of these nanoplatforms are discussed at the cellular levels as well as in the clinics. We believe that this review can offer recent advances in the targeted delivery systems of nanobiomaterials regarding in vitro and in vivo applications and the translation of nanobiomaterials to nanomedicine in anticancer therapy. PMID:24672796

  7. Targeted delivery of doxorubicin by nano-loaded mesenchymal stem cells for lung melanoma metastases therapy

    PubMed Central

    Zhao, Yuekui; Tang, Shanshan; Guo, Jiamin; Alahdal, Murad; Cao, Shunxiu; Yang, Zhaocong; Zhang, Fangfang; Shen, Yumeng; Sun, Minjie; Mo, Ran; Zong, Li; Jin, Liang

    2017-01-01

    Poor antigenic presentation of tumor tissues and a lack of specific targets currently limit the success of nanoparticle delivery system. Cellular carrier technique has been recently explored extensively as a substitutive or supplement for traditional targeting delivery system. Here, we demonstrate the usage of mesenchymal stem cells (MSCs) loaded with doxorubicin containing polymer nanoparticles in pulmonary melanoma metastases therapy, as a modified technique of targeted delivery system. The characterizations of prepared nanoparticles and MSCs sensitivity to DOX and PLGA-DOX were measured. In vitro tumor tropism, and in vivo distributions of nanoparticles loaded MSCs were also investigated. The findings have demonstrated that, the modified system not only integrates the controlled-release property of nanoparticles but also exhibits tumor tropism and penetrative characteristics of MSCs. Furthermore, the in vitro and in vivo anti-tumor study has demonstrated that drug loaded MSCs had potent efficacy in lung melanoma metastases treatment. PMID:28303966

  8. Targeted delivery of doxorubicin by nano-loaded mesenchymal stem cells for lung melanoma metastases therapy.

    PubMed

    Zhao, Yuekui; Tang, Shanshan; Guo, Jiamin; Alahdal, Murad; Cao, Shunxiu; Yang, Zhaocong; Zhang, Fangfang; Shen, Yumeng; Sun, Minjie; Mo, Ran; Zong, Li; Jin, Liang

    2017-03-17

    Poor antigenic presentation of tumor tissues and a lack of specific targets currently limit the success of nanoparticle delivery system. Cellular carrier technique has been recently explored extensively as a substitutive or supplement for traditional targeting delivery system. Here, we demonstrate the usage of mesenchymal stem cells (MSCs) loaded with doxorubicin containing polymer nanoparticles in pulmonary melanoma metastases therapy, as a modified technique of targeted delivery system. The characterizations of prepared nanoparticles and MSCs sensitivity to DOX and PLGA-DOX were measured. In vitro tumor tropism, and in vivo distributions of nanoparticles loaded MSCs were also investigated. The findings have demonstrated that, the modified system not only integrates the controlled-release property of nanoparticles but also exhibits tumor tropism and penetrative characteristics of MSCs. Furthermore, the in vitro and in vivo anti-tumor study has demonstrated that drug loaded MSCs had potent efficacy in lung melanoma metastases treatment.

  9. Targeted delivery of nano-PTX to the brain tumor-associated macrophages

    PubMed Central

    Zou, Lei; Tao, Youhua; Payne, Gregory; Do, Linh; Thomas, Tima; Rodriguez, Juan; Dou, Huanyu

    2017-01-01

    Nanoparticles containing mixed lipid monolayer shell, biodegradable polymer core and rabies virus glycoprotein (RVG) peptide as brain targeting ligand, were developed for brain targeted delivery of paclitaxel (PTX) to treat malignant glioma. RVG conjugated PTX loaded NPs (RVG-PTX-NPs) had the desirable size (~140 nm), narrow size distribution and spherical shape. RVG-PTX-NPs showed poor uptake by neurons and selective targeting to the brain tumor associated macrophages (TAMs) with controlled release and tumor specific toxicity. In vivo studies revealed that RVG-PTX-NPs were significant to cross the blood-brain barrier (BBB) and had specific targeting to the brain. Most importantly, RVG-PTX-NPs showed effectiveness for anti-glioma therapy on human glioma of mice model. We concluded that RVG-PTX-NPs provided an effective approach for brain-TAMs targeted delivery for the treatment of glioma. PMID:28036254

  10. Transferrin Decorated Thermoresponsive Nanogels as Magnetic Trap Devices for Circulating Tumor Cells.

    PubMed

    Asadian-Birjand, Mazdak; Biglione, Catalina; Bergueiro, Julian; Cappelletti, Ariel; Rahane, Chinmay; Chate, Govind; Khandare, Jayant; Klemke, Bastian; Strumia, Miriam C; Calderón, Marcelo

    2016-03-01

    A rational design of magnetic capturing nanodevices, based on a specific interaction with circulating tumor cells (CTCs), can advance the capturing efficiency and initiate the development of modern smart nanoformulations for rapid isolation and detection of these CTCs from the bloodstream. Therefore, the development and evaluation of magnetic nanogels (MNGs) based on magnetic nanoparticles and linear thermoresponsive polyglycerol for the capturing of CTCs with overexpressed transferrin (Tf(+) ) receptors has been presented in this study. The MNGs are synthesized using a strain-promoted "click" approach which has allowed the in situ surface decoration with Tf-polyethylene glycol (PEG) ligands of three different PEG chain lengths as targeting ligands. An optimal value of around 30% of cells captures is achieved with a linker of eight ethylene glycol units. This study shows the potential of MNGs for the capture of CTCs and the necessity of precise control over the linkage of the targeting moiety to the capturing device.

  11. Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery.

    PubMed

    Xu, Minghui; Qian, Junmin; Liu, Xuefeng; Liu, Ting; Wang, Hongjie

    2015-05-01

    In recent years, stimuli-sensitive prodrugs have been extensively studied for the rapid "burst" release of antitumor drugs to enhance chemotherapeutic efficiency. In this study, a novel stimuli-sensitive prodrug containing galactosamine as a targeting moiety, poly(ethylene glycol)-doxorubicin (PEG-DOX) conjugate, was developed for targeting HepG2 human liver cancer cells. To obtain the PEG-DOX conjugate, both galactosamine-decorated poly(ethylene glycol) aldehyde (Gal-PEG-CHO) and methoxy poly(ethylene glycol) aldehyde (mPEG-CHO) were firstly synthesized and functionalized with dithiodipropionate dihydrazide (TPH) through direct reductive amination via Schiff's base formation, and then DOX molecules were chemically conjugated to the hydrazide end groups of TPH-functionalized Gal-/m-PEG chains via pH-sensitive hydrazone linkages. The chemical structures of TPH-functionalized PEG and PEG-DOX prodrug were confirmed by (1)H NMR analysis. The PEG-DOX conjugate could self-assemble into spherical nanomicelles with a mean diameter of 140 nm, as indicated by transmission electron microscopy and dynamic light scattering. The drug loading content and loading efficiency in the prodrug nanomicelles were as high as 20 wt.% and 75 wt.%, respectively. In vitro drug release studies showed that DOX was released rapidly from the prodrug nanomicelles at the intracellular levels of pH and reducing agent. Cellular uptake and MTT experiments demonstrated that the galactosamine-decorated prodrug nanomicelles were more efficiently internalized into HepG2 cells via a receptor-mediated endocytosis process and exhibited a higher toxicity, compared with pristine prodrug nanomicelles. These results suggest that the novel Gal-PEG-DOX prodrug nanomicelles have tremendous potential for targeted liver cancer therapy.

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

    PubMed Central

    2011-01-01

    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

  13. Delivery of Small Interfering RNA by Peptide-Targeted Mesoporous Silica Nanoparticle-Supported Lipid Bilayers

    PubMed Central

    Ashley, Carlee E.; Carnes, Eric C.; Epler, Katharine E.; Padilla, David P.; Phillips, Genevieve K.; Castillo, Robert E.; Wilkinson, Dan C.; Wilkinson, Brian S.; Burgard, Cameron A.; Sewell, Robin M.; Townson, Jason L.; Chackerian, Bryce; Willman, Cheryl L.; Peabody, David S.; Wharton, Walker; Brinker, C. Jeffrey

    2012-01-01

    The therapeutic potential of small interfering RNAs (siRNAs) is severely limited by the availability of delivery platforms that protect siRNA from degradation, deliver it to the target cell with high specificity and efficiency, and promote its endosomal escape and cytosolic dispersion. Here we report that mesoporous silica nanoparticle-supported lipid bilayers (or ‘protocells’), exhibit multiple properties that overcome many of the limitations of existing delivery platforms. Protocells have a 10- to 100-fold greater capacity for siRNA than corresponding lipid nanoparticles and are markedly more stable when incubated under physiological conditions. Protocells loaded with a cocktail of siRNAs bind to cells in a manner dependent on the presence of an appropriate targeting peptide and, through an endocytic pathway followed by endosomal disruption, promote delivery of the silencing nucleotides to the cytoplasm. The expression of each of the genes targeted by the siRNAs was shown to be repressed at the protein level, resulting in a potent induction of growth arrest and apoptosis. Incubation of control cells that lack expression of the antigen recognized by the targeting peptide with siRNA-loaded protocells induced neither repression of protein expression nor apoptosis, indicating the precise specificity of cytotoxic activity. In terms of loading capacity, targeting capabilities, and potency of action, protocells provide unique attributes as a delivery platform for therapeutic oligonucleotides. PMID:22309035

  14. Delivery of small interfering RNA by peptide-targeted mesoporous silica nanoparticle-supported lipid bilayers.

    PubMed

    Ashley, Carlee E; Carnes, Eric C; Epler, Katharine E; Padilla, David P; Phillips, Genevieve K; Castillo, Robert E; Wilkinson, Dan C; Wilkinson, Brian S; Burgard, Cameron A; Kalinich, Robin M; Townson, Jason L; Chackerian, Bryce; Willman, Cheryl L; Peabody, David S; Wharton, Walker; Brinker, C Jeffrey

    2012-03-27

    The therapeutic potential of small interfering RNAs (siRNAs) is severely limited by the availability of delivery platforms that protect siRNA from degradation, deliver it to the target cell with high specificity and efficiency, and promote its endosomal escape and cytosolic dispersion. Here we report that mesoporous silica nanoparticle-supported lipid bilayers (or "protocells") exhibit multiple properties that overcome many of the limitations of existing delivery platforms. Protocells have a 10- to 100-fold greater capacity for siRNA than corresponding lipid nanoparticles and are markedly more stable when incubated under physiological conditions. Protocells loaded with a cocktail of siRNAs bind to cells in a manner dependent on the presence of an appropriate targeting peptide and, through an endocytic pathway followed by endosomal disruption, promote delivery of the silencing nucleotides to the cytoplasm. The expression of each of the genes targeted by the siRNAs was shown to be repressed at the protein level, resulting in a potent induction of growth arrest and apoptosis. Incubation of control cells that lack expression of the antigen recognized by the targeting peptide with siRNA-loaded protocells induced neither repression of protein expression nor apoptosis, indicating the precise specificity of cytotoxic activity. In terms of loading capacity, targeting capabilities, and potency of action, protocells provide unique attributes as a delivery platform for therapeutic oligonucleotides.

  15. Characterization of Magnetic Viral Complexes for Targeted Delivery in Oncology

    PubMed Central

    Almstätter, Isabella; Mykhaylyk, Olga; Settles, Marcus; Altomonte, Jennifer; Aichler, Michaela; Walch, Axel; Rummeny, Ernst J.; Ebert, Oliver; Plank, Christian; Braren, Rickmer

    2015-01-01

    Oncolytic viruses are promising new agents in cancer therapy. Success of tumor lysis is often hampered by low intra-tumoral titers due to a strong anti-viral host immune response and insufficient tumor targeting. Previous work on the co-assembly of oncolytic virus particles (VPs) with magnetic nanoparticles (MNPs) was shown to provide shielding from inactivating immune response and improve targeting by external field gradients. In addition, MNPs are detected by magnet resonance imaging (MRI) enabling non-invasive therapy monitoring. In this study two selected core-shell type iron oxide MNPs were assembled with adenovirus (Ad) or vesicular stomatitis virus (VSV). The selected MNPs were characterized by high r2 and r2* relaxivities and thus could be quantified non-invasively by 1.5 and 3.0 tesla MRI with a detection limit below 0.001 mM iron in tissue-mimicking phantoms. Assembly and cell internalization of MNP-VP complexes resulted in 81 - 97 % reduction of r2 and 35 - 82 % increase of r2* compared to free MNPs. The relaxivity changes could be attributed to the clusterization of particles and complexes shown by transmission electron microscopy (TEM). In a proof-of-principle study the non-invasive detection of MNP-VPs by MRI was shown in vivo in an orthotopic rat hepatocellular carcinoma model. In conclusion, MNP assembly and compartmentalization have a major impact on relaxivities, therefore calibration measurements are required for the correct quantification in biodistribution studies. Furthermore, our study provides first evidence of the in vivo applicability of selected MNP-VPs in cancer therapy. PMID:25897333

  16. Laser-induced disruption of systemically administered liposomes for targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Mackanos, Mark A.; Larabi, Malika; Shinde, Rajesh; Simanovskii, Dmitrii M.; Guccione, Samira; Contag, Christopher H.

    2009-07-01

    Liposomal formulations of drugs have been shown to enhance drug efficacy by prolonging circulation time, increasing local concentration and reducing off-target effects. Controlled release from these formulations would increase their utility, and hyperthermia has been explored as a stimulus for targeted delivery of encapsulated drugs. Use of lasers as a thermal source could provide improved control over the release of the drug from the liposomes with minimal collateral tissue damage. Appropriate methods for assessing local release after systemic delivery would aid in testing and development of better formulations. We use in vivo bioluminescence imaging to investigate the spatiotemporal distribution of luciferin, used as a model small molecule, and demonstrate laser-induced release from liposomes in animal models after systemic delivery. These liposomes were tested for luciferin release between 37 and 45 °C in PBS and serum using bioluminescence measurements. In vivo studies were performed on transgenic reporter mice that express luciferase constitutively throughout the body, thus providing a noninvasive readout for controlled release following systemic delivery. An Nd:YLF laser was used (527 nm) to heat tissues and induce rupture of the intravenously delivered liposomes in target tissues. These data demonstrate laser-mediated control of small molecule delivery using thermally sensitive liposomal formulations.

  17. Barriers to Liposomal Gene Delivery: from Application Site to the Target

    PubMed Central

    Saffari, Mostafa; Moghimi, Hamid Reza; Dass, Crispin R

    2016-01-01

    Gene therapy is a therapeutic approach to deliver genetic material into cells to alter their function in entire organism. One promising form of gene delivery system (DDS) is liposomes. The success of liposome-mediated gene delivery is a multifactorial issue and well-designed liposomal systems might lead to optimized gene transfection particularly in vivo. Liposomal gene delivery systems face different barriers from their site of application to their target, which is inside the cells. These barriers include presystemic obstacles (epithelial barriers), systemic barriers in blood circulation and cellular barriers. Epithelial barriers differ depending on the route of administration. Systemic barriers include enzymatic degradation, binding and opsonisation. Both of these barriers can act as limiting hurdles that genetic material and their vector should overcome before reaching the cells. Finally liposomes should overcome cellular barriers that include cell entrance, endosomal escape and nuclear uptake. These barriers and their impact on liposomal gene delivery will be discussed in this review. PMID:28228799

  18. Multifunctional hybrid-carbon nanotubes: new horizon in drug delivery and targeting.

    PubMed

    Mehra, Neelesh Kumar; Jain, Narendra Kumar

    2016-01-01

    Carbon nanotubes (CNTs) have emerged as an intriguing nanotechnological tool for numerous biomedical applications including biocompatible modules for the bioactives delivery ascribed to their unique properties, such as greater loading efficiency, biocompatibility, non-immunogenicity, high surface area and photoluminescence, that make them ideal candidate in pharmaceutical and biomedical science. The design of multifunctional hybrid-CNTs for drug delivery and targeting may differ from the conventional drug delivery system. The conventional nanocarriers have few limitations, such as inappropriate availability of surface-chemical functional groups for conjugation, low entrapment/loading efficiency as well as stability as per ICH guidelines with generally regarded as safe (GRAS) prominences. The multifunctional hybrid-CNTs will sparked and open a new door for researchers, scientist of the pharmaceutical and biomedical arena. This review summarizes the vivid aspects of CNTs like characterization, supramolecular chemistry of CNTs-dendrimer, CNTs-nanoparticles, CNTs-quantum dots conjugate for delivery of bioactives, not discussed so far.

  19. Targeted delivery of doxorubicin to mitochondria using mesoporous silica nanoparticle nanocarriers

    NASA Astrophysics Data System (ADS)

    Qu, Qiuyu; Ma, Xing; Zhao, Yanli

    2015-10-01

    A lot of investigations have been conducted using mesoporous silica nanoparticles (MSNPs) functionalized with different targeting ligands in order to deliver various hydrophobic and hydrophilic drugs to targeted cancer cells. However, the utilization of MSNPs to deliver drug molecules to targeted subcellular organelles has been rarely reported. In this work, we applied targeting ligand-conjugated MSNPs with an average diameter of 80 nm to deliver the anticancer drug doxorubicin (DOX) to mitochondria. Triphenoylphosphonium (TPP) was functionalized on MSNPs as a mitochondria targeting ligand. Mitochondria targeting efficiency was demonstrated in HeLa cells by a co-localization study of mitochondria and functionalized MSNPs as well as by fluorescence analysis in isolated mitochondria. In addition, enhanced cancer cell killing efficacy was achieved when using DOX-loaded and TPP-functionalized MSNPs for mitochondria-targeted delivery. Lowered adenosine triphosphate (ATP) production and decreased mitochondrial membrane potential were observed, demonstrating the mitochondria dysfunction caused by delivered DOX. The positive results indicate promising application potential of MSNPs in targeted subcellular drug delivery.A lot of investigations have been conducted using mesoporous silica nanoparticles (MSNPs) functionalized with different targeting ligands in order to deliver various hydrophobic and hydrophilic drugs to targeted cancer cells. However, the utilization of MSNPs to deliver drug molecules to targeted subcellular organelles has been rarely reported. In this work, we applied targeting ligand-conjugated MSNPs with an average diameter of 80 nm to deliver the anticancer drug doxorubicin (DOX) to mitochondria. Triphenoylphosphonium (TPP) was functionalized on MSNPs as a mitochondria targeting ligand. Mitochondria targeting efficiency was demonstrated in HeLa cells by a co-localization study of mitochondria and functionalized MSNPs as well as by fluorescence analysis

  20. Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors.

    PubMed

    Buckway, Brandon; Wang, Yongjian; Ray, Abhijit; Ghandehari, Hamidreza

    2013-11-01

    Delivery of macromolecules to pancreatic cancer is inhibited by a dense extracellular matrix composed of hyaluronic acid, smooth muscle actin and collagen fibers. Hyaluronic acid causes a high intratumoral fluidic pressure which prevents diffusion and penetration into the pancreatic tumor. This study involves the breaking down of hyaluronic acid by treating CAPAN-1 xenograft tumors in athymic nu/nu mice with targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers radiolabeled with (111)In for single photon emission computerized tomography (SPECT) imaging. Two targeting strategies were investigated including αvβ3 integrin and HER2 receptors. HPMA copolymers were targeted to these receptors by conjugating short peptide ligands cRGDfK and KCCYSL to the side chains of the copolymer. Results demonstrate that tumor targeting can be achieved in vivo after treatment with hyaluronidase. This approach shows promise for enhanced delivery of polymer-peptide conjugates to solid tumors.

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

    NASA Astrophysics Data System (ADS)

    Wan, Long; Jiao, Jian; Cui, Yu; Guo, Jingwen; Han, Ning; Di, Donghua; Chang, Di; Wang, Pu; Jiang, Tongying; Wang, Siling

    2016-04-01

    In this paper, hyaluronic acid (HA) functionalized uniform mesoporous carbon spheres (UMCS) were synthesized for targeted enzyme responsive drug delivery using a facile electrostatic attraction strategy. This HA modification ensured stable drug encapsulation in mesoporous carbon nanoparticles in an extracellular environment while increasing colloidal stability, biocompatibility, cell-targeting ability, and controlled cargo release. The cellular uptake experiments of fluorescently labeled mesoporous carbon nanoparticles, with or without HA functionalization, demonstrated that HA-UMCS are able to specifically target cancer cells overexpressing CD44 receptors. Moreover, the cargo loaded doxorubicin (DOX) and verapamil (VER) exhibited a dual pH and hyaluronidase-1 responsive release in the tumor microenvironment. In addition, VER/DOX/HA-UMCS exhibited a superior therapeutic effect on an in vivo HCT-116 tumor in BALB/c nude mice. In summary, it is expected that HA-UMCS will offer a new method for targeted co-delivery of drugs to tumors overexpressing CD44 receptors.

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

    PubMed Central

    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

    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

  3. Transferrin receptor-targeted theranostic gold nanoparticles for photosensitizer delivery in brain tumors

    NASA Astrophysics Data System (ADS)

    Dixit, Suraj; Novak, Thomas; Miller, Kayla; Zhu, Yun; Kenney, Malcolm E.; Broome, Ann-Marie

    2015-01-01

    Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to untargeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging.

  4. Magnetic nanoparticles for targeted therapeutic gene delivery and magnetic-inducing heating on hepatoma

    NASA Astrophysics Data System (ADS)

    Yuan, Chenyan; An, Yanli; Zhang, Jia; Li, Hongbo; Zhang, Hao; Wang, Ling; Zhang, Dongsheng

    2014-08-01

    Gene therapy holds great promise for treating cancers, but their clinical applications are being hampered due to uncontrolled gene delivery and expression. To develop a targeted, safe and efficient tumor therapy system, we constructed a tissue-specific suicide gene delivery system by using magnetic nanoparticles (MNPs) as carriers for the combination of gene therapy and hyperthermia on hepatoma. The suicide gene was hepatoma-targeted and hypoxia-enhanced, and the MNPs possessed the ability to elevate temperature to the effective range for tumor hyperthermia as imposed on an alternating magnetic field (AMF). The tumoricidal effects of targeted gene therapy associated with hyperthermia were evaluated in vitro and in vivo. The experiment demonstrated that hyperthermia combined with a targeted gene therapy system proffer an effective tool for tumor therapy with high selectivity and the synergistic effect of hepatoma suppression.

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

    PubMed Central

    Ronaldson, Patrick T; Davis, Thomas P

    2012-01-01

    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

  6. A targeted drug delivery system based on dopamine functionalized nano graphene oxide

    NASA Astrophysics Data System (ADS)

    Masoudipour, Elham; Kashanian, Soheila; Maleki, Nasim

    2017-01-01

    The cellular targeting property of a biocompatible drug delivery system can widely increase the therapeutic effect against various diseases. Here, we report a dopamine conjugated nano graphene oxide (DA-nGO) carrier for cellular delivery of the anticancer drug, Methotrexate (MTX) into DA receptor positive human breast adenocarcinoma cell line. The material was characterized using scanning electron microscopy, atomic force microscopy, Fourier transform infrared spectroscopy and UV-vis spectroscopy. Furthermore, the antineoplastic action of MTX loaded DA-nGO against DA receptor positive and negative cell lines were explored. The results presented in this article demonstrated that the application of DA functionalized GO as a targeting drug carrier can improve the drug delivery efficacy for DA receptor positive cancer cell lines and promise future designing of carrier conjugates based on it.

  7. Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery.

    PubMed

    Islam, Md Mirazul; Mohamed, Zahurin

    2015-01-01

    The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery.

  8. Colon-targeted delivery of live bacterial cell biotherapeutics including microencapsulated live bacterial cells

    PubMed Central

    Prakash, Satya; Malgorzata Urbanska, Aleksandra

    2008-01-01

    There has been an ample interest in delivery of therapeutic molecules using live cells. Oral delivery has been stipulated as best way to deliver live cells to humans for therapy. Colon, in particular, is a part of gastrointestinal (GI) tract that has been proposed to be an oral targeted site. The main objective of these oral therapy procedures is to deliver live cells not only to treat diseases like colorectal cancer, inflammatory bowel disease, and other GI tract diseases like intestinal obstruction and gastritis, but also to deliver therapeutic molecules for overall therapy in various diseases such as renal failure, coronary heart disease, hypertension, and others. This review provides a comprehensive summary of recent advancement in colon targeted live bacterial cell biotherapeutics. Current status of bacterial cell therapy, principles of artificial cells and its potentials in oral delivery of live bacterial cell biotherapeutics for clinical applications as well as biotherapeutic future perspectives are also discussed in our review. PMID:19707368

  9. Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

    PubMed Central

    Islam, Md. Mirazul; Mohamed, Zahurin

    2015-01-01

    The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery. PMID:26579539

  10. Targeted chimera delivery to ovarian cancer cells by heterogeneous gold magnetic nanoparticle

    NASA Astrophysics Data System (ADS)

    Chen, Yao; Xu, Mengjiao; Guo, Yi; Tu, Keyao; Wu, Weimin; Wang, Jianjun; Tong, Xiaowen; Wu, Wenjuan; Qi, Lifeng; Shi, Donglu

    2017-01-01

    Efficient delivery of small interfering RNAs (siRNAs) to the targeted cells has remained a significant challenge in clinical applications. In the present study, we developed a novel aptamer-siRNA chimera delivery system mediated by cationic Au-Fe3O4 nanoparticles (NPs). The chimera constructed by VEGF RNA aptamer and Notch3 siRNA was bonded with heterogeneous Au-Fe3O4 nanoparticles by electrostatic interaction. The obtained complex exhibited much higher silencing efficiency against Notch3 gene compared with chimera alone and lipofectamine-siRNA complex, and improved the antitumor effects of the loaded chimera. Moreover, the efficient delivery of the chimera by Au-Fe3O4 NPs could reverse multi-drug resistance (MDR) of ovarian cancer cells against the chemotherapeutic drug cisplatin, indicating its potential capability for future targeted cancer therapy while overcoming MDR.

  11. Hydrodynamic modeling of targeted magnetic-particle delivery in a blood vessel.

    PubMed

    Weng, Huei Chu

    2013-03-01

    Since the flow of a magnetic fluid could easily be influenced by an external magnetic field, its hydrodynamic modeling promises to be useful for magnetically controllable delivery systems. It is desirable to understand the flow fields and characteristics before targeted magnetic particles arrive at their destination. In this study, we perform an analysis for the effects of particles and a magnetic field on biomedical magnetic fluid flow to study the targeted magnetic-particle delivery in a blood vessel. The fully developed solutions of velocity, flow rate, and flow drag are derived analytically and presented for blood with magnetite nanoparticles at body temperature. Results reveal that in the presence of magnetic nanoparticles, a minimum magnetic field gradient (yield gradient) is required to initiate the delivery. A magnetic driving force leads to the increase in velocity and has enhancing effects on flow rate and flow drag. Such a magnetic driving effect can be magnified by increasing the particle volume fraction.

  12. Target-tracking deliveries on an Elekta linac: a feasibility study

    NASA Astrophysics Data System (ADS)

    McQuaid, D.; Partridge, M.; Symonds-Tayler, J. R.; Evans, P. M.; Webb, S.

    2009-06-01

    A target-tracking, intensity-modulated delivery on an Elekta MLCi system was assessed by film measurement with a simulated target-motion trajectory. A toroidally shaped idealized target surrounding an organ at risk necessitating multiple field segments to irradiate the target and spare the organ at risk was defined in a solid-water phantom. The phantom was programmed to move following a reproducible 2D elliptical trajectory in the beam's-eye view with a period of 10 s. Static and target-tracking treatments were planned for delivery on a standard Elekta Precise series linac with integrated MLCi system. Dose was delivered in three ways: (i) a static treatment to a static phantom, (ii) a static treatment to a moving phantom and (iii) a target-tracking treatment to a moving phantom. The dose delivered was assessed by film measurement on the central plane through the target and organ at risk. The target dose blurring was quantified by the standard deviation of the dose to the target which was evaluated as 2.8% for the static treatment to the static phantom, 7.2% for the static treatment to the moving phantom and 2.6% for the tracking treatment to the moving phantom. The mean organ-at-risk dose was 38.2%, 54.0% and 38.2% of the prescription dose for each delivery case. We have therefore shown that the linac is capable of delivering target-tracking fields with MLCs for the target trajectories tested.

  13. Target-tracking deliveries on an Elekta linac: a feasibility study.

    PubMed

    McQuaid, D; Partridge, M; Symonds-Tayler, J R; Evans, P M; Webb, S

    2009-06-07

    A target-tracking, intensity-modulated delivery on an Elekta MLCi system was assessed by film measurement with a simulated target-motion trajectory. A toroidally shaped idealized target surrounding an organ at risk necessitating multiple field segments to irradiate the target and spare the organ at risk was defined in a solid-water phantom. The phantom was programmed to move following a reproducible 2D elliptical trajectory in the beam's-eye view with a period of 10 s. Static and target-tracking treatments were planned for delivery on a standard Elekta Precise series linac with integrated MLCi system. Dose was delivered in three ways: (i) a static treatment to a static phantom, (ii) a static treatment to a moving phantom and (iii) a target-tracking treatment to a moving phantom. The dose delivered was assessed by film measurement on the central plane through the target and organ at risk. The target dose blurring was quantified by the standard deviation of the dose to the target which was evaluated as 2.8% for the static treatment to the static phantom, 7.2% for the static treatment to the moving phantom and 2.6% for the tracking treatment to the moving phantom. The mean organ-at-risk dose was 38.2%, 54.0% and 38.2% of the prescription dose for each delivery case. We have therefore shown that the linac is capable of delivering target-tracking fields with MLCs for the target trajectories tested.

  14. Systemic Delivery of Blood-Brain Barrier Targeted Polymeric Nanoparticles Enhances Delivery to Brain Tissue

    PubMed Central

    Saucier-Sawyer, Jennifer K.; Deng, Yang; Seo, Young-Eun; Cheng, Christopher J.; Zhang, Junwei; Quijano, Elias; Saltzman, W. Mark

    2016-01-01

    Delivery of therapeutic agents to the central nervous system is a significant challenge, hindering progress in the treatment of diseases such as glioblastoma. Due to the presence of the blood-brain barrier (BBB), therapeutic agents do not readily transverse the brain endothelium to enter the parenchyma. Previous reports suggest that surface modification of polymer nanoparticles can improve their ability to cross the BBB, but it is unclear whether the observed enhancements in transport are large enough to enhance therapy. In this study, we synthesized two degradable polymer nanoparticle systems surface-modified with ligands previously suggested to improve BBB transport, and tested their ability to cross the BBB after intravenous injection in mice. All nanoparticle preparations were able to cross the BBB, although generally in low amounts (<0.5% of the injected dose), which was consistent with prior reports. One nanoparticle produced significantly higher brain uptake (~0.8% of the injected dose): a block copolymer of polylactic acid and hyperbranched polyglycerol, surface modified with adenosine (PLA-HPG-Ad). PLA-HPG-Ad nanoparticles provided controlled release of camptothecin, killing U87 glioma cells in culture. When administered intravenously in mice with intracranial U87 tumors, they failed to increase survival. These results suggest that enhancing nanoparticle transport across the BBB does not necessarily yield proportional pharmacological effects. PMID:26453169

  15. Alveolar targeting of aerosol pentamidine. Toward a rational delivery system

    SciTech Connect

    Simonds, A.K.; Newman, S.P.; Johnson, M.A.; Talaee, N.; Lee, C.A.; Clarke, S.W. )

    1990-04-01

    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.

  16. Novel Bone-Targeting Agent for Enhanced Delivery of Vancomycin to Bone

    PubMed Central

    Albayati, Zaineb A. F.; Sunkara, Manjula; Schmidt-Malan, Suzannah M.; Karau, Melissa J.; Morris, Andrew J.; Steckelberg, James M.; Patel, Robin; Breen, Philip J.; Smeltzer, Mark S.; Taylor, K. Grant; Merten, Kevyn E.

