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1

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

NASA Astrophysics Data System (ADS)

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 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. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06714b

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

2015-02-01

2

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

PubMed

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. PMID:25613320

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

2015-02-21

3

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

NASA Astrophysics Data System (ADS)

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

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

2014-09-01

4

Thermosensitive P(NIPAAm-co-PAAc-co-HEMA) nanogels conjugated with transferrin for tumor cell targeting delivery  

NASA Astrophysics Data System (ADS)

Multifunctional and thermosensitive poly(N-isopropylacrylamide-co-propyl acrylic acid-co-hydroxyethyl methacrylate) (P(NIPAAm-co-PAAc-co-HEMA)) nanogels were prepared by miniemulsion polymerization. The mean sizes of the nanogels measured by dynamic light scattering (DLS) varied from 120 to 400 nm with an increase in temperature. Transmission electron microscopy (TEM) showed that the nanogels displayed well-dispersed spherical morphology. The nanogels were conjugated by human transferrin (Tf) and the coupling of transferrin molecules with nanogels was verified by UV-vis spectroscopy. The cytotoxicity study indicated that the nanogels did not exhibit apparent cytotoxicity. Fluorescence spectroscopy analysis as well as confocal laser scanning microscopy (CLSM) was used to confirm that the Tf-conjugated nanogels could specifically bind to A549 tumor cells. In addition, the Tf-conjugated nanogels loaded with Doxorubicin (Dox) could efficiently release the drug inside the cell, suggesting that the Tf-conjugated nanogels are useful drug carriers for tumor cell targeting.

Quan, Chang-Yun; Sun, Yun-Xia; Cheng, Han; Cheng, Si-Xue; Zhang, Xian-Zheng; Zhuo, Ren-Xi

2008-07-01

5

Polymer nanogels: a versatile nanoscopic drug delivery platform  

PubMed Central

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

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

2012-01-01

6

Chemosensitization of cancer cells by siRNA using targeted nanogel delivery  

Microsoft Academic Search

BACKGROUND: Chemoresistance is a major obstacle in cancer treatment. Targeted therapies that enhance cancer cell sensitivity to chemotherapeutic agents have the potential to increase drug efficacy while reducing toxic effects on untargeted cells. Targeted cancer therapy by RNA interference (RNAi) is a relatively new approach that can be used to reversibly silence genes in vivo by selectively targeting genes such

Erin B Dickerson; William H Blackburn; Michael H Smith; Laura B Kapa; L Andrew Lyon; John F McDonald

2010-01-01

7

Surface-modified P(HEMA-co-MAA) nanogel carriers for oral vaccine delivery: design, characterization, and in vitro targeting evaluation.  

PubMed

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

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

2014-07-14

8

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

PubMed

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 ?g/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. PMID:22342466

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

2012-05-10

9

ICAM-1 Targeted Nanogels Loaded with Dexamethasone Alleviate Pulmonary Inflammation  

PubMed Central

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

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

2014-01-01

10

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

PubMed

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

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

2012-01-01

11

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

PubMed

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

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

2014-04-15

12

Modular ‘Click-in-Emulsion’ Bone-Targeted Nanogels  

E-print Network

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 ...

Heller, Daniel A.

13

Fabrication of a novel pH-sensitive glutaraldehyde cross-linked pectin nanogel for drug delivery.  

PubMed

A novel pH-sensitive nanogel based on pectin cross-linked with glutaraldehyde (PT-GA) was designed and synthesized for drug delivery. Transmission electron microscope observation shows that the nano-sized gel particles exhibit a spherical morphology. The optical absorbance study of nanogel suspension reveals its pH sensitivity. Cytotoxicity study shows that the nanogel has no apparent inhibitory effect on cells. The in vitro drug-release behavior of the drug-loaded nanogel particles in three kinds of media, i.e., simulated gastric fluid, simulated intestine fluid and simulated colon fluid, was studied. PT-GA nanogel exhibits a faster release at a high pH, and the release could be further accelerated in the presence of pectinolytic enzyme, indicating that the nanogel may be used for colon-specific drug delivery. PMID:17988522

Chang, Cong; Wang, Zong-Chun; Quan, Chang-Yun; Cheng, Han; Cheng, Si-Xue; Zhang, Xian-Zheng; Zhuo, Ren-Xi

2007-01-01

14

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

PubMed

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

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

2014-09-23

15

Anti-cancer vaccination by transdermal delivery of antigen peptide-loaded nanogels via iontophoresis.  

PubMed

Transdermal vaccination with cancer antigens is expected to become a useful anti-cancer therapy. However, it is difficult to accumulate enough antigen in the epidermis for effective exposure to Langerhans cells because of diffusion into the skin and muscle. Carriers, such as liposomes and nanoparticles, may be useful for the prevention of antigen diffusion. Iontophoresis, via application of a small electric current, is a noninvasive and efficient technology for transdermal drug delivery. Previously, we succeeded in the iontophoretic transdermal delivery of liposomes encapsulating insulin, and accumulation of polymer-based nanoparticle nanogels in the stratum corneum of the skin. Therefore, in the present study, we examined the use of iontophoresis with cancer antigen gp-100 peptide KVPRNQDWL-loaded nanogels for anti-cancer vaccination. Iontophoresis resulted in the accumulation of gp-100 peptide and nanogels in the epidermis, and subsequent increase in the number of Langerhans cells in the epidermis. Moreover, tumor growth was significantly suppressed by iontophoresis of the antigen peptide-loaded nanogels. Thus, iontophoresis of the antigen peptide-loaded nanogels may serve as an effective transdermal delivery system for anti-cancer vaccination. PMID:25681719

Toyoda, Mao; Hama, Susumu; Ikeda, Yutaka; Nagasaki, Yukio; Kogure, Kentaro

2015-04-10

16

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

NASA Astrophysics Data System (ADS)

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

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

2010-07-01

17

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

PubMed

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-?-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

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

2015-03-01

18

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

PubMed Central

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

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

2014-01-01

19

Dual responsive supramolecular nanogels for intracellular drug delivery.  

PubMed

Supramolecular nanogels cross-linked by host-guest interaction between dextran grafted benzimidazole (Dex-g-BM) and thiol-?-cyclodextrin were designed. Their special supramolecular pH-sensitivity under acidic conditions (pH < 6, within the range of malignant cellular endosomes) and reduction sensitivity in response to biologically relevant stimuli will be of great advantage to the future of cancer chemotherapeutics. PMID:24519486

Chen, Xiaofei; Chen, Li; Yao, Xuemei; Zhang, Zhe; He, Chaoliang; Zhang, Jingping; Chen, Xuesi

2014-04-14

20

Design and engineering of nanogels for cancer treatment  

PubMed Central

Here, we provide a comprehensive insight into current advances in the use of nanogel-mediated chemotherapy for cancer treatment. Nanogels are composed of cross-linked three-dimensional polymer chain networks that are formed via covalent linkages or self-assembly processes. The porosity between the cross-linked networks of nanogels not only provides an ideal reservoir for loading drugs, oligonucleotides and imaging agents, but also protects them from environmental degradation and hazards. Here, we focus mainly on novel synthetic strategies and key considerations in the design of nanogel-based drug delivery systems for controlled and targeted cancer therapeutic applications. PMID:21414419

Yallapu, Murali Mohan; Jaggi, Meena; Chauhan, Subhash

2011-01-01

21

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

PubMed

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. PMID:25791835

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

2015-05-28

22

Biodistribution and renal clearance of biocompatible lung targeted poly(ethylene glycol) (PEG) nanogel aggregates.  

PubMed

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 HiLyte Fluor™ 750 (DYE-SANPs) to facilitate ex vivo imaging. Biodistribution of intravenous DYE-SANPs (30 ?m, 4 mg in 500 ?L PBS) in male Sprague-Dawley rats was compared to free HiLyte Fluor™ 750 DYE alone (1mg in 500 ?L 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 min 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

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

2012-11-28

23

Skin permeating nanogel for the cutaneous co-delivery of two anti-inflammatory drugs  

PubMed Central

The aim of this study was to develop an effective drug delivery system for the simultaneous topical delivery of two anti-inflammatory drugs, spantide II (SP) and ketoprofen (KP). To achieve this primary goal we have developed a skin permeating nanogel system (SPN) containing surface modified polymeric bilayered nanoparticles along with a gelling agent. Poly-(lactide-co-glycolic acid) and chitosan were used to prepare bilayered nanoparticles (NPS) and the surface was modified with oleic acid (NPSO). Hydroxypropyl methyl cellulose (HPMC) and Carbopol with the desired viscosity were utilized to prepare the nanogels. The nanogel system was further investigated for in vitro skin permeation, drug release and stability studies. Allergic contact dermatitis (ACD) and psoriatic plaque like model were used to assess the effectiveness of SPN. Dispersion of NPSO in HPMC (SPN) produced a stable and uniform dispersion. In vitro permeation studies revealed increase in deposition of SP for the SP-SPN or SP+KP-SPN in the epidermis and dermis by 8.5 and 9.5 folds, respectively than SP-gel. Further, the deposition of KP for KP-SPN or SP+KP-SPN in epidermis and dermis was 9.75 and 11.55 folds higher, respectively than KP-gel. Similarly the amount of KP permeated for KP-SPN or SP+KP-SPN was increased by 9.92 folds than KP-gel. The ear thickness in ACD model and the expression of IL-17 and IL-23; PASI score and TEWL values in psoriatic plaque like model were significantly less (p<0.001) for SPN compared to control gel. Our results suggest that SP+KP-SPN have significant potential for the percutaneous delivery of SP and KP to the deeper skin layers for treatment of various skin inflammatory disorders. PMID:22118820

Shah, Punit; Desai, Pinaki; Patel, Apurva; Singh, Mandip

2011-01-01

24

Dual targeting of a thermosensitive nanogel conjugated with transferrin and RGD-containing peptide for effective cell uptake and drug release  

NASA Astrophysics Data System (ADS)

In this paper, both arginine-glycine-aspartic acid (RGD)-containing peptide and transferrin (Tf) were conjugated to the thermosensitive poly(N-isopropylacrylamide-co-propyl acrylic acid) (poly(NIPAAm-co-PAAc)) nanogel to prepare a dual-targeting drug carrier. The obtained nanogel was characterized in terms of fluorescence spectroscopy, UV-vis spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). In order to track the dual-ligand conjugated nanogel, fluorescein isothiocyanate (FITC) was further conjugated to the nanogel. A cell internalization experiment showed that the dual-ligand conjugated nanogel exhibited obviously enhanced endocytosis by HeLa cells as compared with non-tumorous cells (COS-7 cells). The drug-loaded dual-ligand conjugated nanogel could be transported efficiently into the target tumor cells and the anti-tumor effect was enhanced significantly, suggesting that the dual-ligand conjugated nanogel has great potential as a tumor targeting drug carrier.

Quan, Chang-Yun; Chang, Cong; Wei, Hua; Chen, Chang-Sheng; Xu, Xiao-Ding; Cheng, Si-Xue; Zhang, Xian-Zheng; Zhuo, Ren-Xi

2009-08-01

25

Targeted nanogel conjugate for improved stability and cellular permeability of curcumin: synthesis, pharmacokinetics, and tumor growth inhibition.  

PubMed

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-?B, TNF-?, 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

Wei, Xin; Senanayake, Thulani H; Bohling, Anna; Vinogradov, Serguei V

2014-09-01

26

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

PubMed

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

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

2014-05-21

27

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

PubMed

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. PMID:25665867

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

2015-05-10

28

Self-assembled lysozyme/carboxymethylcellulose nanogels for delivery of methotrexate.  

PubMed

Nanogels (NGs) were fabricated with lysozyme and carboxymethylcellulose via a green self-assembly method. The prepared NGs were characterized by dynamic light scattering (DLS), zeta potential, Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM). Pyrene and isothiocyanate were introduced as fluorescent probes to research the hydrophobic area of the NGs and cells endocytosis, respectively. Methotrexate (MTX) was used to investigate the drug encapsulation property of the NGs. It turned out to be that the drug loaded NGs were regular spherical shape with a hydrodynamic diameter of about 123nm. The drug loading efficiency was about 14.2%. The NGs can slowly release the drug and increase the bioavailability of the loaded drug. The NGs are promising carriers for the delivery of drugs and other bioactive molecules. PMID:25637692

Li, Zhenshun; Xu, Wei; Zhang, Chunlan; Chen, Yijie; Li, Bin

2015-04-01

29

Quantum dots loaded nanogels for low cytotoxicity, pH-sensitive fluorescence, cell imaging and drug delivery.  

PubMed

Nanogels (NGs) with drug tracking and delivery possess promising usage in clinical treatment. In this study, an available, low toxic and facile approach was developed to synthesize CdTe quantum dots loaded nanogels (QDs-NGs). The QDs-NGs retained the intrinsic pH sensitivity of the QDs with regard to the fluorescence intensity. The QDs-NGs were easily internalized by the cells as fluorescence probes, and acted as carriers for delivering methotrexate (MTX). The cellular uptake indicated that the QDs-NGs can protect QDs from decomposition in cytoplasm and retain the native fluorescence intensity. MTT assay demonstrated that the QDs-NGs greatly decreased the cytotoxicity of the QDs. The MTX loaded QDs-NGs exhibited slow release property in PBS buffer. Moreover, the MTX loaded QDs-NGs distinctly enhanced the availability of drug. The QDs-NGs are potential nanocarriers for the cell imaging and drug delivery. PMID:25659723

Li, Zhenshun; Xu, Wei; Wang, Yuntao; Shah, Bakht Ramin; Zhang, Chunlan; Chen, Yijie; Li, Yan; Li, Bin

2015-05-01

30

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

PubMed Central

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

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

2015-01-01

31

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

PubMed

Abstract 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. PMID:24512347

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

2014-02-10

32

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

PubMed Central

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

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

2013-01-01

33

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

PubMed

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

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

2013-04-17

34

Therapeutic Effect of Nanogel-Based Delivery of Soluble FGFR2 with S252W Mutation on Craniosynostosis  

PubMed Central

Apert syndrome is an autosomal dominantly inherited disorder caused by missense mutations in fibroblast growth factor receptor 2 (FGFR2). Surgical procedures are frequently required to reduce morphological and functional defects in patients with Apert syndrome; therefore, the development of noninvasive procedures to treat Apert syndrome is critical. Here we aimed to clarify the etiological mechanisms of craniosynostosis in mouse models of Apert syndrome and verify the effects of purified soluble FGFR2 harboring the S252W mutation (sFGFR2IIIcS252W) on calvarial sutures in Apert syndrome mice in vitro. We observed increased expression of Fgf10, Esrp1, and Fgfr2IIIb, which are indispensable for epidermal development, in coronal sutures in Apert syndrome mice. Purified sFGFR2IIIcS252W exhibited binding affinity for fibroblast growth factor (Fgf) 2 but also formed heterodimers with FGFR2IIIc, FGFR2IIIcS252W, and FGFR2IIIbS252W. Administration of sFGFR2IIIcS252W also inhibited Fgf2-dependent proliferation, phosphorylation of intracellular signaling molecules, and mineralization of FGFR2S252W-overexpressing MC3T3-E1 osteoblasts. sFGFR2IIIcS252W complexed with nanogels maintained the patency of coronal sutures, whereas synostosis was observed where the nanogel without sFGFR2S252W was applied. Thus, based on our current data, we suggest that increased Fgf10 and Fgfr2IIIb expression may induce the onset of craniosynostosis in patients with Apert syndrome and that the appropriate delivery of purified sFGFR2IIIcS252W could be effective for treating this disorder. PMID:25003957

Yokota, Masako; Kobayashi, Yukiho; Morita, Jumpei; Suzuki, Hiroyuki; Hashimoto, Yoshihide; Sasaki, Yoshihiro; Akiyoshi, Kazunari; Moriyama, Keiji

2014-01-01

35

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

PubMed

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

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

2014-12-19

36

Carboxymethylcellulose (CMC) formed nanogels with branched poly(ethyleneimine) (bPEI) for inhibition of cytotoxicity in human MSCs as a gene delivery vehicles.  

PubMed

Specific vehicles are necessary for safe and efficient gene transfection into cells. Nano-type hydrogels (nanogel) comprising carboxymethylcellulose (CMC) complexed with branched type cationic poly(ethleneimine) (bPEI) were used as gene delivery vehicles. When complexes of CMC and bPEI were used in vitro, CMC showed nano-gel type properties, as shown by the results of a viscosity test, and bPEI showed low cytotoxicity comparing to bPEI alone. Together, these properties are shown to maintain high gene transfection efficiency. In viability experiments using three types of adult stem cells, cell viability varied depending on the branch form of PEI and whether or not it is in a complex with CMC. The gene delivery efficacy showed that the CMC nanogel complexed with bPEI (CMC-bPEI) showed more uptaking and gene transfection ability in hMSCs comparing to bPEI alone. In osteogenesis, the CMC-bPEI complexed with OSX pDNA showed more easy internalization than bPEI alone complexed with OSX pDNA in hMSCs. Specific genes and proteins related in osteogenic differentiation were expressed in hMSCs when the CMC-bPEI complexed with OSX pDNA was used. PMID:25817668

Yang, Han Na; Park, Ji Sun; Jeon, Su Yeon; Park, Keun-Hong

2015-05-20

37

Curcumin encapsulated pH sensitive gelatin based interpenetrating polymeric network nanogels for anti cancer drug delivery.  

PubMed

Interpenetrating polymeric network nanogels (IPN-NGs) composed of natural gelatin biological protein macromolecules and poly(acrylamidoglycolic acid) were produced by simple free radical emulsion polymerization. The developed IPN-NGs were characterized by Fourier-transform infra-red spectroscopy to confirm the formation of NGs. The hydrophobic curcumin drug was loaded successfully into these NGs using an in-situ method. The curcumin-encapsulated NGs were well dispersed in aqueous solutions and showed good bioavailability. Curcumin was dispersed molecularly in the IPN-NGs, which was confirmed by differential scanning calorimetry and X-ray diffraction. The NGs exhibited pH sensitive properties according to dynamic light scattering and the zeta size potentials. Transmission electron microscopy revealed the NGs to be spherical, approximately 100nm in size. The encapsulation efficiency of these IPN-NGs drug formulations ranged from 42 to 48%. In addition, the release of curcumin from the NGs was examined in phosphate buffer medium. The cytotoxicity of the IPN-NGs was studied using in vitro cultures of fibroblasts and a colorectal cancer cell line. The results suggest that the newly developed pH sensitive gelatin-poly(acrylamidoglycolic acid)-curcumin NGs can be applied for colorectal cancer drug delivery applications. PMID:25528297

Madhusudana Rao, K; Krishna Rao, K S V; Ramanjaneyulu, G; Ha, Chang-Sik

2015-01-30

38

Nanostructured lipid carriers based nanogel for meloxicam delivery: mechanistic, in-vivo and stability evaluation.  

PubMed

Abstract Aim: Our investigation was aimed to investigate the potential suitability of meloxicam-loaded nanostructured lipid carriers (MLX-NLC) gel for topical application. Main methods: MLX-NLC gel was prepared and in vivo skin penetration ability of the NLC gel was evaluated using confocal laser scanning microscopy. We studied the effect of MLX-NLC gel on the changes in lipid profile of skin to get an insight into its skin penetration enhancement mechanism. Acetic acid induced writhing test was performed to evaluate the analgesic effect. Drug concentration-time profile of MLX in rat plasma and skin after topical and oral treatment with MLX-NLC gel and oral MLX-solution, respectively, was observed. MLX-NLC gel was subjected to primary skin irritation test, sub-acute dermal toxicity study. Storage stability of MLX-NLC gel was also assessed for 90 days. Key findings: NLC gel was effective in permeating Rhodamine 123 to deeper layers of rat skin. Changes in skin lipid prolife were observed in the rat skin on treatment with MLX-NLC gel and the results supported skin lipid extraction as a possible penetration enhancement mechanism. MLX-NLC gel demonstrated sustained pain inhibitory effect. Pharmacokinetics study established that topical application of MLX-NLC gel had the potential to avoid systemic uptake and hence the risk of systemic adverse effects. MLX-NLC gel demonstrated good skin tolerability and biosafety. Excellent physical stability of nanogel was observed at 4?±?2?°C. Significance: The study revealed that NLC gel is a promising carrier system for the topical application of MLX without side effects. PMID:25151872

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

2014-08-25

39

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

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.

Wu, Weitai [City University of New York (CUNY); Shen, Jing [City University of New York (CUNY); Gai, Zheng [ORNL; Hong, Kunlun [ORNL; Banerjeea, Probal [City University of New York (CUNY); Zhou, Shuiqin [City University of New York (CUNY)

2011-01-01

40

Nanoparticles for Targeted Drug Delivery  

E-print Network

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

Chow, Gan-Moog

41

COLON TARGETED DRUG DELIVERY SYSTEMS  

Microsoft Academic Search

Colon targeted drug delivery systems have the potential to deliver drugs for the treatment of a variety of colonic diseases and to deliver proteins and peptides to the colon for their systemic absorption. In recent years, various pharmaceutical approaches have been developed for targeting the drugs to the colon include, formation of prodrugs, coating of pH-sensitive polymers, use of colon

Ceyda Tuba

42

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...

43

Facile one-pot synthesis of glucose-sensitive nanogel via thiol-ene click chemistry for self-regulated drug delivery.  