    2015-01-01

    We examined the pharmacokinetic properties of vancomycin conjugated to a bone-targeting agent (BT) with high affinity for hydroxyapatite after systemic intravenous administration. The results confirm enhanced persistence of BT-vancomycin in plasma and enhanced accumulation in bone relative to vancomycin. This suggests that BT-vancomycin may be a potential carrier for the systemic targeted delivery of vancomycin in the treatment of bone infections, potentially reducing the reliance on surgical debridement to achieve the desired therapeutic outcome. PMID:26666918

  17. Sodium dependent multivitamin transporter (SMVT): a potential target for drug delivery.

    PubMed

    Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Mitra, Ashim K

    2012-06-01

    Sodium dependent multivitamin transporter (SMVT; product of the SLC5A6 gene) is an important transmembrane protein responsible for translocation of vitamins and other essential cofactors such as biotin, pantothenic acid and lipoic acid. Hydropathy plot (Kyte-Dolittle algorithm) revealed that human SMVT protein consists of 635 amino acids and 12 transmembrane domains with both amino and carboxyl termini oriented towards the cytoplasm. SMVT is expressed in various tissues such as placenta, intestine, brain, liver, lung, kidney, cornea, retina and heart. This transporter displays broad substrate specificity and excellent capacity for utilization in drug delivery. Drug absorption is often limited by the presence of physiological (epithelial tight junctions), biochemical (efflux transporters and enzymatic degradation) and chemical (size, lipophilicity, molecular weight, charge etc.) barriers. These barriers may cause many potential therapeutics to be dropped from the preliminary screening portfolio and subsequent entry into the market. Transporter targeted delivery has become a powerful approach to deliver drugs to target tissues because of the ability of the transporter to translocate the drug to intracellular organelles at a higher rate. This review highlights studies employing SMVT transporter as a target for drug delivery to improve bioavailability and investigate the feasibility of developing SMVT targeted drug delivery systems.

  18. Ligands located within a cholesterol domain enhance gene delivery to the target tissue

    PubMed Central

    Xu, Long; Betker, Jamie; Yin, Hao; Anchordoquy, Thomas J.

    2012-01-01

    Targeted gene delivery provides enormous potential for clinical treatment of many incurable diseases. Liposomes formulated with targeting ligands have been tested extensively both in vitro and in vivo, and many studies have strived to identify more efficacious ligands. However, the environment of the ligand within the delivery vehicle is generally not considered, and this study assesses the effect of ligand micoenvironment by utilizing a lipoplex possessing a cholesterol domain. Our recent work has shown that the presence of the targeting ligand within the cholesterol domain promotes more productive transfection in cultured cells. In the present study, lipoplexes having the identical lipid composition were formulated with different conjugates of the folate ligand such that the ligand was included in, or excluded from, the cholesterol domain. The effect of locating the ligand within the cholesterol domain was then tested in a xenograft tumor model in mice. Lipoplexes that included the ligand within the cholesterol domain showed significantly higher luciferase expression and plasmid accumulation in tumors as compared to lipoplexes in which the ligand was excluded from the domain. These results demonstrate that the microenvironment of the ligand can affect gene delivery to tumors, and show that ligand-mediated delivery can be enhanced by locating targeting ligands within a cholesterol domain. PMID:22440429

  19. Method for Targeted Therapeutic Delivery of Proteins into Cells | NCI Technology Transfer Center | TTC

    Cancer.gov

    The Protein Expression Laboratory at the National Cancer Institute in Frederick, MD is seeking statements of capability or interest from parties interested in collaborative research to further develop a platform technology for the targeted intra-cellular delivery of proteins using virus-like particles (VLPs).

  20. A lupus anti-DNA autoantibody mediates autocatalytic, targeted delivery of nanoparticles to tumors.

    PubMed

    Chen, Zeming; Patel, Jaymin M; Noble, Philip W; Garcia, Cesar; Hong, Zhangyong; Hansen, James E; Zhou, Jiangbing

    2016-09-13

    Strategies to target nanoparticles to tumors that rely on surface modification with ligands that bind molecules overexpressed on cancer cells or the tumor neovasculature suffer from a major limitation: with delivery of toxic agents the amount of molecules available for targeting decreases with time; consequently, the efficiency of nanoparticle delivery is reduced. To overcome this limitation, here we propose an autocatalytic tumor-targeting mechanism based on targeting extracellular DNA (exDNA). exDNA is enriched in the tumor microenviroment and increases with treatment with cytotoxic agents, such as doxorubicin (DOX), due to release of DNA by dying tumor cells. We tested this approach using poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface-conjugated with fragments of 3E10 (3E10EN), a lupus anti-DNA autoantibody. We demonstrated that 3E10EN-conjugated nanoparticles bound to DNA and preferentially localized to tumors in vivo. The efficiency of tumor localization of 3E10EN-conjugated, DOX-loaded nanoparticles increased with time and subsequent treatments, demonstrating an autocatalytic effect. 3E10EN-conjugated DOX-loaded nanoparticles exhibited a significant anti-tumor effect that was superior to all controls. This work demonstrates the promise of autocatalytic drug delivery mechanisms and establishes proof of concept for a new anti-DNA autoantibody-based approach for enhancing delivery of nanoparticles to tumors.

  1. A lupus anti-DNA autoantibody mediates autocatalytic, targeted delivery of nanoparticles to tumors

    PubMed Central

    Chen, Zeming; Patel, Jaymin M.; Noble, Philip W.; Garcia, Cesar; Hong, Zhangyong; Hansen, James E.; Zhou, Jiangbing

    2016-01-01

    Strategies to target nanoparticles to tumors that rely on surface modification with ligands that bind molecules overexpressed on cancer cells or the tumor neovasculature suffer from a major limitation: with delivery of toxic agents the amount of molecules available for targeting decreases with time; consequently, the efficiency of nanoparticle delivery is reduced. To overcome this limitation, here we propose an autocatalytic tumor-targeting mechanism based on targeting extracellular DNA (exDNA). exDNA is enriched in the tumor microenviroment and increases with treatment with cytotoxic agents, such as doxorubicin (DOX), due to release of DNA by dying tumor cells. We tested this approach using poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface-conjugated with fragments of 3E10 (3E10EN), a lupus anti-DNA autoantibody. We demonstrated that 3E10EN-conjugated nanoparticles bound to DNA and preferentially localized to tumors in vivo. The efficiency of tumor localization of 3E10EN-conjugated, DOX-loaded nanoparticles increased with time and subsequent treatments, demonstrating an autocatalytic effect. 3E10EN-conjugated DOX-loaded nanoparticles exhibited a significant anti-tumor effect that was superior to all controls. This work demonstrates the promise of autocatalytic drug delivery mechanisms and establishes proof of concept for a new anti-DNA autoantibody-based approach for enhancing delivery of nanoparticles to tumors. PMID:27494868

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

    NASA Astrophysics Data System (ADS)

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

    2010-10-01

    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.

  3. TARGETED DELIVERY OF INHALED PHARMACEUTICALS USING AN IN SILICO DOSIMETRY MODEL

    EPA Science Inventory

    We present an in silico dosimetry model which can be used for inhalation toxicology (risk assessment of inhaled air pollutants) and aerosol therapy ( targeted delivery of inhaled drugs). This work presents scientific and clinical advances beyond the development of the original in...

  4. Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery.

    PubMed

    Yang, Emmy; Qian, Weiping; Cao, Zehong; Wang, Liya; Bozeman, Erica N; Ward, Christina; Yang, Bin; Selvaraj, Periasamy; Lipowska, Malgorzata; Wang, Y Andrew; Mao, Hui; Yang, Lily

    2015-01-01

    Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.

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

    NASA Astrophysics Data System (ADS)

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

    2011-02-01

    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.

  6. 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

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

    2013-01-01

    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

  7. 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

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

    2013-03-26

    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 cross-linking 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.

  8. Mechanism-Based Enhanced Delivery of Drug-Loaded Targeted Nanoparticles for Breast Cancer Therapy

    DTIC Science & Technology

    2012-02-01

    of the reaction mixtures, against (1) 0.5% aqueous ammonia in the presence of ethylenediaminetetraacetic acid (EDTA), and (2) distilled water. The...organs of the reticuloendothelial system such as the liver and spleen . Such high uptake of nanoparticles in liver and spleen has been reported for...0.4 Liver 147 425 2.9 Spleen 218 1601 7.3 Kidney 75 69 0.9 Lung 222 90 0.4 aAUC ratio = AUC of DOX-loaded nanogels/AUC of free DOX Fig. 4

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

    PubMed

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

    2014-12-01

    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.

  10. Targeted delivery of doxorubicin to mitochondria using mesoporous silica nanoparticle nanocarriers.

    PubMed

    Qu, Qiuyu; Ma, Xing; Zhao, Yanli

    2015-10-28

    A lot of investigations have been conducted using mesoporous silica nanoparticles (MSNPs) functionalized with different targeting ligands in order to deliver various hydrophobic and hydrophilic drugs to targeted cancer cells. However, the utilization of MSNPs to deliver drug molecules to targeted subcellular organelles has been rarely reported. In this work, we applied targeting ligand-conjugated MSNPs with an average diameter of 80 nm to deliver the anticancer drug doxorubicin (DOX) to mitochondria. Triphenoylphosphonium (TPP) was functionalized on MSNPs as a mitochondria targeting ligand. Mitochondria targeting efficiency was demonstrated in HeLa cells by a co-localization study of mitochondria and functionalized MSNPs as well as by fluorescence analysis in isolated mitochondria. In addition, enhanced cancer cell killing efficacy was achieved when using DOX-loaded and TPP-functionalized MSNPs for mitochondria-targeted delivery. Lowered adenosine triphosphate (ATP) production and decreased mitochondrial membrane potential were observed, demonstrating the mitochondria dysfunction caused by delivered DOX. The positive results indicate promising application potential of MSNPs in targeted subcellular drug delivery.

  11. The implications of recent advances in carboxymethyl chitosan based targeted drug delivery and tissue engineering applications.

    PubMed

    Upadhyaya, Laxmi; Singh, Jay; Agarwal, Vishnu; Tewari, Ravi Prakash

    2014-07-28

    Over the last decade carboxymethyl chitosan (CMCS) has emerged as a promising biopolymer for the development of new drug delivery systems and improved scaffolds along with other tissue engineering devices for regenerative medicine that is currently one of the most rapidly growing fields in the life sciences. CMCS is amphiprotic ether, derived from chitosan, exhibiting enhanced aqueous solubility, excellent biocompatibility, controllable biodegradability, osteogenesis ability and numerous other outstanding physicochemical and biological properties. More strikingly, it can load hydrophobic drugs and displays strong bioactivity which highlight its suitability and extensive usage for preparing different drug delivery and tissue engineering formulations respectively. This review provides a comprehensive introduction to various types of CMCS based formulations for delivery of therapeutic agents and tissue regeneration and further describes their preparation procedures and applications in different tissues/organs. Detailed information of CMCS based nano/micro systems for targeted delivery of drugs with emphasis on cancer specific and organ specific drug delivery have been described. Further, we have discussed various CMCS based tissue engineering biomaterials along with their preparation procedures and applications in different tissues/organs. The article then, gives a brief account of therapy combining drug delivery and tissue engineering. Finally, identification of major challenges and opportunities for current and ongoing application of CMCS based systems in the field are summarised.

  12. Influence of Red Blood Cells on Nanoparticle Targeted Delivery in Microcirculation.

    PubMed

    Tan, Jifu; Thomas, Antony; Liu, Yaling

    2011-12-22

    Multifunctional nanomedicine holds considerable promise as the next generation of medicine that allows for targeted therapy with minimal toxicity. Most current studies on Nanoparticle (NP) drug delivery consider a Newtonian fluid with suspending NPs. However, blood is a complex biological fluid composed of deformable cells, proteins, platelets, and plasma. For blood flow in capillaries, arterioles and venules, the particulate nature of the blood needs to be considered in the delivery process. The existence of the cell-free-layer and NP-cell interaction will largely influence both the dispersion and binding rates, thus impact targeted delivery efficacy. In this paper, a particle-cell hybrid model is developed to model NP transport, dispersion, and binding dynamics in blood suspension. The motion and deformation of red blood cells is captured through the Immersed Finite Element Method. The motion and adhesion of individual NPs are tracked through Brownian adhesion dynamics. A mapping algorithm and an interaction potential function are introduced to consider the cell-particle collision. NP dispersion and binding rates are derived from the developed model under various rheology conditions. The influence of red blood cells, vascular flow rate, and particle size on NP distribution and delivery efficacy is characterized. A non-uniform NP distribution profile with higher particle concentration near the vessel wall is observed. Such distribution leads to over 50% higher particle binding rate compared to the case without RBC considered. The tumbling motion of RBCs in the core region of the capillary is found to enhance NP dispersion, with dispersion rate increases as shear rate increases. Results from this study contribute to the fundamental understanding and knowledge on how the particulate nature of blood influences NP delivery, which will provide mechanistic insights on the nanomedicine design for targeted drug delivery applications.

  13. Influence of Red Blood Cells on Nanoparticle Targeted Delivery in Microcirculation

    PubMed Central

    Tan, Jifu; Thomas, Antony; Liu, Yaling

    2012-01-01

    Multifunctional nanomedicine holds considerable promise as the next generation of medicine that allows for targeted therapy with minimal toxicity. Most current studies on Nanoparticle (NP) drug delivery consider a Newtonian fluid with suspending NPs. However, blood is a complex biological fluid composed of deformable cells, proteins, platelets, and plasma. For blood flow in capillaries, arterioles and venules, the particulate nature of the blood needs to be considered in the delivery process. The existence of the cell-free-layer and NP-cell interaction will largely influence both the dispersion and binding rates, thus impact targeted delivery efficacy. In this paper, a particle-cell hybrid model is developed to model NP transport, dispersion, and binding dynamics in blood suspension. The motion and deformation of red blood cells is captured through the Immersed Finite Element Method. The motion and adhesion of individual NPs are tracked through Brownian adhesion dynamics. A mapping algorithm and an interaction potential function are introduced to consider the cell-particle collision. NP dispersion and binding rates are derived from the developed model under various rheology conditions. The influence of red blood cells, vascular flow rate, and particle size on NP distribution and delivery efficacy is characterized. A non-uniform NP distribution profile with higher particle concentration near the vessel wall is observed. Such distribution leads to over 50% higher particle binding rate compared to the case without RBC considered. The tumbling motion of RBCs in the core region of the capillary is found to enhance NP dispersion, with dispersion rate increases as shear rate increases. Results from this study contribute to the fundamental understanding and knowledge on how the particulate nature of blood influences NP delivery, which will provide mechanistic insights on the nanomedicine design for targeted drug delivery applications. PMID:22375153

  14. HER2 Targeting Peptides Screening and Applications in Tumor Imaging and Drug Delivery

    PubMed Central

    Geng, Lingling; Wang, Zihua; Jia, Xiangqian; Han, Qiuju; Xiang, Zhichu; Li, Dan; Yang, Xiaoliang; Zhang, Di; Bu, Xiangli; Wang, Weizhi; Hu, Zhiyuan; Fang, Qiaojun

    2016-01-01

    Herein, computational-aided one-bead-one-compound (OBOC) peptide library design combined with in situ single-bead sequencing microarray methods were successfully applied in screening peptides targeting at human epidermal growth factor receptor-2 (HER2), a biomarker of human breast cancer. As a result, 72 novel peptides clustered into three sequence motifs which are PYL***NP, YYL***NP and PPL***NP were acquired. Particularly one of the peptides, P51, has nanomolar affinity and high specificity for HER2 in ex vivo and in vivo tests. Moreover, doxorubicin (DOX)-loaded liposome nanoparticles were modified with peptide P51 or P25 and demonstrated to improve the targeted delivery against HER2 positive cells. Our study provides an efficient peptide screening method with a combination of techniques and the novel screened peptides with a clear binding site on HER2 can be used as probes for tumor imaging and targeted drug delivery. PMID:27279916

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

    PubMed

    Gao, Huile; Pang, Zhiqing; Jiang, Xinguo

    2013-10-01

    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.

  16. Targeted delivery by smart capsules for controlling two-phase flow in porous media

    NASA Astrophysics Data System (ADS)

    Fan, Jing; Abbaspourrad, Alireza; Weitz, David; Harvard Weitzgroup Team

    2015-11-01

    Two-phase flow in porous media is significantly influenced by the physical properties of the fluids and the geometry of the medium. We develop a variety of smart microcapsules that can deliver and release specific substances to the target location in the porous medium, and therefore change the fluid property or medium geometry at certain locations. In this talk, I will present two types of smart capsules for targeted surfactant delivery to the vicinity of oil-water interface and targeted microgel delivery for improving the homogeneity of the porous medium, respectively. We further prove the concept by monitoring the capsule location and the fluid structure in the porous media by micro-CT and confocal microscopy. This technique not only is of particular importance to the relevant industry applications especially in the oil industry but also opens a new window to study the mechanism of two-phase flow in porous media. Advanced Energy Consortium BEG08-027.

  17. Efficient Management of Fruit Pests by Pheromone Nanogels

    PubMed Central

    Bhagat, Deepa; Samanta, Suman K.; Bhattacharya, Santanu

    2013-01-01

    Environment-friendly management of fruit flies involving pheromones is useful in reducing the undesirable pest populations responsible for decreasing the yield and the crop quality. A nanogel has been prepared from a pheromone, methyl eugenol (ME) using a low-molecular mass gelator. This was very stable at open ambient conditions and slowed down the evaporation of pheromone significantly. This enabled its easy handling and transportation without refrigeration, and reduction in the frequency of pheromone recharging in the orchard. Notably the involvement of the nano-gelled pheromone brought about an effective management of Bactrocera dorsalis, a prevalent harmful pest for a number of fruits including guava. Thus a simple, practical and low cost green chemical approach is developed that has a significant potential for crop protection, long lasting residual activity, excellent efficacy and favorable safety profiles. This makes the present invention well-suited for pest management in a variety of crops. PMID:23416455

  18. Nanogel Aerogel as Load Bearing Insulation for Cryogenic Systems

    NASA Astrophysics Data System (ADS)

    Koravos, J. J.; Miller, T. M.; Fesmire, J. E.; Coffman, B. E.

    2010-04-01

    Load support structures in cryogenic storage, transport and processing systems are large contributors to the total heat leak of the system. Conventional insulation systems require the use of these support members in order to stabilize the process fluid enclosure and prevent degradation of insulation performance due to compression. Removal of these support structures would substantially improve system efficiency. Nanogel aerogel insulation performance is tested at vacuum pressures ranging from high vacuum to atmospheric pressure and under loads from loosely packed to greater than 10,000 Pa. Insulation performance is determined using boil-off calorimetry with liquid nitrogen as the latent heat recipient. Two properties of the aerogel insulation material suit it to act as a load bearing "structure" in a process vessel: (1) Ability to maintain thermal performance under load; (2) Elasticity when subjected to load. Results of testing provide positive preliminary indication that these properties allow Nanogel aerogel to effectively be used as a load bearing insulation in cryogenic systems.

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

    PubMed Central

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

    2013-01-01

    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

  20. Phage display: development of nanocarriers for targeted drug delivery to the brain

    PubMed Central

    Bakhshinejad, Babak; Karimi, Marzieh; Khalaj-Kondori, Mohammad

    2015-01-01

    The blood brain barrier represents a formidable obstacle for the transport of most systematically administered neurodiagnostics and neurotherapeutics to the brain. Phage display is a high throughput screening strategy that can be used for the construction of nanomaterial peptide libraries. These libraries can be screened for finding brain targeting peptide ligands. Surface functionalization of a variety of nanocarriers with these brain homing peptides is a sophisticated way to develop nanobiotechnology-based drug delivery platforms that are able to cross the blood brain barrier. These efficient drug delivery systems raise our hopes for the diagnosis and treatment of various brain disorders in the future. PMID:26199590

  1. Delivery of Hydrogen Sulfide by Ultrasound Targeted Microbubble Destruction Attenuates Myocardial Ischemia-reperfusion Injury.

    PubMed

    Chen, Gangbin; Yang, Li; Zhong, Lintao; Kutty, Shelby; Wang, Yuegang; Cui, Kai; Xiu, Jiancheng; Cao, Shiping; Huang, Qiaobing; Liao, Wangjun; Liao, Yulin; Wu, Juefei; Zhang, Wenzhu; Bin, Jianping

    2016-07-29

    Hydrogen sulfide (H2S) is an attractive agent for myocardial ischemia-reperfusion injury, however, systemic delivery of H2S may cause unwanted side effects. Ultrasound targeted microbubble destruction has become a promising tool for organ specific delivery of bioactive substance. We hypothesized that delivery of H2S by ultrasound targeted microbubble destruction attenuates myocardial ischemia-reperfusion injury and could avoid unwanted side effects. We prepared microbubbles carrying hydrogen sulfide (hs-MB) with different H2S/C3F8 ratios (4/0, 3/1, 2/2, 1/3, 0/4) and determined the optimal ratio. Release of H2S triggered by ultrasound was investigated. The cardioprotective effect of ultrasound targeted hs-MB destruction was investigated in a rodent model of myocardial ischemia-reperfusion injury. The H2S/C3F8 ratio of 2/2 was found to be an optimal ratio to prepare stable hs-MB with higher H2S loading capability. Ultrasound targeted hs-MB destruction triggered H2S release and increased the concentration of H2S in the myocardium and lung. Ultrasound targeted hs-MB destruction limited myocardial infarct size, preserved left ventricular function and had no influence on haemodynamics and respiratory. This cardioprotective effect was associated with alleviation of apoptosis and oxidative stress. Delivery of H2S to the myocardium by ultrasound targeted hs-MB destruction attenuates myocardial ischemia-reperfusion injury and may avoid unwanted side effects.

  2. Delivery of Hydrogen Sulfide by Ultrasound Targeted Microbubble Destruction Attenuates Myocardial Ischemia-reperfusion Injury

    PubMed Central

    Chen, Gangbin; Yang, Li; Zhong, Lintao; Kutty, Shelby; Wang, Yuegang; Cui, Kai; Xiu, Jiancheng; Cao, Shiping; Huang, Qiaobing; Liao, Wangjun; Liao, Yulin; Wu, Juefei; Zhang, Wenzhu; Bin, Jianping

    2016-01-01

    Hydrogen sulfide (H2S) is an attractive agent for myocardial ischemia-reperfusion injury, however, systemic delivery of H2S may cause unwanted side effects. Ultrasound targeted microbubble destruction has become a promising tool for organ specific delivery of bioactive substance. We hypothesized that delivery of H2S by ultrasound targeted microbubble destruction attenuates myocardial ischemia-reperfusion injury and could avoid unwanted side effects. We prepared microbubbles carrying hydrogen sulfide (hs-MB) with different H2S/C3F8 ratios (4/0, 3/1, 2/2, 1/3, 0/4) and determined the optimal ratio. Release of H2S triggered by ultrasound was investigated. The cardioprotective effect of ultrasound targeted hs-MB destruction was investigated in a rodent model of myocardial ischemia-reperfusion injury. The H2S/C3F8 ratio of 2/2 was found to be an optimal ratio to prepare stable hs-MB with higher H2S loading capability. Ultrasound targeted hs-MB destruction triggered H2S release and increased the concentration of H2S in the myocardium and lung. Ultrasound targeted hs-MB destruction limited myocardial infarct size, preserved left ventricular function and had no influence on haemodynamics and respiratory. This cardioprotective effect was associated with alleviation of apoptosis and oxidative stress. Delivery of H2S to the myocardium by ultrasound targeted hs-MB destruction attenuates myocardial ischemia-reperfusion injury and may avoid unwanted side effects. PMID:27469291

  3. Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma.

    PubMed

    Varshosaz, Jaleh; Farzan, Maryam

    2015-11-14

    Hepatocellular carcinoma (HCC) is the 5(th) most common malignancy which is responsible for more than half million annual mortalities; also, it is the third leading cause of cancer related death. Unfavorable systemic side-effects of chemotherapeutic agents and susceptibility to the degradation of small interfering RNAs (siRNAs), which can knock down a specific gene involved in the disease, have hampered their clinical application. So, it could be beneficial to develop an efficient carrier for the stabilization and specific delivery of drugs and siRNA to cells. Targeted nanoparticles have gained considerable attention as an efficient drug and gene delivery system, which is due to their capability in achieving the highest accumulation of cytotoxic agents in tumor tissue, modifiable drug pharmacokinetic- and bio-distribution, improved effectiveness of treatment, and limited side-effects. Recent studies have shed more light on the advantages of novel drug loaded carrier systems vs free drugs. Most of the animal studies have reported improvement in treatment efficacy and survival rate using novel carrier systems. Targeted delivery may be achieved passively or actively. In passive targeting, no ligand as homing device is used, while targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. However, in active targeting, the therapeutic agent or carrier system is conjugated to a tissue or cell-specific receptor which is over-expressed in a special malignancy using a ligand called a homing device. This review covers a broad spectrum of targeted nanoparticles as therapeutic and non-viral siRNA delivery systems, which are developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and their characteristics and opportunities for the clinical applications of drugs and therapeutic siRNA are discussed in this article. Asialoglycoprotein receptors, low-density lipoprotein

  4. Nanoparticles for targeted delivery of therapeutics and small interfering RNAs in hepatocellular carcinoma

    PubMed Central

    Varshosaz, Jaleh; Farzan, Maryam

    2015-01-01

    Hepatocellular carcinoma (HCC) is the 5th most common malignancy which is responsible for more than half million annual mortalities; also, it is the third leading cause of cancer related death. Unfavorable systemic side-effects of chemotherapeutic agents and susceptibility to the degradation of small interfering RNAs (siRNAs), which can knock down a specific gene involved in the disease, have hampered their clinical application. So, it could be beneficial to develop an efficient carrier for the stabilization and specific delivery of drugs and siRNA to cells. Targeted nanoparticles have gained considerable attention as an efficient drug and gene delivery system, which is due to their capability in achieving the highest accumulation of cytotoxic agents in tumor tissue, modifiable drug pharmacokinetic- and bio-distribution, improved effectiveness of treatment, and limited side-effects. Recent studies have shed more light on the advantages of novel drug loaded carrier systems vs free drugs. Most of the animal studies have reported improvement in treatment efficacy and survival rate using novel carrier systems. Targeted delivery may be achieved passively or actively. In passive targeting, no ligand as homing device is used, while targeting is achieved by incorporating the therapeutic agent into a macromolecule or nanoparticle that passively reaches the target organ. However, in active targeting, the therapeutic agent or carrier system is conjugated to a tissue or cell-specific receptor which is over-expressed in a special malignancy using a ligand called a homing device. This review covers a broad spectrum of targeted nanoparticles as therapeutic and non-viral siRNA delivery systems, which are developed for enhanced cellular uptake and targeted gene silencing in vitro and in vivo and their characteristics and opportunities for the clinical applications of drugs and therapeutic siRNA are discussed in this article. Asialoglycoprotein receptors, low-density lipoprotein

  5. Nanogels as imaging agents for modalities spanning the electromagnetic spectrum

    PubMed Central

    Chan, Minnie

    2016-01-01

    In the past few decades, advances in imaging equipment and protocols have expanded the role of imaging in in vivo diagnosis and disease management, especially in cancer. Traditional imaging agents have rapid clearance and low specificity for disease detection. To improve accuracy in disease identification, localization and assessment, novel nanomaterials are frequently explored as imaging agents to achieve high detection specificity and sensitivity. A promising material for this purpose are hydrogel nanoparticles, whose high hydrophilicity, biocompatibility, and tunable size in the nanometer range make them ideal for imaging. These nanogels (10 to 200 nm) can circumvent uptake by the reticuloendothelial system, allowing longer circulation times than small molecules. In addition, their size/surface properties can be further tailored to optimize their pharmacokinetics for imaging of a particular disease. Herein, we provide a comprehensive review of nanogels as imaging agents in various modalities with sources of signal spanning the electromagnetic spectrum, including MRI, NIR, UV-vis, and PET. Many materials and formulation methods will be reviewed to highlight the versatility of nanogels as imaging agents. PMID:27398218

  6. Nanogels as imaging agents for modalities spanning the electromagnetic spectrum.

    PubMed

    Chan, Minnie; Almutairi, Adah

    2016-01-21

    In the past few decades, advances in imaging equipment and protocols have expanded the role of imaging in in vivo diagnosis and disease management, especially in cancer. Traditional imaging agents have rapid clearance and low specificity for disease detection. To improve accuracy in disease identification, localization and assessment, novel nanomaterials are frequently explored as imaging agents to achieve high detection specificity and sensitivity. A promising material for this purpose are hydrogel nanoparticles, whose high hydrophilicity, biocompatibility, and tunable size in the nanometer range make them ideal for imaging. These nanogels (10 to 200 nm) can circumvent uptake by the reticuloendothelial system, allowing longer circulation times than small molecules. In addition, their size/surface properties can be further tailored to optimize their pharmacokinetics for imaging of a particular disease. Herein, we provide a comprehensive review of nanogels as imaging agents in various modalities with sources of signal spanning the electromagnetic spectrum, including MRI, NIR, UV-vis, and PET. Many materials and formulation methods will be reviewed to highlight the versatility of nanogels as imaging agents.

  7. Method for tracking nanogel particles in vivo and in vitro.

    PubMed

    Seal, Brandon L; Lien, Yeong-Hau H; Mazar, Carla; Salkini, Mohamad W; Cai, Tong; Hu, Zhibing; Marquez, Manuel; Garcia, Antonio A

    2008-07-01

    Hydrogels made of N-isopropylacrylamide (NIPA) can be synthesized in the form of highly monodispersed nanoparticles. After synthesis, NIPA hydrogel nanoparticles (nanogels) can be labeled by Alexa Fluor 488 carboxylic acid, 2,3,5,6-tetrafluorophenyl ester through amine-terminated functional groups. This choice of dye is complementary to other biological labeling methods for in vivo studies. When the nanogel/dye nanoparticles are injected into rabbits, they can be imaged via tissue sectioning and confocal microscopy, while nanoparticle concentration can be determined by fluorescent microplate assays. Time-course persistence of nanoparticles in the circulatory system can be readily tracked by direct assay of plasma and urine samples using 485 nm excitation and 538 emission wavelengths to keep background fluorescence to nearly the same level as that found using an empty well. Depending upon how the nanoparticles are injected, circulatory system concentrations can reach high concentrations and diminish to low levels or gradually increase and gradually decrease over time. Injection in the femoral artery results in a rapid spike in circulating nanogel/dye concentration, while injection into the renal artery results in a more gradual increase.

  8. Oxidation-Induced Degradable Nanogels for Iron Chelation

    NASA Astrophysics Data System (ADS)

    Liu, Zhi; Wang, Yan; Purro, Max; Xiong, May P.

    2016-02-01

    Iron overload can increase cellular oxidative stress levels due to formation of reactive oxygen species (ROS); untreated, it can be extremely destructive to organs and fatal to patients. Since elevated oxidative stress levels are inherent to the condition in such patients, oxidation-induced degradable nanogels for iron chelation were rationally designed by simultaneously polymerizing oxidation-sensitive host-guest crosslinkers between β-cyclodextrin (β-CD) and ferrocene (Fc) and iron chelating moieties composed of deferoxamine (DFO) into the final gel scaffold in reverse emulsion reaction chambers. UV-Vis absorption and atomic absorption spectroscopy (AAS) was used to verify iron chelating capability of nanogels. These materials can degrade into smaller chelating fragments at rates proportional to the level of oxidative stress present. Conjugating DFO reduces the cytotoxicity of the chelator in the macrophage cells. Importantly, the nanogel can effectively reduce cellular ferritin expression in iron overloaded cells and regulate intracellular iron levels at the same time, which is important for maintaining a homeostatic level of this critical metal in cells.

  9. Oxidation-Induced Degradable Nanogels for Iron Chelation

    PubMed Central

    Liu, Zhi; Wang, Yan; Purro, Max; Xiong, May P.

    2016-01-01

    Iron overload can increase cellular oxidative stress levels due to formation of reactive oxygen species (ROS); untreated, it can be extremely destructive to organs and fatal to patients. Since elevated oxidative stress levels are inherent to the condition in such patients, oxidation-induced degradable nanogels for iron chelation were rationally designed by simultaneously polymerizing oxidation-sensitive host-guest crosslinkers between β-cyclodextrin (β-CD) and ferrocene (Fc) and iron chelating moieties composed of deferoxamine (DFO) into the final gel scaffold in reverse emulsion reaction chambers. UV-Vis absorption and atomic absorption spectroscopy (AAS) was used to verify iron chelating capability of nanogels. These materials can degrade into smaller chelating fragments at rates proportional to the level of oxidative stress present. Conjugating DFO reduces the cytotoxicity of the chelator in the macrophage cells. Importantly, the nanogel can effectively reduce cellular ferritin expression in iron overloaded cells and regulate intracellular iron levels at the same time, which is important for maintaining a homeostatic level of this critical metal in cells. PMID:26868174

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

    NASA Astrophysics Data System (ADS)

    Shah, Dhiral Ashwin

    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

  11. Non-polymeric nano-carriers in HIV/AIDS drug delivery and targeting.

    PubMed

    Gupta, Umesh; Jain, Narendra K

    2010-03-18

    Development of an effective drug delivery approach for the treatment of HIV/AIDS is a global challenge. The conventional drug delivery approaches including Highly Active Anti Retroviral Therapy (HAART) have increased the life span of the HIV/AIDS patient. However, the eradication of HIV is still not possible with these approaches due to some limitations. Emergence of polymeric and non-polymeric nanotechnological approaches can be opportunistic in this direction. Polymeric carriers like, dendrimers and nanoparticles have been reported for the targeting of anti HIV drugs. The synthetic pathways as well polymeric framework create some hurdles in their successful formulation development as well as in the possible drug delivery approaches. In the present article, we have discussed the general physiological aspects of the infection along with the relevance of non-polymeric nanocarriers like liposomes, solid lipid nanoparticles (SLN), ethosomes, etc. in the treatment of this disastrous disease.