PubMed

A novel glucose-sensitive nanogel was conveniently prepared through one-pot thiol-ene copolymerization of pentaerythritol tetra(3-mercaptopropionate), poly(ethylene glycol) diacrylate, methoxyl poly(ethylene glycol) acrylate and N-acryloyl-3-aminophenylboronic acid. The formation of core-shell nanogel was verified by proton nuclear magnetic resonance, dynamic laser scattering (DLS) and transmission electron microscopy. The successful incorporation of phenylboronic acid (PBA) in the nanogel was confirmed through Fourier transform infrared spectroscopy, inductively coupled plasma mass spectrometry and fluorescence technology. Owing to the presence of PBA, the nanogel exhibited high glucose sensitivity in phosphate-buffered saline determined by DLS and fluorescence technology. The increased amount of glucose causes an increase in the hydrodrodynamic radius and a decrease in the fluorescence intensity of PBA-alizarin red S (ARS) complex in the nanogel at pH 7.4 because of the competitive substitution of ARS to form the hydrophilic PBA-glucose complex. ARS and insulin were loaded into this glucose-sensitive nanogel. In vitro release profiles revealed that the drug release from the nanogel could be triggered by the presence of glucose. The more glucose in the release medium, the more drug was released and the faster the release rate. Furthermore, in vitro methyl thiazolyl tetrazolium assay, lactate dehydrogenase assay and hemolysis test suggested that the nanogel was biocompatible. Therefore, the PBA-incorporated nanogel with high glucose-sensitivity and good biocompatibility may have great potential for self-regulated drug release. PMID:23403168

Zhao, Li; Xiao, Chunsheng; Ding, Jianxun; He, Pan; Tang, Zhaohui; Pang, Xuan; Zhuang, Xiuli; Chen, Xuesi

2013-05-01

44

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

PubMed

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

Abu Samah, Nor H; Heard, Charles M

2014-02-01

45

Aptamers for Targeted Drug Delivery  

PubMed Central

Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment (SELEX). SELEX has traditionally been performed using purified proteins, and cell surface receptors may be challenging to purify in their properly folded and modified conformations. Therefore, relatively few aptamers have been generated that bind cell surface receptors. However, improvements in recombinant fusion protein technology have increased the availability of receptor extracellular domains as purified protein targets, and the development of cell-based selection techniques has allowed selection against surface proteins in their native configuration on the cell surface. With cell-based selection, a specific protein target is not always chosen, but selection is performed against a target cell type with the goal of letting the aptamer choose the target. Several studies have demonstrated that aptamers that bind cell surface receptors may have functions other than just blocking receptor-ligand interactions. All cell surface proteins cycle intracellularly to some extent, and many surface receptors are actively internalized in response to ligand binding. Therefore, aptamers that bind cell surface receptors have been exploited for the delivery of a variety of cargoes into cells. This review focuses on recent progress and current challenges in the field of aptamer-mediated delivery.

Ray, Partha; White, Rebekah R.

2010-01-01

46

Biocompatibility of a self-assembled glycol chitosan nanogel.  

PubMed

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. PMID:25482991

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

2015-04-01

47

Preparation and characterisation of gelatin-gum arabic aldehyde nanogels via inverse miniemulsion technique.  

PubMed

Gelatin-gum arabic aldehyde nanogels designed by a nanoreactor concept using inverse miniemulsion technique were reported. Stable separate miniemulsions were prepared from gelatin (Gel) and gum arabic aldehyde (GAA). These emulsions were intermixed under sonication to obtain cross-linked nanogels. During fusion, cross-linking occurred between aldehyde groups of GAA and amino groups of gelatin. The concentration of the surfactant and weight fraction of water in the inverse miniemulsion was optimised so as to yield nanogels with controlled particle size. Properties of the nanogels were studied by FT-IR spectroscopy, particle size analysis and XRD. Surface morphology of the nanogels was established by Scanning Electron Microscopy (SEM). SEM and particle size analysis confirmed that nanogels possess spherical morphology with an average diameter of 151±6nm. Hemolysis property of the nanogels was examined and the results indicated that the nanogels were hemocompatible. The in vitro cytotoxicity of the nanogels towards MCF-7 cells was evaluated by MTT assay and the nanogels showed nontoxic behaviour towards the cells. All these studies confirm that these nanogels are potential candidates in applications such as drug and gene delivery. PMID:25748843

Sarika, P R; James, Nirmala Rachel

2015-05-01

48

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

PubMed

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. PMID:25385004

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

2015-03-01

49

Mucoadhesive polyacrylamide nanogel as a potential hydrophobic drug carrier for intravesical bladder cancer therapy.  

PubMed

In this paper, amine-functionalized polyacrylamide nanogels (PAm-NH2) loaded with docetaxel (DTX) were evaluated as a mucoadhesive and sustained intravesical drug delivery (IDD) system for potential bladder cancer therapy. Nanogels have not been applied for such therapy before. The mucoadhesiveness of the PAm-NH2 nanogels, which is a critical factor for IDD application, was investigated using the mucin-particle method and by analyzing the direct attachment of the PAm-NH2 nanogels onto the luminal surface of porcine urinary bladder. DTX, as a model hydrophobic drug, was successfully loaded into hydrophilic PAm-NH2 nanogels with high loading efficiency (>90%), and sustained release of DTX from the nanogels over 9days in artificial urine was achieved. The nanogels were also taken in by bladder cancer cells in a concentration-dependent manner. The efficiency of the DTX-loaded nanogels in killing UMUC3 and T24 bladder cancer cells was determined to be equivalent to free DTX, and the morphology of the bladder urothelium was not adversely altered by the PAm-NH2 nanogels. These findings indicate that such mucoadhesive nanogels are potentially a promising candidate for intravesical delivery of hydrophobic drugs in bladder cancer therapy. PMID:25772330

Lu, Shengjie; Neoh, Koon Gee; Kang, En-Tang; Mahendran, Ratha; Chiong, Edmund

2015-05-25

50

Targeted Retrograde Gene Delivery for Neuronal Protection  

Microsoft Academic Search

The cellular heterogeneity and complex circuitry of the central nervous system make it difficult to achieve precise delivery of experimental and therapeutic agents. We report here an in vivo retrograde gene delivery strategy to target mature projection neurons using adeno-associated virus, a vector with low toxicity and the capacity for long-term gene expression. Viral delivery to axon terminal fields in

Brian K. Kaspar; Dawn Erickson; David Schaffer; Linda Hinh; Fred H. Gage; Daniel A. Peterson

2002-01-01

51

Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates.  

PubMed

A majority of nanoencapsulated drugs that have shown promise in cancer chemotherapy are administered intravenously. Development of effective oral nanoformulations presents a very challenging medical goal. Here, we describe successful applications of innovative polymeric nanogels in the form of conjugates with activated nucleoside analogs for oral administration in cancer chemotherapy. Previously, we reported the synthesis of amphiphilic polyvinyl alcohol and dextrin-based nanogel conjugates with the phosphorylated 5-FU nucleoside Floxuridine and demonstrated their enhanced activity against regular and drug-resistant cancers (T.H. Senanayake, G. Warren, S.V. Vinogradov, Novel anticancer polymeric conjugates of activated nucleoside analogs, Bioconjug. Chem. 22 (2011) 1983-1993). In this study, we synthesized and evaluated oral applications of nanogel conjugates of a protected Gemcitabine, the drug never used in oral therapies. These conjugates were able to quickly release an active form of the drug (Gemcitabine 5'-mono-, di- and triphosphates) by specific enzymatic activities, or slowly during hydrolysis. Gemcitabine conjugates demonstrated up to 127 times higher in vitro efficacy than the free drug against various cancer cells, including the lines resistant to nucleoside analogs. Surprisingly, these nanogel-drug conjugates were relatively stable in gastric conditions and able to actively penetrate through the gastrointestinal barrier based on permeability studies in Caco-2 cell model. In tumor xenograft models of several drug-resistant human cancers, we observed an efficient inhibition of tumor growth and extended the life-span of the animals by 3 times that of the control with orally treated Gemcitabine- or Floxuridine-nanogel conjugates. Thus, we have demonstrated a potential of therapeutic nanogel conjugates with the activated and stabilized Gemcitabine as a successful oral drug form against Gemcitabine-resistant and other drug-resistant tumors. PMID:23385032

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

2013-04-28

52

Targeted delivery of therapeutics to endothelium  

PubMed Central

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

Simone, Eric; Ding, Bi-Sen

2009-01-01

53

Mathematical modelling of magnetically targeted drug delivery  

Microsoft Academic Search

A mathematical model for targeted drug delivery using magnetic particles is developed. This includes a diffusive flux of particles arising from interactions between erythrocytes in the microcirculation. The model is used to track particles in a vessel network. Magnetic field design is discussed and we show that it is impossible to specifically target internal regions using an externally applied field.

Andrew D. Grief; Giles Richardson

2005-01-01

54

Nanoparticles for intracellular-targeted drug delivery  

NASA Astrophysics Data System (ADS)

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.

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

2011-12-01

55

Nanogels based on alginic aldehyde and gelatin by inverse miniemulsion technique: synthesis and characterization.  

PubMed

Nanogels were developed from alginic aldehyde and gelatin by an inverse miniemulsion technique. Stable inverse miniemulsions were prepared by sonication of noncontinuous aqueous phase (mixture of alginic aldehyde and gelatin) in a continuous organic phase (Span 20 dissolved in cyclohexane). Cross-linking occurred between alginic aldehyde (AA) and gelatin (gel) in the presence of borax by Schiff's base reaction during the formation of inverse miniemulsion. The effects of surfactant (Span 20) concentration, volume of the aqueous phase and AA/gel weight ratio on the size of the alginic aldehyde-gelatin (AA-gel) nanoparticles were studied. Nanogels were characterized by DLS, FT-IR spectroscopy, TGA, SEM and TEM. DLS, TEM and SEM studies demonstrated nanosize and spherical morphology of the nanogels. Hemocompatibility and in vitro cytocompatibility analyses of the nanogels proved their nontoxicity. The results indicated the potential of the present nanogel system as a candidate for drug- and gene-delivery applications. PMID:25563951

Sarika, P R; Anil Kumar, P R; Raj, Deepa K; James, Nirmala Rachel

2015-03-30

56

Intranasal drug delivery for brain targeting.  

PubMed

Many drugs are not being effectively and efficiently delivered using conventional drug delivery approach to brain or central nervous system (CNS) due to its complexity. The brain and the central nervous system both have limited accessibility to blood compartment due to a number of barriers. Many advanced and effective approaches to brain delivery of drugs have emerged in recent years. Intranasal drug delivery is one of the focused delivery options for brain targeting, as the brain and nose compartments are connected to each other via the olfactory route and via peripheral circulation. Realization of nose to brain transport and the therapeutic viability of this route can be traced from the ancient times and has been investigated for rapid and effective transport in the last two decades. Various models have been designed and studied by scientists to establish the qualitative and quantitative transport through nasal mucosa to brain. The development of nasal drug products for brain targeting is still faced with enormous challenges. A better understanding in terms of properties of the drug candidate, nose to brain transport mechanism, and transport to and within the brain is of utmost importance. This review will discuss some pertinent issues to be considered and challenges to brain targeted intranasal drug delivery. A few marketed and investigational drug formulations will also be discussed. PMID:16305417

Vyas, Tushar K; Shahiwala, Aliasgar; Marathe, Sudhanva; Misra, Ambikanandan

2005-04-01

57

Magnetizable implants for targeted drug delivery  

NASA Astrophysics Data System (ADS)

The capability to deliver high effective dosages to specific sites in the human body has become the holy grail of drug delivery research. Drugs with proven effectiveness under in vitro investigation often reach a major roadblock under in vivo testing due to a lack of an effective delivery strategy. In addition, many clinical scenarios require delivery of agents that are therapeutic at the desired delivery point, but otherwise systemically toxic. This project proposes a method for targeted drug delivery by applying high magnetic field gradients within the body to an injected superparamagnetic colloidal fluid carrying a drug, with the aid of modest uniform magnetic field. The design involves patterning of endovascular implants, such as coronary stents, with soft magnetic coatings capable of applying high local magnetic field gradients within the body. Examination of the feasibility of the design has been focused around the treatment of coronary restenosis following angioplasty. Drug-eluting stents, which have debuted in hospitals over the past two years, have thus far reduced restenosis rates to below 10%. Our local drug delivery system is a viable alternative or enhancement to drug-eluting stents, offering increased clinician control of dose size, the ability to treat a site repeatedly, and a wide array of applications for treatment of other pathologies. The theoretical models, parallel plate and pipe flow analysis, and cell culture models presented give insight into the use of micron and sub-micron scale magnetic particles for site-specific delivery of pharmaceuticals and magnetically labeled cells.

Forbes, Zachary Graham

58

AS1411 aptamer for targetable photosensitizer delivery  

Microsoft Academic Search

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

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

2009-01-01

59

Functionalized nanospheres for targeted delivery of paclitaxel.  

PubMed

Targeted delivery of anti-cancer agents to cancer cells is a mature line of investigation that has yet to realize its full potential. In this study we report on the development of a delivery platform with the future goal of merging two thus far parallel methods for selective elimination of cancer cells: targeted nanospheres and pretargeted radioimmunotherapy. Several clinical trials have shown the promise of pretargeted radioimmunotherapy, which leverages the specificity of antibodies for targeted cell populations and delivers a localized dose of a biotinylated radionuclide that is most often administered following binding of a biotinylated antibody and streptavidin (StA) to the target cells. The work presented here describes the development of biotinylated nanospheres based on an ABA-type copolymer comprised of a tyrosine-derived oligomer as the B-block and poly(ethylene glycol) (PEG) A-blocks. The biotinylated nanospheres encapsulate paclitaxel (PTX) to the same extent as unbiotinylated nanospheres. Efficacy of targeting was shown on CD44 positive cells in the SUM159 breast cancer cell line by incubating the cells sequentially with a biotinylated anti-CD44 antibody, StA and the biotinylated nanospheres encapsulating PTX. Targeted nanospheres achieved the half maximal inhibitory concentration of PTX on SUM159 cells at a 5-10 fold lower concentration than that of PTX applied in either non-targeted nanospheres or free drug approaches. Moreover, targeted nanospheres selectively eliminated CD44 positive SUM159 cells compared to free PTX and untargeted nanospheres. This new generation of nano-sized carrier offers a versatile platform that can be adopted for a wide variety of drug and target specific applications and has the potential to be combined with the clinically emerging method of pretargeted radioimmunotherapy. PMID:23792807

Bushman, Jared; Vaughan, Asa; Sheihet, Larisa; Zhang, Zheng; Costache, Marius; Kohn, Joachim

2013-11-10

60

Nanogel for dermal application of the triterpenoids isolated from Ganoderma lucidum (GLT) for frostbite treatment.  

PubMed

Abstract Objective: The purpose of this study was to formulate stable Ganoderma lucidum (GLT) nanogels suitable for topical delivery with a view to improve the therapeutic effect for frostbite. Methods: GLT nanosuspensions were formulated using the high-pressure homogenization technique and then suitably gelled for characterized. In order to confirm the advantages of GLT nanogel for dermal application, skin permeation studies in vitro and pharmacodynamic evaluation in vivo were studied and compared with GLT-carbopol gel. Results: The particle size analysis and SEM studies revealed that GLT nanosuspensions were still stably kept their particle size after suitably gelled by carbopol preparation. The drug content, pH, and spreadability of the GLT nanogel was found to be 99.23?±?1.8%, 6.07?±?0.1, and 26.42 (g·cm)/s, which were within acceptable limits. In vitro permeation studies through rat skin indicated that the amount of GLT permeated through skin of GLT nanogel after 24?h was higher than GLT-carbopol gel, and GLT nanogel increased the accumulative amount of GLT in epidermis five times than GLT-carbopol gel. No oedema and erythema were observed after administration of GLT nanogel on the rabbits' skin. Pharmacodynamic study showed that GLT nanogel was more effective than GLT-carbopol gel in treatment of frostbite. Conclusion: The GLT nanogel possess superior therapeutic effect for frostbite compared with the GLT-carbopol gel, which indicates that nanogels are eligible for the use as a suitable nanomedicine for dermal delivery of poorly soluble drugs such as GLT. PMID:24963753

Shen, Cheng-Ying; Xu, Ping-Hua; Shen, Bao-de; Min, Hong-Yan; Li, Xiao-Rong; Han, Jin; Yuan, Hai-Long

2014-06-25

61

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

E-print Network

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

Barthelat, Francois

62

Targeted estrogen delivery reverses the metabolic syndrome  

PubMed Central

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

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

2013-01-01

63

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

PubMed Central

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

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

2014-01-01

64

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

PubMed

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. PMID:24881520

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

2014-07-01

65

Magnetizable implants for targeted drug delivery  

Microsoft Academic Search

The capability to deliver high effective dosages to specific sites in the human body has become the holy grail of drug delivery research. Drugs with proven effectiveness under in vitro investigation often reach a major roadblock under in vivo testing due to a lack of an effective delivery strategy. In addition, many clinical scenarios require delivery of agents that are

Zachary Graham Forbes

2005-01-01

66

Giant Fullerenes for Target Specific Drug Delivery  

NASA Astrophysics Data System (ADS)

Carbon nano-structures, such as giant fullerenes, have a great potential for biological and medical applications. Most of the previous research is dedicated to investigate the use of fullerenes as vehicles for carrying medication which is chemisorbed on the outside surface of the fullerenes. In contrast, using fullerenes as an enclosure was largely abandoned due to the high strength of the carbon-carbon bonds which has been perceived to prevent the rupturing of the fullerene to release their cargo. We performed atomistic computations based on classical force fields that will address this perception. Specifically we explore the physics and chemistry of OH functionalized carbon based giant fullerenes with diameters from 0.72 nm (60 atoms) to 5.7 nm (3840 atoms). The preliminary results show that OH functionalization on these fullerenes is not only viable but also provides a pH sensitive release mechanism. Furthermore our current results show that carbon-carbon bonds can be broken in low energy biological environments in the presence of a flow induced strain field. These insights may have implications for target specific drug delivery in general and cancer treatment in particular.

Courtney, Robert; Kiefer, Boris

2013-03-01

67

POSTER PRESENTATION Open Access Targeted delivery to inflammatory monocytes for  

E-print Network

mouse Ly6Chigh monocyte subset and its human counterpart, defined as CD14+ CD16- , represent a valuablePOSTER PRESENTATION Open Access Targeted delivery to inflammatory monocytes for efficient RNAi evidences for the selective delivery of a siRNA-containing lipid formulation to the Ly-6Chigh monocyte

Paris-Sud XI, Université de

68

Targeted Drug Delivery Systems for Cancer Therapy  

Microsoft Academic Search

The role of cyclodextrin’s (CD) in drug delivery has advanced in recent years and this may be attributed to its biocompatibility and well established synthesis. Chemical modification of CDs has shown to extend the physicochemical properties and the host capacity for a variety of drugs. ?-CD has been widely used in the early stages of pharmaceutical applications because of its

Antonio Clementi; Christine OConnor; Mary McNamara; A. Mazzaglia; M. C. Aversa; A. Giuffrida

2008-01-01

69

Subcellular targeting strategies for drug design and delivery  

Microsoft Academic Search

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

Lawrence Rajendran; Hans-Joachim Knölker; Kai Simons

2010-01-01

70

Tumor Regression by Targeted Gene Delivery to the  

E-print Network

Tumor Regression by Targeted Gene Delivery to the Neovasculature John D. Hood,1 Mark Bednarski,2 to an integrin v 3­targeting ligand can deliver genes selectively to angiogenic blood vessels in tumor factors. Systemic injection of the NP into mice resulted in apoptosis of the tumor- associated endothelium

Gleeson, Joseph G.

71

Antiproliferative activity of fucan nanogel.  

PubMed

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

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

2012-09-01

72

Antiproliferative Activity of Fucan Nanogel  

PubMed Central

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

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

2012-01-01

73

Monitoring the Erosion of Hydrolytically-Degradable Nanogels via Multiangle Light Scattering Coupled to Asymmetrical Flow Field-Flow Fractionation  

PubMed Central

We describe the synthesis and characterization of degradable nanogels that display bulk erosion under physiologic conditions (pH = 7.4, 37 °C). Erodible poly(N-isopropylmethacrylamide) nanogels were synthesized by copolymerization with N,O-(dimethacryloyl)hydroxylamine, a cross-linker previously used in the preparation of non-toxic and biodegradable bulk hydrogels. To monitor particle degradation, we employed multiangle light scattering and differential refractometry detection following asymmetrical flow field-flow fractionation. This approach allowed the detection of changes in nanogel molar mass and topology as a function of both temperature and pH. Particle erosion was evident from both an increase in nanogel swelling and a decrease in scattering intensity as a function of time. Following these analyses, the samples were recovered for subsequent characterization by direct particle tracking, which yields hydrodynamic size measurements and enables number density determination. Additionally, we confirmed the conservation of nanogel stimuli-responsivity through turbidity measurements. Thus, we have demonstrated the synthesis of degradable nanogels that erode under conditions and on timescales that are relevant for many drug delivery applications. The combined separation and light scattering detection method is demonstrated to be a versatile means to monitor erosion and should also find applicability in the characterization of other degradable particle constructs. PMID:20000662

Smith, Michael H.; South, Antoinette B.; Gaulding, Jeffrey C.; Lyon, L. Andrew

2009-01-01

74

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

PubMed Central

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

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

2012-01-01

75

Functionalized Nanosystems for Targeted Mitochondrial Delivery  

PubMed Central

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

Durazo, Shelley A.; Kompella, Uday B.