  12. Sequence-defined shuttles for targeted nucleic acid and protein delivery.

    PubMed

    Röder, Ruth; Wagner, Ernst

    2014-01-01

    Molecular medicine opens into a space of novel specific therapeutic agents: intracellularly active drugs such as peptides, proteins or nucleic acids, which are not able to cross cell membranes and enter the intracellular space on their own. Through the development of cell-targeted shuttles for specific delivery, this restriction in delivery has the potential to be converted into an advantage. On the one hand, due to the multiple extra- and intracellular barriers, such carrier systems need to be multifunctional. On the other hand, they must be precise and reproducibly manufactured due to pharmaceutical reasons. Here we review the design of precise sequence-defined delivery carriers, including solid-phase synthesized peptides and nonpeptidic oligomers, or nucleotide-based carriers such as aptamers and origami nanoboxes.

  13. Targeted drug delivery for cancer therapy: the other side of antibodies

    PubMed Central

    2012-01-01

    Therapeutic monoclonal antibody (TMA) based therapies for cancer have advanced significantly over the past two decades both in their molecular sophistication and clinical efficacy. Initial development efforts focused mainly on humanizing the antibody protein to overcome problems of immunogenicity and on expanding of the target antigen repertoire. In parallel to naked TMAs, antibody-drug conjugates (ADCs) have been developed for targeted delivery of potent anti-cancer drugs with the aim of bypassing the morbidity common to conventional chemotherapy. This paper first presents a review of TMAs and ADCs approved for clinical use by the FDA and those in development, focusing on hematological malignancies. Despite advances in these areas, both TMAs and ADCs still carry limitations and we highlight the more important ones including cancer cell specificity, conjugation chemistry, tumor penetration, product heterogeneity and manufacturing issues. In view of the recognized importance of targeted drug delivery strategies for cancer therapy, we discuss the advantages of alternative drug carriers and where these should be applied, focusing on peptide-drug conjugates (PDCs), particularly those discovered through combinatorial peptide libraries. By defining the advantages and disadvantages of naked TMAs, ADCs and PDCs it should be possible to develop a more rational approach to the application of targeted drug delivery strategies in different situations and ultimately, to a broader basket of more effective therapies for cancer patients. PMID:23140144

  14. Construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles for multifunctional intracellular drug delivery.

    PubMed

    Song, Nijia; Ding, Mingming; Pan, Zhicheng; Li, Jiehua; Zhou, Lijuan; Tan, Hong; Fu, Qiang

    2013-12-09

    New strategies for the construction of versatile nanovehicles to overcome the multiple challenges of targeted delivery are urgently needed for cancer therapy. To address these needs, we developed a novel targeting-clickable and tumor-cleavable polyurethane nanomicelle for multifunctional delivery of antitumor drugs. The polyurethane was synthesized from biodegradable poly(ε-caprolactone) (PCL) and L-lysine ethyl ester diisocyanate (LDI), further extended by a new designed L-cystine-derivatized chain extender bearing a redox-responsive disulfide bond and clickable alkynyl groups (Cys-PA), and finally terminated by a detachable methoxyl-poly(ethylene glycol) with a highly pH-sensitive benzoic-imine linkage (BPEG). The obtained polymers show attractive self-assembly characteristics and stimuli-responsiveness, good cytocompatibility, and high loading capacity for doxorubicin (DOX). Furthermore, folic acid (FA) as a model targeting ligand was conjugated to the polyurethane micelles via an efficient click reaction. The decoration of FA results in an enhanced cellular uptake and improved drug efficacy toward FA-receptor positive HeLa cancer cells in vitro. As a proof-of-concept, this work provides a facile approach to the design of extracellularly activatable nanocarriers for tumor-targeted and programmed intracellular drug delivery.

  15. Versatile surface engineering of porous nanomaterials with bioinspired polyphenol coatings for targeted and controlled drug delivery

    NASA Astrophysics Data System (ADS)

    Li, Juan; Wu, Shuxian; Wu, Cuichen; Qiu, Liping; Zhu, Guizhi; Cui, Cheng; Liu, Yuan; Hou, Weijia; Wang, Yanyue; Zhang, Liqin; Teng, I.-Ting; Yang, Huang-Hao; Tan, Weihong

    2016-04-01

    The development of biocompatible drug delivery systems with targeted recognition and controlled release has experienced a number of design challenges, including, for example, complicated preparation steps and premature drug release. Herein, we address these problems through an in situ self-polymerization method that synthesizes biodegradable polyphenol-coated porous nanomaterials for targeted and controlled drug delivery. As a proof of concept, we synthesized polyphenol-coated mesoporous silica nanoparticles, termed MSN@polyphenol. The polyphenol coatings not only improved colloidal stability and prevented premature drug leakage, but also provided a scaffold for immobilization of targeting moieties, such as aptamers. Both immobilization of targeting aptamers and synthesis of polyphenol coating are easily accomplished without the aid of any other organic reagents. Importantly, the polyphenol coating (EGCg) used in this study could be biodegraded by acidic pH and intracellular glutathione, resulting in the release of trapped anticancer drugs. Based on confocal fluorescence microscopy and cytotoxicity experiments, drug-loaded and polyphenol-coated MSNs were shown to possess highly efficient internalization and an apparent cytotoxic effect on target cancer, but not control, cells. Our results suggest that these highly biocompatible and biodegradable polyphenol-coated MSNs are promising vectors for controlled-release biomedical applications and cancer therapy.The development of biocompatible drug delivery systems with targeted recognition and controlled release has experienced a number of design challenges, including, for example, complicated preparation steps and premature drug release. Herein, we address these problems through an in situ self-polymerization method that synthesizes biodegradable polyphenol-coated porous nanomaterials for targeted and controlled drug delivery. As a proof of concept, we synthesized polyphenol-coated mesoporous silica nanoparticles

  16. Preparation of Pickering emulsions through interfacial adsorption by soft cyclodextrin nanogels

    PubMed Central

    Kawano, Shintaro; Akashi, Mitsuru; Sato, Hirofumi; Shizuma, Motohiro

    2015-01-01

    Summary Background: Emulsions stabilized by colloidal particles are known as Pickering emulsions. To date, soft microgel particles as well as inorganic and organic particles have been utilized as Pickering emulsifiers. Although cyclodextrin (CD) works as an attractive emulsion stabilizer through the formation of a CD–oil complex at the oil–water interface, a high concentration of CD is normally required. Our research focuses on an effective Pickering emulsifier based on a soft colloidal CD polymer (CD nanogel) with a unique surface-active property. Results: CD nanogels were prepared by crosslinking heptakis(2,6-di-O-methyl)-β-cyclodextrin with phenyl diisocyanate and subsequent immersion of the resulting polymer in water. A dynamic light scattering study shows that primary CD nanogels with 30–50 nm diameter assemble into larger CD nanogels with 120 nm diameter by an increase in the concentration of CD nanogel from 0.01 to 0.1 wt %. The CD nanogel has a surface-active property at the air–water interface, which reduces the surface tension of water. The CD nanogel works as an effective Pickering emulsion stabilizer even at a low concentration (0.1 wt %), forming stable oil-in-water emulsions through interfacial adsorption by the CD nanogels. Conclusion: Soft CD nanogel particles adsorb at the oil–water interface with an effective coverage by forming a strong interconnected network and form a stable Pickering emulsion. The adsorption property of CD nanogels on the droplet surface has great potential to become new microcapsule building blocks with porous surfaces. These microcapsules may act as stimuli-responsive nanocarriers and nanocontainers. PMID:26734085

  17. Light-Controlled Delivery of Monoclonal Antibodies for Targeted Photoinactivation of Ki-67.

    PubMed

    Wang, Sijia; Hüttmann, Gereon; Zhang, Zhenxi; Vogel, Alfred; Birngruber, Reginald; Tangutoori, Shifalika; Hasan, Tayyaba; Rahmanzadeh, Ramtin

    2015-09-08

    The selective inhibition of intracellular and nuclear molecules such as Ki-67 holds great promise for the treatment of cancer and other diseases. However, the choice of the target protein and the intracellular delivery of the functional agent remain crucial challenges. Main hurdles are (a) an effective delivery into cells, (b) endosomal escape of the delivered agents, and (c) an effective, externally triggered destruction of cells. Here we show a light-controlled two-step approach for selective cellular delivery and cell elimination of proliferating cells. Three different cell-penetrating nano constructs, including liposomes, conjugates with the nuclear localization sequence (NLS), and conjugates with the cell penetrating peptide Pep-1, delivered the light activatable antibody conjugate TuBB-9-FITC, which targets the proliferation associated protein Ki-67. HeLa cells were treated with the photosensitizer benzoporphyrin monoacid derivative (BPD) and the antibody constructs. In the first optically controlled step, activation of BPD at 690 nm triggered a controlled endosomal escape of the TuBB-9-FITC constructs. In more than 75% of Ki-67 positive, irradiated cells TuBB-9-FITC antibodies relocated within 24 h from cytoplasmic organelles to the cell nucleus and bound to Ki-67. After a second light irradiation at 490 nm, which activated FITC, cell viability decreased to approximately 13%. Our study shows an effective targeting strategy, which uses light-controlled endosomal escape and the light inactivation of Ki-67 for cell elimination. The fact that liposomal or peptide-assisted delivery give similar results leads to the additional conclusion that an effective mechanism for endosomal escape leaves greater variability for the choice of the delivery agent.

  18. Tumor-targeted delivery of paclitaxel using low density lipoprotein-mimetic solid lipid nanoparticles.

    PubMed

    Kim, Jin-Ho; Kim, Youngwook; Bae, Ki Hyun; Park, Tae Gwan; Lee, Jung Hee; Park, Keunchil

    2015-04-06

    Water-insoluble anticancer drugs, including paclitaxel, present severe clinical side effects when administered to patients, primarily associated with the toxicity of reagents used to solubilize the drugs. In efforts to develop alternative formulations of water-insoluble anticancer drugs suitable for intravenous administration, we developed biocompatible anticancer therapeutic solid lipid nanoparticles (SLNs), mimicking the structure and composition of natural particles, low-density lipoproteins (LDLs), for tumor-targeted delivery of paclitaxel. These therapeutic nanoparticles contained water-insoluble paclitaxel in the core with tumor-targeting ligand covalently conjugated on the polyethylene glycol (PEG)-modified surface (targeted PtSLNs). In preclinical human cancer xenograft mouse model studies, the paclitaxel-containing tumor-targeting SLNs exhibited pronounced in vivo stability and enhanced biocompatibility. Furthermore, these SLNs had superior antitumor activity to in-class nanoparticular therapeutics in clinical use (Taxol and Genexol-PM) and yielded long-term complete responses. The in vivo targeted antitumor activities of the SLN formulations in a mouse tumor model suggest that LDL-mimetic SLN formulations can be utilized as a biocompatible, tumor-targeting platform for the delivery of various anticancer therapeutics.

  19. Targeted magnetic delivery and tracking of cells using a magnetic resonance imaging system.

    PubMed

    Riegler, Johannes; Wells, Jack A; Kyrtatos, Panagiotis G; Price, Anthony N; Pankhurst, Quentin A; Lythgoe, Mark F

    2010-07-01

    The success of cell therapies depends on the ability to deliver the cells to the site of injury. Targeted magnetic cell delivery is an emergent technique for localised cell transplantation therapy. The use of permanent magnets limits such a treatment to organs close to the body surface or an implanted magnetic source. A possible alternative method for magnetic cell delivery is magnetic resonance targeting (MRT), which uses magnetic field gradients inherent to all magnetic resonance imaging system, to steer ferromagnetic particles to their target region. In this study we have assessed the feasibility of such an approach for cell targeting, using a range of flow rates and different super paramagnetic iron oxide particles in a vascular bifurcation phantom. Using MRT we have demonstrated that 75% of labelled cells could be guided within the vascular bifurcation. Furthermore we have demonstrated the ability to image the labelled cells before and after magnetic targeting, which may enable interactive manipulation and assessment of the distribution of cellular therapy. This is the first demonstration of cellular MRT and these initial findings support the potential value of MRT for improved targeting of intravascular cell therapies.

  20. Intranasal microemulsion for targeted nose to brain delivery in neurocysticercosis: Role of docosahexaenoic acid.

    PubMed

    Shinde, Rajshree L; Bharkad, Gopal P; Devarajan, Padma V

    2015-10-01

    Intranasal Microemulsions (MEs) for nose to brain delivery of a novel combination of Albendazole sulfoxide (ABZ-SO) and Curcumin (CUR) for Neurocysticercosis (NCC), a brain infection are reported. MEs prepared by simple solution exhibited a globule size <20nm, negative zeta potential and good stability. The docosahexaenoic acid (DHA) ME revealed high and rapid ex vivo permeation of drugs through sheep nasal mucosa. Intranasal DHA ME resulted in high brain concentrations and 10.76 (ABZ-SO) and 3.24 (CUR) fold enhancement in brain area-under-the-curve (AUC) compared to intravenous DHA MEs at the same dose. Direct nose to brain transport (DTP) of >95% was seen for both drugs. High drug targeting efficiency (DTE) to the brain compared to Capmul ME and drug solution (P<0.05) suggested the role of DHA in aiding nose to brain delivery. Histopathology study confirmed no significant changes. High efficacy of ABZ-SO: CUR (100:10ng/mL) DHA ME in vitro on Taenia solium cysts was confirmed by complete ALP inhibition and disintegration of cysts at 96h. Considering that the brain concentration at 24h was 1400±160.1ng/g (ABZ-SO) and 120±35.2ng/g (CUR), the in vitro efficacy seen at a 10 fold lower concentration of the drugs strongly supports the assumption of clinical efficacy. The intranasal DHA ME is a promising delivery system for targeted nose to brain delivery.

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

    PubMed Central

    Mortensen, Luke J.; Levy, Oren; Phillips, Joseph P.; Stratton, Tara; Triana, Brian; Ruiz, Juan P.; Gu, Fangqi; Karp, Jeffrey M.; Lin, Charles P.

    2013-01-01

    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 quantification. Here we examine Mesenchymal Stem Cells (MSCs) labeled with a series of 4 membrane dyes from which we select the optimal dye combination for pair-wise comparisons of delivery to inflamed tissue in the mouse ear using confocal fluorescence imaging. The use of an optimized dye pair for simultaneous tracking of two cell populations in the same animal enables quantification of a test population that is referenced to an internal control population, thereby eliminating intra-subject variations and variations in injected cell numbers. Consistent results were obtained even when the administered cell number varied by more than an order of magnitude, demonstrating an ability to neutralize one of the largest sources of in vivo experimental error and to greatly reduce the number of cells required to evaluate cell delivery. With this method, we are able to show a small but significant increase in the delivery of cytokine pre-treated MSCs (TNF-α & IFN-γ) compared to control MSCs. Our results suggest future directions for screening cell strategies using our in vivo cell delivery assay, which may be useful to develop methods to maximize cell therapeutic potential. PMID:24205131

  2. Nanogel-Conjugated Reverse Transcriptase Inhibitors and Their Combinations as Novel Antiviral Agents with Increased Efficacy against HIV-1 Infection.

    PubMed

    Senanayake, T H; Gorantla, S; Makarov, E; Lu, Y; Warren, G; Vinogradov, S V

    2015-12-07

    Nucleoside reverse transcriptase inhibitors (NRTIs) are an integral part of the current antiretroviral therapy (ART), which dramatically reduced the mortality from AIDS and turned the disease from lethal to chronic. The further steps in curing the HIV-1 infection must include more effective targeting of infected cells and virus sanctuaries inside the body and modification of drugs and treatment schedules to reduce common complications of the long-term treatment and increase patient compliancy. Here, we describe novel NRTI prodrugs synthesized from cholesteryl-ε-polylysine (CEPL) nanogels by conjugation with NRTI 5'-succinate derivatives (sNRTI). Biodegradability, small particle size, and high NRTI loading (30% by weight) of these conjugates; extended drug release, which would allow a weekly administration schedule; high therapeutic index (>1000) with a lower toxicity compared to NRTIs; and efficient accumulation in macrophages known as carriers for HIV-1 infection are among the most attractive properties of new nanodrugs. Nanogel conjugates of zidovudine (AZT), lamivudine (3TC), and abacavir (ABC) have been investigated individually and in formulations similar to clinical NRTI cocktails. Nanodrug formulations demonstrated 10-fold suppression of reverse transcriptase activity (EC90) in HIV-infected macrophages at 2-10, 2-4, and 1-2 μM drug levels, respectively, for single nanodrugs and dual and triple nanodrug cocktails. Nanogel conjugate of lamivudine was the most effective single nanodrug (EC90 2 μM). Nanodrugs showed a more favorable pharmacokinetics compared to free NRTIs. Infrequent iv injections of PEGylated CEPL-sAZT alone could efficiently suppress HIV-1 RT activity to background level in humanized mouse (hu-PBL) HIV model.

  3. Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

    NASA Astrophysics Data System (ADS)

    Etame, Arnold B.

    The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non

  4. Targeted delivery of miRNA therapeutics for cardiovascular diseases: opportunities and challenges.

    PubMed

    Kwekkeboom, Rick F J; Lei, Zhiyong; Doevendans, Pieter A; Musters, René J P; Sluijter, Joost P G

    2014-09-01

    Dysregulation of miRNA expression has been associated with many cardiovascular diseases in animal models, as well as in patients. In the present review, we summarize recent findings on the role of miRNAs in cardiovascular diseases and discuss the opportunities, possibilities and challenges of using miRNAs as future therapeutic targets. Furthermore, we focus on the different approaches that can be used to deliver these newly developed miRNA therapeutics to their sites of action. Since siRNAs are structurally homologous with the miRNA therapeutics, important lessons learned from siRNA delivery strategies are discussed that might be applicable to targeted delivery of miRNA therapeutics, thereby reducing costs and potential side effects, and improving efficacy.

  5. Exploitation of pleiotropic actions of statins by using tumour-targeted delivery systems.

    PubMed

    Licarete, Emilia; Sesarman, Alina; Banciu, Manuela

    2015-01-01

    Statins are drugs traditionally used to lower cholesterol levels in blood. At concentrations 100- to 500-fold higher than those needed for reaching cholesterol lowering activity, they have anti-tumour activity. This anti-tumour activity is based on statins pleiotropic effects derived from their ability to inhibit the mevalonate synthesis and include anti-proliferative, pro-apoptotic, anti-angiogenic, anti-inflammatory, anti-metastatic actions and modulatory effects on intra-tumour oxidative stress. Thus, in this review, we summarise the possible pleiotropic actions of statins involved in tumour growth inhibition. Since the administration of these high doses of statins is accompanied by severe side effects, targeted delivery of statins seems to be the appropriate strategy for efficient application of statins in oncology. Therefore, we also present an overview of the current status of targeted delivery systems for statins with possible utilisation in oncology.

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

    PubMed Central

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

    2011-01-01

    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

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

    PubMed

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

    2013-01-01

    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.

  8. Collagen Coated Nanoliposome as a Targeted and Controlled Drug Delivery System

    NASA Astrophysics Data System (ADS)

    Krishnamoorthy, G.; Stephen, P.; Prabhu, M.; Sehgal, P. K.; Sadulla, S.

    2010-10-01

    The collagen coated nanoliposome (CCNL) have been prepared and characterized in order to develop a targeted and controlled drug delivery system. The zeta potential (ZP) measurement, Fourier transform infrared (FT-IR) spectral and Scanning Electron Microscopy (SEM) and Cell viability assay data showed that the collagen coated nanoliposome particle size and charges, structural interaction and surface morphology and high bio-cyto-compatibility of collagen coated nanoliposome. The particle sizes of nanoliposome (NL) and collagen coated nanoliposome are 20-300 nm and 0.1-10 μm respectively. The introduction of triple helical, coiled coil and fibrous protein of collagen into nanoliposome can improves the stability of nanoliposome, resistant to phospholipase activities and decreasing the phagocytosis of liposomes by reticuloendothelial system. The collagen coated nanoliposome is expected to be used as for targeted and controlled drug delivery system, and tissue engineering application.

  9. An interbacterial NAD(P)(+) glycohydrolase toxin requires elongation factor Tu for delivery to target cells.

    PubMed

    Whitney, John C; Quentin, Dennis; Sawai, Shin; LeRoux, Michele; Harding, Brittany N; Ledvina, Hannah E; Tran, Bao Q; Robinson, Howard; Goo, Young Ah; Goodlett, David R; Raunser, Stefan; Mougous, Joseph D

    2015-10-22

    Type VI secretion (T6S) influences the composition of microbial communities by catalyzing the delivery of toxins between adjacent bacterial cells. Here, we demonstrate that a T6S integral membrane toxin from Pseudomonas aeruginosa, Tse6, acts on target cells by degrading the universally essential dinucleotides NAD(+) and NADP(+). Structural analyses of Tse6 show that it resembles mono-ADP-ribosyltransferase proteins, such as diphtheria toxin, with the exception of a unique loop that both excludes proteinaceous ADP-ribose acceptors and contributes to hydrolysis. We find that entry of Tse6 into target cells requires its binding to an essential housekeeping protein, translation elongation factor Tu (EF-Tu). These proteins participate in a larger assembly that additionally directs toxin export and provides chaperone activity. Visualization of this complex by electron microscopy defines the architecture of a toxin-loaded T6S apparatus and provides mechanistic insight into intercellular membrane protein delivery between bacteria.

  10. Targeted Delivery of Glucan Particle Encapsulated Gallium Nanoparticles Inhibits HIV Growth in Human Macrophages

    PubMed Central

    Soto, Ernesto R.; O'Connell, Olivia; Dikengil, Fusun; Peters, Paul J.; Clapham, Paul R.

    2016-01-01

    Glucan particles (GPs) are hollow, porous 3–5 μm microspheres derived from the cell walls of Baker's yeast (Saccharomyces cerevisiae). The 1,3-β-glucan outer shell provides for receptor-mediated uptake by phagocytic cells expressing β-glucan receptors. GPs have been used for macrophage-targeted delivery of a wide range of payloads (DNA, siRNA, protein, small molecules, and nanoparticles) encapsulated inside the hollow GPs or bound to the surface of chemically derivatized GPs. Gallium nanoparticles have been proposed as an inhibitory agent against HIV infection. Here, macrophage targeting of gallium using GPs provides for more efficient delivery of gallium and inhibition of HIV infection in macrophages compared to free gallium nanoparticles. PMID:27965897

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

    NASA Astrophysics Data System (ADS)

    Liu, JianCheng

    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

  12. Virus-Mimetic Fusogenic Exosomes for Direct Delivery of Integral Membrane Proteins to Target Cell Membranes.

    PubMed

    Yang, Yoosoo; Hong, Yeonsun; Nam, Gi-Hoon; Chung, Jin Hwa; Koh, Eunee; Kim, In-San

    2017-02-06

    An efficient system for direct delivery of integral membrane proteins is successfully developed using a new biocompatible exosome-based platform. Fusogenic exosomes harboring viral fusogen, vascular stomatitis virus (VSV)-G protein, can fuse with and modify plasma membranes in a process called "membrane editing." This can facilitate the transfer of biologically active membrane proteins into the target cell membranes both in vitro and in vivo.

  13. Dual surface-functionalized Janus nanocomposites for targeted stimulus responsive drug delivery.

    NASA Astrophysics Data System (ADS)

    Wang, Feng; Wang, Yilong; Pauletti, Giovanni; Shi, Donglu

    2014-03-01

    A novel superparamagnetic Janus nanocomposite (SJNC) of polystyrene/Fe3O4@SiO2 was designed and developed for the first time using a miniemulsion method. Both surfaces were readily functionalized for bio-medical application. Folic acid (FA) and doxorubicin (DOX) were conjugated stepwise to the surfaces. It was found that SJNCs achieved cell-targeted drug delivery in a pH-responsive manner.

  14. Optical steering of thermally generated microbubbles in a liquid for targeted metallic nanoparticle delivery

    NASA Astrophysics Data System (ADS)

    Krishnappa, Arjun; Abeywickrema, Ujitha; Banerjee, Partha

    2016-09-01

    A novel mathematical model is developed to investigate the behavior of thermally generated microbubbles in the presence of optical radiation to understand the mechanism of their steering. Forces acting on a bubble are studied in detail using a general force model. It has been proposed that these microbubbles with agglomerated metallic nanoparticles can be used for targeted drug delivery. The model can be extended to include the steering of bubbles with agglomerated silver or gold nanoparticles on their surface.

  15. Transferrin receptors and the targeted delivery of therapeutic agents against cancer

    PubMed Central

    Daniels, Tracy R.; Bernabeu, Ezequiel; Rodríguez, José A.; Patel, Shabnum; Kozman, Maggie; Chiappetta, Diego A.; Holler, Eggehard; Ljubimova, Julia Y.; Helguera, Gustavo; Penichet, Manuel L.

    2012-01-01

    Background Traditional cancer therapy can be successful in destroying tumors, but can also cause dangerous side effects. Therefore, many targeted therapies are in development. The transferrin receptor (TfR) functions in cellular iron uptake through its interaction with transferrin. This receptor is an attractive molecule for the targeted therapy of cancer since it is upregulated on the surface of many cancer types and is efficiently internalized. This receptor can be targeted in two ways: 1) for the delivery of therapeutic molecules into malignant cells or 2) to block the natural function of the receptor leading directly to cancer cell death. Scope of review In the present article we discuss the strategies used to target the TfR for the delivery of therapeutic agents into cancer cells. We provide a summary of the vast types of anti-cancer drugs that have been delivered into cancer cells employing a variety of receptor binding molecules including Tf, anti-TfR antibodies, or TfR-binding peptides alone or in combination with carrier molecules including nanoparticles and viruses. Major conclusions Targeting the TfR has been shown to be effective in delivering many different therapeutic agents and causing cytotoxic effects in cancer cells in vitro and in vivo. General significance The extensive use of TfR for targeted therapy attests to the versatility of targeting this receptor for therapeutic purposes against malignant cells. More advances in this area are expected to further improve the therapeutic potential of targeting the TfR for cancer therapy leading to an increase in the number of clinical trials of molecules targeting this receptor. PMID:21851850

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

    NASA Astrophysics Data System (ADS)

    Wang, Ziheng; Acosta, Edgar

    2013-12-01

    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.

  17. Pathology-targeted cell delivery via injectable micro-scaffold capsule mediated by endogenous TGase.

    PubMed

    Qi, Chunxiao; Li, Yaqian; Badger, Patrick; Yu, Hongsheng; You, Zhifeng; Yan, Xiaojun; Liu, Wei; Shi, Yan; Xia, Tie; Dong, Jiahong; Huang, Chenyu; Du, Yanan

    2017-05-01

    Targeted cell delivery to lesion sites via minimally invasive approach remains an unmet need in regenerative medicine to endow satisfactory therapeutic efficacy and minimized side-effects. Here, we rationally designed a pathology-targeted cell delivery strategy leveraging injectable micro-scaffolds as cell-loading capsule and endogenous tissue transglutaminase (TGase) at lesion site as adhesive. Up-regulated TGase post-liver injury catalyzed chemical bonding between the glutamine and lysine residues on liver surface and micro-scaffolds both ex vivo and in vivo, facilitating sufficient adhesion on the pathological liver. Upon intraperitoneal injection, Mesenchymal Stem Cell-loaded capsules, exhibiting cell protection from shear-induced damage and post-transplantation anoikis, adhered to the CCl4-treated liver with a hundred-fold improvement in targeting efficiency (70.72%) compared to free-cell injection, which dramatically improved mice survival (33.3% vs. 0% for free-cell therapy) even with low-dosage treatment. This unique and widely-applicable cell delivery mechanism and strategy hold great promise for transforming cell therapy for refractory diseases.

  18. Inter-molecular β-sheet structure facilitates lung-targeting siRNA delivery

    PubMed Central

    Zhou, Jihan; Li, Dong; Wen, Hao; Zheng, Shuquan; Su, Cuicui; Yi, Fan; Wang, Jue; Liang, Zicai; Tang, Tao; Zhou, Demin; Zhang, Li-He; Liang, Dehai; Du, Quan

    2016-01-01

    Size-dependent passive targeting based on the characteristics of tissues is a basic mechanism of drug delivery. While the nanometer-sized particles are efficiently captured by the liver and spleen, the micron-sized particles are most likely entrapped within the lung owing to its unique capillary structure and physiological features. To exploit this property in lung-targeting siRNA delivery, we designed and studied a multi-domain peptide named K-β, which was able to form inter-molecular β-sheet structures. Results showed that K-β peptides and siRNAs formed stable complex particles of 60 nm when mixed together. A critical property of such particles was that, after being intravenously injected into mice, they further associated into loose and micron-sized aggregates, and thus effectively entrapped within the capillaries of the lung, leading to a passive accumulation and gene-silencing. The large size aggregates can dissociate or break down by the shear stress generated by blood flow, alleviating the pulmonary embolism. Besides the lung, siRNA enrichment and targeted gene silencing were also observed in the liver. This drug delivery strategy, together with the low toxicity, biodegradability, and programmability of peptide carriers, show great potentials in vivo applications. PMID:26955887

  19. Tobacco mosaic virus-based protein nanoparticles and nanorods for chemotherapy delivery targeting breast cancer

    PubMed Central

    Bruckman, Michael A.; Czapar, Anna E.; VanMeter, Allen; Randolph, Lauren N.; Steinmetz, Nicole F.

    2016-01-01

    Drug delivery systems are required for drug targeting to avoid adverse effects associated with chemotherapy treatment regimes. Our approach is focused on the study and development of plant virus-based materials as drug delivery systems; specifically, this work focuses on the tobacco mosaic virus (TMV). Native TMV forms a hollow, high aspect-ratio nanotube measuring 300 × 18 nm with a 4 nm-wide central channel. Heat-transformation can be applied to TMV yielding spherical nanoparticles (SNPs) measuring ~50 nm in size. While bioconjugate chemistries have been established to modify the TMV rod, such methods have not yet been described for the SNP platform. In this work, we probed the reactivity of SNPs toward bioconjugate reactions targeting lysine, glutamine/aspartic acid, and cysteine residues. We demonstrate functionalization of SNPs using these chemistries yielding efficient payload conjugation. In addition to covalent labeling techniques, we developed encapsulation techniques, where the cargo is loaded into the SNP during heat-transition from rod-to-sphere. Finally, we developed TMV and SNP formulations loaded with the chemotherapeutic doxorubicin, and we demonstrate the application of TMV rods and spheres for chemotherapy delivery targeting breast cancer. PMID:26941034

  20. Tobacco mosaic virus-based protein nanoparticles and nanorods for chemotherapy delivery targeting breast cancer.

    PubMed

    Bruckman, Michael A; Czapar, Anna E; VanMeter, Allen; Randolph, Lauren N; Steinmetz, Nicole F

    2016-06-10

    Drug delivery systems are required for drug targeting to avoid adverse effects associated with chemotherapy treatment regimes. Our approach is focused on the study and development of plant virus-based materials as drug delivery systems; specifically, this work focuses on the tobacco mosaic virus (TMV). Native TMV forms a hollow, high aspect-ratio nanotube measuring 300×18nm with a 4nm-wide central channel. Heat-transformation can be applied to TMV yielding spherical nanoparticles (SNPs) measuring ~50nm in size. While bioconjugate chemistries have been established to modify the TMV rod, such methods have not yet been described for the SNP platform. In this work, we probed the reactivity of SNPs toward bioconjugate reactions targeting lysine, glutamine/aspartic acid, and cysteine residues. We demonstrate functionalization of SNPs using these chemistries yielding efficient payload conjugation. In addition to covalent labeling techniques, we developed encapsulation techniques, where the cargo is loaded into the SNP during heat-transition from rod-to-sphere. Finally, we developed TMV and SNP formulations loaded with the chemotherapeutic doxorubicin, and we demonstrate the application of TMV rods and spheres for chemotherapy delivery targeting breast cancer.

  1. Inter-molecular β-sheet structure facilitates lung-targeting siRNA delivery

    NASA Astrophysics Data System (ADS)

    Zhou, Jihan; Li, Dong; Wen, Hao; Zheng, Shuquan; Su, Cuicui; Yi, Fan; Wang, Jue; Liang, Zicai; Tang, Tao; Zhou, Demin; Zhang, Li-He; Liang, Dehai; Du, Quan

    2016-03-01

    Size-dependent passive targeting based on the characteristics of tissues is a basic mechanism of drug delivery. While the nanometer-sized particles are efficiently captured by the liver and spleen, the micron-sized particles are most likely entrapped within the lung owing to its unique capillary structure and physiological features. To exploit this property in lung-targeting siRNA delivery, we designed and studied a multi-domain peptide named K-β, which was able to form inter-molecular β-sheet structures. Results showed that K-β peptides and siRNAs formed stable complex particles of 60 nm when mixed together. A critical property of such particles was that, after being intravenously injected into mice, they further associated into loose and micron-sized aggregates, and thus effectively entrapped within the capillaries of the lung, leading to a passive accumulation and gene-silencing. The large size aggregates can dissociate or break down by the shear stress generated by blood flow, alleviating the pulmonary embolism. Besides the lung, siRNA enrichment and targeted gene silencing were also observed in the liver. This drug delivery strategy, together with the low toxicity, biodegradability, and programmability of peptide carriers, show great potentials in vivo applications.

  2. BDNF gene delivery mediated by neuron-targeted nanoparticles is neuroprotective in peripheral nerve injury.

    PubMed

    Lopes, Cátia D F; Gonçalves, Nádia P; Gomes, Carla P; Saraiva, Maria J; Pêgo, Ana P

    2017-03-01

    Neuron-targeted gene delivery is a promising strategy to treat peripheral neuropathies. Here we propose the use of polymeric nanoparticles based on thiolated trimethyl chitosan (TMCSH) to mediate targeted gene delivery to peripheral neurons upon a peripheral and minimally invasive intramuscular administration. Nanoparticles were grafted with the non-toxic carboxylic fragment of the tetanus neurotoxin (HC) to allow neuron targeting and were explored to deliver a plasmid DNA encoding for the brain-derived neurotrophic factor (BDNF) in a peripheral nerve injury model. The TMCSH-HC/BDNF nanoparticle treatment promoted the release and significant expression of BDNF in neural tissues, which resulted in an enhanced functional recovery after injury as compared to control treatments (vehicle and non-targeted nanoparticles), associated with an improvement in key pro-regenerative events, namely, the increased expression of neurofilament and growth-associated protein GAP-43 in the injured nerves. Moreover, the targeted nanoparticle treatment was correlated with a significantly higher density of myelinated axons in the distal stump of injured nerves, as well as with preservation of unmyelinated axon density as compared with controls and a protective role in injury-denervated muscles, preventing them from denervation. These results highlight the potential of TMCSH-HC nanoparticles as non-viral gene carriers to deliver therapeutic genes into the peripheral neurons and thus, pave the way for their use as an effective therapeutic intervention for peripheral neuropathies.

  3. MRI-visible liposome nanovehicles for potential tumor-targeted delivery of multimodal therapies

    NASA Astrophysics Data System (ADS)

    Ren, Lili; Chen, Shizhen; Li, Haidong; Zhang, Zhiying; Ye, Chaohui; Liu, Maili; Zhou, Xin

    2015-07-01

    Real-time diagnosis and monitoring of disease development, and therapeutic responses to treatment, are possible by theranostic magnetic resonance imaging (MRI). Here we report the synthesis of a multifunctional liposome, which contains Gd-DOTA (an MRI probe), paclitaxel and c(RGDyk) (a targeted peptide). This nanoparticle overcame the insolubility of paclitaxel, reduced the side effects of FDA-approved formulation of PTX-Cre (Taxol®) and improved drug delivery efficiency to the tumor. c(RGDyk) modification greatly enhanced the cytotoxicity of the drug in tumor cells A549. The T1 relaxivity in tumor cells treated with the targeted liposome formulation was increased 16-fold when compared with the non-targeted group. In vivo, the tumors in mice were visualized using T1-weighted imaging after administration of the liposome. Also the tumor growth could be inhibited well after the treatment. Fluorescence images in vitro and ex vivo also showed the targeting effect of this liposome in tumor cells, indicating that this nanovehicle could limit the off-target side effects of anticancer drugs and contrast agents. These findings lay the foundation for further tumor inhibition study and application of this delivery vehicle in cancer therapy settings.

  4. Magnetic chitosan nanoparticles as a drug delivery system for targeting photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Sun, Yun; Chen, Zhi-long; Yang, Xiao-xia; Huang, Peng; Zhou, Xin-ping; Du, Xiao-xia

    2009-04-01

    Photodynamic therapy (PDT) has become an increasingly recognized alternative to cancer treatment in clinic. However, PDT therapy agents, namely photosensitizer (PS), are limited in application as a result of prolonged cutaneous photosensitivity, poor water solubility and inadequate selectivity, which are encountered by numerous chemical therapies. Magnetic chitosan nanoparticles provide excellent biocompatibility, biodegradability, non-toxicity and water solubility without compromising their magnetic targeting. Nevertheless, no previous attempt has been reported to develop an in vivo magnetic drug delivery system with chitosan nanoparticles for magnetic resonance imaging (MRI) monitored targeting photodynamic therapy. In this study, magnetic targeting chitosan nanoparticles (MTCNPs) were prepared and tailored as a drug delivery system and imaging agents for PS, designated as PHPP. Results showed that PHPP-MTCNPs could be used in MRI monitored targeting PDT with excellent targeting and imaging ability. Non-toxicity and high photodynamic efficacy on SW480 carcinoma cells both in vitro and in vivo were achieved with this method at the level of 0-100 µM. Notably, localization of nanoparticles in skin and hepatic tissue was significantly less than in tumor tissue, therefore photosensitivity and hepatotoxicity can be attenuated.

  5. 'One-pot' synthesis of multifunctional GSH-CdTe quantum dots for targeted drug delivery.

    PubMed

    Chen, Xiaoqin; Tang, Yajun; Cai, Bing; Fan, Hongsong

    2014-06-13

    A novel quantum dots-based multifunctional nanovehicle (DOX-QD-PEG-FA) was designed for targeted drug delivery, fluorescent imaging, tracking, and cancer therapy, in which the GSH-CdTe quantum dots play a key role in imaging and drug delivery. To exert curative effects, the antineoplastic drug doxorubicin hydrochloride (DOX) was loaded on the GSH-CdTe quantum dots through a condensation reaction. Meanwhile, a polyethylene glycol (PEG) shell was introduced to wrap the DOX-QD, thus stabilizing the structure and preventing clearance and drug release during systemic circulation. To actively target cancer cells and prevent the nanovehicles from being absorbed by normal cells, the nanoparticles were further decorated with folic acid (FA), allowing them to target HeLa cells that express the FA receptor. The multifunctional DOX-QD-PEG-FA conjugates were simply prepared using the 'one pot' method. In vitro study demonstrated that this simple, multifunctional nanovehicle can deliver DOX to the targeted cancer cells and localize the nanoparticles. After reaching the tumor cells, the FA on the DOX-QD-PEG surface allowed folate receptor recognition and increased the drug concentration to realize a higher curative effect. This novel, multifunctional DOX-QD-PEG-FA system shows great potential for tumor imaging, targeting, and therapy.

  6. P-selectin is a nanotherapeutic delivery target in the tumor microenvironment.

    PubMed

    Shamay, Yosi; Elkabets, Moshe; Li, Hongyan; Shah, Janki; Brook, Samuel; Wang, Feng; Adler, Keren; Baut, Emily; Scaltriti, Maurizio; Jena, Prakrit V; Gardner, Eric E; Poirier, John T; Rudin, Charles M; Baselga, José; Haimovitz-Friedman, Adriana; Heller, Daniel A

    2016-06-29

    Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor.

  7. Intracellular targeting delivery of liposomal drugs to solid tumors based on EPR effects.

    PubMed

    Maruyama, Kazuo

    2011-03-18

    The success of an effective drug delivery system using liposomes for solid tumor targeting based on EPR effects is highly dependent on both size ranging from 100-200 nm in diameter and prolonged circulation half-life in the blood. A major development was the synthesis of PEG-liposomes with a prolonged circulation time in the blood. Active targeting of immunoliposomes to the solid tumor tissue can be achieved by the Fab' fragment which is better than whole IgG in terms of designing PEG-immunoliposomes with prolonged circulation. For intracellular targeting delivery to solid tumors based on EPR effects, transferrin-PEG-liposomes can stay in blood circulation for a long time and extravasate into the extravascular of tumor tissue by the EPR effect as PEG-liposomes. The extravasated transferrin-PEG-liposomes can maintain anti cancer drugs in interstitial space for a longer period, and deliver them into the cytoplasm of tumor cells via transferrin receptor-mediated endocytosis. Transferrin-PEG-liposomes improve the safety and efficacy of anti cancer drug by both passive targeting by prolonged circulation and active targeting by transferrin.

  8. Self-assembled nanoplatform for targeted delivery of chemotherapy agents via affinity-regulated molecular interactions.

    PubMed

    Park, Spencer; Kang, Sungkwon; Veach, Alexander J; Vedvyas, Yogindra; Zarnegar, Rasa; Kim, Ju-Young; Jin, Moonsoo M

    2010-10-01

    Site-specific delivery of drugs while minimizing unwanted distribution has been one of the pursued goals in cancer therapy. In this endeavor, we have developed targeted polymeric nanoparticles called amphiphilic urethane acrylate nonionomer (UAN) for encapsulation of diverse water-insoluble drugs and diagnostic agents, as well as for simple and reproducible surface conjugation of targeting ligands. Using monoclonal antibodies or lymphocyte function-associated antigen-1 (LFA-1) I domain engineered for varying affinities to intercellular adhesion molecule (ICAM)-1, we were able to deliver UAN nanoparticles to human cancer cells with the efficiency dependent on the strength of the molecular interactions and the degree of ICAM-1 expression on cell surface. Compared to non-specific uptake of free drugs, targeted delivery of UAN nanoparticles carrying equal amount of drugs produced more potent cytotoxicity. Notably, without the targeting ligands attached, UAN nanoparticles were largely precluded from non-specific uptake by the cells, resulting in much lower toxicity. The versatility of our UAN nanoparticles in both payload encapsulation and presentation of targeting ligands may facilitate developing a robust platform for evaluating various combinations of cancer drugs and molecular interactions toward developing effective cancer therapy formulations.

  9. P-selectin is a nanotherapeutic delivery target in the tumor microenvironment

    PubMed Central

    Shamay, Yosi; Elkabets, Moshe; Li, Hongyan; Shah, Janki; Brook, Samuel; Wang, Feng; Adler, Keren; Baut, Emily; Scaltriti, Maurizio; Jena, Prakrit V.; Gardner, Eric E.; Poirier, John T.; Rudin, Charles M.; Baselga, José; Haimovitz-Friedman, Adriana; Heller, Daniel A.

    2016-01-01

    Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor. PMID:27358497

  10. Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides

    PubMed Central

    Liu, Shuang

    2008-01-01

    Receptor-based radiopharmaceuticals are of great current interest in early molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals. PMID:18538888

  11. The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery

    PubMed Central

    Corbo, Claudia; Molinaro, Roberto; Parodi, Alessandro; Toledano Furman, Naama E; Salvatore, Francesco; Tasciotti, Ennio

    2016-01-01

    In a perfect sequence of events, nanoparticles (NPs) are injected into the bloodstream where they circulate until they reach the target tissue. The ligand on the NP surface recognizes its specific receptor expressed on the target tissue and the drug is released in a controlled manner. However, once injected in a physiological environment, NPs interact with biological components and are surrounded by a protein corona (PC). This can trigger an immune response and affect NP toxicity and targeting capabilities. In this review, we provide a survey of recent findings on the NP–PC interactions and discuss how the PC can be used to modulate both cytotoxicity and the immune response as well as to improve the efficacy of targeted delivery of nanocarriers. PMID:26653875

  12. The impact of nanoparticle protein corona on cytotoxicity, immunotoxicity and target drug delivery.

    PubMed

    Corbo, Claudia; Molinaro, Roberto; Parodi, Alessandro; Toledano Furman, Naama E; Salvatore, Francesco; Tasciotti, Ennio

    2016-01-01

    In a perfect sequence of events, nanoparticles (NPs) are injected into the bloodstream where they circulate until they reach the target tissue. The ligand on the NP surface recognizes its specific receptor expressed on the target tissue and the drug is released in a controlled manner. However, once injected in a physiological environment, NPs interact with biological components and are surrounded by a protein corona (PC). This can trigger an immune response and affect NP toxicity and targeting capabilities. In this review, we provide a survey of recent findings on the NP-PC interactions and discuss how the PC can be used to modulate both cytotoxicity and the immune response as well as to improve the efficacy of targeted delivery of nanocarriers.

  13. Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood-brain barrier opening.

    PubMed

    Sierra, Carlos; Acosta, Camilo; Chen, Cherry; Wu, Shih-Ying; Karakatsani, Maria E; Bernal, Manuel; Konofagou, Elisa E

    2017-04-01

    Focused ultrasound in conjunction with lipid microbubbles has fully demonstrated its ability to induce non-invasive, transient, and reversible blood-brain barrier opening. This study was aimed at testing the feasibility of our lipid-coated microbubbles as a vector for targeted drug delivery in the treatment of central nervous system diseases. These microbubbles were labeled with the fluorophore 5-dodecanoylaminfluorescein. Focused ultrasound targeted mouse brains in vivo in the presence of these microbubbles for trans-blood-brain barrier delivery of 5-dodecanoylaminfluorescein. This new approach, compared to previously studies of our group, where fluorescently labeled dextrans and microbubbles were co-administered, represents an appreciable improvement in safety outcome and targeted drug delivery. This novel technique allows the delivery of 5-dodecanoylaminfluorescein at the region of interest unlike the alternative of systemic exposure. 5-dodecanoylaminfluorescein delivery was assessed by ex vivo fluorescence imaging and by in vivo transcranial passive cavitation detection. Stable and inertial cavitation doses were quantified. The cavitation dose thresholds for estimating, a priori, successful targeted drug delivery were, for the first time, identified with inertial cavitation were concluded to be necessary for successful delivery. The findings presented herein indicate the feasibility and safety of the proposed microbubble-based targeted drug delivery and that, if successful, can be predicted by cavitation detection in vivo.

  14. Magnetic graphene oxide as a carrier for targeted delivery of chemotherapy drugs in cancer therapy

    NASA Astrophysics Data System (ADS)

    Huang, Ya-Shu; Lu, Yu-Jen; Chen, Jyh-Ping

    2017-04-01

    A magnetic targeted functionalized graphene oxide (GO) complex is constituted as a nanocarrier for targeted delivery and pH-responsive controlled release of chemotherapy drugs to cancer cells. Magnetic graphene oxide (mGO) was prepared by chemical co-precipitation of Fe3O4 magnetic nanoparticles on GO nano-platelets. The mGO was successively modified by chitosan and mPEG-NHS through covalent bindings to synthesize mGOC-PEG. The polyethylene glycol (PEG) moiety is expected to prolong the circulation time of mGO by reducing the reticuloendothelial system clearance. Irinotecan (CPT-11) or doxorubicin (DOX) was loaded to mGOC-PEG through π-π stacking interactions for magnetic targeted delivery of the cancer chemotherapy drug. The best values of loading efficiency and loading content of CPT-11 were 54% and 2.7% respectively; whereas for DOX, they were 65% and 393% The pH-dependent drug release profile was further experimented at different pHs, in which 60% of DOX was released at pH 5.4 and 10% was released at pH 7.4. In contrast, 90% CPT-11 was released at pH 5.4 and 70% at pH 7.4. Based on the drug loading and release characteristics, mGOC-PEG/DOX was further chosen for in vitro cytotoxicity tests against U87 human glioblastoma cell line. The IC50 value of mGOC-PEG/DOX was found to be similar to that of free DOX but was reduced dramatically when subject to magnetic targeting. It is concluded that with the high drug loading and pH-dependent drug release properties, mGOC-PEG will be a promising drug carrier for targeted delivery of chemotherapy drugs in cancer therapy.

  15. Folic acid-conjugated amphiphilic alternating copolymer as a new active tumor targeting drug delivery platform

    PubMed Central

    Li, Xia; Szewczuk, Myron R; Malardier-Jugroot, Cecile

    2016-01-01

    Targeted drug delivery using polymeric nanostructures is an emerging cancer research area, engineered for safer, more efficient, and effective use of chemotherapeutic drugs. A pH-responsive, active targeting delivery system was designed using folic acid functionalized amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA). The polymeric template is pH responsive, forming amphiphilic nanostructures at pH 7, allowing the encapsulation of hydrophobic drugs on its interior. Moreover, the structure is stable only at neutral pH and collapses in the acidic tumor microenvironment, releasing drugs on-site from its core. The delivery vehicle is investigated using human pancreatic PANC-1 cancer cells and RAW-Blue™ mouse macrophage reporter cell line, both of which have overly expression of folic acid receptors. To trace the cellular uptake by both cell lines, curcumin was selected as a dye and drug mimic owing to its fluorescence nature and hydrophobic properties. Fluorescent microscopy of FA-DABA-SMA loaded with curcumin revealed a significant internalization of the dye by human pancreatic PANC-1 cancer cells compared to those with unfunctionalized polymers (SMA). Moreover, the FA-DABA-SMA polymers exhibit rodlike association specific to the cells. Both empty SMA and FA-DABA-SMA show little toxicity to PANC-1 cells as characterized by WST-1 cell proliferation assay. These results clearly indicate that FA-DABA-SMA polymers show potential as an active tumor targeting drug delivery system with the ability to internalize hydrophobic chemotherapeutics after they specifically attach to cancer cells. PMID:28008233

  16. Engineered Polymer-Transferrin Conjugates as Self-Assembling Targeted Drug Delivery Systems.

    PubMed

    Makwana, Hiteshri; Mastrotto, Francesca; Magnusson, Johannes Pall; Sleep, Darrell; Hay, Joanna; Nicholls, Karl J; Allen, Stephanie; Alexander, Cameron

    2017-03-28

    Polymer-protein conjugates can be engineered to self-assemble into discrete and well-defined drug delivery systems which combine the advantages of receptor targeting and controlled drug release. We designed specific conjugates of the iron-binding and transport protein, transferrin (Tf), to combine the advantages of this serum-stable protein as a targeting agent for cancer cells with self-assembling polymers to act as carriers of cytotoxic drugs. Tf variants were expressed with cysteine residues at sites spanning different regions of the protein surface and the polymer conjugates grown from these variants were compared with polymer conjugates grown from non-selectively derivatised sites on native Tf. The resulting synthetic biopolymer hybrids were evaluated for self-assembly properties, size and topology, ability to carry an anti-cancer drug (paclitaxel) and cytotoxicity with and without a drug payload in a representative human colon cancer cell line. The results demonstrated that the engineered Tf variant polymer conjugates formed better-defined self-assembled nanoparticles than the non-selectively derivatised conjugates and showed greater efficacy in paclitaxel delivery. A polymer conjugate grown from a specific Tf variant, S415C was found to be taken up rapidly into cancer cells expressing the Tf-receptor, and, while tolerated well by cells in the absence of drugs, was as cytotoxic as free paclitaxel when loaded with the drug. Importantly, the S415C conjugate polymer was not the most active variant in Tf-receptor binding, suggesting that the nanoscale self-assembly of the polymer-protein hybrid is also a key factor in delivery efficacy. The data overall suggest new design rules for polymer-biopolymer hybrids and therapeutic delivery systems which include engineering specific residues for conjugation which mediate nanoscale assembly as well as control of ligand-receptor interactions to target specific cell types.

  17. Targeted delivery using peptide-functionalised gold nanoparticles to white adipose tissues of obese rats

    NASA Astrophysics Data System (ADS)

    Thovhogi, Ntevheleni; Sibuyi, Nicole; Meyer, Mervin; Onani, Martin; Madiehe, Abram

    2015-02-01

    Obesity is a complex metabolic disease of excessive fat accumulation. It is a worldwide epidemic affecting billions of people. Current pharmacological treatment of obesity remains limited and ineffective due to systemic drug toxicity and undesirable side effects. The current epidemic raises a serious need for development of safer drugs to treat obesity. Nanotechnology-based drug delivery system for administering pharmaceutical compound to achieve therapeutic effects is currently an exciting field in cancer treatment. Drug delivery involves either modification of drug release profile, absorption, distribution and/or elimination, for the benefit of improving drug efficacy and safety. Therefore, nanotechnology holds promise in the treatment of diseases including obesity. Gold nanoparticles (GNPs) functionalised with different biomolecules have been successfully used as drug delivery, labelling and imaging tools in biomedical research. In this study, the binding-specificity and targeting ability of adipose homing peptide (AHP)-functionalised GNPs (AHP-GNPs) were evaluated using flow cytometry and inductively coupled plasma-optical emission spectroscopy. Caco-2 cells and rats fed either chow or a high-fat diet were treated with either unfunctionalised GNPs or AHP-GNPs. Cellular uptake of GNPs was detected in cells treated with AHP-GNPs and not those treated with GNPs alone. Binding of AHP to cells was both temperature- and concentration-dependent. Compared to rats treated with GNPs alone, treatment of obese rats with AHP-GNPs resulted in the targeted delivery of the GNPs to the white adipose tissue (WAT). This paper reports the successful targeting of AHP-functionalised GNPs to WAT of obese rats.

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

    PubMed Central

    Gullotti, Emily; Yeo, Yoon

    2009-01-01

    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

  19. Integrin Targeting and Toxicological Assessment of Peptide-Conjugated Liposome Delivery Systems to Activated Endothelial Cells.

    PubMed

    Kermanizadeh, Ali; Villadsen, Klaus; Østrem, Ragnhild G; Jensen, Knud J; Møller, Peter; Loft, Steffen

    2017-04-01

    Utilization of functionalized liposomes as the means of targeted delivery of therapeutics may enhance specific transport of biologically active drugs to target tissues, while avoiding or reducing undesired side effects. In the present investigation, peptide-conjugated cationic liposomes were constructed with the aim of targeting integrins (i.e. vitronectin and/or fibronectin receptors) on activated endothelial cells. The peptide-conjugated liposomes induced only cytotoxicity at the highest concentration in non-activated or activated endothelial cells, as well as in co-culture of endothelial cells and macrophages. There was unaltered secretion of cytokines after exposure of peptide-conjugated liposomes to endothelial cells, indicating that the materials were not inflammogenic. Liposomes with a peptide targeting the fibronectin receptor (integrin α5β1) were more effective in targeting of activated endothelial cells, as compared to a liposome with a peptide that targeted both the fibronectin and vitronectin receptors, as well as liposomes with a control peptide. The liposome targeted to the fibronectin receptor also displayed uptake in endothelial cells in co-culture with activated macrophages. Therefore, this study demonstrates the feasibility of constructing a peptide-conjugated cationic liposome, which displays targeting to activated endothelial cells at concentrations that are not cytotoxic or inflammogenic to the cells.

  20. Synthesis of a novel, sequentially active-targeted drug delivery nanoplatform for breast cancer therapy.

    PubMed

    Satsangi, Arpan; Roy, Sudipa S; Satsangi, Rajiv K; Tolcher, Anthony W; Vadlamudi, Ratna K; Goins, Beth; Ong, Joo L

    2015-08-01

    Breast cancer is the leading cause of cancer deaths among women. Paclitaxel (PTX), an important breast cancer medicine, exhibits reduced bioavailability and therapeutic index due to high hydrophobicity and indiscriminate cytotoxicity. PTX encapsulation in one-level active targeting overcomes such barriers, but enhances toxicity to normal tissues with cancer-similar expression profiles. This research attempted to overcome this challenge by increasing selectivity of cancer cell targeting while maintaining an ability to overcome traditional pharmacological barriers. Thus, a multi-core, multi-targeting construct for tumor specific delivery of PTX was fabricated with (i) an inner-core prodrug targeting the cancer-overexpressed cathepsin B through a cathepsin B-cleavable tetrapeptide that conjugates PTX to a poly(amidoamine) dendrimer, and (ii) the encapsulation of this prodrug (PGD) in an outer core of a RES-evading, folate receptor (FR)-targeting liposome. Compared to traditional FR-targeting PTX liposomes, this sequentially active-targeted dendrosome demonstrated better prodrug retention, an increased cytotoxicity to cancer cells (latter being true when FR and cathepsin B activities were both at moderate-to-high levels) and higher tumor reduction. This research may eventually evolve a product platform with reduced systemic toxicity inherent with traditional chemotherapy and localized toxicity inherent to single-target nanoplatforms, thereby allowing for better tolerance of higher therapeutic load in advanced disease states.

  1. A Study of Shrinkage Stress Reduction and Mechanical Properties of Nanogel-Modified Resin Systems.

    PubMed

    Liu, Jiancheng; Howard, Gregory D; Lewis, Steven H; Barros, Matthew D; Stansbury, Jeffrey W

    2012-11-01

    A series of nanogel compositions were prepared from urethane dimethacrylate (UDMA) and isobornyl methacrylate (IBMA) in the presence of a thiol chain transfer agent. The linear oligomer of IBMA was synthesized by a similar solution polymerization technique. The nanogels were prepared with different crosslinker concentrations to achieve varied branching densities and molecular weights. The prepolymers were dispersed in triethylene glycol dimethacrylate at loading levels ranging from 10 wt% to 50 wt%. Photopolymerization reaction kinetics of all prepolymer modified systems were enhanced relative to the nanogel-free control during early stage polymerization while limiting conversion was similar for most samples. Volumetric polymerization shrinkage was reduced proportionally with the prepolymer content while the corresponding decrease in polymerization stress was potentially greater than an additive linear behavior. Flexural strength for inert linear polymer-modified systems decreased significantly with the increase in the prepolymer content; however, with an increase in the crosslinker concentration within the nanogel additives, and an increase in the concentration of residual pendant reactive sites, flexural strength was maintained or improved regardless of the nanogel loading level. This demonstrates that covalent attachment rather than just physical entanglement with the polymer matrix is important for effective polymer mechanical reinforcement by nanogel additives. Reactive nanogel additives can be considered as a practical, generic means to achieve substantial reductions in polymerization shrinkage and shrinkage stress in common polymers.

  2. A Study of Shrinkage Stress Reduction and Mechanical Properties of Nanogel-Modified Resin Systems

    PubMed Central

    Liu, JianCheng; Howard, Gregory D.; Lewis, Steven H.; Barros, Matthew D.; Stansbury, Jeffrey W.

    2012-01-01

    A series of nanogel compositions were prepared from urethane dimethacrylate (UDMA) and isobornyl methacrylate (IBMA) in the presence of a thiol chain transfer agent. The linear oligomer of IBMA was synthesized by a similar solution polymerization technique. The nanogels were prepared with different crosslinker concentrations to achieve varied branching densities and molecular weights. The prepolymers were dispersed in triethylene glycol dimethacrylate at loading levels ranging from 10 wt% to 50 wt%. Photopolymerization reaction kinetics of all prepolymer modified systems were enhanced relative to the nanogel-free control during early stage polymerization while limiting conversion was similar for most samples. Volumetric polymerization shrinkage was reduced proportionally with the prepolymer content while the corresponding decrease in polymerization stress was potentially greater than an additive linear behavior. Flexural strength for inert linear polymer-modified systems decreased significantly with the increase in the prepolymer content; however, with an increase in the crosslinker concentration within the nanogel additives, and an increase in the concentration of residual pendant reactive sites, flexural strength was maintained or improved regardless of the nanogel loading level. This demonstrates that covalent attachment rather than just physical entanglement with the polymer matrix is important for effective polymer mechanical reinforcement by nanogel additives. Reactive nanogel additives can be considered as a practical, generic means to achieve substantial reductions in polymerization shrinkage and shrinkage stress in common polymers. PMID:23109731

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

    PubMed

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

    2013-12-01

    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.

  4. On the scattered light by dilute aqueous dispersions of nanogel particles.

    PubMed

    Callejas-Fernández, J; Ramos, J; Forcada, J; Moncho-Jordá, A

    2015-07-15

    This work deals with the scattered light by nanoparticles formed by a temperature sensitive polymer networks, namely nanogel particles. The scattered light is measured as a function of the scattering angle at temperatures below and above the volume phase transition temperature (VPTT) of nanogel particles. Our experimental results indicate that nanogel particles have a core-shell structure, formed by a uniform highly cross-linked core surrounded by a fuzzy shell where the polymer density decays to zero gradually for swollen configurations and sharply for shrunken states. The theoretical fitting of the experimental curves shows that the scattered light at low angle obeys a decreasing power law with the scattering vector, q(-α). The value of exponent α provides information about the radial dependence of the polymer density at the external shell of the particles for swollen nanogels, and about the degree of roughness of the surface for the case of shrunken nanogels. On the one hand, at low temperatures (below the VPPT), the nanogel particle is in the swollen state and the light scattering data show that its shell structure follows a fractal behaviour, with a polymer density that decays as r(α-3), where r is the distance to the particle centre. On the other hand, above the VPPT the results indicate that nanogel collapses into a core of uniform polymer density and a rough shell, with a fractal surface dimension of 2.5.

  5. Targeted delivery of 5-fluorouracil to cholangiocarcinoma cells using folic acid as a targeting agent.

    PubMed

    Ngernyuang, Nipaporn; Seubwai, Wunchana; Daduang, Sakda; Boonsiri, Patcharee; Limpaiboon, Temduang; Daduang, Jureerut

    2016-03-01

    There are limits to the standard treatment for cholangiocarcinoma (CCA) including drug resistance and side effects. The objective of this study was to develop a new technique for carrying drugs by conjugation with gold nanoparticles and using folic acid as a targeting agent in order to increase drug sensitivity. Gold nanoparticles (AuNPs) were functionalized with 5-fluorouracil (5FU) and folic acid (FA) using polyethylene glycol (PEG) shell as a linker (AuNPs-PEG-5FU-FA). Its cytotoxicity was tested in CCA cell lines (M139 and M213) which express folic acid receptor (FA receptor). The results showed that AuNPs-PEG-5FU-FA increased the cytotoxic effects in the M139 and M213 cells by 4.76% and 7.95%, respectively compared to those treated with free 5FU+FA. It is found that the cytotoxicity of the AuNPs-PEG-5FU-FA correlates with FA receptor expression suggested the use of FA as a targeted therapy. The mechanism of cytotoxicity was mediated via mitochondrial apoptotic pathway as determined by apoptosis array. In conclusion, our findings shed some light on the use of gold nanoparticles for conjugation with potential compounds and FA as targeted therapy which contribute to the improvement of anti-cancer drug efficacy. In vivo study should be warranted for its effectiveness of stability, biosafety and side effect reduction.

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

    PubMed

    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

    2010-06-15

    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 sub-endothelial 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.

  7. A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy.

    PubMed

    Johnsen, Kasper Bendix; Gudbergsson, Johann Mar; Skov, Martin Najbjerg; Pilgaard, Linda; Moos, Torben; Duroux, Meg

    2014-08-01

    Exosomes denote a class of secreted nanoparticles defined by size, surface protein and lipid composition, and the ability to carry RNA and proteins. They are important mediators of intercellular communication and regulators of the cellular niche, and their altered characteristics in many diseases, such as cancer, suggest them to be important both for diagnostic and therapeutic purposes, prompting the idea of using exosomes as drug delivery vehicles, especially for gene therapy. This review covers the current status of evidence presented in the field of exosome-based drug delivery systems. Components for successful exosome-based drug delivery, such as choice of donor cell, therapeutic cargo, use of targeting peptide, loading method and administration route are highlighted and discussed with a general focus pertaining to the results obtained in models of different cancer types. In addition, completed and on-going clinical trials are described, evaluating exosome-based therapies for the treatment of different cancer types. Due to their endogenous origin, exosome-based drug delivery systems may have advantages in the treatment of cancer, but their design needs further refinement to justify their usage on the clinical scale.