2011-01-01

76

Colon Targeted Delivery Systems: Review of Polysaccharides for Encapsulation and Delivery  

Microsoft Academic Search

Colon-targeted delivery of bioactives has recently gained importance in addressing specific needs in the therapy of colon-based diseases. Many approaches have been attempted for the development of colon-specific delivery systems, with not much success in the past. Recent research into the utilization of the metabolic activity and the colonic microenvironment in the lower gastrointestinal tract has attained great value in

Shantha L. Kosaraju

2005-01-01

77

IFE Target Fabrication, Delivery, and Cost Estimates  

E-print Network

development is an essential component of any inertial fusion concept... · Three main IFE concepts - Strong-effective target supply for inertial fusion energy", Nuclear Fusion 44 (2004). 160' 100' QA/QC Lab Control Room- concentricity (NC) is a "wall uniformity" defect 0% 20% 40% 60% 80% 100% 0 1 2 3 4 5 6 7 8 9 10 % Non

78

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

PubMed

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. PMID:24505028

Kim, Jihyun; Chong, Youhoon; Mok, Hyejung

2014-06-01

79

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

NASA Astrophysics Data System (ADS)

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.

Yadav, Reeta

80

Synthetic LDL as targeted drug delivery vehicle  

DOEpatents

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

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

2012-08-28

81

Targeted drug delivery and enhanced intracellular release using functionalized liposomes  

Microsoft Academic Search

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

Ashish Garg

2009-01-01

82

Development of colon targeted drug delivery systems for mebendazole  

Microsoft Academic Search

The objective of the present study is to develop colon targeted drug delivery systems for mebendazole using guar gum as a carrier. Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for drug content uniformity, and were subjected to in vitro drug release studies. The

Y. S. R Krishnaiah; P Veer Raju; B Dinesh Kumar; P Bhaskar; V Satyanarayana

2001-01-01

83

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

NASA Astrophysics Data System (ADS)

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

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

2014-06-01

84

Self-Assembling Peptide Amphiphiles for Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

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

Moyer, Tyson

85

Clinical implementation of target tracking by breathing synchronized delivery  

SciTech Connect

Target-tracking techniques can be categorized based on the mechanism of the feedback loop. In real time tracking, breathing-delivery phase correlation is provided to the treatment delivery hardware. Clinical implementation of target tracking in real time requires major hardware modifications. In breathing synchronized delivery (BSD), the patient is guided to breathe in accordance with target motion derived from four-dimensional computed tomography (4D-CT). Violations of mechanical limitations of hardware are to be avoided at the treatment planning stage. Hardware modifications are not required. In this article, using sliding window IMRT delivery as an example, we have described step-by-step the implementation of target tracking by the BSD technique: (1) A breathing guide is developed from patient's normal breathing pattern. The patient tries to reproduce this guiding cycle by following the display in the goggles; (2) 4D-CT scans are acquired at all the phases of the breathing cycle; (3) The average tumor trajectory is obtained by deformable image registration of 4D-CT datasets and is smoothed by Fourier filtering; (4) Conventional IMRT planning is performed using the images at reference phase (full exhalation phase) and a leaf sequence based on optimized fluence map is generated; (5) Assuming the patient breathes with a reproducible breathing pattern and the machine maintains a constant dose rate, the treatment process is correlated with the breathing phase; (6) The instantaneous average tumor displacement is overlaid on the dMLC position at corresponding phase; and (7) DMLC leaf speed and acceleration are evaluated to ensure treatment delivery. A custom-built mobile phantom driven by a computer-controlled stepper motor was used in the dosimetry verification. A stepper motor was programmed such that the phantom moved according to the linear component of tumor motion used in BSD treatment planning. A conventional plan was delivered on the phantom with and without motion. The BSD plan was also delivered on the phantom that moved with the prescheduled pattern and synchronized with the delivery of each beam. Film dosimetry showed underdose and overdose in the superior and inferior regions of the target, respectively, if the tumor motion is not compensated during the delivery. BSD delivery resulted in a dose distribution very similar to the planned treatments.

Tewatia, Dinesh; Zhang Tiezhi; Tome, Wolfgang; Paliwal, Bhudatt; Metha, Minesh [Department of Human Oncology, University of Wisconsin, Madison, Wisconsin 53705 (United States); Department of Radiation Oncology, William Beaumant Hospital, Royal Oak, Michigan 48073 (United States); Department of Human Oncology, University of Wisconsin, Madison, Wisconsin 53705 (United States)

2006-11-15

86

Clinical implementation of target tracking by breathing synchronized delivery.  

PubMed

Target-tracking techniques can be categorized based on the mechanism of the feedback loop. In real time tracking, breathing-delivery phase correlation is provided to the treatment delivery hardware. Clinical implementation of target tracking in real time requires major hardware modifications. In breathing synchronized delivery (BSD), the patient is guided to breathe in accordance with target motion derived from four-dimensional computed tomography (4D-CT). Violations of mechanical limitations of hardware are to be avoided at the treatment planning stage. Hardware modifications are not required. In this article, using sliding window IMRT delivery as an example, we have described step-by-step the implementation of target tracking by the BSD technique: (1) A breathing guide is developed from patient's normal breathing pattern. The patient tries to reproduce this guiding cycle by following the display in the goggles; (2) 4D-CT scans are acquired at all the phases of the breathing cycle; (3) The average tumor trajectory is obtained by deformable image registration of 4D-CT datasets and is smoothed by Fourier filtering; (4) Conventional IMRT planning is performed using the images at reference phase (full exhalation phase) and a leaf sequence based on optimized fluence map is generated; (5) Assuming the patient breathes with a reproducible breathing pattern and the machine maintains a constant dose rate, the treatment process is correlated with the breathing phase; (6) The instantaneous average tumor displacement is overlaid on the dMLC position at corresponding phase; and (7) DMLC leaf speed and acceleration are evaluated to ensure treatment delivery. A custom-built mobile phantom driven by a computer-controlled stepper motor was used in the dosimetry verification. A stepper motor was programmed such that the phantom moved according to the linear component of tumor motion used in BSD treatment planning. A conventional plan was delivered on the phantom with and without motion. The BSD plan was also delivered on the phantom that moved with the prescheduled pattern and synchronized with the delivery of each beam. Film dosimetry showed underdose and overdose in the superior and inferior regions of the target, respectively, if the tumor motion is not compensated during the delivery. BSD delivery resulted in a dose distribution very similar to the planned treatments. PMID:17153412

Tewatia, Dinesh; Zhang, Tiezhi; Tome, Wolfgang; Paliwal, Bhudatt; Metha, Minesh

2006-11-01

87

Targeted delivery of multifunctional magnetic nanoparticles.  

PubMed

Magnetic nanoparticles and their magnetofluorescent analogues have become important tools for in vivo imaging using magnetic resonance imaging and fluorescent optical methods. A number of monodisperse magnetic nanoparticle preparations have been developed over the last decade for angiogenesis imaging, cancer staging, tracking of immune cells (monocyte/macrophage, T cells) and for molecular and cellular targeting. Phage display and data mining have enabled the procurement of novel tissue- or receptor-specific peptides, while high-throughput screening of diversity-oriented synthesis libraries has identified small molecules that permit or prevent uptake by specific cell types. Next-generation magnetic nanoparticles are expected to be truly multifunctional, incorporating therapeutic functionalities and further enhancing an already diverse repertoire of capabilities. PMID:17716118

McCarthy, Jason R; Kelly, Kimberly A; Sun, Eric Y; Weissleder, Ralph

2007-04-01

88

Targeted Liposomal Drug Delivery to Monocytes and Macrophages  

PubMed Central

As the role of monocytes and macrophages in a range of diseases is better understood, strategies to target these cell types are of growing importance both scientifically and therapeutically. As particulate carriers, liposomes naturally target cells of the mononuclear phagocytic system (MPS), particularly macrophages. Loading drugs into liposomes can therefore offer an efficient means of drug targeting to MPS cells. Physicochemical properties including size, charge and lipid composition can have a very significant effect on the efficiency with which liposomes target MPS cells. MPS cells express a range of receptors including scavenger receptors, integrins, mannose receptors and Fc-receptors that can be targeted by the addition of ligands to liposome surfaces. These ligands include peptides, antibodies and lectins and have the advantages of increasing target specificity and avoiding the need for cationic lipids to trigger intracellular delivery. The goal for targeting monocytes/macrophages using liposomes includes not only drug delivery but also potentially a role in cell ablation and cell activation for the treatment of conditions including cancer, atherosclerosis, HIV, and chronic inflammation. PMID:21512579

Kelly, Ciara; Jefferies, Caroline; Cryan, Sally-Ann

2011-01-01

89

Targeted Drug Delivery to Treat Pain and Cerebral Hypoxia  

PubMed Central

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

Davis, Thomas P.

2013-01-01

90

Charge-conversional and reduction-sensitive poly(vinyl alcohol) nanogels for enhanced cell uptake and efficient intracellular doxorubicin release.  

PubMed

Charge-conversional and reduction-sensitive polyvinyl alcohol (PVA) nanogels were developed for efficient cancer treatment by enhanced cell uptake and intracellular triggered doxorubicin (DOX) release. These PVA nanogels were prepared in a straightforward manner by inverse nanoprecipitation via "click" reaction with an average diameter of 118nm. The introduction of COOH into the PVA nanogels efficiently improved the DOX encapsulation due to the electrostatic interaction. The in vitro release result showed that the decrease of electrostatic interaction between COOH and DOX under a mimicking endosomal pH, in combination with the cleavage of the intervening disulfide bonds in response to a high glutathione (GSH) concentration led to a fast and complete release of DOX. Furthermore, confocal laser scanning microscopy (CLSM) revealed that the ultra pH-sensitive terminal groups allowed nanogels to reverse their surface charge from negative to positive under a tumor extracellular pH (6.5-6.8) which facilitated cell internalization. MTT assays and real time cell analysis (RTCA) showed that these DOX-loaded charge-conversional and reducible PVA nanogels had much better cell toxicity than DOX-loaded non-charge-conversional or reduction-insensitive PVA nanogels following 48h of incubation. These novel charge-conversional and stimuli-responsive PVA nanogels are highly promising for targeted intracellular anticancer drug release. PMID:25445693

Chen, Wei; Achazi, Katharina; Schade, Boris; Haag, Rainer

2015-05-10

91

Progress toward a Colon Targeting Nanoparticle Based Drug Delivery System  

E-print Network

......................................................... 11 2.2.1 Colon targeting oral drug delivery ....................................................... 11 2.2.2 Polysaccharide based pH sensitive and biodegradable hydrogels ....... 12 2.3 In vitro drug release models... of particles? size and surface charges .................... 20 3.3.1.2 Encapsulation efficiency and stability of PAX NPs in different pH of the aqueous solutions ........................................................ 22 3.3.2 LbL self...

Yu, Xiao

2012-07-16

92

Multifunctional Inorganic Nanoparticles for Imaging, Targeting, and Drug Delivery  

PubMed Central

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

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

2009-01-01

93

pH sensitive swelling and releasing behavior of nano-gels based on polyaspartamide graft copolymers.  

PubMed

pH sensitive nano-gels based on polyaspartamide graft copolymers are prepared by UV crosslinking the self-assembled nano-aggregates in the presence of a series of hydrophobic and hydrophilic grafting segments. While the physical nano-aggregates dissociate via ionization of the pH sensitive moiety, the nano-gels synthesized in this study swell instead. The chemical structure and morphology of the resulting nano-gels were analyzed using FTIR, (1)H FTNMR, and TEM. The pH dependence of the particle size, 120-250 nm, was investigated using a light scattering analyzer. The swelling behavior of the nano-cores under acidic conditions triggered abrupt release of the drug; this pH dependence occurs reversibly and quickly. The nano-gels prepared may have endosomal rupturing characteristics, as their buffering capacity is as strong as that of uncrosslinked nano-aggregates. The nano-gels synthesized as such possess potential application as sustained releasing drug carriers for intracellular delivery. PMID:21276976

Kim, Sunmi; Kim, Ji-Heung; Kim, Dukjoon

2011-04-01

94

Targeted drug delivery utilizing protein-like molecular architecture  

PubMed Central

Nanotechnology-based drug delivery systems (nanoDDSs) have seen recent popularity due to their favorable physical, chemical, and biological properties, and great efforts have been made to target nanoDDSs to specific cellular receptors. CD44/chondroitin sulfate proteoglycan (CSPG) is among the receptors overexpressed in metastatic melanoma, and the sequence to which it binds within the type IV collagen triple-helix has been identified. A triple-helical “peptide-amphiphile” (?1(IV)1263-1277 PA) which binds CD44/CSPG has been constructed and incorporated into liposomes of differing lipid compositions. Liposomes containing distearoyl phosphatidylcholine (DSPC) as the major bilayer component, in combination with distearoyl phosphatidylglycerol (DSPG) and cholesterol, were more stable than analogous liposomes containing dipalmitoyl phosphatidylcholine (DPPC) instead of DSPC. When dilauroyl phosphatidylcholine (DLPC):DSPG:cholesterol liposomes were prepared, monotectic behavior was observed. The presence of the ?1(IV)1263-1277 PA conferred greater stability to the DPPC liposomal systems and did not affect the stability of the DSPC liposomes. A positive correlation was observed for cellular fluorophore delivery by the ?1(IV)1263-1277 PA liposomes and CD44/CSPG receptor content in metastatic melanoma and fibroblast cell lines. Conversely, non-targeted liposomes delivered minimal fluorophore to these cells regardless of the CD44/CSPG receptor content. When metastatic melanoma cells and fibroblasts were treated with exogeneous ?1(IV)1263-1277, prior to incubation with ?1(IV)1263-1277 PA liposomes, to potentially disrupt receptor/liposome interactions, a dose-dependent decrease in the amount of fluorophore delivered was observed. Overall, our results suggest that PA-targeted liposomes can be constructed and rationally fine-tuned for drug delivery applications based on lipid composition. The selectivity of ?1(IV)1263-1277 PA liposomes for CD44/CSPG-containing cells represents a targeted-Nano-DDS with potential for further development and application. PMID:17397150

Rezler, Evonne M.; Khan, David R.; Lauer-Fields, Janelle; Cudic, Mare; Baronas-Lowell, Diane; Fields, Gregg B.

2008-01-01

95

pH/temperature sensitive magnetic nanogels conjugated with Cy5.5-labled lactoferrin for MR and fluorescence imaging of glioma in rats.  

PubMed

Glioma is the most common primary brain tumor and causes a disproportionate level of morbidity and mortality across a wide range of individuals. From previous clinical practices, definition of glioma margin is the key point for surgical resection. In order to outline the exact margin of glioma and provide a guide effect for the physicians both at pre-surgical planning stage and surgical resection stage, pH/temperature sensitive magnetic nanogels conjugated with Cy5.5-labled lactoferrin (Cy5.5-Lf-MPNA nanogels) were developed as a promising contrast agent. Due to its pH/te mperature sensitivity, Cy5.5-Lf-MPNA nanogels could change in its hydrophilic/hydrophobic properties and size at different pH and temperatures. Under physiological conditions (pH 7.4, 37 °C), Cy5.5-Lf-MPNA nanogels were hydrophilic and swollen, which could prolong the blood circulation time. In the acidic environment of tumor tissues (pH 6.8, 37 °C), Cy5.5-Lf-MPNA nanogels became hydrophobic and shrunken, which could be more easily accumulated in tumor tissue and internalized by tumor cells. In addition, lactoferrin, an effective targeting ligand for glioma, provides active tumor targeting ability. In vivo studies on rats bearing in situ glioma indicated that the MR/fluorescence imaging with high sensitivity and specificity could be acquired using Cy5.5-Lf-MPNA nanogels due to active targeting function of the Lf and enhancement of cellular uptake by tailoring the hydrophilic/hydrophobic properties of the nanogels. With good biocompatibility shown by cytotoxicity assay and histopathological analysis, Cy5.5-Lf-MPNA nanogels are hopeful to be developed as a specific and high-sensitive contrast agent for preoperative MRI and intraoperative fluorescence imaging of glioma. PMID:23810255

Jiang, Lingyu; Zhou, Qing; Mu, Ketao; Xie, Hui; Zhu, Yanhong; Zhu, Wenzhen; Zhao, Yanbing; Xu, Huibi; Yang, Xiangliang

2013-10-01

96

Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems  

PubMed Central

The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed. PMID:24212620

Fillat, Cristina; Jose, Anabel; Ros, Xavier Bofill-De; Mato-Berciano, Ana; Maliandi, Maria Victoria; Sobrevals, Luciano

2011-01-01

97

Specifically targeted delivery of protein to phagocytic macrophages  

PubMed Central

Macrophages play important roles in the pathogenesis of various diseases, and are important potential therapeutic targets. Furthermore, macrophages are key antigen-presenting cells and important in vaccine design. In this study, we report on the novel formulation (bovine serum albumin [BSA]-loaded glucan particles [GMP-BSA]) based on ?-glucan particles from cell walls of baker’s yeast for the targeted delivery of protein to macrophages. Using this formulation, chitosan, tripolyphosphate, and alginate were used to fabricate colloidal particles with the model protein BSA via electrostatic interactions, which were caged and incorporated BSA very tightly within the ?-glucan particle shells. The prepared GMP-BSA exhibited good protein-release behavior and avoided protein leakage. The particles were also highly specific to phagocytic macrophages, such as Raw 264.7 cells, primary bone marrow-derived macrophages, and peritoneal exudate macrophages, whereas the particles were not taken up by nonphagocytic cells, including NIH3T3, AD293, HeLa, and Caco-2. We hypothesize that these tightly encapsulated protein-loaded glucan particles deliver various types of proteins to macrophages with notably high selectivity, and may have broad applications in targeted drug delivery or vaccine design against macrophages. PMID:25784802

Yu, Min; Chen, Zeming; Guo, Wenjun; Wang, Jin; Feng, Yupeng; Kong, Xiuqi; Hong, Zhangyong

2015-01-01

98

Specifically targeted delivery of protein to phagocytic macrophages.  

PubMed

Macrophages play important roles in the pathogenesis of various diseases, and are important potential therapeutic targets. Furthermore, macrophages are key antigen-presenting cells and important in vaccine design. In this study, we report on the novel formulation (bovine serum albumin [BSA]-loaded glucan particles [GMP-BSA]) based on ?-glucan particles from cell walls of baker's yeast for the targeted delivery of protein to macrophages. Using this formulation, chitosan, tripolyphosphate, and alginate were used to fabricate colloidal particles with the model protein BSA via electrostatic interactions, which were caged and incorporated BSA very tightly within the ?-glucan particle shells. The prepared GMP-BSA exhibited good protein-release behavior and avoided protein leakage. The particles were also highly specific to phagocytic macrophages, such as Raw 264.7 cells, primary bone marrow-derived macrophages, and peritoneal exudate macrophages, whereas the particles were not taken up by nonphagocytic cells, including NIH3T3, AD293, HeLa, and Caco-2. We hypothesize that these tightly encapsulated protein-loaded glucan particles deliver various types of proteins to macrophages with notably high selectivity, and may have broad applications in targeted drug delivery or vaccine design against macrophages. PMID:25784802

Yu, Min; Chen, Zeming; Guo, Wenjun; Wang, Jin; Feng, Yupeng; Kong, Xiuqi; Hong, Zhangyong

2015-01-01

99

Enhanced solubility and targeted delivery of curcumin by lipopeptide micelles.  

PubMed

A lipopeptide (LP)-containing KKGRGDS as the hydrophilic heads and lauric acid (C12) as the hydrophobic tails has been designed and prepared by standard solid-phase peptide synthesis technique. LP can self-assemble into spherical micelles with the size of ~30 nm in PBS (phosphate buffer saline) (pH 7.4). Curcumin-loaded LP micelles were prepared in order to increase the water solubility, sustain the releasing rate, and improve the tumor targeted delivery of curcumin. Water solubility, cytotoxicity, in vitro release behavior, and intracellular uptake of curcumin-loaded LP micelles were investigated. The results showed that LP micelles can increase the water solubility of curcumin 1.1 × 10(3) times and sustain the release of curcumin in a low rate. Curcumin-loaded LP micelles showed much higher cell inhibition than free curcumin on human cervix carcinoma (HeLa) and HepG2 cells. When incubating these curcumin-loaded micelles with HeLa and COS7 cells, due to the over-expression of integrins on cancer cells, the micelles can efficiently use the tumor-targeting function of RGD (functionalized peptide sequences: Arg-Gly-Asp) sequence to deliver the drug into HeLa cells, and better efficiency of the self-assembled LP micelles for curcumin delivery than crude curcumin was also confirmed by LCSM (laser confocal scanning microscope) assays. Combined with the enhanced solubility and higher cell inhibition, LP micelles reported in this study may be promising in clinical application for targeted curcumin delivery. PMID:25621942

Liang, Ju; Wu, Wenlan; Lai, Danyu; Li, Junbo; Fang, Cailin

2015-04-01

100

Targeted drug delivery utilizing protein-like molecular architecture.  

PubMed

Nanotechnology-based drug delivery systems (nanoDDSs) have seen recent popularity due to their favorable physical, chemical, and biological properties, and great efforts have been made to target nanoDDSs to specific cellular receptors. CD44/chondroitin sulfate proteoglycan (CSPG) is among the receptors overexpressed in metastatic melanoma, and the sequence to which it binds within the type IV collagen triple-helix has been identified. A triple-helical "peptide-amphiphile" (alpha1(IV)1263-1277 PA), which binds CD44/CSPG, has been constructed and incorporated into liposomes of differing lipid compositions. Liposomes containing distearoyl phosphatidylcholine (DSPC) as the major bilayer component, in combination with distearoyl phosphatidylglycerol (DSPG) and cholesterol, were more stable than analogous liposomes containing dipalmitoyl phosphatidylcholine (DPPC) instead of DSPC. When dilauroyl phosphatidylcholine (DLPC):DSPG:cholesterol liposomes were prepared, monotectic behavior was observed. The presence of the alpha1(IV)1263-1277 PA conferred greater stability to the DPPC liposomal systems and did not affect the stability of the DSPC liposomes. A positive correlation was observed for cellular fluorophore delivery by the alpha1(IV)1263-1277 PA liposomes and CD44/CSPG receptor content in metastatic melanoma and fibroblast cell lines. Conversely, nontargeted liposomes delivered minimal fluorophore to these cells regardless of the CD44/CSPG receptor content. When metastatic melanoma cells and fibroblasts were treated with exogeneous alpha1(IV)1263-1277, prior to incubation with alpha1(IV)1263-1277 PA liposomes, to potentially disrupt receptor/liposome interactions, a dose-dependent decrease in the amount of fluorophore delivered was observed. Overall, our results suggest that PA-targeted liposomes can be constructed and rationally fine-tuned for drug delivery applications based on lipid composition. The selectivity of alpha1(IV)1263-1277 PA liposomes for CD44/CSPG-containing cells represents a targeted-nanoDDS with potential for further development and application. PMID:17397150

Rezler, Evonne M; Khan, David R; Lauer-Fields, Janelle; Cudic, Mare; Baronas-Lowell, Diane; Fields, Gregg B

2007-04-25

101

Multifunctional DNA-gold nanoparticles for targeted doxorubicin delivery.  

PubMed

In this report we describe the synthesis, characterization, and cytotoxic properties of DNA-capped gold nanoparticles having attached folic acid (FA), a thermoresponsive polymer (p), and/or poly(ethylene glycol) (PEG) oligomers that could be used to deliver the anticancer drug doxorubicin (DOX) in chemotherapy. The FA-DNA oligomer used in the construction of the delivery vehicle was synthesized through the reaction of the isolated folic acid N-hydroxysuccinimide ester with the amino-DNA and the conjugated DNA product was purified using high performance liquid chromatography (HPLC). This approach ultimately allowed control of the amount of FA attached to the surface of the delivery vehicle. Cytotoxicity studies using SK-N-SH neuroblastoma cells with drug loaded delivery vehicles were carried out using a variety of exposure times (1-48 h) and recovery times (1-72 h), and in order to access the effects of varying amounts of attached FA, in culture media deficient in FA. DOX loaded delivery vehicles having 50% of the DNA strands with attached FA were more cytotoxic than when all of the strands contained FA. Since FA stimulates cell growth, the reduced cytotoxicity of vehicles fully covered with FA suggests that the stimulatory effects of FA can more than compensate for the cytotoxic effects of the drug on the cell population. While attachment of hexa-ethylene glycol PEG(18) to the surface of the delivery vehicle had no effect on cytotoxicity, 100% FA plus the thermoresponsive polymer resulted in IC50 = 0.48 ± 0.01 for an exposure time of 24 h and a recovery time of 1 h, which is an order of magnitude more cytotoxic than free DOX. Confocal microscopic studies using fluorescence detection showed that SK-N-SH neuroblastoma cells exposed to DOX-loaded vehicles have drug accumulation inside the cell and, in the case of vehicles with attached FA and thermoresponsive polymer, the drug appears more concentrated. Since the biological target of DOX is DNA, the latter observation is consistent with the high cytotoxicity of vehicles having both FA and the thermoresponsive polymer. The study highlights the potential of DNA-capped gold nanoparticles as delivery vehicles for doxorubicin in cancer chemotherapy. PMID:24911830

Alexander, Colleen M; Hamner, Kristen L; Maye, Mathew M; Dabrowiak, James C

2014-07-16

102

Nanostructured porous Si-based nanoparticles for targeted drug delivery  

PubMed Central

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

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

2012-01-01

103

Pharmaceutical approaches to colon targeted drug delivery systems  

Microsoft Academic Search

Purpose. Although oral delivery has become a widely accepted route of administration of therapeutic drugs, the gastrointestinal tract presents several formidable barriers to drug delivery. Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon but also for its potential for the delivery of proteins

M. K. Chourasia; S. K. Jain

104

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

PubMed

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

Keshavarz, M; Kaffashi, B

2014-12-01

105

Targeted intracellular delivery of proteins with spatial and temporal control.  

PubMed

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

Morales, Demosthenes P; Braun, Gary B; Pallaoro, Alessia; Chen, Renwei; Huang, Xiao; Zasadzinski, Joseph A; Reich, Norbert O

2015-02-01

106

Targeted biodegradable nanoparticles for drug delivery to smooth muscle cells.  

PubMed

Targeted delivery of therapeutic agents to prevent smooth muscle cell (SMC) proliferation is important in averting restenosis (a narrowing of blood vessels). Since platelet derived growth factor (PDGF) receptors are over-expressed in proliferating SMCs after injury from cardiovascular interventions, such as angioplasty and stent implantation, our hypothesis is that conjugation of PDGF-BB (platelet-derived growth factor BB (homodimer)) peptides to biodegradable poly (D,L-lactic-co-glycolide) (PLGA) nanoparticles (NPs) would exhibit an increased uptake of these NPs by proliferating SMCs. In this study, poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles containing dexamethasone were formulated and conjugated with PDGF-BB peptides. These NPs were stable, biocompatible, and exhibited a sustained drug release over 14 days. Various particle uptake studies using HASMCs (human aortic smooth muscle cells) demonstrated that PDGF-BB peptide-conjugated nanoparticles significantly increased cellular uptake and decreased proliferation of HASMCs compared to control nanoparticles (without conjugation of PDGF-BB peptides). These NPs were internalized primarily by clathrin-mediated endocytosis and macropinocytosis. Our in vitro results suggest that PDGF-BB peptide-conjugated NPs could represent as an effective targeted, sustained therapeutic delivery system to reduce restenosis and neointimal hyperplasia. PMID:22523971

Kona, Soujanya; Specht, Danyel; Rahimi, Maham; Shah, Bhavik P; Gilbertson, Timothy A; Nguyen, Kytai T

2012-01-01

107

Targeted electrohydrodynamic printing for micro-reservoir drug delivery systems  

NASA Astrophysics Data System (ADS)

Microfluidic drug delivery systems consisting of a drug reservoir and microfluidic channels have shown the possibility of simple and robust modulation of drug release rate. However, the difficulty of loading a small quantity of drug into drug reservoirs at a micro-scale limited further development of such systems. Electrohydrodynamic (EHD) printing was employed to fill micro-reservoirs with controlled amount of drugs in the range of a few hundreds of picograms to tens of micrograms with spatial resolution of as small as 20 µm. Unlike most EHD systems, this system was configured in combination with an inverted microscope that allows in situ targeting of drug loading at micrometer scale accuracy. Methylene blue and rhodamine B were used as model drugs in distilled water, isopropanol and a polymer solution of a biodegradable polymer and dimethyl sulfoxide (DMSO). Also tetracycline-HCl/DI water was used as actual drug ink. The optimal parameters of EHD printing to load an extremely small quantity of drug into microscale drug reservoirs were investigated by changing pumping rates, the strength of an electric field and drug concentration. This targeted EHD technique was used to load drugs into the microreservoirs of PDMS microfluidic drug delivery devices and their drug release performance was demonstrated in vitro.

Hwang, Tae Heon; Kim, Jin Bum; Som Yang, Da; Park, Yong-il; Ryu, WonHyoung

2013-03-01

108

Efficient delivery of therapeutic agents by using targeted albumin nanoparticles.  

PubMed

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. PMID:25819278

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

2015-01-01

109

Micro- and nanogels with labile crosslinks - from synthesis to biomedical applications.  

PubMed

Micro- or nanosized three-dimensional crosslinked polymeric networks have been designed and described for various biomedical applications, including living cell encapsulation, tissue engineering, and stimuli responsive controlled delivery of bioactive molecules. For most of these applications, it is necessary to disintegrate the artificial scaffold into nontoxic residues with smaller dimensions to ensure renal clearance for better biocompatibility of the functional materials. This can be achieved by introducing stimuli-cleavable linkages into the scaffold structures. pH, enzyme, and redox potential are the most frequently used biological stimuli. Moreover, some external stimuli, for example light and additives, are also used to trigger the disintegration of the carriers or their assembly. In this review, we highlight the recent progress in various chemical and physical methods for synthesizing and crosslinking micro- and nanogels, as well as their development for incorporation of cleavable linkages into the network of micro- and nanogels. PMID:25620415

Zhang, Xuejiao; Malhotra, Shashwat; Molina, Maria; Haag, Rainer

2015-04-01

110

Potential of magnetic nanoparticles for targeted drug delivery  

PubMed Central

Nanoparticles (NPs) play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs) with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some newly developed methods to synthesize and modify the surfaces of MNPs and their biomedical applications. PMID:24198498

Yang, Hung-Wei; Hua, Mu-Yi; Liu, Hao-Li; Huang, Chiung-Yin; Wei, Kuo-Chen

2012-01-01

111

Targeted drug delivery and enhanced intracellular release using functionalized liposomes  

NASA Astrophysics Data System (ADS)

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

Garg, Ashish

112

Cubosomes as targeted drug delivery systems - a biopharmaceutical approach.  

PubMed

Cubosomes are reversed bicontinuous cubic phases and possess unique physicochemical properties. These special systems are receiving much attention for the delivery of various hydrophilic, hydrophobic and amphiphilic drugs with enhanced bioavailability and high loading capacity. A wide variety of drugs are applicable for cubosome formulation for various routes of delivery. The lipids used in cubosome formulation are more stable and offer stability to the formulation during shelf-life. The article reviews about the back ground, techniques of cubosome preparation such as high pressure homogenization, probe ultrasonication and automated cubosome preparation; and also methods of cubosomes preparation such as top down, bottom up and other methods with pictorial presentation. This article emphasizes the phase transition and also targeted approaches of cubosomes. The characterization studies for cubosomes such as cryo transmission electron microscopy, differential scanning calorimetry and scanning electron microscopy followed by in-vitro and in-vivo evaluation studies of cubosomes were explained with appropriate examples. Recent applications of cubosomes were explained with reference to flurbiprofen, odorranalectin, diazepam and dexamethasone. The advantages, disadvantages and limitations of cubosomal technology were emphasized. PMID:24836404

Lakshmi, Naga M; Yalavarthi, Prasanna R; Vadlamudi, Harini C; Thanniru, Jyotsna; Yaga, Gowri; K, Haritha

2014-01-01

113

Dual stimuli-responsive polymeric hollow nanogels designed as carriers for intracellular triggered drug release.  

PubMed

Dual stimuli-responsive hollow nanogel spheres serving as an efficient intracellular drug delivery platform were obtained from the spontaneous coassociation of two graft copolymers into the vesicle architecture in aqueous phase. Both copolymers comprise acrylic acid (AAc) and 2-methacryloylethyl acrylate (MEA) units as the backbone and either poly(N-isopropylacrylamide) (PNIPAAm) alone or both PNIPAAm and monomethoxypoly(ethylene glycol) (mPEG) chain segments as the grafts. The assemblies were then subjected to covalent stabilization within vesicle walls with ester-containing cross-links by radical polymerization of MEA moieties, thereby leading to hollow nanogel particles. Taking the advantage of retaining a low quantity of payload within polymer layer-enclosed aqueous chambers through the entire loading process, doxorubicin (DOX) in the external bulk phase can be effectively transported into the gel membrane and bound therein via electrostatic interactions with ionized AAc residues and hydrogen-bond pairings with PNIPAAm grafts at pH 7.4. With the environmental pH being reduced (e.g., from 7.4 to 5.0) at 37 °C, the extensive disruption of AAc/DOX complexes due to the reduced ionization of AAc residues within the gel layer and the pronounced shrinkage of nanogels enable the rapid release of DOX species from drug-loaded hollow nanogels. By contrast, the drug liberation at 4 °C was severally restricted, particularly at pH 7.4 at which the DOX molecules remain strongly bound with ionized AAc residues and PNIPAAm grafts. The in vitro characterizations suggest that the DOX-loaded hollow nanogel particles after being internalized by HeLa cells via endocytosis can rapidly release the payload within acidic endosomes or lysosomes. This will then lead to significant drug accumulation in nuclei (within 1 h) and a cytotoxic effect comparable to free drug. This work demonstrates that the novel DOX-loaded hollow nanogel particles show great promise of therapeutic efficacy for potential anticancer treatment. PMID:23036055

Chiang, Wen-Hsuan; Ho, Viet Thang; Huang, Wen-Chia; Huang, Yi-Fong; Chern, Chorng-Shyan; Chiu, Hsin-Cheng

2012-10-23

114

Lactosylated liposomes for targeted delivery of doxorubicin to hepatocellular carcinoma  

PubMed Central

Background N-lactosyl-dioleoylphosphatidylethanolamine (Lac-DOPE) was synthesized and evaluated as a liver-specific targeting ligand via asialoglycoprotein receptors for liposomal delivery of doxorubicin. Methods Lactosylated liposomes encapsulating calcein (Lac-L-calcein) or doxorubicin (Lac-L-DOX) composed of egg phosphatidylcholine, cholesterol, monomethoxy polyethylene glycol 2000-distearoyl phosphatidylethanolamine, and Lac-DOPE at 50:35:5:10 (mol/mol) were prepared by polycarbonate membrane extrusion and evaluated in human hepatocellular carcinoma HepG2 cells. Cellular uptake of Lac-L-calcein was monitored by confocal microscopy and by flow cytometry. The cytotoxicity of Lac-L-DOX was evaluated by MTT assay. The pharmacokinetic properties of Lac-L-DOX were studied in normal mice, and its biodistribution and antitumor activity were studied in nude mice with HepG2 xenografts. Results The size of Lac-L-DOX was less than 100 nm and the liposomes demonstrated excellent colloidal stability. In vitro uptake of Lac-L-calcein by HepG2 cells was four times greater than that of non-targeted L-calcein. In the presence of 20 mM lactose, the uptake of Lac-L-calcein was inhibited, suggesting that asialoglycoprotein receptors mediated the observed cellular uptake. Lac-L-DOX exhibited enhanced in vivo cytotoxicity compared with the nontargeted liposomal doxorubicin (L-DOX), and its pharmacokinetic parameters indicate that Lac-L-DOX has a long blood circulation time (t1/2 8.73 hours). Tissue distribution and therapeutic efficacy studies in nude mice bearing HepG2 xenografts show that Lac-L-DOX had significantly stronger tumor inhibitory activity compared with L-DOX and free doxorubicin, along with a higher accumulation of drug within the tumor site and greater cellular uptake by tumor cells. Conclusion These data suggest that lactosylated liposomes are promising drug delivery vehicles for hepatocellular carcinoma. PMID:23093902

Zhou, Xiaoju; Zhang, Mengzi; Yung, Bryant; Li, Hong; Zhou, Chenguang; Lee, L James; Lee, Robert J

2012-01-01

115

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

NASA Astrophysics Data System (ADS)

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

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

2014-10-01

116

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

Microsoft Academic Search

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)

Anil K. Philip; Betty Philip

2010-01-01

117

Physical blends of starch graft copolymers as matrices for colon targeting drug delivery systems  

Microsoft Academic Search

Colon targeting drug delivery systems have attracted many researchers due to the distinct advantages they present such as near neutral pH, longer transit time and reduced enzymatic activity. Moreover, in recent studies, colon specific drug delivery systems are gaining importance for use in the treatment of local pathologies of the colon and also for the systemic delivery of protein and

I. Silva; M. Gurruchaga; I. Goñi

2009-01-01

118

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

PubMed

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

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

2014-11-01

119

Imaging in targeted delivery of therapy to cancer.  

PubMed

We review the current status of imaging as applied to targeted therapy with particular focus on antibody-based therapeutics. Antibodies have high tumor specificity and can be engineered to optimize delivery to, and retention within, the tumor. Whole antibodies can activate natural immune effector mechanisms and can be conjugated to beta- and alpha-emitting radionuclides, toxins, enzymes, and nanoparticles for enhanced therapeutic effect. Imaging is central to the development of these agents and is used for patient selection, performing dosimetry and assessment of response. gamma- and positron-emitting radionuclides may be used to image the distribution of antibody-targeted therapeutics While some radionuclides such as iodine-131 emit both beta and gamma radiation and are therefore suitable for both imaging and therapy, others are more suited to imaging or therapy alone. Hence for radionuclide therapy of neuroendocrine tumors, patients can be selected for therapy on the basis of gamma-emitting indium-111-octreotide imaging and treated with beta-emitting yttrium-90-octreotate. Positron-emitting radionuclides can give greater sensitivity that gamma-emitters but only a single radionuclide can be imaged at one time and the range of radionuclides is more limited. The multiple options for antibody-based therapeutic molecules, imaging technologies and therapeutic scenarios mean that very large amounts of diverse data are being acquired. This can be most effectively shared and progress accelerated by use of common data standards for imaging, biological, and clinical data. PMID:19838639

Dancey, Gairin; Begent, Richard H; Meyer, Tim

2009-09-01

120

Design and Application of Nanogel-Based Polymer Networks  

NASA Astrophysics Data System (ADS)

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 densely crosslinked, small monomer free dental materials. Nanogel-based networks showed no decrease in flexural modulus between the dry and water-equilibrated states in contrast to nanogel-monomer composites that exhibited a decrease in modulus upon water infiltration. The nanogel networks also exhibited higher conversion and lower volumetric shrinkage compared to the composite networks. Adhesive nanogels were designed with amphiphilic character and specific hydrogen-bonding groups. These nanogels gelled within 10 s of low intensity UV light exposure and demonstrated the ability to bond strongly to both hydrophilic and hydrophobic substrates that were dry or under water. Nanogel-based coatings were explored as a means to create multistructured, multifunctional polymer networks. Shape memory polymers were coated with nanogels through a dip-coating and subsequent photocrosslinking method. The presence of the coating did not affect the shape recovery of the polymer, and coatings formed with dexamethasone-loaded nanogels were demonstrated to release a physiologically relevant amount of the anti-inflammatory drug. These materials have potential application as minimally invasive implantable devices. Coatings were also formed from interfacial redox polymerizations. Nanogels with varying crosslinking density were coated onto dexamethasone-loaded networks, which had the effect of changing the diffusion coefficient of dexamethasone as it was released from the core network. A fluorescein-loaded nanogel was coated onto a rhodamine-loaded network, which provided multidrug release from both the coating and the core material through two distinct release profiles.

Dailing, Eric Alan

121

Chimeric aptamers in cancer cell-targeted drug delivery  

PubMed Central

Aptamers are single-stranded structured oligonucleotides (DNA or RNA) that can bind to a wide range of targets ("apatopes") with high affinity and specificity. These nucleic acid ligands, generated from pools of random-sequence by an in vitro selection process referred to as systematic evolution of ligands by exponential enrichment (SELEX), have now been identified as excellent tools for chemical biology, therapeutic delivery, diagnosis, research, and monitoring therapy in real-time imaging. Today, aptamers represent an interesting class of modern Pharmaceuticals which with their low immunogenic potential mimic extend many of the properties of monoclonal antibodies in diagnostics, research, and therapeutics. More recently, chimeric aptamer approach employing many different possible types of chimerization strategies has generated more stable and efficient chimeric aptamers with aptamer-aptamer, aptamer-nonaptamer biomacromolecules (siRNAs, proteins) and aptamer-nanoparticle chimeras. These chimeric aptamers when conjugated with various biomacromolecules like locked nucleic acid (LNA) to potentiate their stability, biodistribution, and targeting efficiency, have facilitated the accurate targeting in preclinical trials. We developed LNA-aptamer (anti-nucleolin and EpCAM) complexes which were loaded in iron-saturated bovine lactofeerin (Fe-blf)-coated dopamine modified surface of superparamagnetic iron oxide (Fe3O4) nanoparticles (SPIONs). This complex was used to deliver the specific aptamers in tumor cells in a co-culture model of normal and cancer cells. This review focuses on the chimeric aptamers, currently in development that are likely to find future practical applications in concert with other therapeutic molecules and modalities. PMID:21955150

Kanwar, Jagat R; Roy, Kislay; Kanwar, Rupinder K

2011-01-01

122

Mannosylated biodegradable polyethyleneimine for targeted DNA delivery to dendritic cells  

PubMed Central

Background To establish a potential gene-delivery system with the ability to deliver plasmid DNA to dendritic cells (DCs) more efficiently and specifically, we designed and synthesized a low-molecular-weight polyethyleneimine and triethyleneglycol polymer (PEI–TEG) and a series of its mannosylated derivatives. Methods PEI–TEG was synthesized from PEI2000 and PEI600 with TEG as the cross-linker. PEI–TEG was then linked to mannose via a phenylisothiocyanate bridge to obtain man-PEI–TEG conjugates. The DNA conveyance abilities of PEI–TEG, man-PEI–TEG, as well as control PEI25k were evaluated by measuring their zeta potential, particle size, and DNA-binding abilities. The in vitro cytotoxicity, cell uptake, and transfection efficiency of these PEI/DNA complexes were examined on the DC2.4 cell line. Finally, a maturation experiment evaluated the effect of costimulatory molecules CD40, CD80, and CD86 on murine bone marrow-derived DCs (BMDCs) using flow cytometry. Results PEI–TEG and man-PEI–TEG were successfully synthesized and were shown to retain the excellent properties of PEI25k for condensing DNA. Compared with PEI–TEG as well as PEI25k, the man-PEI–TEG had less cytotoxicity and performed better in both cellular uptake and transfection assays in vitro. The results of the maturation experiment showed that all the PEI/DNA complexes induced an adequate upregulation of surface markers for DC maturation. Conclusion These results demonstrated that man-PEI–TEG can be employed as a DC-targeting gene-delivery system. PMID:22745554

Sun, Xun; Chen, Simu; Han, Jianfeng; Zhang, Zhirong

2012-01-01

123

Targeted Delivery of Proteins across the Blood-Brain Barrier  

Microsoft Academic Search

Treatment of many neuronal degenerative disorders will require delivery of a therapeutic protein to neurons or glial cells across the whole CNS. The presence of the blood-brain barrier hampers the delivery of these proteins from the blood, thus necessitating a new method for delivery. Receptors on the blood-brain barrier bind ligands to facilitate their transport to the CNS; therefore, we

Brian J. Spencer; Inder M. Verma

2007-01-01

124

Electrospun Nanofibers of Guar Galactomannan for Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

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 without any attached support. As composites of aligned nanofibers, yarns potentially combine the inherent advantages of nanofibers with the strength and pliability of larger sized fibers. As such, we became interested in exploring the potential of nanofiber yarns as drug carriers. Our study evolved to accommodate comparative studies between the behavior of traditional nonwoven mats and nanofiber yarns. Throughout the process, we sought to answer the bigger question: Can guar galactomannan nanofibers be used as a new biodegradable platform for drug delivery?