  8. Cell-specific targeting strategies for electroporation-mediated gene delivery in cells and animals.

    PubMed

    Dean, David A

    2013-10-01

    The use of electroporation to facilitate gene transfer is an extremely powerful and useful method for both in vitro and in vivo applications. One of its great strengths is that it induces functional destabilization and permeabilization of cell membranes throughout a tissue leading to widespread gene transfer to multiple cells and cell types within the electric field. While this is a strength, it can also be a limitation in terms of cell-specific gene delivery. The ability to restrict gene delivery and expression to particular cell types is of paramount importance for many types of gene therapy, since ectopic expression of a transgene could lead to deleterious host inflammatory responses or dysregulation of normal cellular functions. At present, there are relatively few ways to obtain cell-specific targeting of nonviral vectors, molecular probes, small molecules, and imaging agents. We have developed a novel means of restricting gene delivery to desired cell types based on the ability to control the transport of plasmids into the nuclei of desired cell types. In this article, we discuss the mechanisms of this approach and several applications in living animals to demonstrate the benefits of the combination of electroporation and selective nuclear import of plasmids for cell-specific gene delivery.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    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

    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

  11. Peptide-22 and Cyclic RGD Functionalized Liposomes for Glioma Targeting Drug Delivery Overcoming BBB and BBTB.

    PubMed

    Chen, Cuitian; Duan, Ziqing; Yuan, Yan; Li, Ruixiang; Pang, Liang; Liang, Jianming; Xu, Xinchun; Wang, Jianxin

    2017-02-22

    Chemotherapy outcomes for the treatment of glioma remain unsatisfied due to the inefficient drug transport across BBB/BBTB and poor drug accumulation in the tumor site. Nanocarriers functionalized with different targeting ligands are considered as one of the most promising alternatives. However, few studies were reported to compare the targeting efficiency of the ligands and develop nanoparticles to realize BBB/BBTB crossing and brain tumor targeting simultaneously. In this study, six peptide-based ligands (Angiopep-2, T7, Peptide-22, c(RGDfK), D-SP5 and Pep-1), widely used for brain delivery, were selected to decorate liposomes, respectively, so as to compare their targeting ability to BBB or BBTB. Based on the in vitro cellular uptake results on BCECs and HUVECs, Peptide-22 and c(RGDfK) were picked to construct a BBB/BBTB dual-crossing, glioma-targeting liposomal drug delivery system c(RGDfK)/Pep-22-DOX-LP. In vitro cellular uptake demonstrated that the synergetic effect of c(RGDfK) and Peptide-22 could significantly increase the internalization of liposomes on U87 cells. In vivo imaging further verified that c(RGDfK)/Pep-22-LP exhibited higher brain tumor distribution than single ligand modified liposomes. The median survival time of glioma-bearing mice treated with c(RGDfK)/Pep-22-DOX-LP (39.5 days) was significantly prolonged than those treated with free doxorubicin or other controls. In conclusion, the c(RGDfK) and Peptide-22 dual-modified liposome was constructed based on the targeting ability screening of various ligands. The system could effectively overcome BBB/BBTB barriers, target to tumor cells and inhibit the growth of glioma, which proved its potential for improving the efficacy of chemotherapeutics for glioma therapy.

  12. Bacteriophages and phage-inspired nanocarriers for targeted delivery of therapeutic cargos.

    PubMed

    Karimi, Mahdi; Mirshekari, Hamed; Moosavi Basri, Seyed Masoud; Bahrami, Sajad; Moghoofei, Mohsen; Hamblin, Michael R

    2016-11-15

    The main goal of drug delivery systems is to target therapeutic cargoes to desired cells and to ensure their efficient uptake. Recently a number of studies have focused on designing bio-inspired nanocarriers, such as bacteriophages, and synthetic carriers based on the bacteriophage structure. Bacteriophages are viruses that specifically recognize their bacterial hosts. They can replicate only inside their host cell and can act as natural gene carriers. Each type of phage has a particular shape, a different capacity for loading cargo, a specific production time, and their own mechanisms of supramolecular assembly, that have enabled them to act as tunable carriers. New phage-based technologies have led to the construction of different peptide libraries, and recognition abilities provided by novel targeting ligands. Phage hybridization with non-organic compounds introduces new properties to phages and could be a suitable strategy for construction of bio-inorganic carriers. In this review we try to cover the major phage species that have been used in drug and gene delivery systems, and the biological application of phages as novel targeting ligands and targeted therapeutics.

  13. RNA nanoparticle as a vector for targeted siRNA delivery into glioblastoma mouse model.

    PubMed

    Lee, Tae Jin; Haque, Farzin; Shu, Dan; Yoo, Ji Young; Li, Hui; Yokel, Robert A; Horbinski, Craig; Kim, Tae Hyong; Kim, Sung-Hak; Kwon, Chang-Hyuk; Nakano, Ichiro; Kaur, Balveen; Guo, Peixuan; Croce, Carlo M

    2015-06-20

    Systemic siRNA administration to target and treat glioblastoma, one of the most deadly cancers, requires robust and efficient delivery platform without immunogenicity. Here we report newly emerged multivalent naked RNA nanoparticle (RNP) based on pRNA 3-way-junction (3WJ) from bacteriophage phi29 to target glioblastoma cells with folate (FA) ligand and deliver siRNA for gene silencing. Systemically injected FA-pRNA-3WJ RNPs successfully targeted and delivered siRNA into brain tumor cells in mice, and efficiently reduced luciferase reporter gene expression (4-fold lower than control). The FA-pRNA-3WJ RNP also can target human patient-derived glioblastoma stem cells, thought to be responsible for tumor initiation and deadly recurrence, without accumulation in adjacent normal brain cells, nor other major internal organs. This study provides possible application of pRNA-3WJ RNP for specific delivery of therapeutics such as siRNA, microRNA and/or chemotherapeutic drugs into glioblastoma cells without inflicting collateral damage to healthy tissues.

  14. Cardiological biopharmaceuticals in the conception of drug targeting delivery: practical results and research perspectives.

    PubMed

    Maksimenko, A V

    2012-07-01

    The results of the clinical use of thrombolytic and antithrombotic preparations developed on the basis of protein conjugates obtained within the framework of the conception of drug targeting delivery in the organism are considered. A decrease has been noted in the number of biomedical projects focused on these derivatives as a result of various factors: the significant depletion of financial and organizational funds, the saturation of the pharmaceutical market with preparations of this kind, and the appearance of original means for interventional procedures. Factors that actively facilitate the conspicuous potentiation of the efficacy of bioconjugates were revealed: the biomedical testing of protein domains and their selected combinations, the optimization of molecular sizes for the bioconjugates obtained, the density of target localization, the application of cell adhesion molecules as targets, and the application of connected enzyme activities. Enzyme antioxidants and the opportunity for further elaboration of the drug delivery conception via the elucidation and formation of therapeutic targets for effective drug reactions by means of pharmacological pre- and postconditioning of myocardium arouse significant interest.

  15. Construction of hydroxypropyl-β-cyclodextrin copolymer nanoparticles and targeting delivery of paclitaxel

    NASA Astrophysics Data System (ADS)

    Miao, Qinghua; Li, Suping; Han, Siyuan; Wang, Zhi; Wu, Yan; Nie, Guangjun

    2012-08-01

    A novel amphiphilic copolymer with p-maleimidophenyl isocyanate-hydroxypropyl-β-cyclodextrin-polylactide-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine to generate copolymer nanoparticles (NPs) has been designed. In order to develop an active targeting system, integrin αvβ3-specific targeting peptide cyclo(Arg-Gly-Asp-D-Phe-Cys), cRGD, was conjugated to the surface of NPs (NPs-RGD). These NPs were used to encapsulate anti-tumor drug, paclitaxel. The resulting NPs exhibited high drug-loading capacity and controlled drug release in vitro at acidic pH. In vitro cytotoxicity assay demonstrates that paclitaxel-loaded NPs-RGD significantly inhibited B16 tumor cell (high αvβ3) proliferation relative to free paclitaxel and paclitaxel-loaded NPs at high concentrations. Paclitaxel-loaded NPs-RGD localized mainly in lysosomes in B16 cells as revealed by confocal microscopy. These results suggest a novel strategy for fabrication—functionalizing hydroxypropyl-β-cyclodextrin copolymer nanoparticles for targeting delivery of paclitaxel to integrin αvβ3-rich tumor cells. These nanocarriers can be readily extended to couple other bioactive molecules for active targeting and delivery of various chemotherapeutic drugs.

  16. Cancer Nanotheranostics: Improving Imaging and Therapy by Targeted Delivery across Biological Barriers

    PubMed Central

    Kievit, Forrest M.; Zhang, Miqin

    2012-01-01

    Cancer nanotheranostics aims to combine imaging and therapy of cancer through use of nanotechnology. The ability to engineer nanomaterials to interact with cancer cells at the molecular level can significantly improve the effectiveness and specificity of therapy to cancers that are currently difficult to treat. In particular, metastatic cancers, drug-resistant cancers, and cancer stem cells impose the greatest therapeutic challenge that requires targeted therapy to treat effectively. Targeted therapy can be achieved with appropriate designed drug delivery vehicles such as nanoparticles, adult stem cells, or T cells in immunotherapy. In this article, we first review the different types of materials commonly used to synthesize nanotheranostic particles and their use in imaging. We then discuss biological barriers that these nanoparticles encounter and must bypass to reach the target cancer cells, including the blood, liver, kidneys, spleen, and particularly the blood-brain barrier. We then review how nanotheranostics can be used to improve targeted delivery and treatment of cancer cells using nanoparticles, adult stem cells, and T cells in immunotherapy. Finally, we discuss development of nanoparticles to overcome current limitations in cancer therapy. PMID:21842473

  17. Medicinal chemistry based approaches and nanotechnology-based systems to improve CNS drug targeting and delivery.

    PubMed

    Vlieghe, Patrick; Khrestchatisky, Michel

    2013-05-01

    The central nervous system (CNS) is protected by various barriers, which regulate nervous tissue homeostasis and control the selective and specific uptake, efflux, and metabolism of endogenous and exogenous molecules. Among these barriers is the blood-brain barrier (BBB), a physical and physiological barrier that filters very efficiently and selectively the entry of compounds from the blood to the brain and protects nervous tissue from harmful substances and infectious agents present in the bloodstream. The BBB also prevents the entry of potential drugs. As a result, various drug targeting and delivery strategies are currently being developed to enhance the transport of drugs from the blood to the brain. Following a general introduction, we briefly overview in this review article the fundamental physiological properties of the BBB. Then, we describe current strategies to bypass the BBB (i.e., invasive methods, alternative approaches, and temporary opening) and to cross it (i.e., noninvasive approaches). This section is followed by a chapter addressing the chemical and technological solutions developed to cross the BBB. A special emphasis is given to prodrug-targeting approaches and targeted nanotechnology-based systems, two promising strategies for BBB targeting and delivery of drugs to the brain.

  18. Going beyond the liver: progress and challenges of targeted delivery of siRNA therapeutics.

    PubMed

    Lorenzer, Cornelia; Dirin, Mehrdad; Winkler, Anna-Maria; Baumann, Volker; Winkler, Johannes

    2015-04-10

    Therapeutic gene silencing promises significant progress in pharmacotherapy, including considerable expansion of the druggable target space and the possibility for treating orphan diseases. Technological hurdles have complicated the efficient use of therapeutic oligonucleotides, and siRNA agents suffer particularly from insufficient pharmacokinetic properties and poor cellular uptake. Intense development and evolution of delivery systems have resulted in efficient uptake predominantly in liver tissue, in which practically all nanoparticulate and liposomal delivery systems show the highest accumulation. The most efficacious strategies include liposomes and bioconjugations with N-acetylgalactosamine. Both are in early clinical evaluation stages for treatment of liver-associated diseases. Approaches for achieving knockdown in other tissues and tumors have been proven to be more complicated. Selective targeting to tumors may be enabled through careful modulation of physical properties, such as particle size, or by taking advantage of specific targeting ligands. Significant barriers stand between sufficient accumulation in other organs, including endothelial barriers, cellular membranes, and the endosome. The brain, which is shielded by the blood-brain barrier, is of particular interest to facilitate efficient oligonucleotide therapy of neurological diseases. Transcytosis of the blood-brain barrier through receptor-specific docking is investigated to increase accumulation in the central nervous system. In this review, the current clinical status of siRNA therapeutics is summarized, as well as innovative and promising preclinical concepts employing tissue- and tumor-targeted ligands. The requirements and the respective advantages and drawbacks of bioconjugates and ligand-decorated lipid or polymeric particles are discussed.

  19. RNA nanoparticle as a vector for targeted siRNA delivery into glioblastoma mouse model

    PubMed Central

    Lee, Tae Jin; Haque, Farzin; Shu, Dan; Yoo, Ji Young; Li, Hui; Yokel, Robert A.; Horbinski, Craig; Kim, Tae Hyong; Kim, Sung-Hak; Kwon, Chang-Hyuk; Nakano, Ichiro; Kaur, Balveen; Guo, Peixuan; Croce, Carlo M.

    2015-01-01

    Systemic siRNA administration to target and treat glioblastoma, one of the most deadly cancers, requires robust and efficient delivery platform without immunogenicity. Here we report newly emerged multivalent naked RNA nanoparticle (RNP) based on pRNA 3-way-junction (3WJ) from bacteriophage phi29 to target glioblastoma cells with folate (FA) ligand and deliver siRNA for gene silencing. Systemically injected FA-pRNA-3WJ RNPs successfully targeted and delivered siRNA into brain tumor cells in mice, and efficiently reduced luciferase reporter gene expression (4-fold lower than control). The FA-pRNA-3WJ RNP also can target human patient-derived glioblastoma stem cells, thought to be responsible for tumor initiation and deadly recurrence, without accumulation in adjacent normal brain cells, nor other major internal organs. This study provides possible application of pRNA-3WJ RNP for specific delivery of therapeutics such as siRNA, microRNA and/or chemotherapeutic drugs into glioblastoma cells without inflicting collateral damage to healthy tissues. PMID:25885522

  20. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery

    NASA Astrophysics Data System (ADS)

    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.

    2012-06-01

    Nanoparticles are used for delivering therapeutics into cells. 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 efficacy. A variety of materials have been explored for delivering small interfering RNAs (siRNAs)--a therapeutic agent that suppresses the expression of targeted genes. 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, a lack of tissue specificity and potential toxicity. 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 controlled precisely. We show that at least three folate molecules per nanoparticle are 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).

  1. Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery.

    PubMed

    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

    2012-06-03

    Nanoparticles are used for delivering therapeutics into cells. 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 efficacy. A variety of materials have been explored for delivering small interfering RNAs (siRNAs)--a therapeutic agent that suppresses the expression of targeted genes. 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, a lack of tissue specificity and potential toxicity. 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 controlled precisely. We show that at least three folate molecules per nanoparticle are 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 (t(1/2) ≈ 24.2 min) than the parent siRNA (t(1/2) ≈ 6 min).

  2. Peptide-conjugated micelles as a targeting nanocarrier for gene delivery

    NASA Astrophysics Data System (ADS)

    Lin, Wen Jen; Chien, Wei Hsuan

    2015-09-01

    The aim of this study was to develop peptide-conjugated micelles possessing epidermal growth factor receptor (EGFR) targeting ability for gene delivery. A sequence-modified dodecylpeptide, GE11(2R), with enhancing EGF receptor binding affinity, was applied in this study as a targeting ligand. The active targeting micelles were composed of poly( d,l-lactide- co-glycolide)-poly(ethylene glycol) (PLGA-PEG) copolymer conjugated with GE11(2R)-peptide. The particle sizes of peptide-free and peptide-conjugated micelles were 277.0 ± 5.1 and 308.7 ± 14.5 nm, respectively. The peptide-conjugated micelles demonstrated the cellular uptake significantly higher than peptide-free micelles in EGFR high-expressed MDA-MB-231 and MDA-MB-468 cells due to GE11(2R)-peptide specificity. Furthermore, the peptide-conjugated micelles were able to encapsulate plasmid DNA and expressed cellular transfection higher than peptide-free micelles in EGFR high-expressed cells. The EGFR-targeting delivery micelles enhanced DNA internalized into cells and achieved higher cellular transfection in EGFR high-expressed cells.

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

    NASA Astrophysics Data System (ADS)

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

    2013-01-01

    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.

  4. Emulsomes Meet S-layer Proteins: An Emerging Targeted Drug Delivery System

    PubMed Central

    Ucisik, Mehmet H.; Sleytr, Uwe B.; Schuster, Bernhard

    2015-01-01

    Here, the use of emulsomes as a drug delivery system is reviewed and compared with other similar lipidic nanoformulations. In particular, we look at surface modification of emulsomes using S-layer proteins, which are self-assembling proteins that cover the surface of many prokaryotic organisms. It has been shown that covering emulsomes with a crystalline S-layer lattice can protect cells from oxidative stress and membrane damage. In the future, the capability to recrystallize S-layer fusion proteins on lipidic nanoformulations may allow the presentation of binding functions or homing protein domains to achieve highly specific targeted delivery of drug-loaded emulsomes. Besides the discussion on several designs and advantages of composite emulsomes, the success of emulsomes for the delivery of drugs to fight against viral and fungal infections, dermal therapy, cancer, and autoimmunity is summarized. Further research might lead to smart, biocompatible emulsomes, which are able to protect and reduce the side effects caused by the drug, but at the same time are equipped with specific targeting molecules to find the desired site of action. PMID:25697368

  5. Biocompatible and biodegradable fibrinogen microspheres for tumor-targeted doxorubicin delivery.

    PubMed

    Joo, Jae Yeon; Park, Gil Yong; An, Seong Soo A

    2015-01-01

    In the development of effective drug delivery carriers, many researchers have focused on the usage of nontoxic and biocompatible materials and surface modification with targeting molecules for tumor-specific drug delivery. Fibrinogen (Fbg), an abundant glycoprotein in plasma, could be a potential candidate for developing drug carriers because of its biocompatibility and tumor-targeting property via arginine-glycine-aspartate (RGD) peptide sequences. Doxorubicin (DOX), a chemotherapeutic agent, was covalently conjugated to Fbg, and the microspheres were prepared. Acid-labile and non-cleavable linkers were used for the conjugation of DOX to Fbg, resulting in an acid-triggered drug release under a mild acidic condition and a slow-controlled drug release, respectively. In vitro cytotoxicity tests confirmed low cytotoxicity in normal cells and high antitumor effect toward cancer cells. In addition, it was discovered that a longer linker could make the binding of cells to Fbg drug carriers easier. Therefore, DOX-linker-Fbg microspheres could be a suitable drug carrier for safer and effective drug delivery.

  6. Targeted Delivery of Amoxicillin to C. trachomatis by the Transferrin Iron Acquisition Pathway.

    PubMed

    Hai, Jun; Serradji, Nawal; Mouton, Ludovic; Redeker, Virginie; Cornu, David; El Hage Chahine, Jean-Michel; Verbeke, Philippe; Hémadi, Miryana

    2016-01-01

    Weak intracellular penetration of antibiotics makes some infections difficult to treat. The Trojan horse strategy for targeted drug delivery is among the interesting routes being explored to overcome this therapeutic difficulty. Chlamydia trachomatis, as an obligate intracellular human pathogen, is responsible for both trachoma and sexually transmitted diseases. Chlamydia develops in a vacuole and is therefore protected by four membranes (plasma membrane, bacterial inclusion membrane, and bacterial membranes). In this work, the iron-transport protein, human serum-transferrin, was used as a Trojan horse for antibiotic delivery into the bacterial vacuole. Amoxicillin was grafted onto transferrin. The transferrin-amoxicillin construct was characterized by mass spectrometry and absorption spectroscopy. Its affinity for transferrin receptor 1, determined by fluorescence emission titration [KaffTf-amox = (1.3 ± 1.0) x 108], is very close to that of transferrin [4.3 x 108]. Transmission electron and confocal microscopies showed a co-localization of transferrin with the bacteria in the vacuole and were also used to evaluate the antibiotic capability of the construct. It is significantly more effective than amoxicillin alone. These promising results demonstrate targeted delivery of amoxicillin to suppress Chlamydia and are of interest for Chlamydiaceae and maybe other intracellular bacteria therapies.

  7. Quetiapine Nanoemulsion for Intranasal Drug Delivery: Evaluation of Brain-Targeting Efficiency.

    PubMed

    Boche, Mithila; Pokharkar, Varsha

    2016-05-20

    To evaluate the possibility of improved drug delivery of quetiapine fumarate (QTP), a nanoemulsion system was developed for intranasal delivery. Effects of different HLBs of Emalex LWIS 10, PEG 400 and Transcutol P, as co-surfactants, were studied on isotropic region of pseudoternary-phase diagrams of nanoemulsion system composed of capmul MCM (CPM) as oil phase, Tween 80 as surfactant and water. Phase behaviour, globule size, transmission electron microscope (TEM) photographs and brain-targeting efficiency of quetiapine nanoemulsion were investigated. In vitro dissolution study of optimised nanoemulsion formulation, with mean diameter 144 ± 0.5 nm, showed more than twofold increase in drug release as compared with pure drug. According to results of in vivo tissue distribution study in Wistar rats, intranasal administration of QTP-loaded nanoemulsion had shorter T max compared with that of intravenous administration. Higher drug transport efficiency (DTE%) and direct nose-to-brain drug transport (DTP%) was achieved by nanoemulsion. The nanoemulsion system may be a promising strategy for brain-targeted delivery of QTP.

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

    NASA Astrophysics Data System (ADS)

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

    2012-12-01

    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.

  9. Olfactory targeting through intranasal delivery of biopharmaceutical drugs to the brain: current development.

    PubMed

    Wen, Ming Ming

    2011-06-01

    Many therapeutic drugs are difficult to reach the central nervous system (CNS) from the systemic blood circulation because the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) form a very effective barrier which prevents most molecules from passing through. To bypass BBB, drugs can be delivered through olfactory region for nose-to-brain targeting. Peptide and protein drugs have been developed for the treatment of various neurodegenerative diseases. Drug delivery of these therapeutic proteins is facing several challenges because of the instability, high enzymatic metabolism, low gastrointestinal absorption, rapid renal elimination, and potential immunogenicity. New genetically engineered biotechnology products, such as recombinant human nerve growth factor, human VEGF, and interferons, are now possible to be delivered into the brain from the non-invasive intranasal route. For gene therapy, intranasal route is also a promising alternative method to deliver plasmid DNA to the brain. This review provides an overview of strategies to improve the drug delivery to the brain and the latest development of protein, peptide, and gene intranasal delivery for brain targeting.

  10. Mechanistic study of IR-780 dye as a potential tumor targeting and drug delivery agent.

    PubMed

    Zhang, Erlong; Luo, Shenglin; Tan, Xu; Shi, Chunmeng

    2014-01-01

    IR-780 iodide, a near-infrared fluorescent heptamethine dye, has been recently characterized to exhibit preferential accumulation property in the mitochondria of tumor cells. In this study, we investigated the possible mechanisms for its tumor selective activity and its potential as a drug delivery carrier. Results showed that the energy-dependent uptake of IR-780 iodide into the mitochondria of tumor cells was affected by glycolysis and plasma membrane potential. Moreover, OATP1B3 subtype of organic anion transporter peptides (OATPs) may play a dominant role in the transportation of IR-780 iodide into tumor cells, while cellular endocytosis, mitochondrial membrane potential and the ATP-binding cassette transporters did not show significant influence to its accumulation. We further evaluated the potential of IR-780 iodide as a drug delivery carrier by covalent conjugation of IR-780 with nitrogen mustard (IR-780NM). In vivo imaging showed that IR-780NM remained the tumor targeting property, indicating that IR-780 iodide could be potentially applied as a drug delivery agent for cancer targeted imaging and therapy.

  11. Targeted Delivery of Amoxicillin to C. trachomatis by the Transferrin Iron Acquisition Pathway

    PubMed Central

    Hai, Jun; Serradji, Nawal; Mouton, Ludovic; Redeker, Virginie; Cornu, David; El Hage Chahine, Jean-Michel

    2016-01-01

    Weak intracellular penetration of antibiotics makes some infections difficult to treat. The Trojan horse strategy for targeted drug delivery is among the interesting routes being explored to overcome this therapeutic difficulty. Chlamydia trachomatis, as an obligate intracellular human pathogen, is responsible for both trachoma and sexually transmitted diseases. Chlamydia develops in a vacuole and is therefore protected by four membranes (plasma membrane, bacterial inclusion membrane, and bacterial membranes). In this work, the iron-transport protein, human serum-transferrin, was used as a Trojan horse for antibiotic delivery into the bacterial vacuole. Amoxicillin was grafted onto transferrin. The transferrin-amoxicillin construct was characterized by mass spectrometry and absorption spectroscopy. Its affinity for transferrin receptor 1, determined by fluorescence emission titration [KaffTf-amox = (1.3 ± 1.0) x 108], is very close to that of transferrin [4.3 x 108]. Transmission electron and confocal microscopies showed a co-localization of transferrin with the bacteria in the vacuole and were also used to evaluate the antibiotic capability of the construct. It is significantly more effective than amoxicillin alone. These promising results demonstrate targeted delivery of amoxicillin to suppress Chlamydia and are of interest for Chlamydiaceae and maybe other intracellular bacteria therapies. PMID:26919720

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

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

    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.

  13. Locally Targeted Cardiac Gene Delivery by AAV Microbubble Destruction in a Large Animal Model.

    PubMed

    Schlegel, Philipp; Huditz, Regina; Meinhardt, Eric; Rapti, Kleopatra; Geis, Nicolas; Most, Patrick; Katus, Hugo A; Müller, Oliver J; Bekeredjian, Raffi; Raake, Philip W

    2016-04-01

    Cardiac gene therapy is a promising approach for treating heart diseases. Although clinical studies are ongoing, effective and targeted transgene delivery is still a major obstacle. We sought to improve and direct transgene expression in myocardium by ultrasound-targeted microbubble destruction (UTMD). In pigs, adeno-associated virus-derived (AAV) vectors harboring the luciferase reporter gene were delivered via retroinfusion into the anterior interventricular coronary vein (AIV). AAV vectors were either loaded to lipid microbubbles before injection or injected unmodified. Upon injection of AAV/microbubble solution, UTMD was performed. After 4 weeks, reporter gene expression levels in the anterior wall (target area), in the posterior wall (control area), and in noncardiac organs were analyzed. Retroinfusion of AAV-luciferase vectors loaded to lipid microbubbles led to a significant increase in transgene expression, with an increase in UTMD targeted areas of the anterior wall. Moreover, off-target expression was reduced in comparison to control animals, receiving AAV-luciferase without microbubbles. Besides an increase in overall target area transgene expression, UTMD alters the spatial expression of the luciferase transgene, focusing expression to ultrasound-targeted left ventricular wall. These data suggest UTMD as a promising approach for directing AAV to specific cardiac segments.

  14. Synthesis and Characterization of Polymer Nanocarriers for the Targeted Delivery of Therapeutic Enzymes

    PubMed Central

    Simone, Eric; Dziubla, Thomas; Shuvaev, Vladimir; Muzykantov, Vladimir R.

    2011-01-01

    Protein drugs, such as recombinant enzymes useful for detoxification and replacement therapies, have extraordinary specificity and potency. However, inherently inadequate delivery to target sites and rapid inactivation limit their medical utility. Using chaperone polymeric particles designed within an injectible size range (sub-micron) may help solve these shortcomings. Such nanocarriers would (i) prevent premature inactivation of encapsulated therapeutic protein cargoes, (ii) provide a carrier that can be surface decorated by targeting ligands, and (iii) optimize sub-cellular localization of the drug. This chapter describes the techniques successfully employed for the preparation of polymer nanocarriers (PNC) loaded with the antioxidant enzyme, catalase, and targeted to endothelial cells. Methods of PNC synthesis, loading with catalase, characterization, coupling of a targeting moiety, and in vitro testing of the enzymatic and targeting activities are provided here. Advantages and disadvantages of specific designs are discussed. Due to the modular nature of the targeting methodology employed, it is believed that these protocols will provide a solid foundation for the formulation of a wide variety of enzymatic drug targeting strategies. PMID:20013177

  15. Tenside-free preparation of nanogels with high functional β-cyclodextrin content.

    PubMed

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

    2012-09-25

    We present the preparation of ultrafine (R(h), 50 -150 nm) nanogels through tenside-free condensation of reactive prepolymers with β-cyclodextrin (β-CD) in water. These nanogels possess a maximum content of 60 wt % functional β-CD that can form inclusion complexes as demonstrated by dye sorption with phenolphthalein. Aside of this extremely high uptake capacity to hydrophobic molecules, the nanogels also show good adhesion to surfaces in homogeneous distribution with size of R(h) of 25 nm under dry conditions.

  16. Templateless synthesis of polyacrylamide-based Nanogels via RAFT dispersion polymerization.

    PubMed

    Ma, Kai; Xu, Yuanyuan; An, Zesheng

    2015-03-01

    This paper reports on the synthesis of well-defined polyacrylamide-based nanogels via reversible addition-fragmentation chain transfer (RAFT) dispersion polymerization, highlighting a templateless route for the efficient synthesis of nanogels based on water-soluble polymers. RAFT dispersion polymerization of acrylamide in co-nonsolvents of water-tert-butanol mixtures by chain extension from poly(dimethylacrylamide) shows well-controlled polymerization process, uniform nanogel size, and excellent colloidal stability. The versatility of this approach is further demonstrated by introducing a hydrophobic co-monomer (butyl acrylate) without disturbing the dispersion polymerization process.

  17. Tunable Enzymatic Activity and Enhanced Stability of Cellulase Immobilized in Biohybrid Nanogels.

    PubMed

    Peng, Huan; Rübsam, Kristin; Jakob, Felix; Schwaneberg, Ulrich; Pich, Andrij

    2016-11-14

    This paper reports a facile approach for encapsulation of enzymes in nanogels. Our approach is based on the use of reactive copolymers able to get conjugated with enzyme and build 3D colloidal networks or biohybrid nanogels. In a systematic study, we address the following question: how the chemical structure of nanogel network influences the biocatalytic activity of entrapped enzyme? The developed method allows precise control of the enzyme activity and improvement of enzyme resistance against harsh store conditions, chaotropic agents, and organic solvents. The nanogels were constructed via direct chemical cross-linking of water-soluble reactive copolymers poly(N-vinylpyrrolidone-co-N-methacryloxysuccinimide) with proteins such as enhanced green fluorescent protein (EGFP) and cellulase in water-in-oil emulsion. The water-soluble reactive copolymers with controlled amount of reactive succinimide groups and narrow dispersity were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Poly(ethylene glycol) bis(3-aminopropyl) and branched polyethylenimine were utilized as model cross-linkers to optimize synthesis of nanogels with different architectures in the preliminary experiments. Biofluorescent nanogels with different loading amount of EGFP and varying cross-linking densities were obtained. We demonstrate that the biocatalytic activity of cellulase-conjugated nanogels (CNG) can be elegantly tuned by control of their cross-linking degrees. Circular dichroism (CD) spectra demonstrated that the secondary structures of the immobilized cellulase were changed in the aspect of α-helix contents. The secondary structures of cellulase in highly cross-linked nanogels were strongly altered compared with loosely cross-linked nanogels. The fluorescence resonance energy transfer (FRET) based study further revealed that nanogels with lower cross-linking degree enable higher substrate transport rate, providing easier access to the active site of

  18. Hyaluronic acid grafted PLGA copolymer nanoparticles enhance the targeted delivery of Bromelain in Ehrlich's Ascites Carcinoma.

    PubMed

    Bhatnagar, Priyanka; Pant, Aditya Bhushan; Shukla, Yogeshwer; Panda, Amulya; Gupta, Kailash Chand

    2016-08-01

    Rapidly increasing malignant neoplastic disease demands immediate attention. Several dietary compounds have recently emerged as strong anti-cancerous agents. Among, Bromelain (BL), a protease from pineapple plant, was used to enhance its anti-cancerous efficacy using nanotechnology. In lieu of this, hyaluronic acid (HA) grafted PLGA copolymer, having tumor targeting ability, was developed. BL was encapsulated in copolymer to obtain BL-copolymer nanoparticles (NPs) that ranged between 140 to 281nm in size. NPs exhibited higher cellular uptake and cytotoxicity in cells with high CD44 expression as compared with non-targeted NPs. In vivo results on tumor bearing mice showed that NPs were efficient in suppressing the tumor growth. Hence, the formulation could be used as a self-targeting drug delivery cargo for the remission of cancer.

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

    PubMed Central

    Veiseh, Omid; Gunn, Jonathan; Zhang, Miqin

    2009-01-01

    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

  20. Single walled carbon nanotubes as drug delivery vehicles: targeting doxorubicin to tumors.

    PubMed

    Meng, Lingjie; Zhang, Xiaoke; Lu, Qinghua; Fei, Zhaofu; Dyson, Paul J

    2012-02-01

    Single walled carbon nanotubes (SWNTs) are emerging as promising delivery vehicles for cancer diagnostics and chemotherapies due to their unique properties, including, remarkable cell membrane penetrability, high drug-carrying capacities, pH-dependent therapeutic unloading, prolonged circulating times and intrinsic fluorescent, photothermal, photoacoustic and Raman properties. In this leading opinion paper, we systemically discuss and evaluate the relationship of the biological safety of SWNTs with their physicochemical properties such as their length, purity, agglomeration state, concentration and surface functionalization. Other relevant issues, including the cellular uptake mechanism, biodistribution and metabolism of SWNTs are also reviewed. The design and preparation of SWNT-based drug delivery systems (DDSs) and their pharmacokinetic, cancer targeting and therapeutic properties both in vitro and in vivo are highlighted. Future opportunities and challenges of SWNT-based DDSs are also discussed.