Chu, Hsiao Mei Annie

2011-12-01

125

siRNA specific delivery system for targeting dendritic cells.  

PubMed

siRNA therapy offers immense potential for clinical application. Under physiological conditions, however, siRNA was demonstrated to have a short half-life. Additionally, it may also cause ubiquitous gene silencing as it does not possess a tissue-specific homing mechanism. Thus, the rate-limiting step in the emergence of siRNA as a potential therapeutic agent is the current lack of a safe and tissue- or cell-specific in vivo delivery system. Herein, we propose a novel, cell-specific method for the in vivo delivery of siRNA to dendritic cells (DCs) with the purpose of inducing immune modulation. CD40 siRNA was incorporated within the interior of 86 nm liposomes, which were decorated with surface-bound mAb NLDC-145 as a targeting mechanism. The siRNA encapsulation efficiency was determined to be approximately 7%. CD40 siRNA immunoliposomes (CD40 siILs) were able to specifically bind to DCs and silence CD40 expression in vitro. Furthermore, in vitro CD40-silenced DCs significantly inhibited the proliferation of alloreactive T cells in an MLR. Upon in vivo administration, siIL-encapsulated, Cy3-labeled siRNA exhibited moderate uptake by the liver at an early time point following administration with greater accumulation in the spleen at a later time point. In contrast, naked siRNA primarily accumulated in the kidney immediately after administration and circulated out in a short time period. To address in vivo gene silencing and immune modulation, mice were simultaneously immunized with KLH and subcutaneously injected with DC-specific CD40 siILs, siILs containing negative control siRNA, naked CD40 siRNA, or PBS. A second injection of CD40 siILs, or control treatments, followed 24 h later. Flow cytometry, reverse transcriptase PCR, and quantitative real-time PCR analysis of CD11c(+) DCs from mice treated with CD40 siILs demonstrated reduced expression of CD40, in comparison with control groups. CD11c(-) cells were also analyzed by flow cytometry, but no differences were observed between treatment groups. Furthermore, CD40 siIL-treated mice were found to have an increased proportion of Treg cells (CD4(+)CD25(+) FoxP3(+)), and DCs cells from these mice were able to inhibit T cell proliferation in an antigen-specific recall response. In summary, CD40 siILs were shown to specifically target and deliver CD40 siRNA to DCs, significantly reducing CD40 expression and resulting in DC-mediated immune modulation as well as generation of Treg cells. These findings highlight the therapeutic potential for siRNA-based and DC-mediated immunotherapy in the clinic. To the best of our knowledge, this is the first study to use siILs for targeted delivery of siRNA to DCs and for immune modulation. PMID:20217551

Zheng, Xiufen; Vladau, Costin; Shunner, Aminah; Min, Wei-Ping

2010-01-01

126

Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyl transferase 1 (DNMT1) depletion  

PubMed Central

DNA Methyltransferase 1 (DNMT1) promotes DNA methylation to maintain cancer drug resistance. The epigenetic drug, decitabine (DAC) is a potent hypomethylating agent, but its effect is transient because of its instability. We tested the efficacy of DAC-loaded nanogels in doxorubicin-resistant breast cancer cells, DAC-resistant melanoma cells, and leukemia cells. DAC in nanogel sustained DNMT1 depletion, prolonged cell arrest in the G2/M cell-cycle phase, and significantly enhanced antiproliferative effect of DAC. The efficacy of DAC-loaded nanogels was more significant in resistant than sensitive cells. Our data suggest that effective delivery of DAC and prolonged DNMT1 depletion are critical to overcoming drug resistance. PMID:23305699

Vijayaraghavalu, Sivakumar; Labhasetwar, Vinod

2013-01-01

127

Buparvaquone loaded solid lipid nanoparticles for targeted delivery in theleriosis  

PubMed Central

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 circulation and biodistrbution study confirmed high RES uptake (75%) in RES organs like liver lung spleen etc. Conclusion: The high RES uptake suggests BPQ SLN as a promising approach for targeted and improved delivery in theileriosis. PMID:24459400

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

2014-01-01

128

Oligoperoxide Based Physically Detectable Nanocomposites for Cell Targeting, Visualization and Treatment  

NASA Astrophysics Data System (ADS)

Novel promising routes for the obtaining luminescent, magnetic, plasmon resonance capable nanocomposites as well as drug delivery systems are proposed and studied. These routes are based on the synthesis and application of original type of functional oligoperoxides, their coordinating complexes of transition including rare earth metal cations for controlled synthesis of block, comb-like or nanogel oligoelectrolytes as well as for template synthesis of functional polymer and polymer-mineral nanoparticles. Developed nanoscale delivery systems were tested as medicines for cancer administration in vitro and in vivo. Physically detectable lectin-conjugated nanocomposites were studied as biomarkers for pathological cell targeting and visualization.

Zaichenko, A.; Mitina, N.; Shevchuk, O.; Shapoval, O.; Boiko, N.; Bilyy, R.; Stoika, R.; Voloshinovskii, A.; Horak, D.

2010-10-01

129

Dexamethasone eye drops containing ?-cyclodextrin-based nanogels.  

PubMed

Sustained release aqueous eye drops of dexamethasone, based on cyclodextrin (CD) nanogels, were designed and tested in vivo. ?CD units were cross-linked in the form of nanogels by means of an emulsification/solvent evaporation process. The composition of the nanogels was optimized with regard to drug loading and release rate. The eye drops consisted of an aqueous solution of dexamethasone in 2-hydroxypropyl-?-cyclodextrin (HP?CD) medium containing ?CD nanogels. The nanogel eye drops (containing 25 mg dexamethasone per ml) were tested in rabbits and compared to the commercially available product Maxidex(®) (suspension with 1 mg dexamethasone per ml). One drop administration of the nanogel eye drops resulted in nearly constant dexamethasone concentration for at least 6h in the tear fluid (mean concentration±SD=295±59 ?g/ml) whereas the concentration after administration of Maxidex(®) fell rapidly from 9.72±3.45 ?g/ml 1 h after application to 3.76±3.26 ?g/ml 3 h after application. The maximum dexamethasone concentration in the aqueous humor (2 h after application) was 136±24 mg/ml after application of the nanogel eye drops, and only 44.4±7.8 ?g/ml after application of Maxidex(®). The dexamethasone nanogel eye drops were well tolerated with no macroscopic signs of irritation, redness or other toxic effects. PMID:23149258

Moya-Ortega, Maria D; Alves, Tiago F G; Alvarez-Lorenzo, Carmen; Concheiro, Angel; Stefánsson, Einar; Thorsteinsdóttir, Margrét; Loftsson, Thorsteinn

2013-01-30

130

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

PubMed

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 ?-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 permeability of CP-GFX was reduced across the conjunctiva. However, the cornea and SCRPE permeability of CP-GFX was not affected by nicotinic acid. APM-GFX did not show any improvement in permeability when compared to GFX across the cornea, conjunctiva, and SCRPE. Based on solubility and permeability, DMAP-GFX was selected for in vivo studies. DMAP-GFX showed 3.6- and 1.95-fold higher levels in vitreous humor and CRPE compared to that of GFX at 1 h after topical dosing. In vivo conversion of DMAP-GFX prodrug to GFX was quantified in tissues isolated at 1 h after dosing. The parent drug-to-prodrug ratio was 8, 70, 24, 21, 29, 13, 55, and 60% in the cornea, conjunctiva, iris-ciliary body, aqueous humor, sclera, CRPE, retina, and vitreous humor, respectively. In conclusion, DMAP-GFX prodrug enhanced solubility, log D, as well as OCT mediated delivery of gatifloxacin to the back of the eye. PMID:23003105

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

2012-11-01

131

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

PubMed Central

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

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

2013-01-01

132

Mucoadhesive platforms for targeted delivery to the colon.  

PubMed

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

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

2011-11-25

133

HSA nanocapsules functionalized with monoclonal antibodies for targeted drug delivery.  

PubMed

The chronic autoimmune disorder rheumatoid arthritis (RA) affects millions of adults and children every year. Chronically activated macrophages secreting enzymes and inflammatory cytokines play a key role in RA. Distinctive marker molecules on the macrophage surface could be used to design a targeted drug delivery device for the treatment of RA without affecting healthy cells and tissues. Here, different methods for covalent attachment of antibodies (mAb) recognizing MHC class II molecules found on macrophages onto human serum albumin (HSA) nanocapsules were compared. HSA nanocapsules were prepared with a hydrodynamic diameter of 500.7 ± 9.4 nm and a narrow size distribution as indicated by a polydispersity index (PDI) of 0.255 ± 0.024. This was achieved by using a sonochemical process avoiding toxic cross linking agents and emulsifiers. Covalent binding of mAb on the surface of HSA nanocapsules was realized using polyethyleneglycol (PEG)3000 as spacer molecule. The presence of mAb was confirmed by confocal laser scanning microscopy (CLSM) and enzyme-linked immunosorbent assay (ELISA). Specific binding of mAb-HSA nanocapsules to MHC class II molecules on antigen-presenting cells was demonstrated by flow cytometry analysis. PMID:24157344

Rollett, Alexandra; Reiter, Tamara; Ohradanova-Repic, Anna; Machacek, Christian; Cavaco-Paulo, Artur; Stockinger, Hannes; Guebitz, Georg M

2013-12-15

134

Synthesis and swelling behavior of temperature responsive ?-carrageenan nanogels.  

PubMed

Crosslinked ?-carrageenan hydrogel nanoparticles (nanogels) with an average size smaller than 100 nm were prepared using reverse microemulsions combined with thermally induced gelation. The size of the nanogels varied with biopolymer concentration at a constant water/surfactant concentration ratio. The nanogels were found to be thermo-sensitive in a temperature range acceptable for living cells (37-45°C) undergoing reversible volume transitions in response to thermal stimuli. This opens the possibility to explore the application of these nanogels in smart therapeutics such as thermo-sensitive drug carriers. As such, the sustained release of methylene blue from the nanogels was evaluated in in vitro conditions as proof of concept experiments and the release rate was found to be controlled with temperature. PMID:21251667

Daniel-da-Silva, Ana L; Ferreira, Luciana; Gil, Ana M; Trindade, Tito

2011-03-15

135

Engineering targeted proteins for intracellular delivery of biotherapeutics  

E-print Network

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

Pirie, Christopher M

2011-01-01

136

Exploring targeted pulmonary delivery for treatment of lung cancer  

PubMed Central

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

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

2013-01-01

137

Hierarchical targeted hepatocyte mitochondrial multifunctional chitosan nanoparticles for anticancer drug delivery.  

PubMed

The overwhelming majority of drugs exert their pharmacological effects after reaching their target sites of action, however, these target sites are mainly located in the cytosol or intracellular organelles. Consequently, delivering drugs to the specific organelle is the key to achieve maximum therapeutic effects and minimum side-effects. In the work reported here, we designed, synthesized, and evaluated a novel mitochondrial-targeted multifunctional nanoparticles (MNPs) based on chitosan derivatives according to the physiological environment of the tumor and the requirement of mitochondrial targeting drug delivery. The intelligent chitosan nanoparticles possess various functions such as stealth, hepatocyte targeting, multistage pH-response, lysosomal escape and mitochondrial targeting, which lead to targeted drug release after the progressively shedding of functional groups, thus realize the efficient intracellular delivery and mitochondrial localization, inhibit the growth of tumor, elevate the antitumor efficacy, and reduce the toxicity of anticancer drugs. It provides a safe and efficient nanocarrier platform for mitochondria targeting anticancer drug delivery. PMID:25818430

Chen, Zhipeng; Zhang, Liujie; Song, Yang; He, Jiayu; Wu, Li; Zhao, Can; Xiao, Yanyu; Li, Wei; Cai, Baochang; Cheng, Haibo; Li, Weidong

2015-06-01

138

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

PubMed Central

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

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

2012-01-01

139

MRI-Visible Micellar Nanomedicine for Targeted Drug Delivery to Lung Cancer Cells  

E-print Network

MRI-Visible Micellar Nanomedicine for Targeted Drug Delivery to Lung Cancer Cells Jagadeesh Setti micelle (MFM) system that is encoded with a lung cancer-targeting peptide (LCP), and encapsulated. The LCP-encoded MFM showed significantly increased Rv 6-dependent cell targeting in H2009 lung cancer

Gao, Jinming

140

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

Microsoft Academic Search

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

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

2002-01-01

141

Cell-mediated Delivery and Targeted Erosion of Noncovalently Crosslinked Hydrogels  

NASA Technical Reports Server (NTRS)

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

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

2013-01-01

142

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

E-print Network

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

Dhar, Shanta

143

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

E-print Network

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

Mortensen, Luke J.

144

A Nonpolycationic Fully Proteinaceous Multiagent System for Potent Targeted Delivery of siRNA  

E-print Network

Protein-based methods of targeted short-interfering RNA (siRNA) delivery have the potential to solve some of the problems faced by nanoparticle-based methods, such as poor pharmacokinetics and biodistribution, low tumor ...

Liu, David V.

145

Pharmaceutical Nanotechnology Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme  

Microsoft Academic Search

The low density lipoprotein (LDL) receptor has been shown to be upregulated in GBM tumor cells and is therefore a potential molecular target for the delivery of therapeutic agents. A synthetic nano-LDL (nLDL) particle was developed and tested to determine its utility as a drug delivery vehicle targeted to GBM tumors. nLDL particles were constructed by combining a synthetic peptide

Mina Nikanjam; Eleanor A. Blakely; Kathleen A. Bjornstad; Xiao Shu; Thomas F. Budinger; Trudy M. Forte

146

Polyaspartic acid functionalized gold nanoparticles for tumor targeted doxorubicin delivery.  

PubMed

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

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

2014-01-01

147

The role of HER2 in cancer therapy and targeted drug delivery  

PubMed Central

HER2 is highly expressed in a significant proportion of breast cancer, ovarian cancer, and gastric cancer. Since the discovery of its role in tumorigenesis, HER2 has received great attention in cancer research during the past two decades. Successful development of the humanized monoclonal anti-HER2 antibody (Trastuzumab) for the treatment of breast cancer further spurred scientists to develop various HER2 specific antibodies, dimerization inhibitors and kinase inhibitors for cancer therapy. On the other hand, the high expression of HER2 and the accessibility of its extracellular domain make HER2 an ideal target for the targeted delivery of anti-tumor drugs as well as imaging agents. Although there is no natural ligand for HER2, various artificial ligands targeting HER2 have been developed and applied in various targeted drug delivery systems. The emphasis of this review is to elucidate the roles of HER2 in cancer therapy and targeted drug delivery. The structure and signal pathway of HER2 will be briefly described. The role of HER2 in tumorigenesis and its relationship with other tumor markers will be discussed. For the HER2 targeted cancer therapy, numerous strategies including the blockage of receptor dimerization, inhibition of the tyrosine kinase activity, and interruption of the downstream signal pathway will be summarized. For the targeted drug delivery to HER2 positive tumor cells, various targeting ligands and their delivery systems will be described in details. PMID:20385184

Tai, Wanyi; Mahato, Rubi; Cheng, Kun

2010-01-01

148

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

PubMed

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

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

2014-10-22

149

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

PubMed Central

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

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

2014-01-01

150

Bacterially-derived nanocells for tumor-targeted delivery of chemotherapeutics and cell cycle inhibitors.  

PubMed

Chemotherapeutic drug therapy in cancer is seriously hampered by severe toxicity primarily due to indiscriminate drug distribution and consequent collateral damage to normal cells. Molecularly targeted drugs such as cell cycle inhibitors are being developed to achieve a higher degree of tumor cell specificity and reduce toxic side effects. Unfortunately, relative to the cytotoxics, many of the molecularly targeted drugs are less potent and the target protein is expressed only at certain stages of the cell cycle thus necessitating regimens like continuous infusion therapy to arrest a significant number of tumor cells in a heterogeneous tumor mass. Here we discuss targeted drug delivery nanovectors and a recently reported bacterially-derived 400 nm sized minicell that can be packaged with therapeutically significant concentrations of chemotherapeutic drugs, targeted to tumor cell surface receptors and effect intracellular drug delivery with highly significant anti-tumor effects in vivo. We also report that molecularly targeted drugs can also be packaged in minicells and targeted to tumor cells with highly significant tumor growth-inhibition and regression in mouse xenografts despite administration of minute amounts of drug. This targeted intracellular drug delivery may overcome many of the hurdles associated with the delivery of cytotoxic and molecularly targeted drugs. PMID:17786046

MacDiarmid, Jennifer A; Madrid-Weiss, Jocelyn; Amaro-Mugridge, Nancy B; Phillips, Leo; Brahmbhatt, Himanshu

2007-09-01

151

Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability  

PubMed Central

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

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

2013-01-01

152

Chitosan/cashew gum nanogels for essential oil encapsulation.  

PubMed

Nanogels based on chitosan and cashew gum were prepared and loaded with Lippia sidoides oil. Several parameters such as cashew gum concentration and relative oil content in the matrix had their influence on nanogel properties investigated. Nanogels were characterized regarding their morphologies, particle size distributions, zeta potential, Fourier transform infrared spectroscopy and essential oil contents. The release profile was investigated by UV/vis spectroscopy and its efficacy was determined through bioassays. Results showed that samples designed using relative ratios matrix:oil 10:2, gum:chitosan 1:1 and 5% gum concentration showed high loading (11.8%) and encapsulation efficiency (70%). Nanogels were found to exhibit average sizes in the range 335-558 nm. In vitro release profiles showed that nanoparticles presented slower and sustained release. Bioassays showed that larval mortality was related mainly to oil loading, with samples presenting more effective larvicide efficacies than the pure L. sidoides oil. PMID:24750942

Abreu, Flávia O M S; Oliveira, Erick F; Paula, Haroldo C B; de Paula, Regina C M

2012-08-01

153

DNA separation by cholesterol-bearing pullulan nanogels.  

PubMed

We present an application of a novel DNA separation matrix, cholesterol-bearing pullulan (CHP) nanogels, for microchip electrophoresis. The solution of the CHP showed a unique phase transition around 30 mg?ml and formed gel phase over this critical concentration. This gel phase consists of the weak hydrophobic interactions between the cholesterols could be easily deformed by external forces, and thus, loading process of the CHP nanogels into microchannels became easier. The high concentration of the CHP nanogels provided excellent resolutions especially for small DNA fragments from 100 to 1500 bp. The separation mechanism was discussed based on Ogston and Reptation models which had developed in gels or polymer solutions. The result of a single molecule imaging gave us an insight of the separation mechanism and the nanogel structures as well. PMID:21045931

Kondo, Keisuke; Kaji, Noritada; Toita, Sayaka; Okamoto, Yukihiro; Tokeshi, Manabu; Akiyoshi, Kazunari; Baba, Yoshinobu

2010-01-01

154

Advances in nanotechnology-based delivery systems for curcumin.  

PubMed

Curcumin (CUR), a bioactive component of turmeric, which is a commonly used spice and nutritional supplement, is isolated from the rhizomes of Curcuma longa Linn. (Zingiberaceae). In recent years, the potential pharmacological actions of CUR in inflammatory disorders, cardiovascular disease, cancer, Alzheimer's disease and neurological disorders have been shown. However, the clinical application of CUR is severely limited by its main drawbacks such as instability, low solubility, poor bioavailability and rapid metabolism. Multifarious nanotechnology-based delivery approaches have been used to enhance the oral bioavailability, biological activity or tissue-targeting ability of CUR. This article reviews potential novel drug delivery systems for CUR including liposomes, polymeric nanoparticles, solid lipid nanoparticles, micelles, nanogels, nanosuspensions, nanoemulsions, complexes and dendrimer/dimer, which provide promising results for CUR to improve its biological activities. PMID:22846093

Sun, Min; Su, Xun; Ding, Buyun; He, Xiuli; Liu, Xiuju; Yu, Aihua; Lou, Hongxiang; Zhai, Guangxi

2012-07-01

155

Organ-targeted high-throughput in vivo biologics screen identifies materials for RNA delivery.  

PubMed

Therapies based on biologics involving delivery of proteins, DNA, and RNA are currently among the most promising approaches. However, although large combinatorial libraries of biologics and delivery vehicles can be readily synthesized, there are currently no means to rapidly characterize them in vivo using animal models. Here, we demonstrate high-throughput in vivo screening of biologics and delivery vehicles by automated delivery into target tissues of small vertebrates with developed organs. Individual zebrafish larvae are automatically oriented and immobilized within hydrogel droplets in an array format using a microfluidic system, and delivery vehicles are automatically microinjected to target organs with high repeatability and precision. We screened a library of lipid-like delivery vehicles for their ability to facilitate the expression of protein-encoding RNAs in the central nervous system. We discovered delivery vehicles that are effective in both larval zebrafish and rats. Our results showed that the in vivo zebrafish model can be significantly more predictive of both false positives and false negatives in mammals than in vitro mammalian cell culture assays. Our screening results also suggest certain structure-activity relationships, which can potentially be applied to design novel delivery vehicles. PMID:25184623

Chang, Tsung-Yao; Shi, Peng; Steinmeyer, Joseph D; Chatnuntawech, Itthi; Tillberg, Paul; Love, Kevin T; Eimon, Peter M; Anderson, Daniel G; Yanik, Mehmet Fatih

2014-10-01

156

Synthesis and characterization of cisplatin-loaded, EGFR-targeted biopolymer and in vitro evaluation for targeted delivery.  

PubMed

The design of smart targeted drug delivery systems that deliver drugs to specific cancer cells will give rise to cancer treatments with better efficacy and lower toxicity levels. We report the development and characterizations of maleimide-functionalized biopolymer (Mal-PGA-Asp) as an effective targeted drug delivery carrier synthesized from an amidation reaction between aspartylated PGA (PGA-Asp) and N-(maleimidohexanoyl)-ethylenediamine (NME). The epidermal growth factor receptor (EGFR) targeting peptide (TP13) was conjugated to Mal-PGA-Asp to obtain the targeting carrier (TP13-Mal-PGA-Asp). Cisplatin was finally loaded by complexation to form a biocompatible and tumor targeted therapeutic drug (TP13-Mal-PGA-Asp3-Pt). The resultant biopolymer with an average size 87 ± 28 nm showed a sustainable release profile with a half-maximal release time (t(1/2)) of approximately 15 h in physiological saline. Fluorescence imaging and flow cytometry analysis revealed that TP13 significantly enhanced the cellular uptake of TP13-Mal-PGA-Asp3-Pt in the human hepatoma cell line SMMC-7721. The IC(50) value demonstrated the superior anticancer activity of TP13-Mal-PGA-Asp3-Pt over PGA-Asp-Pt. Therefore, the newly developed drug carrier (TP13-Mal-PGA-Asp) obtained in this study may provide an efficient and targeted delivery of anticancer drugs, presenting a promising targeted chemotherapy in EGFR-positive cancers. PMID:22678850

Geng, Xu; Ye, Haifeng; Feng, Zhen; Lao, Xun; Zhang, Li; Huang, Jing; Wu, Zi-Rong

2012-10-01

157

Size matters: gold nanoparticles in targeted cancer drug delivery  

PubMed Central

Cancer is the current leading cause of death worldwide, responsible for approximately one quarter of all deaths in the USA and UK. Nanotechnologies provide tremendous opportunities for multimodal, site-specific drug delivery to these disease sites and Au nanoparticles further offer a particularly unique set of physical, chemical and photonic properties with which to do so. This review will highlight some recent advances, by our laboratory and others, in the use of Au nanoparticles for systemic drug delivery to these malignancies and will also provide insights into their rational design, synthesis, physiological properties and clinical/preclinical applications, as well as strategies and challenges toward the clinical implementation of these constructs moving forward. PMID:22834077

Dreaden, Erik C; Austin, Lauren A; Mackey, Megan A; El-Sayed, Mostafa A

2013-01-01

158

Nanomicellar carriers for targeted delivery of anticancer agents  

PubMed Central

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

Zhang, Xiaolan; Huang, Yixian; Li, Song

2014-01-01

159

Magnetic nanoparticle drug delivery systems for targeting tumor  

NASA Astrophysics Data System (ADS)

Tumor hypoxia, or low oxygen concentration, is a result of disordered vasculature that lead to distinctive hypoxic microenvironments not found in normal tissues. Many traditional anti-cancer agents are not able to penetrate into these hypoxic zones, whereas, conventional cancer therapies that work by blocking cell division are not effective to treat tumors within hypoxic zones. Under these circumstances the use of magnetic nanoparticles as a drug delivering agent system under the influence of external magnetic field has received much attention, based on their simplicity, ease of preparation, and ability to tailor their properties for specific biological applications. Hence in this review article we have reviewed current magnetic drug delivery systems, along with their application and clinical status in the field of magnetic drug delivery.

Mody, Vicky V.; Cox, Arthur; Shah, Samit; Singh, Ajay; Bevins, Wesley; Parihar, Harish

2014-04-01

160

Lipoprotein Nanoplatform for Targeted Delivery of Diagnostic and Therapeutic Agents  

Microsoft Academic Search

Low-density lipoprotein (LDL) provides a highly versatile natural nanoplatform for delivery of optical and MRI contrast agents,\\u000a photodynamic therapy agents and chemotherapeutic agents to normal and neoplastic cells that over express LDL receptors (LDLR).\\u000a Extension to other lipoproteins ranging in diameter from ~5-10 nm (high density lipoprotein, HDL) to over a micron (chilomicrons)\\u000a is feasible. Loading of contrast or therapeutic

Jerry D. Glickson; Sissel Lund-Katz; Rong Zhou; Hoon Choi; I-Wei Chen; Hui Li; Ian Corbin; Anatoliy V. Popov; Weiguo Cao; Liping Song; Chenze Qi; Diane Marotta; David S. Nelson; Juan Chen; Britton Chance; Gang Zheng

161

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

PubMed Central

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

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

2012-01-01

162

Magnetic Targeted Delivery of Dexamethasone Acetate across the Round Window Membrane in Guinea Pigs  

PubMed Central

Hypothesis Magnetically susceptible PLGA nanoparticles will effectively target the round window membrane (RWM) for delivery of dexamethasone-acetate (Dex-Ac) to the scala tympani. Background Targeted delivery of therapeutics to specific tissues can be accomplished using different targeting mechanisms. One technology includes iron oxide nanoparticles, susceptible to external magnetic fields. If a nanocomposite composed of biocompatible polymer (PLGA), magnetite, and Dex-Ac can be pulled into and across the mammalian RWM, drug delivery can be enhanced. Method In vitro targeting and release kinetics of PLGA-magnetite-Dex-Ac nanoparticles first were measured using a RWM model. Next, these optimized nanocomposites were targeted to the RWM by filling the niche in anesthetized guinea pigs. A permanent magnet was placed opposite the RWM for 1 hour. Cochlear soft tissues, perilymph, and RWM were harvested after euthanasia and steroid levels were measured using HPLC. Results Membrane transport, in vitro, proved optimal targeting using a lower particle magnetite concentration (1 versus 5 or 10 mg/ml). In vivo targeted PLGA-magnetite-Dex-Ac particles had an average size of 482.8 ± 158 nm (DLS) and an average zeta potential ?19.9 ± 3.3 mV. In 1 hour, there was significantly increased cochlear targeted delivery of Dex or Dex-Ac, compared with diffusion alone. Conclusion Superparamagnetic PLGA-magnetite-Dex-Ac nanoparticles under an external magnetic field (0.26 mT) for 1 hour significantly increased Dex-Ac delivery to the inner ear. The RWM was not completely permeated and also became loaded with nanocomposites, indicating that delivery to the cochlea would continue for weeks by PLGA degradation and passive diffusion. PMID:23187928

Du, Xiaoping; Chen, Kejian; Kuriyavar, Satish; Kopke, Richard D.; Grady, Brian P.; Bourne, David H.; Li, Wei; Dormer, Kenneth J.

2012-01-01

163

Protein engineering for targeted delivery of radionuclides to tumors  

E-print Network

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

Orcutt, Kelly Davis

2010-01-01

164

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

SciTech Connect

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.

Fagaly, R.L.; Alexander, N.B.; Bourque, R.F.; Dahms, C.F.; Lindgren, J.R.; Miller, W.J. (General Atomics, San Diego, CA (United States)); Bittner, D.N.; Hendricks, C.D. (W.J. Schafer Associates, Livermore, CA (United States))

1993-05-01

165

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

SciTech Connect

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.

Fagaly, R.L.; Alexander, N.B.; Bourque, R.F.; Dahms, C.F.; Lindgren, J.R.; Miller, W.J. [General Atomics, San Diego, CA (United States); Bittner, D.N.; Hendricks, C.D. [W.J. Schafer Associates, Livermore, CA (US)

1993-05-01

166

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

PubMed Central

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

Philip, Anil K.; Philip, Betty

2010-01-01

167

Delivery of siRNA into breast cancer cells via phage fusion protein-targeted liposomes  

Microsoft Academic Search

Efficacy of siRNAs as potential anticancer therapeutics can be increased by their targeted delivery into cancer cells via tumor-specific ligands. Phage display offers a unique approach to identify highly specific and selective ligands that can deliver nanocarriers to the site of disease. In this study, we proved a novel approach for intracellular delivery of siRNAs into breast cancer cells through

Deepa Bedi; Tiziana Musacchio; Olusegun A. Fagbohun; James W. Gillespie; Patricia Deinnocentes; R. Curtis Bird; Lonnie Bookbinder; Vladimir P. Torchilin; Valery A. Petrenko

2011-01-01

168

In vivo drug release behavior in dogs from a new colon-targeted delivery system  

Microsoft Academic Search

The colon-targeted delivery capsule (CTDC), a new capsule-type dosage form for colonic delivery of drugs, was investigated for the in vivo drug release behavior in dogs. A CTDC formulation with prednisolone as a model drug and theophylline as a marker substance for gastric emptying was prepared for this study. The enteric-coated capsule (ECC) formulation with a similar composition was also

Takashi Ishibashi; Harumi Hatano; Masao Kobayashi; Masakazu Mizobe; Hiroyuki Yoshino

1999-01-01

169

Choline transporter-targeting and co-delivery system for glioma therapy.  

PubMed

Combination of gene therapy and chemotherapy is a promising approach for glioma therapy. In this study, a co-delivery system of plasmid encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL, Trail) and doxorubicin (DOX) has been simply constructed in two steps. Firstly, DOX was intercalated into Trail to form a stable complex. Secondly, DOX-Trail complex was condensed by Dendrigraft poly-L-lysine (DGL) to form a nanoscaled co-delivery system. Choline transporters are both expressed on blood-brain barrier (BBB) and glioma, Herein, a choline derivate with high choline transporter affinity was chosen as BBB and glioma dual targeting ligand. Choline-derivate modified co-delivery system showed higher cellular uptake efficiency and cytotoxicity than unmodified co-delivery system in U87 MG cells. In comparison with single medication or unmodified delivery system, Choline-derivate modified co-delivery system induced more apoptosis both in vitro and in vivo. The therapeutic efficacy on U87 MG bearing xenografts further confirmed the predominance of this dual targeting and co-delivery system. PMID:23993342

Li, Jianfeng; Guo, Yubo; Kuang, Yuyang; An, Sai; Ma, Haojun; Jiang, Chen

2013-12-01

170

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

PubMed

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

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

2013-11-01

171

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

PubMed Central

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

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

2014-01-01

172

Targeted nonviral delivery vehicles to neural progenitor cells in the mouse subventricular zone  

PubMed Central

Targeted gene therapy can potentially minimize undesirable off-target toxicity due to specific delivery. Neuron-specific gene delivery in the central nervous system is challenging because neurons are non-dividing and also outnumbered by glial cells. One approach is to transfect dividing neural stem and progenitor cells (NSCs and NPCs, respectively). In this work, we demonstrate cell-specific gene delivery to NPCs in the brains of adult mice using a peptide-modified polymeric vector. Tet1, a 12-amino acid peptide which has been shown to bind specifically to neuronal cells, was utilized as a neuronal targeting ligand. The cationic polymer polyethylenimine (PEI) was covalently modified with polyethylene glycol (PEG) for in vivo salt stability and Tet1 for neuron targeting to yield a Tet1-PEG-PEI conjugate. When plasmid DNA encoding the reporter gene luciferase was complexed with Tet1-PEG-PEI and delivered in vivo via an injection into the lateral ventricle, Tet1-PEG-PEI complexes mediated increased luciferase expression levels in brain tissue when compared to unmodified PEI-PEG complexes. In addition, cells transfected by Tet1-PEG-PEI complexes were found to be exclusively adult NPCs whereas untargeted PEG-PEI complexes were found to transfect a heterogenous population of cells. Thus, we have demonstrated targeted, nonviral delivery of nucleic acids to adult NPCs using the Tet1 targeting ligand. These materials could potentially be used to deliver therapeutic genes for the treatment of neurodegenerative diseases. PMID:20004466

Kwon, Ester J.; Lasiene, Jurate; Jacobson, Berit; Park, In-Kyu; Horner, Philip J.; Pun, Suzie H.

2009-01-01

173

Impacts of Blood-Brain Barrier in Drug Delivery and Targeting of Brain Tumors  

PubMed Central

Introduction Entry of blood circulating agents into the brain is highly selectively con-trolled by specific transport machineries at the blood brain barrier (BBB), whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. Methods Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. Results Brain capillary endothelial cells (BCECs) form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics). Conclusion The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent. PMID:23678437

Omidi, Yadollah; Barar, Jaleh

2012-01-01

174

Synthesis and Evaluation of Fluorescent Magnetic Composites as Targeted Drug Delivery Carriers  

NASA Astrophysics Data System (ADS)

We have developed Fe3O4@ZnS-based fluorescent magnetic composites as targeted drug delivery carriers via a facile route. The results indicated that the composites exhibited both magnetic and fluorescent properties. Fe3O4@ZnS possessed high saturation magnetization (68.25 emu/g) at room temperature. Ultraviolet light can be easily obtained by exposing the microspheres to different excitation wavelengths. The drug loading studies showed that Fe3O4@ZnS-based fluorescent magnetic composites had an excellent drug loading performance. These traits made the composites better for the application of medical imaging and magnetic targeted drug delivery.

Jiang, Wei; Chen, Xiaolong; Wu, Juan; Xu, Shanshan; Tian, Renbing

2015-01-01

175

Synthesis and Evaluation of Fluorescent Magnetic Composites as Targeted Drug Delivery Carriers  

NASA Astrophysics Data System (ADS)

We have developed Fe3O4@ZnS-based fluorescent magnetic composites as targeted drug delivery carriers via a facile route. The results indicated that the composites exhibited both magnetic and fluorescent properties. Fe3O4@ZnS possessed high saturation magnetization (68.25 emu/g) at room temperature. Ultraviolet light can be easily obtained by exposing the microspheres to different excitation wavelengths. The drug loading studies showed that Fe3O4@ZnS-based fluorescent magnetic composites had an excellent drug loading performance. These traits made the composites better for the application of medical imaging and magnetic targeted drug delivery.

Jiang, Wei; Chen, Xiaolong; Wu, Juan; Xu, Shanshan; Tian, Renbing

2015-03-01

176

Polymersomes functionalized via ``click'' chemistry with the fibronectin mimetic peptides PR_b and GRGDSP for targeted delivery to cells with  

E-print Network

specific drug delivery agents, thus highlighting them as a promising model targeted drug delivery system functionalized polymersomes to achieve targeted delivery to colon cancer cells was assessed by studying a drug indiscriminately, targeting strategies promote delivery only to the pathological site

Kokkoli, Efie

177

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

PubMed Central

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

2011-01-01

178

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

PubMed Central

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

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

179

Method for Targeted Therapeutic Delivery of Proteins into Cells  

Cancer.gov

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

180

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

PubMed Central

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

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

2011-01-01

181

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

PubMed Central

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

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

2013-01-01

182

Functionalized triazolopeptoids - a novel class for mitochondrial targeted delivery.  

PubMed

Here we introduce linear 1,4-triazolopeptoids as a novel class of cell penetrating peptidomimetics suitable as organ targeting molecular transporters of bioactive cargo. Repetitive triazole moieties with up to three residues were assembled on solid supports using copper-catalyzed alkyne-azide cycloadditions (CuAAC) in a submonomer approach. Depending on the lipophilicity of their side chain appendages the 1,4-triazolopeptoids showed either endosomal localization or a strong colocalization with the mitochondria of HeLa cells with moderate toxicity. While the basic triazolopeptoids mainly target the neuromast cells in zebrafish embryos, the lipophilic ones colocalize with either cartilage in the jaws and the blood vessel system. PMID:25739445

Althuon, Daniela; Rönicke, Franziska; Fürniss, Daniel; Quan, Jasmin; Wellhöfer, Isabelle; Jung, Nicole; Schepers, Ute; Bräse, Stefan

2015-04-14

183

Targeted delivery of multivalent phage display vectors into mammalian cells  

Microsoft Academic Search

Novel peptide motives targeting endocytosing receptors were isolated from phage display libraries of random peptides by recovering internalized phage from mammalian cells. The peptide-presenting phage selected by internalization in HEp-2 and ECV304 human cells were taken up 1000- to 100?000-fold more efficiently than their parent libraries, and from 10 to 100 times faster than phage particles displaying integrin-binding peptides. A

Vasily V. Ivanenkov; Franco Felici; Anil G. Menon

1999-01-01

184

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

PubMed Central

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

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

2013-01-01

185

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

NASA Astrophysics Data System (ADS)

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.

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

2014-08-01

186

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

PubMed

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 ?v?3 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. PMID:23933441

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

2013-11-01

187

Chlorotoxin-conjugated graphene oxide for targeted delivery of an anticancer drug  

PubMed Central

Current chemotherapy for glioma is rarely satisfactory due to low therapeutic efficiency and systemic side effects. We have developed a glioma-targeted drug delivery system based on graphene oxide. Targeted peptide chlorotoxin-conjugated graphene oxide (CTX-GO) sheets were successfully synthesized and characterized. Doxorubicin was loaded onto CTX-GO (CTX-GO/DOX) with high efficiency (570 mg doxorubicin per gram CTX-GO) via noncovalent interactions. Doxorubicin release was pH-dependent and showed sustained-release properties. Cytotoxicity experiments demonstrated that CTX-GO/DOX mediated the highest rate of death of glioma cells compared with free doxorubicin or graphene oxide loaded with doxorubicin only. Further, conjugation with chlorotoxin enhanced accumulation of doxorubicin within glioma cells. These findings indicate that CTX-GO is a promising platform for drug delivery and provide a rationale for developing a glioma-specific drug delivery system. PMID:24672236

Wang, Hao; Gu, Wei; Xiao, Ning; Ye, Ling; Xu, Qunyuan

2014-01-01

188

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

PubMed Central

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

Prakash, Satya; Malgorzata Urbanska, Aleksandra

2008-01-01

189

Gene delivery targeted to the brain using an Angiopep-conjugated polyethyleneglycol-modified polyamidoamine dendrimer  

Microsoft Academic Search

Angiopep targeting to the low-density lipoprotein receptor-related protein-1 (LRP1) was identified to exhibit high transcytosis capacity and parenchymal accumulation. In this study, it was exploited as a ligand for effective brain-targeting gene delivery. Polyamidoamine dendrimers (PAMAM) were modified with angiopep through bifunctional PEG, then complexed with DNA, yielding PAMAM–PEG–Angiopep\\/DNA nanoparticles (NPs). The angiopep-modified NPs were observed to be internalized by

Weilun Ke; Kun Shao; Rongqin Huang; Liang Han; Yang Liu; Jianfeng Li; Yuyang Kuang; Liya Ye; Jinning Lou; Chen Jiang

2009-01-01

190

Chimeric nucleolin aptamer with survivin DNAzyme for cancer cell targeted delivery.  

PubMed

A chimeric aptamer-DNAzyme conjugate was generated for the first time using a nucleolin aptamer (NCL-APT) and survivin Dz (Sur_Dz) and exhibited the targeted killing of cancer cells. This proof of concept of using an aptamer for the delivery of DNAzyme can be applied to other cancer types to target survivin in cancer cells in a specific manner. PMID:25797393

Subramanian, Nithya; Kanwar, Jagat R; Akilandeswari, Balachandran; Kanwar, Rupinder K; Khetan, Vikas; Krishnakumar, Subramanian

2015-04-25

191

Targeted delivery of chlorotoxin-modified DNA-loaded nanoparticles to glioma via intravenous administration  

Microsoft Academic Search

Gene therapy offers great potential for brain glioma. However, therapeutic genes could not reach glioma spontaneously. A glioma-targeting gene delivery system is highly desired to transfer exogenous genes throughout the tumor focus. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the main vector. Chlorotoxin (CTX), which has been demonstrated to bind specifically to receptor expressed in

Rongqin Huang; Weilun Ke; Liang Han; Jianfeng Li; Shuhuan Liu; Chen Jiang

2011-01-01

192

Sodium Dependent Multivitamin Transporter (SMVT): A Potential Target for Drug Delivery  

PubMed Central

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. PMID:22420308

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

2015-01-01

193

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...

194

In vitro studies on guar gum based formulation for the colon targeted delivery of Sennosides  

Microsoft Academic Search

PURPOSE: The objective of the present study is to develop colon targeted drug delivery sys- tems for sennosides using guar gum as a carrier. METHODS: Matrix tablets containing various pro- portions of guar gum were prepared by wet granula- tion technique using starch paste as a binder. The tablets were evaluated for content uniformity and in vitro drug release study

Munira Momin; K. Pundarikakshudu

195

A multi-scale stochastic drug release model for polymer-coated targeted drug delivery systems  

Microsoft Academic Search

A multi-scale mathematical model for drug release of oral targeted drug delivery systems was developed and applied to a commercially available delayed release tablet (Asacol®) that delivers 5-aminosalicyclic acid (5-ASA) to the colon. Underlying physical and biochemical principles governing the involved processes (diffusion and dissolution) were employed to develop the mathematical description. Finite element formulation was used to numerically solve

Nahor Haddish-Berhane; Chell Nyquist; Kamyar Haghighi; Carlos Corvalan; Ali Keshavarzian; Osvaldo Campanella; Jenna Rickus; Ashkan Farhadi

2006-01-01

196

Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo  

Microsoft Academic Search

Low efficiencies of nonviral gene vectors, the receptor-dependent host tropism of adenoviral or low titers of retroviral vectors limit their utility in gene therapy. To overcome these deficiencies, we associated gene vectors with superparamagnetic nanoparticles and targeted gene delivery by application of a magnetic field. This potentiated the efficacy of any vector up to several hundred-fold, allowed reduction of the

F. Scherer; M. Anton; U. Schillinger; J. Henkel; C. Bergemann; A. Kruger; B. Gansbacher; C. Plank

2002-01-01

197

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

NASA Astrophysics Data System (ADS)

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

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

2011-02-01

198

Theranostic Nanoparticles Carrying Doxorubicin Attenuate Targeting Ligand Specific Antibody Responses Following Systemic Delivery  

PubMed Central

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. PMID:25553097

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

199

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

PubMed

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. PMID:25553097

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

200

Stimuli-responsive PEGylated prodrugs for targeted doxorubicin delivery.  