  1. Hydrodynamic interactions for complex-shaped nanocarriers in targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Wang, Yaohong; Eckmann, David; Radhakrishnan, Ravi; Ayyaswamy, Portonovo

    2014-11-01

    Nanocarrier motion in a blood vessel involves hydrodynamic and Brownian interactions, which collectively dictate the efficacy in targeted drug delivery. The shape of nanocarriers plays a crucial role in drug delivery. In order to quantify the flow and association properties of elliptical nanoparticles, we have developed an arbitrary Lagrangian-Eulerian framework with capabilities to simulate the hydrodynamic motion of nanoparticles of arbitrary shapes. We introduce the quaternions for rotational motion, and two collision models, namely, (a) an impulse-based model for wall-particle collision, and (b) the short-range repulsive Gay-Berne potential for particle-particle collision. We also study the red blood cell and nanocarrier (such as ellipsoid) interactions. We compare our results with those obtained for a hard sphere model for both RBCs and nanocarriers. Supported by NIH through grant U01-EB016027.

  2. Investigation of strategies for drug delivery by combination targeting of nanocarriers to multiple epitopes or receptors

    NASA Astrophysics Data System (ADS)

    Papademetriou, Iason Titos

    Development of drug delivery systems (ie. nanocarriers) with controllable composition, architecture, and functionalities is heavily investigated in the field of drug delivery in order to improve clinical interventions. Designing drug nanocarriers which possess targeting properties is critical to enable them to reach the intended site of intervention in the body. To achieve this goal, the surface of drug nanocarriers can be modified with targeting moieties (antibodies, peptides, etc.) addressed to cell surface molecules expressed on the diseased tissues and cells. If these molecules are receptors capable of internalizing bound ligands via endocytosis, targeting can then enable drug transport into cells or across cellular barriers in the body. Yet, addressing nanocarriers to single targets presents limited control over cellular interactions and biodistribution. Since most cell-surface markers are not exclusively expressed in a precise site in vivo, high affinity of targeted nanocarriers may lead to non-desired accumulation in regions of the body associated with low expression. Modification of nanocarriers to achieve combined-targeting (binding to more than one cell-surface receptor) may help modulate binding to cells and also endocytosis, since cell receptors possess distinct functions and features affecting these parameters, such as their expression, location on the plasmalemma, activation in disease, mechanism of endocytosis, etc. Further, targeting nanocarriers to multiple epitopes of the same receptor, a strategy which has never been tested, may also modulate these parameters since they are highly epitope specific. In this dissertation, we investigate the effect of targeting model polymer nanocarriers to: (1) multiple receptors of similar function (intercellular-, platelet-endothelial-, and/or vascular-cell adhesion molecules), (2) multiple receptors of different function (intercellular adhesion molecule 1 and transferrin receptor), or (3) multiple epitopes of

  3. Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide

    PubMed Central

    Li, Chong; Wang, Yixin; Zhang, Xiaolin; Deng, Li; Zhang, Yan; Chen, Zhangbao

    2013-01-01

    Peptide ligands have played an important role in tumor-targeted drug delivery as targeting moieties. The in vivo fate of peptide-mediated drug delivery systems and the following antitumor effects may greatly depend on the stability of the peptide ligand. In the current study, a tumor-targeting cyclic peptide screened by phage display, Lyp-1 (a peptide that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors), was structurally modified by replacement of the original intramolecular disulfide bond with a diseleno bond. The produced analog Syp-1 (seleno derivative of Lyp-1) maintained specific binding ability to the target protein p32 (Kd = 18.54 nM), which is similar to that of Lyp-1 (Kd = 10.59 nM), indicated by surface plasmon resonance assay. Compared with Lyp-1, Syp-1 showed significantly improved stability against serum. After the peptide attached onto the surface of fluorophore-encapsulating liposomes, the more efficient tumor uptake of liposomal fluorophore mediated by Syp-1 was observed. Furthermore, Syp-1 modified liposomal doxorubicin presented the most potent tumor growth inhibitory ability among all the therapeutic groups, with a low half maximal inhibitory concentration of 588 nM against MDA-MB-435 cells in vitro and a high tumor inhibition rate of 73.5% in vivo. These findings clearly indicated that Syp-1 was a stable and effective tumor targeting ligand and suggest that the sulfur-to-selenium replacement strategy may help stabilize the phage-displayed cyclic peptide containing disulfide-bond under physiological conditions and strongly support the validity of peptide-mediated drug targeting. PMID:23515368

  4. A multifunctional metal-organic framework based tumor targeting drug delivery system for cancer therapy

    NASA Astrophysics Data System (ADS)

    Wang, Xiao-Gang; Dong, Zhi-Yue; Cheng, Hong; Wan, Shuang-Shuang; Chen, Wei-Hai; Zou, Mei-Zhen; Huo, Jia-Wei; Deng, He-Xiang; Zhang, Xian-Zheng

    2015-09-01

    Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free ``green'' post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects.Drug delivery systems (DDSs) with biocompatibility and precise drug delivery are eagerly needed to overcome the paradox in chemotherapy that high drug doses are required to compensate for the poor biodistribution of drugs with frequent dose-related side effects. In this work, we reported a metal-organic framework (MOF) based tumor targeting DDS developed by a one-pot, and organic solvent-free ``green'' post-synthetic surface modification procedure, starting from the nanoscale MOF MIL-101. Owing to the multifunctional surface coating, premature drug release from this DDS was prevented. Due to the pH responsive benzoic imine bond and the redox responsive disulfide bond at the modified surface, this DDS exhibited tumor acid environment enhanced cellular uptake and intracellular reducing environment triggered drug release. In vitro and in vivo results showed that DOX loaded into this DDS exhibited effective cancer cell inhibition with much reduced side effects. Electronic supplementary information (ESI) available

  5. pH-responsive hybrid quantum dots for targeting hypoxic tumor siRNA delivery.

    PubMed

    Zhu, HongYan; Zhang, ShengYu; Ling, Yong; Meng, GuoLiang; Yang, Yu; Zhang, Wei

    2015-12-28

    Hypoxia is a characteristic of cancer and plays a key role in tumorigenesis, angiogenesis and resistance to cancer therapies. SiRNA treatment is effective against hypoxic tumors by gene silencing. However, siRNA delivery to the hypoxic regions of solid tumors still presents a challenge due to the distance from blood vessels and the increased presence of efflux transporters. Therefore, tumor therapies would be improved through the immediate development of an effective siRNA delivery system to hypoxic regions. To this end, we synthesized a system to deliver HIF-1α siRNA into hypoxic tumor cells. The system consists of a functional shell composed of 2-deoxyglucose (DG)-polyethylene glycol (PEG) connected with the compound of lipoic acid, lysine and 9-poly-d-arginine (LA-Lys-9R) by a hydrazone bond and a core of CdTe quantum dots (QDs). The molecular structure of DG-PEG-LA-Lys-9R was confirmed by liquid chromatography-mass spectrometry (LC-MS), nuclear magnetic resonance (NMR) spectroscopy, Fourier transform infrared spectroscopy (FTIR), and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The multifunctional CdTe QDs measured approximately 200 nm and showed excellent biocompatibility, perfect siRNA binding capability and enhanced hypoxic tumor targeting. Importantly, the system described here is pH-responsive with a hydrazone bond; therefore, it avoids GLUT1 receptor-mediated endocytic recycling, resulting in irreversible delivery of the siRNA. We used Western blots to confirm the superior gene silencing efficiency induced by the DG-PEG-LA-Lys-9R with hydrazone modified CdTe QDs. Here, we demonstrate high efficacy of the siRNA tumor delivery system using in vitro and in vivo experiments. In addition, these studies demonstrate that pH-responsive hybrid quantum dots show improved antitumor efficacy with decreased organ toxicity, indicating a promising siRNA delivery system for hypoxic cancer therapy.

  6. Nanogel-quantum dot hybrid nanoparticles for live cell imaging

    SciTech Connect

    Hasegawa, Urara; Nomura, Shin-ichiro M.; Kaul, Sunil C.; Hirano, Takashi; Akiyoshi, Kazunari; E-mail: akiyoshi.org@tmd.ac.jp

    2005-06-17

    We report here a novel carrier of quantum dots (QDs) for intracellular labeling. Monodisperse hybrid nanoparticles (38 nm in diameter) of QDs were prepared by simple mixing with nanogels of cholesterol-bearing pullulan (CHP) modified with amino groups (CHPNH{sub 2}). The CHPNH{sub 2}-QD nanoparticles were effectively internalized into the various human cells examined. The efficiency of cellular uptake was much higher than that of a conventional carrier, cationic liposome. These hybrid nanoparticles could be a promising fluorescent probe for bioimaging.

  7. Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle

    NASA Astrophysics Data System (ADS)

    Lapteva, Maria; Möller, Michael; Gurny, Robert; Kalia, Yogeshvar N.

    2015-11-01

    Acne vulgaris is a highly prevalent dermatological disease of the pilosebaceous unit (PSU). An inability to target drug delivery to the PSU results in poor treatment efficacy and the incidence of local side-effects. Cutaneous application of nanoparticulate systems is reported to induce preferential accumulation in appendageal structures. The aim of this work was to prepare stable polymeric micelles containing retinoic acid (RA) using a biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) and to evaluate their ability to deliver RA to skin. An innovative punch biopsy sample preparation method was developed to selectively quantify follicular delivery; the amounts of RA present were compared to those in bulk skin, (i.e. without PSU), which served as the control. RA was successfully incorporated into micelle nanocarriers and protected from photoisomerization by inclusion of Quinoline Yellow. Incorporation into the spherical, homogeneous and nanometer-scale micelles (dn < 20 nm) increased the aqueous solubility of RA by >400-fold. Drug delivery experiments in vitro showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A® Micro (0.04%), a marketed gel containing RA loaded microspheres, (7.1 +/- 1.1% vs. 0.4 +/- 0.1% and 7.5 +/- 0.8% vs. 0.8 +/- 0.1% of the applied dose, respectively). In contrast to a non-colloidal RA solution, Effederm® (0.05%), both the RA loaded MPEG-dihexPLA polymeric micelles (0.005%) and Retin-A® Micro (0.04%) displayed selectivity for delivery to the PSU with 2-fold higher delivery to PSU containing samples than to control samples. Moreover, the micelle formulation outperformed Retin-A® Micro in terms of delivery efficiency to PSU presenting human skin (10.4 +/- 3.2% vs. 0.6 +/- 0.2%, respectively). The results indicate that the polymeric micelle formulation enabled an increased and targeted delivery of RA to the PSU

  8. Tumor-homing peptides as tools for targeted delivery of payloads to the placenta

    PubMed Central

    King, Anna; Ndifon, Cornelia; Lui, Sylvia; Widdows, Kate; Kotamraju, Venkata R.; Agemy, Lilach; Teesalu, Tambet; Glazier, Jocelyn D.; Cellesi, Francesco; Tirelli, Nicola; Aplin, John D.; Ruoslahti, Erkki; Harris, Lynda K.

    2016-01-01

    The availability of therapeutics to treat pregnancy complications is severely lacking mainly because of the risk of causing harm to the fetus. As enhancement of placental growth and function can alleviate maternal symptoms and improve fetal growth in animal models, we have developed a method for targeted delivery of payloads to the placenta. We show that the tumor-homing peptide sequences CGKRK and iRGD bind selectively to the placental surface of humans and mice and do not interfere with normal development. Peptide-coated nanoparticles intravenously injected into pregnant mice accumulated within the mouse placenta, whereas control nanoparticles exhibited reduced binding and/or fetal transfer. We used targeted liposomes to efficiently deliver cargoes of carboxyfluorescein and insulin-like growth factor 2 to the mouse placenta; the latter significantly increased mean placental weight when administered to healthy animals and significantly improved fetal weight distribution in a well-characterized model of fetal growth restriction. These data provide proof of principle for targeted delivery of drugs to the placenta and provide a novel platform for the development of placenta-specific therapeutics. PMID:27386551

  9. Functionalized Single-Walled Carbon Nanotubes as Rationally Designed Vehicles for Tumor-Targeted Drug Delivery

    SciTech Connect

    Chen,J.; Wong,S.; Chen, S.; Zhao, X.; Kuznetsova, L.V.; and Ojima, I.

    2008-11-14

    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.

  10. Membrane domain formation—a key factor for targeted intracellular drug delivery

    PubMed Central

    Popov-Čeleketić, Dušan; van Bergen en Henegouwen, Paul M. P.

    2014-01-01

    Protein molecules, toxins and viruses internalize into the cell via receptor-mediated endocytosis (RME) using specific proteins and lipids in the plasma membrane. The plasma membrane is a barrier for many pharmaceutical agents to enter into the cytoplasm of target cells. In the case of cancer cells, tissue-specific biomarkers in the plasma membrane, like cancer-specific growth factor receptors, could be excellent candidates for RME-dependent drug delivery. Recent data suggest that agent binding to these receptors at the cell surface, resulting in membrane domain formation by receptor clustering, can be used for the initiation of RME. As a result, these pharmaceutical agents are internalized into the cells and follow different routes until they reach their final intracellular targets like lysosomes or Golgi. We propose that clustering induced formation of plasma membrane microdomains enriched in receptors, sphingolipids, and inositol lipids, leads to membrane bending which functions as the onset of RME. In this review we will focus on the role of domain formation in RME and discuss potential applications for targeted intracellular drug delivery. PMID:25520666

  11. Multifunctional Nanoprobes for Cancer Cell Targeting, Imaging and Anticancer Drug Delivery

    NASA Astrophysics Data System (ADS)

    Linkov, Pavel; Laronze-Cochard, Marie; Sapi, Janos; Sidorov, Lev N.; Nabiev, Igor

    The diagnosis and treatment of cancer have been greatly improved with recent developments in bio-nanotechnology, including engineering of multifunctional probes. One of the promising nanoscale tools for cancer imaging is fluorescent quantum dots (QDs), whose small size and unique optical properties allow them to penetrate into cells and ensure highly sensitive optical diagnosis of cancer at the cellular level. Furthermore, novel multi-functional probes have been developed in which QDs are conjugated with one or several functional molecules, including targeting moieties and therapeutic agents. Here, the strategy for engineering novel nanocarriers for controlled nucleus-targeted antitumor drug delivery and real-time imaging by single- or two-photon microscopy is described. A triple multifunctional nanoprobe is being developed that consists of a nitrogen-based heterocyclic derivative, an anticancer agent interacting with a DNA in living cells; a recognized molecule serving as a vector responsible for targeted delivery of the probe into cancer cells; and photoluminescent QDs providing the imaging capability of the probe. Subsequent optimization of the multifunctional nanoprobe will offer new possibilities for cancer diagnosis and treatment.

  12. Development of TMTP-1 targeted designer biopolymers for gene delivery to prostate cancer.

    PubMed

    McBride, John W; Massey, Ashley S; McCaffrey, J; McCrudden, Cian M; Coulter, Jonathan A; Dunne, Nicholas J; Robson, Tracy; McCarthy, Helen O

    2016-03-16

    Designer biopolymers (DBPs) represent state of the art genetically engineered biomacromolecules designed to condense plasmid DNA, and overcome intra- and extra- cellular barriers to gene delivery. Three DBPs were synthesized, each with the tumor molecular targeting peptide-1 (TMTP-1) motif to specifically target metastases. Each DBP was complexed with a pEGFP-N1 reporter plasmid to permit physiochemical and biological assay analysis. Results indicated that two of the biopolymers (RMHT and RM3GT) effectively condensed pEGFP-N1 into cationic nanoparticles <100 nm and were capable of transfecting PC-3 metastatic prostate cancer cells. Conversely the anionic RMGT DBP nanoparticles could not transfect PC-3 cells. RMHT and RM3GT nanoparticles were stable in the presence of serum and protected the cargo from degradation. Additionally it was concluded that cell viability could recover post-transfection with these DBPs, which were less toxic than the commercially available transfection reagent Lipofectamine(®) 2000. With both DBPs, a higher transfection efficacy was observed in PC-3 cells than in the moderately metastatic, DU145, and normal, PNT2-C2, cell lines. Blocking of the TMTP-1 receptors inhibited gene transfer indicating internalization via this receptor. In conclusion RMHT and RM3GT are fully functional DBPs that address major obstacles to gene delivery and target metastatic cells expressing the TMTP-1 receptor.

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

    PubMed Central

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

    2014-01-01

    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

  14. An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease

    PubMed Central

    Zhang, Sufeng; Ermann, Joerg; Succi, Marc D.; Zhou, Allen; Hamilton, Matthew J.; Cao, Bonnie; Korzenik, Joshua R.; Glickman, Jonathan N.; Vemula, Praveen K.; Glimcher, Laurie H.; Traverso, Giovanni; Langer, Robert; Karp, Jeffrey M.

    2016-01-01

    There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD. PMID:26268315

  15. Hyperbranched PEG-based supramolecular nanoparticles for acid-responsive targeted drug delivery.

    PubMed

    Chen, Xiaofei; Yao, Xuemei; Wang, Chunran; Chen, Li; Chen, Xuesi

    2015-06-01

    Herein, hyperbranched poly(ethylene glycol)-based supramolecular nanoparticles with pH-sensitive properties were designed and used for targeted drug delivery. Via host-guest recognition between benzimidazole anchored poly(ethylene glycol)-hyperbranched polyglycerol (PEG-HPG-BM) and folic acid modified CD (FA-CD), targeted supramolecular nanoparticles (TSNs) were fabricated. At neutral aqueous conditions TSNs could load the model drug DOX. While under intracellular acidic conditions the loaded-drug would be released due to the protonation of BM. This protonation allowed the supramolecular nanoparticles to expand or even disassemble, which showes the pH-dependent property. The introduction of the active targeting FA molecule and the specific interactions with the receptor of HeLa cells means that DOX-loaded TSNs show a significantly improved anticancer efficacy. In vitro drug release assays and intracellular experiments confirmed that TSNs had an obvious pH-sensitive property and remarkably improved anticancer effects, which hold great potential for further biomedical applications such as anticancer drug delivery.

  16. Neutrophil targeted nano-drug delivery system for chronic obstructive lung diseases.

    PubMed

    Vij, Neeraj; Min, Taehong; Bodas, Manish; Gorde, Aakruti; Roy, Indrajit

    2016-11-01

    The success of drug delivery to target airway cell(s) remains a significant challenge due to the limited ability of nanoparticle (NP) systems to circumvent protective airway-defense mechanisms. The size, density, surface and physical-chemical properties of nanoparticles are the key features that determine their ability to navigate across the airway-barrier. We evaluated here the efficacy of a PEGylated immuno-conjugated PLGA-nanoparticle (PINP) to overcome this challenge and selectively deliver drug to specific inflammatory cells (neutrophils). We first characterized the size, shape, surface-properties and neutrophil targeting using dynamic laser scattering, transmission electron microscopy and flow cytometry. Next, we assessed the efficacy of neutrophil-targeted PINPs in transporting through the airway followed by specific binding and release of drug to neutrophils. Finally, our results demonstrate the efficacy of PINP mediated non-steroidal anti-inflammatory drug-(ibuprofen) delivery to neutrophils in murine models of obstructive lung diseases, based on its ability to control neutrophilic-inflammation and resulting lung disease.

  17. Mesoporous silica nanoparticles functionalized with folic acid/methionine for active targeted delivery of docetaxel

    PubMed Central

    Khosravian, Pegah; Shafiee Ardestani, Mehdi; Khoobi, Mehdi; Ostad, Seyed Naser; Dorkoosh, Farid Abedin; Akbari Javar, Hamid; Amanlou, Massoud

    2016-01-01

    Mesoporous silica nanoparticles (MSNs) are known as carriers with high loading capacity and large functionalizable surface area for target-directed delivery. In this study, a series of docetaxel-loaded folic acid- or methionine-functionalized mesoporous silica nanoparticles (DTX/MSN-FA or DTX/MSN-Met) with large pores and amine groups at inner pore surface properties were prepared. The results showed that the MSNs were successfully synthesized, having good pay load and pH-sensitive drug release kinetics. The cellular investigation on MCF-7 cells showed better performance of cytotoxicity and cell apoptosis and an increase in cellular uptake of targeted nanoparticles. In vivo fluorescent imaging on healthy BALB/c mice proved that bare MSN-NH2 are mostly accumulated in the liver but MSN-FA or MSN-Met are more concentrated in the kidney. Importantly, ex vivo fluorescent images of tumor-induced BALB/c mice organs revealed the ability of MSN-FA to reach the tumor tissues. In conclusion, DTX/MSNs exhibited a good anticancer activity and enhanced the possibility of targeted drug delivery for breast cancer. PMID:27980423

  18. A double-targeted magnetic nanocarrier with potential application in hydrophobic drug delivery.

    PubMed

    Ding, Guobin; Guo, Yi; Lv, Yanyun; Liu, Xiaofeng; Xu, Li; Zhang, Xuezhong

    2012-03-01

    A double-targeted magnetic nanocarrier based with potential applications in the delivery of hydrophobic drugs has been developed. It consists of magnetite (Fe(3)O(4)) nanoparticles encapsulated in self-assembled micelles of the amphiphilic copolymer MPEG-PLGA [methoxy poly (ethylene glycol)-poly (d,l-lactide-co-glycolide)], and was fabricated using the solvent-evaporation technique. The magnetic nanocarrier has a very stable core-shell structure and is superparamagnetic. Its cytotoxicity was evaluated using the MTT assay with three cell lines-HeLa, MCF-7, and HT1080; it exhibited no cytotoxicity against any tested line at concentrations of up to 400 μg/mL after incubation for 24 h. Its cellular uptake was studied by Prussian blue staining and by fluorescence microscopy after encapsulating a fluorescent probe (hydrophobic quantum dots) into the nanocarrier. Finally, the magnetic targeting property of the magnetic nanocarrier was confirmed by an in vitro test. Overall, the results obtained demonstrate the potential of the double-targeted nanocarrier for the intracellular delivery of hydrophobic drugs.

  19. Polymeric nanocarriers for magnetic targeted drug delivery: preparation, characterization, and in vitro and in vivo evaluation.

    PubMed

    Licciardi, Mariano; Scialabba, Cinzia; Fiorica, Calogero; Cavallaro, Gennara; Cassata, Giovanni; Giammona, Gaetano

    2013-12-02

    In this paper the preparation of magnetic nanocarriers (MNCs), containing superparamagnetic domains, is reported, useful as potential magnetically targeted drug delivery systems. The preparation of MNCs was performed by using the PHEA-IB-p(BMA) graft copolymer as coating material through the homogenization-solvent evaporation method. Magnetic and nonmagnetic nanocarriers containing flutamide (FLU-MNCs) were prepared. The prepared nanocarriers have been exhaustively characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), and magnetic measurements. Biological evaluation was performed by in vitro cytotoxicity and cell uptake tests and in vivo biodistribution studies. Magnetic nanocarriers showed dimensions of about 300 nm with a narrow size distribution, an amount of loaded FLU of 20% (w/w), and a superparamagnetic behavior. Cell culture experiments performed on prostate cancer cell line LNCaP demonstrated the cytotoxic effect of FLU-MNCs. In vivo biodistribution studies carried out by the application of an external magnetic field in rats demonstrated the effect of the external magnet on modifying the biodistribution of FLU-MNCs. FLU-MNCs resulted efficiently internalized by tumor cells and susceptible to magnetic targeting by application of an external magnetic field. The proposed nanocarriers can represent a very promising approach to obtain an efficient magnetically targeted anticancer drug delivery system.

  20. Notch1 targeting siRNA delivery nanoparticles for rheumatoid arthritis therapy.

    PubMed

    Kim, Min Ju; Park, Jong-Sung; Lee, So Jin; Jang, Jiyeon; Park, Jin Su; Back, Seung Hyun; Bahn, Gahee; Park, Jae Hyung; Kang, Young Mo; Kim, Sun Hwa; Kwon, Ick Chan; Jo, Dong-Gyu; Kim, Kwangmeyung

    2015-10-28

    Notch pathway plays a pivotal role in synoviocytes involved in progression of rheumatoid arthritis (RA). Herein, we designed the Notch1 targeting siRNA delivery nanoparticles (siRNA-NPs) in order to confirm the anti-inflammatory effect in collagen-induced arthritis (CIA) model. The siRNA-NPs were successfully produced by encapsulating polymerized siRNA (poly-siRNA) into thiolated glycol chitosan (tGC) nanoparticles in aqueous condition. The in vitro Notch1 inhibition of siRNA-NPs in murine macrophage cell (RAW 264.7) was confirmed using confocal microscopy and real time PCR. Fluorescently labeled siRNA-NPs were successfully transfected in RAW 264.7 and modulated the expression of Notch1 in mRNA level. For in vivo study, siRNA-NPs exhibited the higher targeting efficiency in the arthritic joins of CIA mice, confirmed by the near-infrared fluorescence (NIRF) imaging. Furthermore, inhibition of Notch1 with siRNA-NPs resulted in retarded progression of inflammation, bone erosion, and cartilage damage in CIA mice. Novel Notch1 targeting siRNA delivery system of siRNA-NPs showed effective RA treatment by suppressing Notch1 signaling pathway without undesirable severe toxicity. Thus, Notch1 inhibiting siRNA-NPs demonstrated the great potential in RA therapeutics that was hard to be achieved using conventional drugs.

  1. Folate-conjugated boron nitride nanospheres for targeted delivery of anticancer drugs

    PubMed Central

    Feng, Shini; Zhang, Huijie; Yan, Ting; Huang, Dandi; Zhi, Chunyi; Nakanishi, Hideki; Gao, Xiao-Dong

    2016-01-01

    With its unique physical and chemical properties and structural similarity to carbon, boron nitride (BN) has attracted considerable attention and found many applications. Biomedical applications of BN have recently started to emerge, raising great hopes in drug and gene delivery. Here, we developed a targeted anticancer drug delivery system based on folate-conjugated BN nanospheres (BNNS) with receptor-mediated targeting. Folic acid (FA) was successfully grafted onto BNNS via esterification reaction. In vitro cytotoxicity assay showed that BNNS-FA complexes were non-toxic to HeLa cells up to a concentration of 100 μg/mL. Then, doxorubicin hydrochloride (DOX), a commonly used anticancer drug, was loaded onto BNNS-FA complexes. BNNS-FA/DOX complexes were stable at pH 7.4 but effectively released DOX at pH 5.0, which exhibited a pH sensitive and sustained release pattern. BNNS-FA/DOX complexes could be recognized and specifically internalized by HeLa cells via FA receptor-mediated endocytosis. BNNS-FA/DOX complexes exhibited greater cytotoxicity to HeLa cells than free DOX and BNNS/DOX complexes due to the increased cellular uptake of DOX mediated by the FA receptor. Therefore, BNNS-FA complexes had strong potential for targeted cancer therapy. PMID:27695318

  2. Preparation and characterization of novel chitosan-protamine nanoparticles for nucleus-targeted anticancer drug delivery.

    PubMed

    Yu, Xiwei; Hou, Jiahui; Shi, Yijie; Su, Chang; Zhao, Liang

    It is well known that most anticancer drugs commonly show high toxicity to the DNA of tumor cells and exert effects by combining with the DNA or associated enzymes in the nucleus. Most developed drugs are first delivered into the cytoplasm and then transferred to the nucleus through the membrane pores. Sometimes, the transportation of drugs from cytoplasm to nucleus is not efficient and often results in poor therapeutic effects. In this study, we developed special and novel nanoparticles (NPs) made of chitosan and protamine for targeted nuclear capture of drugs to enhance anticancer effects. The anticancer effects of nuclear targeted-delivery of drugs in NPs were also evaluated by investigating cytotoxicity, cellular uptake mechanism, and cell apoptosis on cells. Chitosan-protamine NPs were characterized by good drug entrapment, sustained release, small average particle size, low polydispersity index, and high encapsulation efficiency; and accomplished the efficient nuclear delivery of fluorouracil (5-Fu). Compared with free 5-Fu and 5-Fu-loaded chitosan NPs, treatment of A549 cells and HeLa cells with 5-Fu-loaded chitosan-protamine NPs showed the highest cytotoxicity and further induced the significant apoptosis of cells. In addition, 5-Fu-loaded chitosan-protamine NPs exhibited the best efficiency in inhibiting tumor growth than the other three formulations. 5-Fu-loaded chitosan-protamine NPs enhanced antitumor efficacy through the targeted nuclear capture of drugs and showed promising potential as a nanodelivery system for quickly locating drugs in the nucleus of cells.

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

    PubMed

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

    2013-07-01

    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.

  4. An inflammation-targeting hydrogel for local drug delivery in inflammatory bowel disease.

    PubMed

    Zhang, Sufeng; Ermann, Joerg; Succi, Marc D; Zhou, Allen; Hamilton, Matthew J; Cao, Bonnie; Korzenik, Joshua R; Glickman, Jonathan N; Vemula, Praveen K; Glimcher, Laurie H; Traverso, Giovanni; Langer, Robert; Karp, Jeffrey M

    2015-08-12

    There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Targeting drugs selectively to the inflamed intestine may improve therapeutic outcomes and minimize systemic toxicity. We report the development of an inflammation-targeting hydrogel (IT-hydrogel) that acts as a drug delivery system to the inflamed colon. Hydrogel microfibers were generated from ascorbyl palmitate, an amphiphile that is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration. IT-hydrogel microfibers loaded with the anti-inflammatory corticosteroid dexamethasone (Dex) were stable, released drug only upon enzymatic digestion, and demonstrated preferential adhesion to inflamed epithelial surfaces in vitro and in two mouse colitis models in vivo. Dex-loaded IT-hydrogel enemas, but not free Dex enemas, administered every other day to mice with colitis resulted in a significant reduction in inflammation and were associated with lower Dex peak serum concentrations and, thus, less systemic drug exposure. Ex vivo analysis of colon tissue samples from patients with ulcerative colitis demonstrated that IT-hydrogel microfibers adhered preferentially to mucosa from inflamed lesions compared with histologically normal sites. The IT-hydrogel drug delivery platform represents a promising approach for targeted enema-based therapies in patients with colonic IBD.

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

    PubMed

    Ma, Jing; DU, Lian Fang; Chen, Ming; Wang, Hang Hui; Xing, Ling Xi; Jing, Li Fang; Li, Yun Hua

    2013-07-01

    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.

  6. Recent development of biotin conjugation in biological imaging, sensing, and target delivery.

    PubMed

    Ren, Wen Xiu; Han, Jiyou; Uhm, Soojin; Jang, Yu Jin; Kang, Chulhun; Kim, Jong-Hoon; Kim, Jong Seung

    2015-07-04

    Despite encouraging results from preliminary studies of anticancer therapies, the lack of tumor specificity remains an important issue in the modern pharmaceutical industry. New findings indicate that biotin or biotin-conjugates could be favorably assimilated by tumor cells that over-express biotin-selective transporters. Furthermore, biotin can form stable complexes with avidin and its bacterial counterpart streptavidin. The strong bridging between avidin and biotin moieties on other molecules is a proven adaptable tool with broad biological applications. Under these circumstances, a biotin moiety is certainly an attractive choice for live-cell imaging, biosensing, and target delivery.

  7. Synthetic Nano-Low Density Lipoprotein as Targeted Drug DeliveryVehicle for Glioblastoma Multiforme

    SciTech Connect

    Nikanjam, Mina; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Shu,Xiao; Budinger, Thomas F.; Forte, Trudy M.

    2006-06-14

    This paper discribes a synthetic low density lipoprotein(LDL) made by complexing a 29 amino acid that consists of a lipid bindingdomain and the LDL receptor binding domain with a lipid microemulsion.The nano-LDL particles were intermdiate in size between LDL and HDL andbound to LDL receptors on GBM brain tumor cells. Synthetic nano-LDLuptake by GBM cells was LDL receptor specific and dependent on cellreceptor number. It is suggested that these synthetic particles can serveas a delivery vehicle for hydophobic anti-tumor drugs by targeting theLDL receptor.

  8. Noninvasive and targeted drug delivery to the brain using focused ultrasound.

    PubMed

    Burgess, Alison; Hynynen, Kullervo

    2013-04-17

    Brain diseases are notoriously difficult to treat due to the presence of the blood-brain barrier (BBB). Here, we review the development of focused ultrasound (FUS) as a noninvasive method for BBB disruption, aiding in drug delivery to the brain. FUS can be applied through the skull to a targeted region in the brain. When combined with microbubbles, FUS causes localized and reversible disruption of the BBB. The cellular mechanisms of BBB disruption are presented. Several therapeutic agents have been delivered to the brain resulting in significant improvements in pathology in models of glioblastoma and Alzheimer's disease. The requirements for clinical translation of FUS will be discussed.