PubMed

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 140nm, 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 20wt.% and 75wt.%, 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. PMID:25746279

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

2015-05-01

201

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

PubMed

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

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

2014-10-13

202

Synthesis of Doxorubicin loaded magnetic chitosan nanoparticles for pH responsive targeted drug delivery.  

PubMed

Targeted drug delivery is a promising alternative to overcome the limitations of classical chemotherapy. In an ideal targeted drug delivery system carrier nanoparticles would be directed to the tumor tissue and selectively release therapeutic molecules. As a novel approach, chitosan coated magnetic nanoparticles (CS MNPs) maintain a pH dependent drug delivery which provides targeting of drugs to the tumor site under a magnetic field. Among various materials, chitosan has a great importance as a pH sensitive, natural, biodegradable, biocompatible and bioadhesive polymer. The aim of this study was to obtain an effective targeted delivery system for Doxorubicin, using chitosan coated MNPs. Different sized CS MNPs were produced by in situ synthesis method. The anti-cancer agent Doxorubicin was loaded onto CS MNPs which were characterized previously. Doxorubicin loading was confirmed by FTIR. Drug loading and release characteristics, and stability of the nanoparticles were investigated. Our results showed that the CS MNPs have pH responsive release characteristics. The cellular internalization of Doxorubicin loaded CS MNPs were visualized by fluorescent microscopy. Doxorubicin loaded CS MNPs are efficiently taken up by MCF-7 (MCF-7/S) and Doxorubicin resistant MCF-7 (MCF-7/1 ?M) breast cancer cells, which increases the efficacy of drug and also maintains overcoming the resistance of Doxorubicin in MCF-7/Dox cells. Consequently, CS MNPs synthesized at various sizes can be effectively used for the pH dependent release of Doxorubicin in cancer cells. Results of this study can provide new insights in the development of pH responsive targeted drug delivery systems to overcome the side effects of conventional chemotherapy. PMID:24931189

Unsoy, Gozde; Khodadust, Rouhollah; Yalcin, Serap; Mutlu, Pelin; Gunduz, Ufuk

2014-10-01

203

Doxorubicin loaded magneto-niosomes for targeted drug delivery.  

PubMed

In chemotherapy the magnetic drug targeting to a specific organ or tissue is proposed on the assumption that magnetic fields are harmless to biological systems. In this light we have vehiculated doxorubicin as model drug by novel magneto-niosomes in order to evaluate the physico-chemical properties of the obtained formulations and the in vitro release profile. Tween 60 and Pluronic L64 have been used as surfactants and the formulation cytotoxicity has been performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolum bromide and trypan blue dye esclusion tests. Results show that niosome dimensions and doxorubicin entrapment efficiencies are influenced by bilayer composition. In addition, formulations are able to control the deliver and release of the drug active form in a retarded manner. No additional toxicity, due to the encapsulation of ferrofluid into niosomes core, has been detected. PMID:23107959

Tavano, Lorena; Vivacqua, Marco; Carito, Valentina; Muzzalupo, Rita; Caroleo, Maria Cristina; Nicoletta, Fiore

2013-02-01

204

Targeted delivery of carbon nanotubes to cancer cells  

NASA Astrophysics Data System (ADS)

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

Chakravarty, Pavitra

205

Characterization of Magnetic Viral Complexes for Targeted Delivery in Oncology  

PubMed Central

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.

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

2015-01-01

206

Cutting-edge technologies in colon-targeted drug delivery systems.  

PubMed

Oral colon-targeted drug delivery systems have gained enormous attention among researchers in the last two decades. The significance of this site-specific drug delivery system can be measured by its usefulness for delivering a variety of therapeutic agents, both for the treatment of local diseases or for systemic therapies. With the arrival of newer innovations, a large number of breakthrough technologies have emerged for targeting a drug molecule to the colon. Researchers have attempted various approaches in the development of these formulation technologies, such as pH-dependent, time-dependent and microflora-activated systems. Recently, a number of approaches have been proposed that utilize a novel concept of di-dependent drug delivery systems, that is, the systems in which the drug release is controlled by two factors: pH and time, and pH and microflora of the colon. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the formulation technologies that have been developed for attaining colon-specific drug delivery. PMID:21933030

Patel, Mayur M

2011-10-01

207

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

PubMed

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

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

2014-12-01

208

PLGA/polymeric liposome for targeted drug and gene co-delivery.  

PubMed

Chemotherapy is one of the most effective approaches to treat cancers in the clinic, but the problems, such as multidrug resistance (MDR), low bioavailability and toxicity, severely constrain the further application of chemotherapy. Our group recently reported that cationic PLGA/folate coated PEGlated polymeric liposome core-shell nanoparticles (PLGA/FPL NPs). It was self-assembled from a hydrophobic PLGA core and a hydrophilic folate coated PEGlated lipid shell for targeting co-delivery of drug and gene. Hydrophobic drugs can be incorporated into the core and the cationic shell of the drug-loaded nanoparticles can be used to bind DNA. The drug-loaded PLGA/FPL NPs/DNA complexes offer advantages to overcome these problems mentioned above, such as co-delivery of drugs and DNA to improving the chemosensitivity of cancer cells at a gene level, and targeting delivery of drug to the cancer tissue that enhance the bioavailability and reduce the toxicity. The experiment showed that nanoparticles have core-shell structure with nanosize, sustained drug release profile and good DNA-binding ability. Importantly, the core-shell nanoparticles achieve the possibility of co-delivering drugs and genes to the same cells with high gene transfection and drug delivery efficiency. Our data suggest that the PLGA/FPL NPs may be a useful drug and gene co-delivery system. PMID:20727587

Wang, Hanjie; Zhao, Peiqi; Su, Wenya; Wang, Sheng; Liao, Zhenyu; Niu, Ruifang; Chang, Jin

2010-11-01

209

Expert Opinion on Drug Delivery: Strategies for the targeted delivery of therapeutics for osteosarcoma  

PubMed Central

Background Conventional therapy for osteosarcoma has reached a plateau of 60-70%, a five-year survival rate that has changed little in two decades, highlighting the need for new approaches. Objective I wished to review the alternate means of delivering effective therapy for osteosarcoma that reach beyond the central venous catheter. Methods Drawing on my own experiences providing care to high-risk osteosarcoma patients and reviewing the last two decades of literature describing sarcoma therapy, I summarize available information about potential osteosarcoma treatments that deliver therapy by a less conventional route. Results/Conclusions Intra-arterial chemotherapy has a limited impact on survival, but may help achieve a better limb salvage. Intrapleural chemotherapy is important for managing malignant effusions. Development of inhalation therapies, treatments that target new bone formation such as bisphosphonates, chemically targeted radiation and antibody-based therapies all have potential to improve osteosarcoma therapy. PMID:19761419

Hughes, DP

2014-01-01

210

Influence of Red Blood Cells on Nanoparticle Targeted Delivery in Microcirculation  

PubMed Central

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

Tan, Jifu; Thomas, Antony; Liu, Yaling

2012-01-01

211

Biodegradable micelles capable of mannose-mediated targeted drug delivery to cancer cells.  

PubMed

A targeted micellar drug delivery system is developed from a biocompatible and biodegradable amphiphilic polyester, poly(Lac-OCA)-b-(poly(Tyr(alkynyl)-OCA)-g-mannose) (PLA-b-(PTA-g-mannose), that is synthesized via controlled ring-opening polymerization of O-carboxyanhydride (OCA) and highly efficient "Click" chemistry. Doxorubicin (DOX), a model lipophilic anticancer drug, can be effectively encapsulated into the micelles, and the mannose moiety allows active targeting of the micelles to cancer cells that specifically express mannose receptors, which thereafter enhances the anticancer efficiency of the drug. Comprised entirely of biodegradable and biocompatible polyesters, this micellar system demonstrates promising potentials for targeted drug delivery and cancer therapy. PMID:25619623

Yin, Lichen; Chen, Yongbing; Zhang, Zhonghai; Yin, Qian; Zheng, Nan; Cheng, Jianjun

2015-03-01

212

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

PubMed

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

Gao, Huile; Pang, Zhiqing; Jiang, Xinguo

2013-10-01

213

Recent advances in lymphatic targeted drug delivery system for tumor metastasis  

PubMed Central

The lymphatic system has an important defensive role in the human body. The metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors; the tumor cells may even transfer to other organs to form other types of tumors. Clinically, lymphatic metastatic tumors develop rapidly. Given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy, the treatment of lymphatic metastatic tumors remains a great challenge. Lymph node metastasis may lead to the further spread of tumors and may be predictive of the endpoint event. Under these circumstances, novel and effective lymphatic targeted drug delivery systems have been explored to improve the specificity of anticancer drugs to tumor cells in lymph nodes. In this review, we summarize the principles of lymphatic targeted drug delivery and discuss recent advances in the development of lymphatic targeted carriers. PMID:25610710

Zhang, Xiao-Yu; Lu, Wei-Yue

2014-01-01

214

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

PubMed Central

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

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

2013-01-01

215

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

PubMed

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. (19)F-NMR can provide unique and powerful tools for mechanistic investigations in chemical biology. This account presents our recent progress, in perspective, on the molecular approaches to the design and development of novel tumor-targeted drug delivery systems for new generation chemotherapy by exploiting the unique nature of fluorine. PMID:23935213

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

2013-08-01

216

MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies, and Immune Modulation  

PubMed Central

Mesenchymal stem cells (MSCs) are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the “first-pass” accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose. PMID:24000286

Kean, Thomas J.; Caplan, Arnold I.; Dennis, James E.

2013-01-01

217

Alveolar targeting of aerosol pentamidine. Toward a rational delivery system  

SciTech Connect

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

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

1990-04-01

218

Targeted delivery of curcumin for treating type 2 diabetes.  

PubMed

Type 2 diabetes is a chronic condition in which cells have reduced insulin signalling, leading to hyperglycemia and long-term complications, including heart, kidney and liver disease. Macrophages activated by dying or stressed cells, induce the transcription factor nuclear factor kappa-B leading to the production of pro-inflammatory cytokines including TNF and IL-6. These inflammatory macrophages in liver and adipose tissue promote insulin resistance, and medications which reduce inflammation and enhance insulin signalling improve glucose control. Curcumin is an anti-oxidant and nuclear factor kappa-B inhibitor derived from turmeric. A number of studies have shown that dietary curcumin reduces inflammation and delays or prevents obesity-induced insulin resistance and associated complications, including atherosclerosis and immune mediate liver disease. Unfortunately dietary curcumin is poorly absorbed by the digestive system and undergoes glucuronidation and excretion rather than being released into the serum and systemically distributed. This confounds understanding of how dietary curcumin exerts its beneficial effects in type 2 diabetes and associated diseases. New improved methods of delivering curcumin are being developed including nanoparticles and lipid/liposome formulations that increase absorption and bioavailability of curcumin. Development and refinement of these technologies will enable cell-directed targeting of curcumin and improved therapeutic outcome. PMID:23495213

Maradana, Muralidhara Rao; Thomas, Ranjeny; O'Sullivan, Brendan J

2013-09-01

219

Nanomaterials for targeted drug delivery to cancer stem cells.  

PubMed

Recent developments in cancer biology have identified the existence of a sub-poplulation of cells - cancer stem cells (CSC) that are resistant to most traditional therapies (e.g. chemotherapy and radiotherapy) and have the ability to repair their damaged DNA. These findings have necessitated a break with traditional oncology management and encouraged new perspectives concerning cancer treatment. Understanding the functional biology of CSCs - especially the signaling pathways that are involved in their self-renewal mechanisms - is crucial for discovering new forms of treatment. In this review, we highlight current and future prospects for potential cancer therapies based on the use of nano-sized materials. Nanomaterials could revolutionize cancer management because of their distinctive features - unique surface chemistry, strong electronic, optic, and magnetic properties - that are found neither in bulk materials nor in single molecules. Based on these distinct properties, we believe that nanomaterials could be excellent candidates for use in CSC research in order to optimize cancer therapeutics. Moreover, we propose these nanomaterials for the inhibition of the self-renewal pathways of CSCs by focusing on the Hedgehog, Notch, and Wnt/?-catenin self-renewal mechanisms. By introducing these methods for the detection, targeting, and destruction of CSCs, an efficient alternative treatment for the incurable disease of cancer could be provided. PMID:24697156

Orza, Anamaria; Casciano, Daniel; Biris, Alexandru

2014-05-01

220

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

NASA Astrophysics Data System (ADS)

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

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

2014-06-01

221

DELIVERY OF siRNA INTO BREAST CANCER CELLS VIA PHAGE FUSION PROTEIN-TARGETED LIPOSOMES  

PubMed Central

Efficacy of siRNAs as potential anticancer therapeutics can be increased by their targeted delivery into cancer cells via tumor-specific ligands. Phage display offers an unique approach to identify highly specific and selective ligands that can deliver nanocarriers to the site of disease. In this study, we proved a novel approach for intracellular delivery of siRNAs into breast cancer cells through their encapsulation into liposomes targeted to the tumor cells with preselected intact phage proteins. The targeted siRNA liposomes were obtained by a fusion of two parental liposomes containing spontaneously inserted siRNA and fusion phage proteins. The presence of pVIII coat protein fused to a MCF-7 cell-targeting peptide DMPGTVLP in the liposomes was confirmed by Western blotting. The novel phage-targeted siRNA-nanopharmaceuticals demonstrate significant down-regulation of PRDM14 gene expression and PRDM14 protein synthesis in the target MCF- 7 cells. This approach offers the potential for development of new anticancer siRNA-based targeted nanomedicines. PMID:21050894

Bedi, Deepa; Musacchio, Tiziana; Fagbohun, Olusegun A.; Gillespie, James W.; Deinnocentes, Patricia; Bird, R. Curtis; Bookbinder, Lonnie; Torchilin, Vladimir P.; Petrenko, Valery A.

2011-01-01

222

Cancer siRNA therapy by tumor selective delivery with ligand-targeted sterically stabilized nanoparticle  

PubMed Central

Potent sequence selective gene inhibition by siRNA ‘targeted’ therapeutics promises the ultimate level of specificity, but siRNA therapeutics is hindered by poor intracellular uptake, limited blood stability and non-specific immune stimulation. To address these problems, ligand-targeted, sterically stabilized nanoparticles have been adapted for siRNA. Self-assembling nanoparticles with siRNA were constructed with polyethyleneimine (PEI) that is PEGylated with an Arg-Gly-Asp (RGD) peptide ligand attached at the distal end of the polyethylene glycol (PEG), as a means to target tumor neovasculature expressing integrins and used to deliver siRNA inhibiting vascular endothelial growth factor receptor-2 (VEGF R2) expression and thereby tumor angiogenesis. Cell delivery and activity of PEGylated PEI was found to be siRNA sequence specific and depend on the presence of peptide ligand and could be competed by free peptide. Intravenous administration into tumor-bearing mice gave selective tumor uptake, siRNA sequence-specific inhibition of protein expression within the tumor and inhibition of both tumor angiogenesis and growth rate. The results suggest achievement of two levels of targeting: tumor tissue selective delivery via the nanoparticle ligand and gene pathway selectivity via the siRNA oligonucleotide. This opens the door for better targeted therapeutics with both tissue and gene selectivity, also to improve targeted therapies with less than ideal therapeutic targets. PMID:15520458

Schiffelers, Raymond M.; Ansari, Aslam; Xu, Jun; Zhou, Qin; Tang, Qingquan; Storm, Gert; Molema, Grietje; Lu, Patrick Y.; Scaria, Puthupparampil V.; Woodle, Martin C.

2004-01-01

223

Targeted drug delivery into reversibly injured myocardium with silica nanoparticles: surface functionalization, natural biodistribution, and acute toxicity  

PubMed Central

The clinical outcome of patients with ischemic heart disease can be significantly improved with the implementation of targeted drug delivery into the ischemic myocardium. In this paper, we present our original findings relevant to the problem of therapeutic heart targeting with use of nanoparticles. Experimental approaches included fabrication of carbon and silica nanoparticles, their characterization and surface modification. The acute hemodynamic effects of nanoparticle formulation as well as nanoparticle biodistribution were studied in male Wistar rats. Carbon and silica nanoparticles are nontoxic materials that can be used as carriers for heart-targeted drug delivery. Concepts of passive and active targeting can be applied to the development of targeted drug delivery to the ischemic myocardial cells. Provided that ischemic heart-targeted drug delivery can be proved to be safe and efficient, the results of this research may contribute to the development of new technologies in the pharmaceutical industry. PMID:20463939

Galagudza, Michael M; Korolev, Dmitry V; Sonin, Dmitry L; Postnov, Viktor N; Papayan, Garry V; Uskov, Ivan S; Belozertseva, Anastasia V; Shlyakhto, Eugene V

2010-01-01

224

Radiofrequency-triggered tumor-targeting delivery system for theranostics application.  

PubMed

In this study, a new type of magnetic tumor-targeting PEGylated gold nanoshell drug delivery system (DOX-TSMLs-AuNSs-PEG) based on doxorubicin-loaded thermosensitive magnetoliposomes was successfully obtained. The reverse-phase evaporation method was used to construct the magnetoliposomes, and then gold nanoshells were coated on the surface of it. The DOX-TSMLs-AuNSs-PEG delivery system was synthesized after SH-PEG2000 modification. This multifunction system was combined with a variety of functions, such as radiofrequency-triggered release, chemo-hyperthermia therapy, and dual-mode magnetic resonance/X-ray imaging. Importantly, the DOX-TSMLs-AuNSs-PEG complex was found to escape from endosomes after cellular uptake by radiofrequency-induced endosome disruption before lysosomal degradation. All results in vitro and in vivo indicated that DOX-TSMLs-AuNSs-PEG is a promising effective drug delivery system for diagnosis and treatment of tumors. PMID:25706857

Wang, Lei; Zhang, Panpan; Shi, Jinjin; Hao, Yongwei; Meng, Dehui; Zhao, Yalin; Yanyan, Yin; Li, Dong; Chang, Junbiao; Zhang, Zhenzhong

2015-03-18

225

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

PubMed Central

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

2012-01-01

226

Feasibility of noninvasive ultrasound delivery for tumor ablation and targeted drug delivery in the brain  

NASA Astrophysics Data System (ADS)

The objective of our research during the past few years has been to develop multichannel ultrasound phased arrays for noninvasive brain interventions. We have been successful in developing methods for correcting the skull induced beam distortions and thus, are able to produce sharp focusing through human skulls. This method is now being tested for thermal ablation of tumors, with results from animal studies demonstrating feasibility. In addition, the ability of ultrasound to open the blood-brain barrier (BBB) locally has been explored in animal models. The results suggest that the transcranial ultrasound exposures can induce BBB opening such that therapeutic agents can be localized in the brain. This tool is especially powerful since the beam can be guided by MR images, thus providing anatomical or functional targeting. This talk will review our current status in this research, which ultimately aims for the clinical use of this methodology.

Hynynen, Kullervo; McDannold, Nathan; Clement, Greg; White, Jason; Treat, Lisa; Yin, Xiangtao; Jolesz, Ferenc; Sheikov, Nickolai; Vykhodtseva, Natalia

2005-04-01

227

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

PubMed

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. PMID:25686010

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

2015-04-01

228

Targeted nanoparticle delivery of doxorubicin into placental tissues to treat ectopic pregnancies.  

PubMed

Abnormal trophoblast growth can cause life-threatening disorders such as ectopic pregnancy, choriocarcinoma, and placenta accreta. EnGeneIC Delivery Vehicles (EDVs) are nanocells that can promote tissue-specific delivery of drugs and may be useful to medically treat such disorders. The objective of this study was to determine whether EDVs loaded with the chemotherapeutic doxorubicin and targeting the epidermal growth factor receptor (EGFR, very highly expressed on the placental surface) can regress placental cells in vitro, ex vivo, and in vivo. In female SCID mice, EGFR-targeted EDVs induced greater inhibition of JEG-3 (choriocarcinoma cells) tumor xenografts, compared with EDVs targeting an irrelevant antigen (nontargeted EDVs) or naked doxorubicin. EGFR-targeted EDVs were more readily taken up by human placental explants ex vivo and induced increased apoptosis (M30 antibody) compared with nontargeted EDVs. In vitro, EGFR-targeted EDVs administered to JEG-3 cells resulted in a dose-dependent inhibition of cell viability, proliferation, and increased apoptosis, a finding confirmed by continuous monitoring by xCELLigence. In conclusion, EGFR-targeted EDVs loaded with doxorubicin significantly inhibited trophoblastic tumor cell growth in vivo and in vitro and induced significant cell death ex vivo, potentially mediated by increasing apoptosis and decreasing proliferation. EDVs may be a novel nanoparticle treatment for ectopic pregnancy and other disorders of trophoblast growth. PMID:23288908

Kaitu'u-Lino, Tu'uhevaha J; Pattison, Scott; Ye, Louie; Tuohey, Laura; Sluka, Pavel; MacDiarmid, Jennifer; Brahmbhatt, Himanshu; Johns, Terrence; Horne, Andrew W; Brown, Jeremy; Tong, Stephen

2013-02-01

229

Gene and doxorubicin co-delivery system for targeting therapy of glioma.  