  9. Enzyme-induced and tumor-targeted drug delivery system based on multifunctional mesoporous silica nanoparticles.

    PubMed

    Cheng, Yin-Jia; Luo, Guo-Feng; Zhu, Jing-Yi; Xu, Xiao-Ding; Zeng, Xuan; Cheng, Dong-Bing; Li, You-Mei; Wu, Yan; Zhang, Xian-Zheng; Zhuo, Ren-Xi; He, Feng

    2015-05-06

    Functional mesoporous silica particles have attracted growing research interest for controlled drug delivery in targeted cancer therapy. For the purpose of efficient targeting tumor cells and reducing the adverse effect of antitumor drug doxorubicin (DOX), biocompatible and enzyme-responsive mesoporous silica nanoparticles (MSNs) with tumor specificity were desired. To construct these functional MSNs, the classic rotaxane structure formed between alkoxysilane tether and α-cyclodextrin (α-CD) was employed to anchor onto the orifices of MSNs as gatekeeper in this work. After subsequent modification by multifunctional peptide (azido-GFLGR7RGDS with tumor-targeting, membrane-penetrating, and cathepsin B-responsive functions) to stabilize the gatekeeper, the resulting functional MSNs showed a strong ability to load and seal DOX in their nanopores. When incubating these DOX-loaded MSNs with tumor and normal cells, the nanoparticles could efficiently employ their surface-encoded RGDS and continuous seven arginine (R7) sequences to target tumor cells, penetrate the cell membrane, and enter tumor cells. Because cathepsin B overexpressed in late endosomes and lysosomes of tumor cells could specifically hydrolyze GFLG sequences of the nanovalves, the DOX-loaded MSNs showed an "off-on" drug release behavior that ∼80% loaded DOX could be released within 24 h and thus showed a high rate of apoptosis. Furthermore, in vitro cellular experiments indicated that DOX-loaded MSNs (DOX@MSN-GFLGR7RGDS/α-CD) had high growth inhibition toward αvβ3-positive HeLa cancerous cells. The research might offer a practical way for designing the tumor-targeted and enzyme-induced drug delivery system for cancer therapy.

  10. Human CD64-targeted non-viral siRNA delivery system for blood monocyte gene modulation

    PubMed Central

    Yong, Seok-Beom; Kim, Hyung Jin; Kim, Jang Kyoung; Chung, Jee Young; Kim, Yong-Hee

    2017-01-01

    A subset of phagocytes including inflammatory monocytes in blood migrate and give rise to macrophages in inflammatory tissues which generated the idea that blood monocytes are the therapeutic targets for drug delivery. Fc gamma receptor I (CD64) is a membrane receptor for the Fc region of immunoglobulin G, primarily expressed on monocyte-lineage, and H22 a monoclonal antibody for human CD64 had shown rapid blood monocyte binding and occupation in clinical studies. Small interfering RNA-mediated gene silencing as a therapeutic has been proposed and is a promising strategy in terms of its “knock-down” ability on the target gene prior to translation. However, its instability and off-targeting effect must be overcome for success in clinical studies. In this study, we developed a non-viral delivery system composed of oligo-nona-arginine (9R) and anti-human CD64 single chain antibodies (H22) for human monocyte-specific siRNA delivery. A targeted and efficient siRNA delivery mediated by anti-CD64 scFv-9R was observed in CD64 positive human leukemia cells, THP-1. With primary human blood cells, anti-CD64 scFv-9R mediated gene silencing was quantitatively confirmed representing blood monocyte selective gene delivery. These results demonstrate the potential of anti-CD64 scFv-9R mediated siRNA delivery for the treatment of human inflammatory diseases via blood monocytes gene delivery. PMID:28169353

  11. Poly(acrylic acid) nanogel as a substrate for cellulase immobilization for hydrolysis of cellulose.

    PubMed

    Ahmed, Ibrahim Nasser; Chang, Ray; Tsai, Wei-Bor

    2017-04-01

    Cellulase was adsorbed onto poly(acrylic acid), PAA, nanogel, that was fabricated via inverse-phase microemulsion polymerization. The PAA nanogel was around 150nm in diameter and enriched with carboxyl groups. The surface charge of PAA nanogel depended on the pHs of the environment and affected the adsorption of cellulase. The temperature stability of the immobilized cellulase was greatly enhanced in comparison to the free enzyme, especially at high temperature. At 80°C, the immobilized cellulase remained ∼75% of hydrolytic activity, in comparison to ∼55% for the free cellulase. Furthermore, the immobilized cellulase was more active than the free enzyme in acidic buffers. The immobilized cellulase could be recovered via centrifugation and can be used repeatedly, although the recovery ratio needs further improvement. In conclusion, PAA nanogel has the potential in the application of enzyme immobilization for biochemical processes.

  12. Amphiphilic polysaccharide nanoballs: a new building block for nanogel biomedical engineering and artificial chaperones.

    PubMed

    Takahashi, Haruko; Sawada, Shin-Ichi; Akiyoshi, Kazunari

    2011-01-25

    Enzymatically synthesized glycogen (ESG), a highly branched (1→4)(1→6)-linked α-glucan, is a new monodisperse spherical hyperbranched nanoparticle (molecular weight, 10(6)-10(7); diameter, 20-30 nm), polysaccharide nanoball. Amphiphilic ESG nanoballs were synthesized by introducing a cholesterol group to enzymatically synthesized glycogen (CHESG). CHESG assembled into a structure containing a few molecules to form cluster nanogels (approximately 35 nm in diameter) in water. The cluster nanogels were dissociated by the addition of cyclodextrin (CD) to form a supramolecular CHESG-CD nanocomplex due to complexation with the cholesterol group and CD. The CHESG nanogel showed high capacity for complexation with proteins, and the CHESG-CD nanocomplex showed high chaperone-like activity for thermal stabilization of enzymes. CHESG has great potential to become a new building block for nanogel biomedical engineering and to act as an artificial chaperone for protein engineering.

  13. Influence of Red Blood Cells on Nanoparticle Targeted Delivery in Microcirculation

    NASA Astrophysics Data System (ADS)

    Tan, Jifu; Thomas, Antony; Liu, Yaling

    2011-11-01

    In this paper, a particle-cell hybrid model is developed to model Nanoparticle (NP) transport, dispersion, and binding dynamics in blood suspension under the influence of Red blood cells (RBCs). The motion and deformation of RBCs is captured through the Immersed Finite Element Method. The motion and adhesion of individual NPs are tracked through Brownian adhesion dynamics. A mapping algorithm and an interaction potential function are introduced to consider the cell-particle collision. NP dispersion and binding rates are derived from the developed model under various rheology conditions. The influence of RBCs, vascular flow rate, and particle size on NP distribution and delivery efficacy is characterized. A non-uniform NP distribution profile with higher particle concentration near the vessel wall is observed. Such distribution leads to over 50% higher particle binding rate compared to the case without RBC considered. The tumbling motion of RBCs in the core region of the capillary is found to enhance NP dispersion, with dispersion rate increases as shear rate increases. Results from this study contribute to the fundamental understanding and knowledge on how the particulate nature of blood influences NP delivery, which will provide mechanistic insights on the nanomedicine design for targeted drug delivery applications.

  14. Targeting of gastrointestinal tract for amended delivery of protein/peptide therapeutics: strategies and industrial perspectives.

    PubMed

    Pawar, Vivek K; Meher, Jaya Gopal; Singh, Yuvraj; Chaurasia, Mohini; Surendar Reddy, B; Chourasia, Manish K

    2014-12-28

    Delivery of proteins/peptides to the gastrointestinal (GI) tract via peroral/oral route involves tremendous challenges due to unfavorable environmental conditions like harsh pH, presence of proteolytic enzymes and absorption barriers. Detailed research is being conducted at the academic and industrial levels to diminish these troubles and various products are under clinical trials. Several approaches have been established to optimize oral delivery of proteins and peptides and can be broadly categorized into chemical and physical strategies. Chemical strategies include site specific mutagenesis, proteinylation, glycosylation, PEGylation and prodrug approaches, whereas physical strategies comprise formulation based approaches including application of absorption enhancers and metabolism modifiers along with delivering them via colloidal carrier systems such as nanoparticles, liposomes, microparticles, and micro- and nano-emulsions. This review stands to accomplish the diverse aspects of oral delivery of proteins/peptides and summarizes the key concepts involved in targeting the biodrugs to specific sites of the GI tract such as the intestine and colon. Furthermore some light has also been shed on the current industrial practices followed in developing oral formulations of such bioactives.

  15. Dual pH-responsive and CD44 receptor targeted multifunctional nanoparticles for anticancer intracellular delivery

    NASA Astrophysics Data System (ADS)

    Chen, Daquan; Sun, Jingfang; Lian, Shengnan; Liu, Zongliang; Sun, Kaoxiang; Liu, Wanhui; Wu, Zimei; Zhang, Qiang

    2014-11-01

    In this article, we prepared a multifunctional oligosaccharides of hyaluronan (oHA) conjugates, oHA-histidine-menthone 1,2-glycerol ketal (oHM). The oHM conjugates possess pH-sensitive menthone 1,2-glycerol ketal (MGK) as hydrophobic moieties and oHA as the target of CD44 receptor. The polymeric mPEG-Chitosan-Ketal (PCK) carrying pH-sensitive ketal group as hydrophobic moieties and PEG group as hydrophilic moieties were synthesized. The two pH-sensitive ketal derivatives were employed to fabricate nanoparticles for anti-tumor drug delivery. The oHM-PCK nanoparticles (oHPN) can spontaneously self-assemble into mixed micellar structure with nano-sized spherical shape of 100-200 nm at pH 7.4 PBS conditions. The oHPN could release encapsulated curcumin with 92.6 % at pH 5.0 compared with 55.3 % at pH 7.4. The results of cytotoxicity assay indicated that encapsulated curcumin in oHPN (Cur-oHPN) have less toxicity compared to curcumin suspension. The anti-tumor efficacy in vivo suggested that Cur-oHPN suppressed tumor growth most efficiently. These results present the promising potential of oHPN as an effective nano-sized pH-sensitive drug delivery system for intracellular delivery.

  16. Targeted drug delivery to bone: pharmacokinetic and pharmacological properties of acidic oligopeptide-tagged drugs.

    PubMed

    Takahashi-Nishioka, Tatsuo; Yokogawa, Koichi; Tomatsu, Shunji; Nomura, Masaaki; Kobayashi, Shinjiro; Miyamoto, Ken-Ichi

    2008-03-01

    Site-specific drug delivery to bone is considered to be achievable by utilizing acidic amino acid homopeptides. We found that fluorescence-labeled acidic amino acid (L-Asp or L-Glu) homopeptides containing six or more residues bound strongly to hydroxyapatite, which is a major component of bone, and were selectively delivered to and retained in bone after systemic administration. We explored the applicability of this result for drug delivery by conjugation of estradiol and levofloxacin with an L-Asp hexapeptide. We also similarly tagged an enzyme, tissue-nonspecific alkaline phosphatase, to see whether this would improve the efficacy of enzyme replacement therapy. The L-Asp hexapeptide-tagged drugs, including the enzyme, were selectively delivered to bone in comparison with the untagged drugs. It was expected that the ester linkage to the hexapeptide would be susceptible to hydrolysis in situ, releasing the drug or enzyme from the acidic oligopeptide. An in vivo experiment confirmed the efficacy of L-Asp hexapeptide-tagged estradiol and levofloxacin, although there was some loss of bioactivity of estradiol and levofloxacin in vitro, suggesting that the acidic hexapeptide was partly removed by hydrolysis in the body after delivery to bone. The adverse effect of estradiol on the uterus was greatly reduced by conjugation to the hexapeptide. These results support the usefulness of acidic oligopeptides as bone-targeting carriers for therapeutic agents. We present some pharmacokinetic and pharmacological properties of the L-Asp hexapeptide-tagged drugs and enzyme.

  17. Targeted delivery of GDNF through the blood-brain barrier by MRI-guided focused ultrasound.

    PubMed

    Wang, Feng; Shi, Yu; 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

    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.

  18. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness.

    PubMed

    Khalin, Igor; Alyautdin, Renad; Kocherga, Ganna; Bakar, Muhamad Abu

    2015-01-01

    Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood-retinal barrier and blood-cochlear barrier, which have a comparable structure to the blood-brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration.

  19. Therapy of Chronic Hepatitis C in the Era of Nanotechnology: Drug Delivery Systems and Liver Targeting.

    PubMed

    Cuestas, Maria Lujan

    2017-01-01

    Since the British scientist Michael Houghton along with George Kuo, Qui-Lim Choo (Chiron Corporation Emeryville), and Daniel W. Bradley (Centers for Disease Control and Prevention) codiscovered the causative agent of hepatitis C in 1989, so much progress has been made for the screening of blood donors and management of this chronic liver disease. In this regard, direct-acting antiviral agents (DAAs) have emerged as the potential "cure" of this slowly progressing and devastating disease. However, improvements are still clearly required since the anti-hepatitis C drugs currently available in the market are so extremely expensive (i.e. $94,500 for a 12-week course of treatment), that many patients will have a denied access to such drugs by their insurers.

    In the last few years, nanotechnology has emerged as a new platform for drug development, contributing significantly to the improvement of the administration and delivery of many drugs. Additionally, nanotechnologies can provide unique solutions even in poorer societies.

    This manuscript reviews the current knowledges on the available anti-hepatitis C drugs and the new drug candidates being investigated as well, and introduces the recent advances in nanocarrier-based delivery systems. Finally, the challenges in the development of drug delivery systems for the targeting of antiviral drugs to the liver are also discussed.

  20. Synthesis of Bisethylnorspermine Lipid Prodrug as Gene Delivery Vector Targeting Polyamine Metabolism in Breast Cancer

    PubMed Central

    Dong, Yanmei; Zhu, Yu; Li, Jing; Zhou, Qing-Hui; Wu, Chao; Oupický, David

    2013-01-01

    Progress in the development of nonviral gene delivery vectors continues to be hampered by low transfection activity and toxicity. Here we proposed to develop a lipid prodrug based on a polyamine analogue bisethylnorspermine (BSP) that can function dually as gene delivery vector and, after intracellular degradation, as active anticancer agent targeting dysregulated polyamine metabolism. We synthesized a prodrug of BSP (LS-BSP) capable of intracellular release of BSP using thiolytically sensitive dithiobenzyl carbamate linker. Biodegradability of LS-BSP contributed to decreased toxicity compared with nondegradable control L-BSP. BSP showed a strong synergistic enhancement of cytotoxic activity of TNF-related apoptosis-inducing ligand (TRAIL) in human breast cancer cells. Decreased enhancement of TRAIL activity was observed for LS-BSP when compared with BSP. LS-BSP formed complexes with plasmid DNA and mediated transfection activity comparable to DOTAP and L-BSP. Our results show that BSP-based vectors are promising candidates for combination drug/gene delivery. PMID:22545813

  1. Targeted delivery of brain-derived neurotrophic factor for the treatment of blindness and deafness

    PubMed Central

    Khalin, Igor; Alyautdin, Renad; Kocherga, Ganna; Bakar, Muhamad Abu

    2015-01-01

    Neurodegenerative causes of blindness and deafness possess a major challenge in their clinical management as proper treatment guidelines have not yet been found. Brain-derived neurotrophic factor (BDNF) has been established as a promising therapy against neurodegenerative disorders including hearing and visual loss. Unfortunately, the blood–retinal barrier and blood–cochlear barrier, which have a comparable structure to the blood–brain barrier prevent molecules of larger sizes (such as BDNF) from exiting the circulation and reaching the targeted cells. Anatomical features of the eye and ear allow use of local administration, bypassing histo-hematic barriers. This paper focuses on highlighting a variety of strategies proposed for the local administration of the BDNF, like direct delivery, viral gene therapy, and cell-based therapy, which have been shown to successfully improve development, survival, and function of spiral and retinal ganglion cells. The similarities and controversies for BDNF treatment of posterior eye diseases and inner ear diseases have been analyzed and compared. In this review, we also focus on the possibility of translation of this knowledge into clinical practice. And finally, we suggest that using nanoparticulate drug-delivery systems may substantially contribute to the development of clinically viable techniques for BDNF delivery into the cochlea or posterior eye segment, which, ultimately, can lead to a long-term or permanent rescue of auditory and optic neurons from degeneration. PMID:25995632

  2. Improved Therapeutic Efficacy in Bone and Joint Disorders by Targeted Drug Delivery to Bone.

    PubMed

    Takahashi, Tatsuo

    2016-01-01

     Site-specific drug delivery to bone is considered achievable using acidic amino acid (L-Asp or L-Glu) homopeptides known as acidic oligopeptides. We found that fluorescence-labeled acidic oligopeptides containing six or more residues bound strongly to hydroxyapatite, which is a major component of bone, and were selectively delivered to and retained in bone after systemic administration. We explored the applicability of this result for drug delivery by conjugation of estradiol and levofloxacin with an L-Asp hexapeptide. We also similarly tagged enzymes (tissue-nonspecific alkaline phosphatase, β-glucuronidase, and N-acetylgalactosamine-6-sulfate sulfatase) and decoy receptors (endogenous secretory receptor for advanced glycation end products and etanercept) to assess whether these would improve therapeutic efficacy. The L-Asp hexapeptide-tagged drugs, including enzymes and decoy receptors, were efficiently delivered to bone in comparison with the untagged drugs. An in vivo experiment confirmed the efficacy of L-Asp hexapeptide-tagged drugs on bone and joint disorders, although there was some loss of bioactivity of estradiol and levofloxacin in vitro, suggesting that the acidic hexapeptide was partly removed by hydrolysis in the body after delivery to bone. It was expected that the ester linkage to the hexapeptide would be susceptible to hydrolysis in situ, releasing the drug from the acidic oligopeptide. These results support the usefulness of acidic oligopeptides as bone-targeting carriers for therapeutic agents. We present some pharmacokinetic and pharmacological properties of the L-Asp hexapeptide-tagged drugs.

  3. Investigation on properties of P((MAA-co-DMAEMA)-g-EG) polyampholyte nanogels

    NASA Astrophysics Data System (ADS)

    Deng, Liandong; Zhai, Yinglei; Guo, Shutao; Jin, Fengmin; Xie, Zhaopeng; He, Xiaohua; Dong, Anjie

    2009-02-01

    P((MAA-co-DMAEMA)-g-EG) polyampholyte nanogels (PANGs) were prepared by distillation-dispersion copolymerization of poly(ethylene glycol) methyl ether methacrylate (MPEGMA), N, N-dimethylaminoethyl methacrylate (DMAEMA), and methacrylic acid (MAA) using acetonitrile (AN) as dispersion medium. The results of FTIR spectra indicate that the composition of P((MAA-co-DMAEMA)-g-EG) PANGs is consistent with the designed structure. The results of TEM and laser particle size analyzer (LPSA) show that P((MAA-co-DMAEMA)-g-EG) PANGs present spherical morphology and a bimodal size distribution after and before swelling. P((MAA-co-DMAEMA)-g-EG) PANGs have typically amphoteric characters responding to pH, whose isoelectric point (IEP) increases with decreasing the ratio of MAA/DMAEMA and equilibrium swelling degree (ESD) is greater than that at IEP when the pH value is distant from IEP. P((MAA-co-DMAEMA)-g-EG) PANGs also represent ionic strength sensitivity. Using the water-soluble chitosan (CS, Mn = 5 kDa) as model drug, in vitro release indicates that CS can be effectively incorporated into PANGs and the release rate of CS at pH 1.89 is an order of magnitude greater than that at pH 8.36. P((MAA-co-DMAEMA)-g-EG) PANGs may be useful in biomedicine, especially in oral drug delivery of biomacromolecule.

  4. Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson’s Disease

    NASA Astrophysics Data System (ADS)

    Fan, Ching-Hsiang; Ting, Chien-Yu; Lin, Chung-Yin; Chan, Hong-Lin; Chang, Yuan-Chih; Chen, You-Yin; Liu, Hao-Li; Yeh, Chih-Kuang

    2016-01-01

    Glial cell line-derived neurotrophic factor (GDNF) supports the growth and survival of dopaminergic neurons. CNS gene delivery currently relies on invasive intracerebral injection to transit the blood-brain barrier. Non-viral gene delivery via systematic transvascular route is an attractive alternative because it is non-invasive, but a high-yield and targeted gene-expressed method is still lacking. In this study, we propose a novel non-viral gene delivery approach to achieve targeted gene transfection. Cationic microbubbles as gene carriers were developed to allow the stable formation of a bubble-GDNF gene complex, and transcranial focused ultrasound (FUS) exposure concurrently interacting with the bubble-gene complex allowed transient gene permeation and induced local GDNF expression. We demonstrate that the focused ultrasound-triggered GDNFp-loaded cationic microbubbles platform can achieve non-viral targeted gene delivery via a noninvasive administration route, outperform intracerebral injection in terms of targeted GDNF delivery of high-titer GDNF genes, and has a neuroprotection effect in Parkinson’s disease (PD) animal models to successfully block PD syndrome progression and to restore behavioral function. This study explores the potential of using FUS and bubble-gene complexes to achieve noninvasive and targeted gene delivery for the treatment of neurodegenerative disease.

  5. Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson's Disease.

    PubMed

    Fan, Ching-Hsiang; Ting, Chien-Yu; Lin, Chung-Yin; Chan, Hong-Lin; Chang, Yuan-Chih; Chen, You-Yin; Liu, Hao-Li; Yeh, Chih-Kuang

    2016-01-20

    Glial cell line-derived neurotrophic factor (GDNF) supports the growth and survival of dopaminergic neurons. CNS gene delivery currently relies on invasive intracerebral injection to transit the blood-brain barrier. Non-viral gene delivery via systematic transvascular route is an attractive alternative because it is non-invasive, but a high-yield and targeted gene-expressed method is still lacking. In this study, we propose a novel non-viral gene delivery approach to achieve targeted gene transfection. Cationic microbubbles as gene carriers were developed to allow the stable formation of a bubble-GDNF gene complex, and transcranial focused ultrasound (FUS) exposure concurrently interacting with the bubble-gene complex allowed transient gene permeation and induced local GDNF expression. We demonstrate that the focused ultrasound-triggered GDNFp-loaded cationic microbubbles platform can achieve non-viral targeted gene delivery via a noninvasive administration route, outperform intracerebral injection in terms of targeted GDNF delivery of high-titer GDNF genes, and has a neuroprotection effect in Parkinson's disease (PD) animal models to successfully block PD syndrome progression and to restore behavioral function. This study explores the potential of using FUS and bubble-gene complexes to achieve noninvasive and targeted gene delivery for the treatment of neurodegenerative disease.

  6. Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson’s Disease

    PubMed Central

    Fan, Ching-Hsiang; Ting, Chien-Yu; Lin, Chung‐Yin; Chan, Hong-Lin; Chang, Yuan-Chih; Chen, You-Yin; Liu, Hao-Li; Yeh, Chih-Kuang

    2016-01-01

    Glial cell line-derived neurotrophic factor (GDNF) supports the growth and survival of dopaminergic neurons. CNS gene delivery currently relies on invasive intracerebral injection to transit the blood-brain barrier. Non-viral gene delivery via systematic transvascular route is an attractive alternative because it is non-invasive, but a high-yield and targeted gene-expressed method is still lacking. In this study, we propose a novel non-viral gene delivery approach to achieve targeted gene transfection. Cationic microbubbles as gene carriers were developed to allow the stable formation of a bubble-GDNF gene complex, and transcranial focused ultrasound (FUS) exposure concurrently interacting with the bubble-gene complex allowed transient gene permeation and induced local GDNF expression. We demonstrate that the focused ultrasound-triggered GDNFp-loaded cationic microbubbles platform can achieve non-viral targeted gene delivery via a noninvasive administration route, outperform intracerebral injection in terms of targeted GDNF delivery of high-titer GDNF genes, and has a neuroprotection effect in Parkinson’s disease (PD) animal models to successfully block PD syndrome progression and to restore behavioral function. This study explores the potential of using FUS and bubble-gene complexes to achieve noninvasive and targeted gene delivery for the treatment of neurodegenerative disease. PMID:26786201

  7. Targeted sustained delivery of antineoplastic agent with multicomponent polylactide stereocomplex micelle.

    PubMed

    Shen, Kexin; Li, Di; Guan, Jingjing; Ding, Jianxun; Wang, Zhongtang; Gu, Jingkai; Liu, Tongjun; Chen, Xuesi

    2017-01-05

    A c(RGDfC)-decorated polylactide stereocomplex micelle (cRGD-SCM) was prepared through the stereocomplex and hydrophobic interactions among 4-arm poly(ethylene glycol)-block-poly(D-lactide) (4-arm PEG-b-PDLA), methoxy poly(ethylene glycol)-block-poly(L-lactide) (mPEG-b-PLLA), and c(RGDfC)-poly(ethylene glycol)-block-poly(L-lactide) (cRGD-PEG-b-PLLA) for targeted treatment of αvβ3 integrin-positive C26 colon cancer. Doxorubicin (DOX), a model antitumor drug, was loaded into cRGD-SCM with a diameter of approximately 100nm, and the drug loading efficiency was 45.9wt.%. cRGD-SCM/DOX with a sustained release pattern exhibited prolonged circulation time, upregulated accumulation in tumor, enhanced tumor inhibition, and decreased side effects compared with free DOX and non-targeting SCM/DOX in vivo. More interestingly, the targeting ligand in the terminal of PEG can be easily replaced with other targeting groups according to the different types of malignancies. Therefore, the cRGD-decorated platform might be a promising targeted drug delivery system for personal chemotherapy clinically.

  8. Mito-DCA: a mitochondria targeted molecular scaffold for efficacious delivery of metabolic modulator dichloroacetate.

    PubMed

    Pathak, Rakesh K; Marrache, Sean; Harn, Donald A; Dhar, Shanta

    2014-05-16

    Tumor growth is fueled by the use of glycolysis, which normal cells use only in the scarcity of oxygen. Glycolysis makes tumor cells resistant to normal death processes. Targeting this unique tumor metabolism can provide an alternative strategy to selectively destroy the tumor, leaving normal tissue unharmed. The orphan drug dichloroacetate (DCA) is a mitochondrial kinase inhibitor that has the ability to show such characteristics. However, its molecular form shows poor uptake and bioavailability and limited ability to reach its target mitochondria. Here, we describe a targeted molecular scaffold for construction of a multiple DCA loaded compound, Mito-DCA, with three orders of magnitude enhanced potency and cancer cell specificity compared to DCA. Incorporation of a lipophilic triphenylphosphonium cation through a biodegradable linker in Mito-DCA allowed for mitochondria targeting. Mito-DCA did not show any significant metabolic effects toward normal cells but tumor cells with dysfunctional mitochondria were affected by Mito-DCA, which caused a switch from glycolysis to glucose oxidation and subsequent cell death via apoptosis. Effective delivery of DCA to the mitochondria resulted in significant reduction in lactate levels and played important roles in modulating dendritic cell (DC) phenotype evidenced by secretion of interleukin-12 from DCs upon activation with tumor antigens from Mito-DCA treated cancer cells. Targeting mitochondrial metabolic inhibitors to the mitochondria could lead to induction of an efficient antitumor immune response, thus introducing the concept of combining glycolysis inhibition with immune system to destroy tumor.

  9. A new targeted delivery approach by functionalizing drug nanocrystals through polydopamine coating.

    PubMed

    Zhan, Honglei; Jagtiani, Tina; Liang, Jun F

    2017-05-01

    Tumor target specificity via chemotherapy is widely considered to be very effective on tumor treatment. For an ideal chemotherapeutic agent like Camptothecin (CPT) (CPT is the abbreviation for Camptothecin), improved therapeutic efficacy and high selectivity are equally important. Inspired by adhesive proteins in mussels, here we developed a novel tumor targeting peptide XQ1 grafted CPT nanocrystals with polydopamine coating as a spacer. In this study, CPT nanocrystals were coated by polymerization of dopamine that was induced by plasma-activated water under an acidic environment, and then the tumor targeting peptide was grafted onto polydopamine (PDA) (PDA is the abbreviation for polydopamine) coated CPT nanocrystals through catechol chemistry. The PDA layer had negligible effects on drug crystallinity and structure but resulted in drug nanocrystals with excellent dispersion properties, improved dissolution rate and drug stability by preventing water hydrolysis. More importantly, tumor targeting peptide XQ1 facilitated a rapid cross-membrane translocation of drug nanocrystals via receptor-mediated endocytosis, leading to efficient intracellular drug delivery. Moreover, this novel drug formulation demonstrated more potent anti-cancer activity against tumor cells in comparison with free CPT and naked CPT nanocrystals and exhibited high selectivity, all of which are attributed to the tumor target specificity property and inherent pH-dependent drug release behavior.

  10. Liposome-protein corona in a physiological environment: challenges and opportunities for targeted delivery of nanomedicines.

    PubMed

    Caracciolo, Giulio

    2015-04-01

    Active targeting that exploits the (over)expression of surface receptors in target cells by ligand incorporation is a central concept in nanomedicine research. Despite unprecedented efforts, no targeted liposome-based therapeutics is commercially available for clinical practice. What is inhibiting the efficient translation of targeted liposome technology from bench to bedside? After introduction in the bloodstream, the lipid surface is immediately modified by the adsorption of a "protein corona" and preserving the surface functionality appears to be challenging. On the other hand, a long-standing corona with receptor-binding sites could associate with the target cell long enough to activate the cell's uptake machinery, triggering liposome endocytosis and intracellular cargo delivery. This opens the intriguing possibility to manipulate the corona composition by liposome design. This review will focus on the emerging field of liposome-protein corona research from basic, descriptive research to readily applicable knowledge and technologies for implementation in drug improvement and development. From the clinical editor: This review is addressing the liposome protein corona research concerning the potential gains in drug improvement and for drug development.

  11. Catechol polymers for pH-responsive, targeted drug delivery to cancer cells.

    PubMed

    Su, Jing; Chen, Feng; Cryns, Vincent L; Messersmith, Phillip B

    2011-08-10

    A novel cell-targeting, pH-sensitive polymeric carrier was employed in this study for delivery of the anticancer drug bortezomib (BTZ) to cancer cells. Our strategy is based on facile conjugation of BTZ to catechol-containing polymeric carriers that are designed to be taken up selectively by cancer cells through cell surface receptor-mediated mechanisms. The polymer used as a building block in this study was poly(ethylene glycol), which was chosen for its ability to reduce nonspecific interactions with proteins and cells. The catechol moiety was exploited for its ability to bind and release borate-containing therapeutics such as BTZ in a pH-dependent manner. In acidic environments, such as in cancer tissue or the subcellular endosome, BTZ dissociates from the polymer-bound catechol groups to liberate the free drug, which inhibits proteasome function. A cancer-cell-targeting ligand, biotin, was presented on the polymer carriers to facilitate targeted entry of drug-loaded polymer carriers into cancer cells. Our study demonstrated that the cancer-targeting drug-polymer conjugates dramatically enhanced cellular uptake, proteasome inhibition, and cytotoxicity toward breast carcinoma cells in comparison with nontargeting drug-polymer conjugates. The pH-sensitive catechol-boronate binding mechanism provides a chemoselective approach for controlling the release of BTZ in targeted cancer cells, establishing a concept that may be applied in the future toward other boronic acid-containing therapeutics to treat a broad range of diseases.

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

    PubMed Central

    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

    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. PMID:25302024

  13. Hyaluronic acid-modified multiwalled carbon nanotubes for targeted delivery of doxorubicin into cancer cells.

    PubMed

    Cao, Xueyan; Tao, Lei; Wen, Shihui; Hou, Wenxiu; Shi, Xiangyang

    2015-03-20

    Development of novel drug carriers for targeted cancer therapy with high efficiency and specificity is of paramount importance and has been one of the major topics in current nanomedicine. Here we report a general approach to using multifunctional multiwalled carbon nanotubes (MWCNTs) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for targeted cancer therapy. In this approach, polyethyleneimine (PEI)-modified MWCNTs were covalently conjugated with fluorescein isothiocyanate (FI) and hyaluronic acid (HA). The formed MWCNT/PEI-FI-HA conjugates were characterized via different techniques and were used as a new carrier system to encapsulate the anticancer drug doxorubicin for targeted delivery to cancer cells overexpressing CD44 receptors. We show that the formed MWCNT/PEI-FI-HA/DOX complexes with a drug loading percentage of 72% are water soluble and stable. In vitro release studies show that the drug release rate under an acidic condition (pH 5.8, tumor cell microenvironment) is higher than that under physiological condition (pH 7.4). Cell viability assay demonstrates that the carrier material has good biocompatibility in the tested concentration range, and the MWCNT/PEI-FI-HA/DOX complexes can specifically target cancer cells overexpressing CD44 receptors and exert growth inhibition effect to the cancer cells. The developed HA-modified MWCNTs hold a great promise to be used as an efficient anticancer drug carrier for tumor-targeted chemotherapy.

  14. An intraocular drug delivery system using targeted nanocarriers attenuates retinal ganglion cell degeneration.

    PubMed

    Zhao, Lei; Chen, Guojun; Li, Jun; Fu, Yingmei; Mavlyutov, Timur A; Yao, Annie; Nickells, Robert W; Gong, Shaoqin; Guo, Lian-Wang

    2017-02-10

    Glaucoma is a common blinding disease characterized by loss of retinal ganglion cells (RGCs). To date, there is no clinically available treatment directly targeting RGCs. We aim to develop an RGC-targeted intraocular drug delivery system using unimolecular micelle nanoparticles (unimNPs) to prevent RGC loss. The unimNPs were formed by single/individual multi-arm star amphiphilic block copolymer poly(amidoamine)-polyvalerolactone-poly(ethylene glycol) (PAMAM-PVL-PEG). While the hydrophobic PAMAM-PVL core can encapsulate hydrophobic drugs, the hydrophilic PEG shell provides excellent water dispersity. We conjugated unimNPs with the cholera toxin B domain (CTB) for RGC-targeting and with Cy5.5 for unimNP-tracing. To exploit RGC-protective sigma-1 receptor (S1R), we loaded unimNPs with an endogenous S1R agonist dehydroepiandrosterone (DHEA) as an FDA-approved model drug. These unimNPs produced a steady DHEA release in vitro for over two months at pH7.4. We then co-injected (mice, intraocular) unimNPs with the glutamate analog N-methyl-d-aspartate (NMDA), which is excito-toxic and induces RGC death. The CTB-conjugated unimNPs (i.e., targeted NPs) accumulated at the RGC layer and effectively preserved RGCs at least for 14days, whereas the unimNPs without CTB (i.e., non-targeted NPs) showed neither accumulation at nor protection of NMDA-treated RGCs. Consistent with S1R functions, targeted NPs relative to non-targeted NPs showed markedly better inhibitory effects on apoptosis and oxidative/inflammatory stresses in the RGC layer. Hence, the DHEA-loaded, CTB-conjugated unimNPs represent an RGC/S1R dual-targeted nanoplatform that generates an efficacious template for further development of a sustainable intraocular drug delivery system to protect RGCs, which may be applicable to treatments directed at glaucomatous pathology.

  15. Targeted Drug Delivery to the Peripheral Nervous System using Gene Therapy

    PubMed Central

    Wolfe, Darren; Mata, Marina; Fink, David J.

    2012-01-01

    Gene transfer to target delivery of neurotrophic factors to the primary sensory afferent for treatment of polyneuropathy, or of inhibitory neurotransmitters for relief of chronic pain, offers the possibility of a highly selective targeted release of bioactive molecules within the nervous system. Preclinical studies with non-replicating herpes simplex virus (HSV)-based vectors injected into the skin to transduce neurons in the dorsal root ganglion have demonstrated efficacy in reducing-pain related behaviors in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer, and in preventing progression of sensory neuropathy caused by toxins, chemotherapeutic drugs or resulting from diabetes. Successful completion of the first phase 1 clinical trial of HSV-mediated gene transfer in patients with intractable pain from cancer has set the stage for further clinical trials of this approach. PMID:22565023

  16. Targeted Delivery of Shear Stress-Inducible Micrornas by Nanoparticles to Prevent Vulnerable Atherosclerotic Lesions

    PubMed Central

    Wong, Wing Tak; Ma, Shuangtao; Tian, Xiao Yu; Gonzalez, Andrea Banuet; Ebong, Eno E.; Shen, Haifa

    2016-01-01

    Atherosclerosis is a chronic inflammatory vascular wall disease, and endothelial cell dysfunction plays an important role in its development and progression. Under the influence of laminar shear stress, however, the endothelium releases homeostatic factors such as nitric oxide and expresses of vasoprotective microRNAs that are resistant to atherosclerosis. Adhesion molecules such as E-selectin, exhibited on the endothelial surface, recruit monocytes that enter the vessel wall to form foam cells. Accumulation of these foam cells form fatty streaks that may progress to atherosclerotic plaques in the blood vessel wall. Interestingly, E-selectin may also serve as an affinity moiety for targeted drug delivery against atherosclerosis. We have recently developed an E-selectin-targeted platform that enriches therapeutic microRNAs in the inflamed endothelium to inhibit formation of vulnerable atherosclerotic plaques. PMID:27826369

  17. Pyroelectric Adaptive Nanodispenser (PYRANA) microrobot for liquid delivery on a target.

    PubMed

    Vespini, Veronica; Coppola, Sara; Grilli, Simonetta; Paturzo, Melania; Ferraro, Pietro

    2011-09-21

    Manipulation of micro-sized objects in lab-on-a-chip and microfluidic environments is essential for different experiments and procedures ranging from chemical to biological applications and for experimental biotechnologies. For example polymeric particles, useful as targets for encapsulating or for being covered by drug vaccines, can be manipulated and controlled with the aim of releasing them to specific sites. Here we show a novel ElectroHydroDynamic tool able to control and manipulate dielectric micro-targets by a touch-less approach. This approach allows one to manipulate liquids and nano-particles simultaneously for specific delivery applications (i.e. decoration and coating). Thus a sort of EHD micro-robot is proposed. This flexible tool provides a new and powerful way to operate various tasks as demonstrated by the experiments reported here.

  18. A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries

    PubMed Central

    Mann, Aman P.; Scodeller, Pablo; Hussain, Sazid; Joo, Jinmyoung; Kwon, Ester; Braun, Gary B.; Mölder, Tarmo; She, Zhi-Gang; Kotamraju, Venkata Ramana; Ranscht, Barbara; Krajewski, Stan; Teesalu, Tambet; Bhatia, Sangeeta; Sailor, Michael J.; Ruoslahti, Erkki

    2016-01-01

    Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries. PMID:27351915

  19. Lipid nanoparticles for targeted siRNA delivery – going from bench to bedside

    PubMed Central

    Zatsepin, Timofei S; Kotelevtsev, Yuri V; Koteliansky, Victor

    2016-01-01

    This review covers the basic aspects of small interfering RNA delivery by lipid nano-particles (LNPs) and elaborates on the current status of clinical trials for these systems. We briefly describe the roles of all LNP components and possible strategies for their improvement. We also focus on the current clinical trials using LNP-formulated RNA and the possible outcomes for therapy in the near future. Also, we present a critical analysis of selected clinical trials that reveals the common logic behind target selection. We address this review to a wide audience, especially to medical doctors who are interested in the application of RNA interference–based treatment platforms. We anticipate that this review may spark interest in this particular audience and generate new ideas in target selection for the disorders they are dealing with. PMID:27462152

  20. Nanocarrier Hydrodynamics and Binding in Targeted Drug Delivery: Challenges in Numerical Modeling and Experimental Validation.

    PubMed

    Ayyaswamy, Portonovo S; Muzykantov, Vladimir; Eckmann, David M; Radhakrishnan, Ravi

    2013-02-01

    This review discusses current progress and future challenges in the numerical modeling of targeted drug delivery using functionalized nanocarriers (NC). Antibody coated nanocarriers of various size and shapes, also called functionalized nanocarriers, are designed to be injected in the vasculature, whereby they undergo translational and rotational motion governed by hydrodynamic interaction with blood particulates as well as adhesive interactions mediated by the surface antibody binding to target antigens/receptors on cell surfaces. We review current multiscale modeling approaches rooted in computational fluid dynamics and nonequilibrium statistical mechanics to accurately resolve fluid, thermal, as well as adhesive interactions governing nanocarrier motion and their binding to endothelial cells lining the vasculature. We also outline current challenges and unresolved issues surrounding the modeling methods. Experimental approaches in pharmacology and bioengineering are discussed briefly from the perspective of model validation.

  1. Cell type specific targeted intracellular delivery into muscle of a monoclonal antibody that binds myosin IIb.

    PubMed

    Weisbart, Richard H; Yang, Fusheng; Chan, Grace; Wakelin, Rika; Ferreri, Kevin; Zack, Debra J; Harrison, Brooke; Leinwand, Leslie A; Cole, Greg M

    2003-03-01

    Methods for cell type specific targeted intracellular delivery of proteins in vivo remain limited. A murine monoclonal anti-dsDNA antibody, mAb 3E10, was selectively transported into skeletal muscle cells in vivo. The antibody bound a 200 kDa protein only found in lysates of skeletal muscle by Western blotting. The 200 kDa protein was purified from muscle lysate by antibody affinity chromatography and identified as the skeletal muscle specific heavy chain of myosin IIb by electrospray mass spectrometry. Antibody binding specificity for myosin IIb was demonstrated in Western blots by binding myosin in skeletal muscle lysates from mice null for myosin IId but not in mice null for myosin IIb. Myosin IIb is implicated in the specific targeting of mAb 3E10 to skeletal muscle.

  2. Enzyme-responsive polyion complex (PIC) nanoparticles for the targeted delivery of antimicrobial polymers.

    PubMed

    Insua, Ignacio; Liamas, Evangelos; Zhang, Zhenyu; Peacock, Anna F A; Krachler, Anne Marie; Fernandez-Trillo, Francisco

    2016-04-21

    Here we present new enzyme-responsive polyion complex (PIC) nanoparticles prepared from antimicrobial poly(ethylene imine) and an anionic enzyme-responsive peptide targeting Pseudomonas aeruginosa's elastase. The synthetic conditions used to prepare these nanomaterials allowed us to optimise particle size and charge, and their stability under physiological conditions. We demonstrate that these enzyme responsive PIC nanoparticles are selectively degraded in the presence of P. aeruginosa elastase without being affected by other endogenous elastases. This enzyme-responsive PIC particle can exert an elastase-specific antimicrobial effect against P. aeruginosa without affecting non-pathogenic strains of these bacteria. These targeted enzyme-responsive PIC nanoparticles constitute a novel platform for the delivery of antimicrobial peptides and polymers, and can be a powerful tool in the current race against antimicrobial resistance.

  3. A peptide for targeted, systemic delivery of imaging and therapeutic compounds into acute brain injuries

    NASA Astrophysics Data System (ADS)

    Mann, Aman P.; Scodeller, Pablo; Hussain, Sazid; Joo, Jinmyoung; Kwon, Ester; Braun, Gary B.; Mölder, Tarmo; She, Zhi-Gang; Kotamraju, Venkata Ramana; Ranscht, Barbara; Krajewski, Stan; Teesalu, Tambet; Bhatia, Sangeeta; Sailor, Michael J.; Ruoslahti, Erkki

    2016-06-01

    Traumatic brain injury (TBI) is a major health and socio-economic problem, but no pharmacological agent is currently approved for the treatment of acute TBI. Thus, there is a great need for advances in this field. Here, we describe a short peptide (sequence CAQK) identified by in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brain, and systemically injected CAQK specifically homes to sites of brain injury in mouse models. The CAQK target is a proteoglycan complex upregulated in brain injuries. Coupling to CAQK increased injury site accumulation of systemically administered molecules ranging from a drug-sized molecule to nanoparticles. CAQK-coated nanoparticles containing silencing oligonucleotides provided the first evidence of gene silencing in injured brain parenchyma by systemically administered siRNA. These findings present an effective targeting strategy for the delivery of therapeutics in clinical management of acute brain injuries.

  4. Thermal treatment of galactose-branched polyelectrolyte microcapsules to improve drug delivery with reserved targetability.

    PubMed

    Zhang, Fu; Wu, Qi; Liu, Li-Jun; Chen, Zhi-Chun; Lin, Xian-Fu

    2008-06-05

    A novel multilayered drug delivery system by LbL assembly of galactosylated polyelectrolyte, which is possible to have the potential in hepatic targeting by the presence of galactose residues at the microcapsule's surface, is designed. Thermal treatment was performed on the capsules and a dramatic thermal shrinkage up to 60% decrease of capsule diameter above 50 degrees C was observed. This thermal behavior was then used to manipulate drug loading capacity and release rate. Heating after drug loading could seal the capsule shell, enhancing the loading capacity and reducing the release rate significantly. Excellent affinity between galactose-binding lectin and heated galactose-containing microcapsules were observed, indicating a stable targeting potential even after high temperature elevating up to 90 degrees C.

  5. Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery

    PubMed Central

    2012-01-01

    Tumor vasculature expresses a distinct set of molecule signatures on the endothelial cell surface different from the resting blood vessels of other organs and tissues in the body. This makes them an attractive target for cancer therapy and molecular imaging. The current technology using the in vivo phage display biopanning allows us to quickly isolate and identify peptides potentially homing to various tumor blood vessels. Tumor-homing peptides in conjugation with chemotherapeutic drugs or imaging contrast have been extensively tested in various preclinical and clinical studies. These tumor-homing peptides have valuable potential as targeting probes for tumor molecular imaging and drug delivery. In this review, we summarize the recent advances about the applications of tumor-homing peptides selected by in vivo phage display library screening against tumor vasculature. We also introduce the characteristics of the latest discovered tumor-penetrating peptides in their potential clinical applications. PMID:23046982

  6. Peptides as targeting probes against tumor vasculature for diagnosis and drug delivery.

    PubMed

    Li, Zhi Jie; Cho, Chi Hin

    2012-09-19

    Tumor vasculature expresses a distinct set of molecule signatures on the endothelial cell surface different from the resting blood vessels of other organs and tissues in the body. This makes them an attractive target for cancer therapy and molecular imaging. The current technology using the in vivo phage display biopanning allows us to quickly isolate and identify peptides potentially homing to various tumor blood vessels. Tumor-homing peptides in conjugation with chemotherapeutic drugs or imaging contrast have been extensively tested in various preclinical and clinical studies. These tumor-homing peptides have valuable potential as targeting probes for tumor molecular imaging and drug delivery. In this review, we summarize the recent advances about the applications of tumor-homing peptides selected by in vivo phage display library screening against tumor vasculature. We also introduce the characteristics of the latest discovered tumor-penetrating peptides in their potential clinical applications.

  7. Folate receptor targeted three-layered micelles and hydrogels for gene delivery to activated macrophages.

    PubMed

    Mohammadi, Mariam; Li, Ying; Abebe, Daniel G; Xie, Yuran; Kandil, Rima; Kraus, Teresa; Gomez-Lopez, Nardhy; Fujiwara, Tomoko; Merkel, Olivia M

    2016-12-28

    New folic acid (FA) coupled three layered micelles (3LM) were designed to encapsulate DNA, and their application as delivery system that specifically targets activated macrophages was investigated for new treatment options in rheumatoid arthritis (RA). FA coupled poly(l-lactide)-b-poly(ethylene glycol) (FA-PEG-PLLA) was synthesized via the NHS-ester activated/amine coupling method. Fluorescein labeled folic acid was used for flow cytometric detection of the expression of functional folic receptor β in LPS-activated and resting macrophages. FA coupled 3LM were formulated in a two-step procedure and characterized regarding hydrodynamic diameters and zeta potentials. The presence of the targeting ligand was shown not to increase the size of the 3LM compared to their non-targeted counterparts. Targeted and non-targeted 3LM were used in vitro to optimize uptake conditions in the RAW 264.7 macrophage cell line. The amount of FA coupled polymer in the final formulation was found to be optimal at 75% FA-PEG-PLLA and 25% PLLA-PEG-PLLA. Subsequently, transgene expression in vitro in RAW 264.7 cells and ex vivo in primary activated and resting mouse macrophages was determined as a function of FR-mediated internalization of 3LM encapsulating GFP expressing plasmid. FR-overexpressing activated cells, as successfully identified by internalization of FA-fluorescein, showed significantly higher GFP expression in vitro and ex vivo than resting macrophages with only a basal level of FR expression. Lastly, injectable hydrogels as depot formulation were formed by stereocomplexation, and their degradation, DNA release profiles, and dissociation into intact 3LM were found to be beneficial for potential in vivo application. Our findings confirm that FA-3LM are taken up by activated macrophages via folate receptor mediated endocytosis and that their hydrogels release intact 3LM for efficient transfection of primary macrophages. Therefore, FA-3LM could become a promising delivery system

  8. Tuning Surface Microstructure and Gradient Property of Polymer by Photopolymerizable Polysiloxane-modified Nanogels

    PubMed Central

    Chen, Cong; Liu, JianCheng; Sun, Fang; Stansbury, Jeffrey W.

    2014-01-01

    This paper reports a series of photopolymerizable polysiloxane-modified nanogels for regulating surface microstructure and gradient property of polymers, which were synthesized by solution polymerization under different feed ratios of a methacrylate-modified polysiloxane, urethane dimethacrylate (UDMA) and isobornyl methacrylate (IBMA) in the presence of a thiol chain transfer agent. The nanogel structure and composition were characterized by proton nuclear magnetic resonance (1H-NMR), Fourier transform-infrared spectroscopy (FT-IR), transmission electron microscope (TEM), gel permeation chromatography (GPC) and differential scanning calorimetry (DSC). The dispersion of these nanogels in triethylene glycol dimethacrylate (TEGDMA) can reduce the onset and magnitude of shrinkage stress during polymerization without compromise to mechanical properties of the resulting polymers. Most importantly, as demonstrated by elemental analysis and X-ray photoelectron spectroscopy (XPS), the nanogels exhibit good self-floating ability in the monomer/polymer matrix and the increase of polysiloxane content in the nanogel can enhance the self-floating capability due to the lower surface tension and energy associated with the polysiloxane component. As a result, the polysiloxane-modified nanogels can spontaneously form a concentration gradient that can be locked in upon photopolymerization leading to a well-controlled heterogeneous polymer that presents a gradient change in thermal stability. With the increase of polysiloxane content, the thermal stability of the polymer was improved significantly. Furthermore, the enrichment of the nanogel on the surface resulting from the good self-floating ability can reduce the dispersion surface energy of gradient polymer film and generate a more hydrophobic surface with altered surface microstructure. These photopolymerizable polysiloxane-modified nanogels are demonstrated to have potential broad application in the preparation of gradient

  9. Targeted delivery of peptide-conjugated biocompatible gold nanoparticles into cancer cell nucleus

    NASA Astrophysics Data System (ADS)

    Qian, Wei; Curry, Taeyjuana; Che, Yong; Kopelman, Raoul

    2013-02-01

    Nucleus remains a significant target for nanoparticles with diagnostic and therapeutic applications because both genetic information of the cell and transcription machinery reside there. Novel therapeutic strategies (for example, gene therapy), enabled by safe and efficient delivery of nanoparticles and drug molecules into the nucleus, are heralded by many as the ultimate treatment for severe and intractable diseases. However, most nanomaterials and macromolecules are incapable of reaching the cell nucleus on their own, because of biological barriers carefully honed by evolution including cellular membrane and nuclear envelope. In this paper, we have demonstrated an approach of fabrication of biocompatible gold nanoparticle (Au NP)-based vehicles which can entering into cancer cell nucleus by modifying Au NPs with both PEG 5000 and two different peptides (RGD and nuclear localization signal (NLS) peptide). The Au NPs used were fabricated via femtosecond laser ablation of Au bulk target in deionized water. The Au NPs produced by this method provide chemical free, virgin surface, which allows us to carry out "Sequential Conjugation" to modify their surface with PEG 5000, RGD, and NLS. "Sequential Conjugation" described in this presentation is very critical for the fabrication of Au NP-based vehicles capable of entering into cancer cell nucleus as it enables the engineering and tuning surface chemistries of Au NPs by independently adjusting amounts of PEG and peptides bound onto surface of Au NPs so as to maximize their nuclear targeting performance and biocompatibility regarding the cell line of interest. Both optical microscopy and transmission electron microscopy (TEM) are used to confirm the in vitro targeted nuclear delivery of peptide-conjugated biocompatible Au NPs by showing their presence in the cancer cell nucleus.

  10. Feasibility of targeted drug delivery to selective areas of the retina

    SciTech Connect

    Ogura, Y.; Guran, T.; Shahidi, M.; Mori, M.T.; Zeimer, R.C. )

    1991-07-01

    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.

  11. Paclitaxel molecularly imprinted polymer-PEG-folate nanoparticles for targeting anticancer delivery: Characterization and cellular cytotoxicity.

    PubMed

    Esfandyari-Manesh, Mehdi; Darvishi, Behrad; Ishkuh, Fatemeh Azizi; Shahmoradi, Elnaz; Mohammadi, Ali; Javanbakht, Mehran; Dinarvand, Rassoul; Atyabi, Fatemeh

    2016-05-01

    The aim of this work was to synthesize molecularly imprinted polymer-poly ethylene glycol-folic acid (MIP-PEG-FA) nanoparticles for use as a controlled release carrier for targeting delivery of paclitaxel (PTX) to cancer cells. MIP nanoparticles were synthesized by a mini-emulsion polymerization technique and then PEG-FA was conjugated to the surface of nanoparticles. Nanoparticles showed high drug loading and encapsulation efficiency, 15.6 ± 0.8 and 100%, respectively. The imprinting efficiency of MIPs was evaluated by binding experiments in human serum. Good selective binding and recognition were found in MIP nanoparticles. In vitro drug release studies showed that MIP-PEG-FA have a controlled release of PTX, because of the presence of imprinted sites in the polymeric structure, which makes it is suitable for sustained drug delivery. The drug release from polymeric nanoparticles was indeed higher at acidic pH. The molecular structure of MIP-PEG-FA was confirmed by Hydrogen-Nuclear Magnetic Resonance (H NMR), Fourier Transform InfraRed (FT-IR), and Attenuated Total Reflection (ATR) spectroscopy, and their thermal behaviors by Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Scanning Electron Microscopy (SEM) and Photon Correlation Spectroscopy (PCS) results showed that nanoparticles have a smooth surface and spherical shape with an average size of 181 nm. MIP-PEG-FA nanoparticles showed a greater amount of intracellular uptake in folate receptor-positive cancer cells (MDA-MB-231 cells) in comparison with the non-folate nanoparticles and free PTX, with half maximal inhibitory concentrations (IC50) of 4.9 ± 0.9, 7.4 ± 0.5 and 32.8 ± 3.8 nM, respectively. These results suggest that MIP-PEG-FA nanoparticles could be a potentially useful drug carrier for targeting drug delivery to cancer cells.

  12. P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery

    PubMed Central

    Davis, Thomas P.; Sanchez-Covarubias, Lucy; Tome, Margaret E.

    2014-01-01

    The primary function of the blood-brain barrier (BBB) /neurovascular unit is to protect the CNS from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain induced changes in P-gp trafficking are associated with changes in P-gp’s association with caveolin-1, a key scaffolding/trafficking protein that co-localizes with P-gp at the luminal membrane of brain microvessels. Changes in co-localization with the phosphorylated and non-phosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization and activation of P-gp “pools” between microvascular endothelial cell subcellular compartments. Since redox sensitive processes may be involved in signaling disassembly of higher order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface providing improved CNS drug delivery. The advantage of therapeutic drug “relocalization” of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription. PMID:25307213

  13. RGD-modified lipid disks as drug carriers for tumor targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Gao, Jie; Xie, Cao; Zhang, Mingfei; Wei, Xiaoli; Yan, Zhiqiang; Ren, Yachao; Ying, Man; Lu, Weiyue

    2016-03-01

    Melittin, the major component of the European bee venom, is a potential anticancer candidate due to its lytic properties. However, in vivo applications of melittin are limited due to its main side effect, hemolysis, especially when applied through intravenous administration. The polyethylene glycol-stabilized lipid disk is a novel type of nanocarrier, and the rim of lipid disks has a high affinity to amphiphilic peptides. In our study, a c(RGDyK) modified lipid disk was developed as a tumor targeted drug delivery system for melittin. Cryo-TEM was used to confirm the shape and size of lipid disks with or without c(RGDyK) modification. In vitro and in vivo hemolysis analyses revealed that the hemolysis effect significantly decreased after melittin associated with lipid disks. Importantly, the results of our in vivo biodistribution and tumor growth inhibitory experiments showed that c(RGDyK) modification increased the distribution of lipid disks in the tumor and the anticancer efficacy of melittin loaded lipid disks. Thus, we successfully achieved a targeted drug delivery system for melittin and other amphiphilic peptides with a good therapeutic effect and low side effects.

  14. Mesoporous Fe{sub 3}O{sub 4}/hydroxyapatite composite for targeted drug delivery

    SciTech Connect

    Gu, Lina; He, Xiaomei; Wu, Zhenyu

    2014-11-15

    Highlights: • Mesoporous Fe{sub 3}O{sub 4}/hydroxyapatite composite was synthesized by a simple, efficient and environmental friendly method. • The prepared material had a large surface area, high pore volume, and good magnetic separability. • DOX-loaded Fe{sub 3}O{sub 4}/hydroxyapatite composite exhibited surprising slow drug release behavior and pH-dependent behavior. - Abstract: In this contribution, we introduced a simple, efficient, and green method of preparing a mesoporous Fe{sub 3}O{sub 4}/hydroxyapatite (HA) composite. The as-prepared material had a large surface area, high pore volume, and good magnetic separability, which made it suitable for targeted drug delivery systems. The chemotherapeutic agent doxorubicin (DOX) was used to investigate the drug release behavior of Fe{sub 3}O{sub 4}/HA composite. The drug release profiles displayed a little burst effect and pH-dependent behavior. The release rate of DOX at pH 5.8 was larger than that at pH 7.4, which could be attributed to DOX protonation in acid medium. In addition, the released DOX concentrations remained at 0.83 and 1.39 μg/ml at pH 7.4 and 5.8, respectively, which indicated slow, steady, and safe release rates. Therefore, the as-prepared Fe{sub 3}O{sub 4}/hydroxyapatite composite could be an efficient platform for targeted anticancer drug delivery.

  15. Formulation, Evaluation and Optimization of Pectin- Bora Rice Beads for Colon Targeted Drug Delivery System

    PubMed Central

    Ramteke, Kuldeep Hemraj; Nath, Lilakant

    2014-01-01

    Purpose: The purpose of this research was to established new polysaccharide for the colon targeted drug delivery system, its formulation and in vitro and in vivo evaluation. Methods: Microspheres containing pectin and bora rice were prepared by ionotropic gelation technique using zinc acetate as cross linking agent and model drug used was glipizide. A 32 full factorial design was employed to study the effect of independent variables, polymer to drug ratio (A), and concentration of cross linking agent (B) on dependent variables, particle size, swelling index, drug entrapment efficiency and percentage drug release. Results: Results of trial batches indicated that polymer to drug ratio and concentration of cross linking agent affects characteristics of beads. Beads were discrete, spherical and free flowing. Beads exhibited small particle size and showed higher percentage of drug entrapment efficiency. The optimized batch P2 exhibited satisfactory drug entrapment efficiency 68% and drug release was also controlled for more than 24 hours. The polymer to drug ratio had a more significant effect on the dependent variables. In vivo gamma scintigraphy study of optimized pectin-bora rice beads demonstrated degradation of beads whenever they reached to the colon. Conclusion: Bora rice is potential polysaccharide for colon targeted drug delivery system. PMID:24511481

  16. Use of Microsphere Technology for Targeted Delivery of Rifampin to Mycobacterium tuberculosis-Infected Macrophages

    PubMed Central

    Barrow, Esther L. W.; Winchester, Gary A.; Staas, Jay K.; Quenelle, Debra C.; Barrow, William W.

    1998-01-01

    Microsphere technology was used to develop formulations of rifampin for targeted delivery to host macrophages. These formulations were prepared by using biocompatible polymeric excipients of lactide and glycolide copolymers. Release characteristics were examined in vitro and also in two monocytic cell lines, the murine J774 and the human Mono Mac 6 cell lines. Bioassay assessment of cell culture supernatants from monocyte cell lines showed release of bioactive rifampin during a 7-day experimental period. Treatment of Mycobacterium tuberculosis H37Rv-infected monocyte cell lines with rifampin-loaded microspheres resulted in a significant decrease in numbers of CFU at 7 days following initial infection, even though only 8% of the microsphere-loaded rifampin was released. The levels of rifampin released from microsphere formulations within monocytes were more effective at reducing M. tuberculosis intracellular growth than equivalent doses of rifampin given as a free drug. These results demonstrate that rifampin-loaded microspheres can be formulated for effective sustained and targeted delivery to host macrophages. PMID:9756777

  17. Intraneural convection enhanced delivery of AAVrh20 for targeting primary sensory neurons.

    PubMed

    Pleticha, Josef; Jeng-Singh, Christian; Rezek, Rahaf; Zaibak, Manal; Beutler, Andreas S

    2014-05-01

    Gene therapy using adeno-associated virus (AAV) is an attractive strategy to treat disorders of the peripheral nervous system (PNS), such as chronic pain or peripheral neuropathies. Although intrathecal (IT) administration of AAV has been the standard in the field for targeting the PNS, it lacks anatomical specificity and results in wide rostro-caudal distribution of the vector. An alternative approach is to deliver AAV directly to the peripheral nerve axon. The present study employed convection-enhanced delivery (CED) of a novel AAV serotype, AAVrh20, expressing enhanced green fluorescent protein (EGFP) into rat sciatic nerve investigating its efficacy, anatomical selectivity, and safety, compared to the IT route. Intraneural CED resulted in transduction confined to the ipsilateral L4 and L5 DRG while IT administration led to promiscuous DRG transduction encompassing the entire lumbar region bilaterally. The transduction rate for intraneural AAV administration was similar to IT delivery (24% for L4 and 31.5% for L5 DRG versus 50% for L4 and 19.5% for L5 DRG). The use of hyperosmotic diluent did not further improve the transduction efficiency. AAVrh20 was superior to reference serotypes previously described to be most active for each route. Intraneural CED of AAV was associated with transient allodynia that resolved spontaneously. These findings establish intraneural CED as an alternative to IT administration for AAV mediated gene transfer to the PNS and, based on a reference rodent model, suggest AAVrh20 as a superior serotype for targeting the PNS.

  18. An interbacterial NAD(P)+ glycohydrolase toxin requires elongation factor Tu for delivery to target cells

    DOE PAGES

    Whitney, John C.; Quentin, Dennis; Sawai, Shin; ...

    2015-10-08

    Type VI secretion (T6S) influences the composition of microbial communities by catalyzing the delivery of toxins between adjacent bacterial cells. Here, we demonstrate that a T6S integral membrane toxin from Pseudomonas aeruginosa, Tse6, acts on target cells by degrading the universally essential dinucleotides NAD+ and NADP+. Structural analyses of Tse6 show that it resembles mono-ADP-ribosyltransferase proteins, such as diphtheria toxin, with the exception of a unique loop that both excludes proteinaceous ADP-ribose acceptors and contributes to hydrolysis. We find that entry of Tse6 into target cells requires its binding to an essential housekeeping protein, translation elongation factor Tu (EF-Tu). Thesemore » proteins participate in a larger assembly that additionally directs toxin export and provides chaperone activity. Lastly, visualization of this complex by electron microscopy defines the architecture of a toxin-loaded T6S apparatus and provides mechanistic insight into intercellular membrane protein delivery between bacteria.« less

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

    NASA Astrophysics Data System (ADS)

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

    2014-09-01

    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 μg) than in other organs.

  20. The exciting potential of nanotherapy in brain-tumor targeted drug delivery approaches

    PubMed Central

    Agrahari, Vivek

    2017-01-01

    Delivering therapeutics to the central nervous system (CNS) and brain-tumor has been a major challenge. The current standard treatment approaches for the brain-tumor comprise of surgical resection followed by immunotherapy, radiotherapy, and chemotherapy. However, the current treatments are limited in providing significant benefits to the patients and despite recent technological advancements; brain-tumor is still challenging to treat. Brain-tumor therapy is limited by the lack of effective and targeted strategies to deliver chemotherapeutic agents across the blood-brain barrier (BBB). The BBB is the main obstacle that must be overcome to allow compounds to reach their targets in the brain. Recent advances have boosted the nanotherapeutic approaches in providing an attractive strategy in improving the drug delivery across the BBB and into the CNS. Compared to conventional formulations, nanoformulations offer significant advantages in CNS drug delivery approaches. Considering the above facts, in this review, the physiological/anatomical features of the brain-tumor and the BBB are briefly discussed. The drug transport mechanisms at the BBB are outlined. The approaches to deliver chemotherapeutic drugs across the CNS into the brain-tumor using nanocarriers are summarized. In addition, the challenges that need to be addressed in nanotherapeutic approaches for their enhanced clinical application in brain-tumor therapy are discussed.

  1. Characterization of cubosomes as a targeted and sustained transdermal delivery system for capsaicin

    PubMed Central

    Peng, Xinsheng; Zhou, Yanfang; Han, Ke; Qin, Lingzhen; Dian, Linghui; Li, Ge; Pan, Xin; Wu, Chuanbin

    2015-01-01

    Phytantriol- and glycerol monooleate-based cubosomes were produced and characterized as a targeted and sustained transdermal delivery system for capsaicin. The cubosomes were prepared by emulsification and homogenization of phytantriol (F1), glycerol monooleate (F2), and poloxamer dispersions, characterized for morphology and particle size distribution by transmission electron microscope and photon correlation spectroscopy. Their Im3m crystallographic space group was confirmed by small-angle X-ray scattering. An in vitro release study showed that the cubosomes provided a sustained release system for capsaicin. An in vitro diffusion study conducted using Franz diffusion cells indicate