PubMed

The combination of gene therapy and chemotherapy is a promising treatment strategy for brain gliomas. In this paper, we designed a co-delivery system (DGDPT/pORF-hTRAIL) loading chemotherapeutic drug doxorubicin and gene agent pORF-hTRAIL, and with functions of pH-trigger and cancer targeting. Peptide HAIYPRH (T7), a transferrin receptor-speci?c peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. T7-modi?ed co-delivery system showed higher ef?ciency in cellular uptake and gene expression than unmodi?ed co-delivery system in U87 MG cells, and accumulated in tumor more ef?ciently in vivo. DOX was covalently conjugated to carrier though pH-trigged hydrazone bond. In vitro incubation of the conjugates in buffers led to a fast DOX release at pH 5.0 (intracellular environment) while at pH 7.4 (blood) the conjugates are relatively stable. The combination treatment resulted in a synergistic growth inhibition (combination index, CI < 1) in U87 MG cells. The synergism effect of DGDPT/pORF-hTRAIL was verified in vitro and in vivo. In vivo anti-glioma ef?cacy study confirmed that DGDPT/pORF-hTRAIL displayed anti-glioma activity but was less toxic. PMID:22484049

Liu, Shuhuan; Guo, Yubo; Huang, Rongqin; Li, Jianfeng; Huang, Shixian; Kuang, Yuyang; Han, Liang; Jiang, Chen

2012-06-01

230

Quantification of Mesenchymal Stem Cell (MSC) delivery to a target site using in vivo confocal microscopy.  

PubMed

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-? & IFN-?) 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

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

231

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

PubMed Central

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-? & IFN-?) 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

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

232

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

NASA Astrophysics Data System (ADS)

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-transport permissive and intact BBB, we also assessed the role of magnetic resonance imaging (MRI) guided focused ultrasound (MRgFUS) disruption of the BBB in enhancing permeation of AuNPs across the intact BBB and tumor BBB in vivo. MRgFUS is a novel technique that can transiently increase BBB permeability thereby allowing delivery of therapeutics into the CNS. We demonstrated enhanced delivery of AuNPs with therapeutic potential into the CNS via MRgFUS. Our study was the first to establish a definitive role for MRgFUS in delivering AuNPs into the CNS. In summary, this thesis describes results from a series of research projects that have contributed to our understanding of the influence of design features on AuNP permeation through the BBB and also the potential role of MRgFUS in AuNP permeation across the BBB.

Etame, Arnold B.

233

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

PubMed Central

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

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

2010-01-01

234

Biotin-conjugated block copolymeric nanoparticles as tumor-targeted drug delivery systems  

Microsoft Academic Search

To achieve targeted drug delivery for chemotherapy, a ligand-mediated nanoparticulate drug carrier was designed, which could\\u000a identify a specific receptor on the surfaces of tumor cells. Biodegradable poly(ethylene oxide)\\/poly(?-caprolactone) (PEG\\/PCL)\\u000a amphiphilic block copolymers coupled to biotin ligands were synthesized with a variety of PEG\\/PCL compositions. Block copolymeric\\u000a nanoparticles harboring the anticancer drug paclitaxel were prepared via micelle formation in aqueous

So Yeon Kim; Seung Hea Cho; Young Moo Lee; Liang-Yin Chu

2007-01-01

235

Design and development of hydrogel beads for targeted drug delivery to the colon  

Microsoft Academic Search

The purpose of this research was to develop and evaluate a multiparticulate system of chitosan hydrogel beads exploiting pH-sensitive\\u000a property and specific biodegradability for colon-targeted delivery of satranidazole. Chitosan hydrogel beads were prepared\\u000a by the cross-linking method followed by enteric coating with Eudragit S100. All formulations were evaluated for particle size,\\u000a encapsulation efficiency, swellability, and in vitro drug release. The

Sanjay K. Jain; Anekant Jain; Yashwant Gupta; Manisha Ahirwar

2007-01-01

236

Transferrin receptors and the targeted delivery of therapeutic agents against cancer  

PubMed Central

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

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

237

Formulation design for target delivery of iron nanoparticles to TCE zones  

NASA Astrophysics Data System (ADS)

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.

Wang, Ziheng; Acosta, Edgar

2013-12-01

238

A functional drug delivery platform for targeting and imaging cancer cells based on Pluronic F127.  

PubMed

Functional polymeric micelles play an important role in the efficient delivery of therapeutic drugs into tumours. In this study, a functional drug delivery platform with ligands for targeting and fluorescent imaging was designed based on Pluronic F127 (PF127). Using folic acid (FA) and fluorescein isothiocyanate (FITC) to chemically conjugate with PF127, two functional polymers, Pluronic F127-FA (PF127-FA) and Pluronic F127-FITC (PF127-FITC), were synthesized. Solasodine-loaded micelles were then prepared via the thin-film hydration method. By employing A549 and HeLa cells, the results of in vitro cell assays performed using confocal laser scanning microscopy and flow cytometry suggested that the proposed micelles could provide the desired specific targeting and fluorescent imaging functions. In addition, the results of in vitro cytotoxicity experiments showed that the growth inhibition rates of A549 and HeLa cells treated with solasodine-loaded micelles were remarkably higher than those of cells treated with free solasodine. Solasodine-loaded micelles exhibited a more distinct inhibitory effect against HeLa cells than against A549 cells. Thus, an effective drug delivery system for targeting and imaging cancer cells was developed. PMID:25780935

Zhang, Denghao; Tao, Liang; Zhao, Hongli; Yuan, Huihui; Lan, Minbo

2015-06-01

239

Hyaluronic acid conjugated ?-cyclodextrin-oligoethylenimine star polymer for CD44-targeted gene delivery.  

PubMed

A new CD44-targeted gene delivery system, the star-shaped cationic polymer containing a ?-cyclodextrin (?-CD) core and multiple branched oligoethylenimine (OEI) arms with conjugated oligomer of hyaluronic acid (HA), was synthesized by reductive amination between ?-CD-OEI star polymer and HA, and was characterized for pDNA condensation and nanoparticle formation, followed by evaluation for targeted gene delivery of luciferase reporter gene and wild type p53 gene in CD44-positive and CD44-negative cell lines. The ?-CD-OEI-HA polymer contained 6 arms of OEI (600Da) and a short HA segment. It could fully condense pDNA to form nanoparticles with sizes ranging from 100 to 200nm at N/P ratios of 8 or higher. The conjugation of HA reduced cytotoxicity of ?-CD-OEI-HA/pDNA polyplexes. It was found that CD44 receptor was highly expressed and localized at the membrane of MDA-MB-231 breast cancer cell line, while no CD44 was found at the membrane of MCF-7 epithelial cell line. Compared with PEI (25kDa) and ?-CD-OEI star polymers, ?-CD-OEI-HA demonstrated significant increased gene transfection efficiency in MDA-MB-231 cells, while such effect was absent in MCF-7 cells. The targeted delivery of wild type p53 gene by ?-CD-OEI-HA in MDA-MB-231 cells resulted in an increased cell cycle arrest at sub-G1 phase. PMID:25681725

Yin, Hui; Zhao, Feng; Zhang, Daohai; Li, Jun

2015-04-10

240

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

PubMed Central

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

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

2014-01-01

241

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

PubMed Central

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

Liu, Shuang

2008-01-01

242

‘One-pot’ synthesis of multifunctional GSH-CdTe quantum dots for targeted drug delivery  

NASA Astrophysics Data System (ADS)

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.

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

2014-06-01

243

J Drug Target . Author manuscript Targeted delivery of a proapoptotic peptide to tumors in vivo  

E-print Network

be expected to provide strong therapeutic benefits with the absence of detrimental side effects, as are seen with conventional chemotherapy. Examples of such targeting have been described for the treatment

Boyer, Edmond

244

Enzymatically crosslinked dendritic polyglycerol nanogels for encapsulation of catalytically active proteins.  

PubMed

The enormous potential of nanogel scaffolds for protein encapsulation has been widely recognized. However, constructing stable polymeric nanoscale networks in a facile, mild, and controllable fashion still remains a technical challenge. Here, we present a novel nanogel formation strategy using horseradish peroxidase (HRP) catalyzed crosslinking on phenolic derivatized dendritic polyglycerol (dPG) in the presence of H2O2 in an inverse miniemulsion. This "enzymatic nanogelation" approach was efficient to produce stable 200 nm dPG nanogel particles, and was performed under physiological conditions, thus making it particularly beneficial for encapsulating biological proteins. Purification of the nanogels was easy to handle and practical because there was no need for a post-quenching step. Interestingly, the use of dPG resulted in higher HRP laden nanogels than for linear polyethylene glycol (PEG) analogs, which illustrates the benefits of dendritic backbones in nanogels for protein encapsulation. In addition, the mild immobilization contributed to the enhanced thermal stability and reusability of HRP. The nanogel preparation could be easily optimized to achieve the best HRP activity. Furthermore, a second enzyme, Candida antarctica lipase B (CalB), was successfully encapsulated and optimized for activity in dPG nanogels by the same enzymatic methodology, which shows the perspective applications of such techniques for encapsulation of diverse proteins. PMID:25519490

Wu, Changzhu; Böttcher, Christoph; Haag, Rainer

2015-02-01

245

Epidermal growth factor receptor-targeted immunoliposomes for delivery of celecoxib to cancer cells.  

PubMed

Cyclooxygenase-2 (COX-2) is highly expressed in many different cancers. Therefore, the inhibition of the COX-2 pathway by a selective COX-2 inhibitor, celecoxib (CLX), may be an alternative strategy for cancer prevention and therapy. Liposomal drug delivery systems can be used to increase the therapeutic efficacy of CLX while minimizing its side effects. Previous studies have reported the encapsulation of CLX within the non-targeted long circulating liposomes and functional effect of these formulations against colorectal cancer cell lines. However, the selectivity and internalization of CLX-loaded liposomes can further be improved by grafting targeting ligands on their surface. Cetuximab (anti-epidermal growth factor receptor - EGFR - monoclonal antibody) is a promising targeting ligand since EGFR is highly expressed in a wide range of solid tumors. The aim of this study was to develop EGFR-targeted immunoliposomes for enhancing the delivery of CLX to cancer cells and to evaluate the functional effects of these liposomes in cancer cell lines. EGFR-targeted ILs, having an average size of 120nm, could encapsulate 40% of the CLX, while providing a sustained drug release profile. Cell association studies have also shown that the immunoliposome uptake was higher in EGFR-overexpressing cells compared to the non-targeted liposomes. In addition, the CLX-loaded-anti-EGFR immunoliposomes were significantly more toxic compared to the non-targeted ones in cancer cells with EGFR-overexpression but not in the cells with low EGFR expression, regardless of their COX-2 expression status. Thus, selective targeting of CLX with anti-EGFR immunoliposomes appears to be a promising strategy for therapy of tumors that overexpress EGFR. PMID:25595386

Limasale, Yanuar Dwi Putra; Tezcaner, Ay?en; Özen, Can; Keskin, Dilek; Banerjee, Sreeparna

2015-02-20

246

Matrix-specific anchors: a new concept for targeted delivery and retention of therapeutic cells.  

PubMed

Biomedical strategies for tissue engineering and repair utilize specific cells, scaffolds, and growth factors to reconstruct elements of damaged tissue. The cellular element of these strategies is limited, however, by poor efficiency of delivery and retention of therapeutic cells in target sites. We propose that the presence of a cellular anchor that is able to specifically bind a defined element of target tissue will facilitate efficient binding and retention of therapeutic cells, thereby promoting repair of the target site. To do so, we engineered an artificial collagen-specific anchor (ACSA) that is able to specifically bind collagen I. The ACSA was engineered by creating a construct comprising rationally designed consecutive domains. The binding specificity of the ACSA was achieved by employing variable regions of a monoclonal antibody that recognizes a unique epitope present in human collagen I. Meanwhile, cell membrane localization of the ACSA was provided by the presence of a transmembrane domain. We determined that the ACSA was localized within cell membranes and interacted with its intended target, that is, collagen I. We have demonstrated that, in comparison to the control, the cells expressing the ACSA attached better to collagen I and exhibited improved retention in sites of seeding. We have also demonstrated that the presence of the ACSA did not interfere with cell proliferation, the biosynthesis of endogenous collagen I, or the biological functions of native collagen receptors. Since the presented cell delivery system utilizes a common characteristic of major connective tissues, namely the presence of collagen I, the findings described here could have a broad positive impact for improving the repair processes of tendon, ligament, bone, intervertebral disc, skin, and other collagen I-rich connective tissues. If successful, the ACSA approach to deliver cells will serve as an outline for developing cell delivery methods that target other elements of extracellular matrices, including other collagen types, laminins, and fibronectins. PMID:25435302

Steplewski, Andrzej; Fertala, Jolanta; Beredjiklian, Pedro; Wang, Mark L; Fertala, Andrzej

2015-04-01

247

Folic acid conjugated nanoparticles of mixed lipid monolayer shell and biodegradable polymer core for targeted delivery of Docetaxel  

Microsoft Academic Search

A system of nanoparticles of mixed lipid monolayer shell and biodegradable polymer core was developed for targeted delivery of anticancer drugs with Docetaxel as a model drug, which provide targeting versatility with a quantitative control of the targeting effect by adjusting the lipid component ratio of the mixed lipid monolayer, and combine the advantages and avoid disadvantages of polymeric nanoparticles

Yutao Liu; Kai Li; Jie Pan; Bin Liu; Si-Shen Feng

2010-01-01

248

Water soluble nanoporous nanoparticle for in vivo targeted drug delivery and controlled release in B cells tumor context  

Microsoft Academic Search

Multitasking nanoparticles are gaining great attention for smart drug delivery systems. The exploration of the nano-scale opens new concrete opportunities for revealing new properties and undiscovered cell-particle interactions. Here we present a biodegradable nanoporous silicon nanoparticle that can be successfully employed for in vivo targeted drug delivery and sustained release. The bare nanoporous nanocarriers can be accurately designed and fabricated

F. de Angelis; A. Pujia; C. Falcone; E. Iaccino; C. Palmieri; C. Liberale; F. Mecarini; P. Candeloro; L. Luberto; A. de Laurentiis; G. Das; G. Scala; E. di Fabrizio

2010-01-01

249

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

PubMed Central

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

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

2012-01-01

250

Targeted doxorubicin delivery by chitosan-galactosylated modified polymer microbubbles to hepatocarcinoma cells.  

PubMed

Targeted drug delivery is a main issue in cancer treatment. Taking advantage of recently developed polyvinyl alcohol (PVA)-based microbubbles, which are characterized by chemical versatility of the polymeric surface thereby allowing coating with different ligands, we set up a strategy for the targeted delivery of the anticancer agent doxorubicin to hepatocarcinoma cells. Such microbubbles are exceptionally efficient ultrasound scatterers and thus represent also an option as potential ultrasound contrast agents. Moreover, the oscillation of microbubbles induced by ultrasound could contribute to favor the release of drugs allocated on shell. Specifically, PVA-based microbubbles were reacted with a galactosylated chitosan complex and loaded with doxorubicin to enable the localization and drug delivery to HepG2 hepatocarcinoma cells overexpressing asialoglycoprotein receptors. We demonstrated selectivity and greater bioadhesive properties of the functionalized microbubbles for tumor cells than to normal fibroblasts, which were influenced by the degree of galactosylation. The presence of galactosylated chitosan did not modify the rate of doxorubicin release from microbubbles, whichwas almost complete within 48h. Cellular uptake of doxorubicin loaded on functionalized microbubbles was higher in HepG2 than in normal fibroblasts, which do not over express the asialoglycoprotein receptors. In addition, doxorubicin loaded onto functionalized microbubbles fully retained its cytotoxic activity. Cells were also irradiated with ultrasound, immediately after exposure to microbubbles. An early enhancement of doxorubicin release and cellular drug uptake associated to a concomitant increase in cytotoxicity was observed in HepG2 cells. Overall, results of the study indicate that galactosylated chitosan microbubbles represent promising devices for the targeted delivery of antitumor agents to liver cancer cells. PMID:23759384

Villa, Raffaella; Cerroni, Barbara; Viganò, Lucia; Margheritelli, Silvia; Abolafio, Gabriella; Oddo, Letizia; Paradossi, Gaio; Zaffaroni, Nadia

2013-10-01

251

Gene delivery with active targeting to ovarian cancer cells mediated by folate receptor alpha.  

PubMed

Folate receptor alpha (FRalpha) is overexpressed on ovarian cancer cells and is a promising molecular target for ovarian cancer gene therapy, but there was still no related report. In this study, folate modified cationic liposomes (F-PEG-CLPs) for ovarian cancer gene delivery were developed for the first time. Folate-poly(ethylene glycol)-succinate-cholesterol (F-PEG-suc-Chol) was firstly synthesized and then used to prepare folate-targeted cationic liposomes/plasmid DNA complexes (F-targeted lipoplexes). F-targeted lipoplexes were prepared by post-insertion method, and displayed membrane structure by transmission electron microscopy observation with the diameter of 193 nm-200 nm and the zeta potential of 35 mV-38 mV. DNase degradation experiments showed that plasmid DNA could be effectively shielded by F-targeted lipoplexes in vitro. F-targeted lipoplexes could transfer gene into human ovarian carcinoma cell line SKOV-3, and 0.1% F-PEG-CLPs composed by DOTAP/Chol/mPEG-Chol/F-PEG-suc-Chol (50:45:5:0.1, molar ratio) had the highest transfection efficiency. The transfection activity of F-targeted lipoplexes could be competitively inhibited by free folic acid, demonstrating that folate-FRalpha interaction caused high transfection efficiency of F-targeted lipoplexes. The uptake mechanism of F-targeted lipoplexes was further validated on human oral carcinoma cell line KB and human liver carcinoma cell line HepG2. The concentration-dependent and time-dependent cytotoxicity of targeted material F-PEG-suc-Chol was observed by MTT assay on SKOV-3 cell and its application would not increase the cytotoxicity of F-targeted lipoplexes in SKOV-3 cells. All the data indicated that F-PEG-CLPs would be a promising gene vector targeting for ovarian cancer therapy. PMID:23802413

He, Zhiyao; Yu, Yiyi; Zhang, Ying; Yan, Yongdong; Zheng, Yu; He, Jun; Xie, Yongmei; He, Gu; Wei, Yuquan; Song, Xiangrong

2013-05-01

252

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

E-print Network

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

Chau, Ying

2005-01-01

253

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

PubMed Central

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

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

2014-01-01

254

Colon-targeted quercetin delivery using natural polymer to enhance its bioavailability.  

PubMed

The aim of the present study is to develop a polymer (Guar Gum)-based matrix tablet (using quercetin as a model drug) with sufficient mechanical strength, and promising in vitro mouth-to-colon release profile. By definition, an oral colonic delivery system should retard drug release in the stomach and small intestine, and allow complete release in the colon. By drug delivery to the colon would therefore ensure direct treatment at the disease site, lower dosing, and fewer systemic side effects. Quercetin is antioxidant in nature and used to treat colon cancer, but they have poor absorption in the upper part of the gastrointestinal tract (GIT). As a site for drug delivery, the colon offers a near neutral pH, reduced digestive enzymatic activity, a long transit time, and an increased responsiveness to absorption enhancers. By achieving a colon-targeted drug delivery system, the absorption of quercetin may be increased, which leads to better bioactivity in fewer doses. PMID:21731393

Singhal, Anil; Jain, H; Singhal, Vipin; Elias, Edwin J; Showkat, Ahmad

2011-01-01

255

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

PubMed

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

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

2012-02-01

256

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

PubMed Central

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

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

2014-01-01

257

Bacillus-shape design of polymer based drug delivery systems with janus-faced function for synergistic targeted drug delivery and more effective cancer therapy.  

PubMed

The particle shape of the drug delivery systems had a strong impact on their in vitro and in vivo performance, but there was limited availability of techniques to produce the specific shaped drug carriers. In this article, the novel methotrexate (MTX) decorated MPEG-PLA nanobacillus (MPEG-PLA-MTX NB) was prepared by the self-assembly technique followed by the extrusion through SPG membrane with high N2 pressure for targeted drug delivery, in which Janus-like MTX was not only used as a specific anticancer drug but could also be served as a tumor-targeting ligand. The MPEG-PLA-MTX NBs demonstrated much higher in vitro and in vivo targeting efficiency compared to the MPEG-PLA-MTX nanospheres (MPEG-PLA-MTX NSs) and MPEG-PLA nanospheres (MPEG-PLA NSs). In addition, the MPEG-PLA-MTX NBs also displayed much more excellent in vitro and in vivo antitumor activity than the MPEG-PLA-MTX NSs and free MTX injection. To our knowledge, this work provided the first example of the integration of the shape design (which mediated an early phase tumor accumulation and a late-phase cell internalization) and Janus-faced function (which mediated an early phase active targeting effect and a late-phase anticancer effect) on the basis of nanoscaled drug delivery systems. The highly convergent and cooperative drug delivery strategy opens the door to more drug delivery systems with new shapes and functions for cancer therapy. PMID:25710590

Cui, Fei; Lin, Jinyan; Li, Yang; Li, Yanxiu; Wu, Hongjie; Yu, Fei; Jia, Mengmeng; Yang, Xiangrui; Wu, Shichao; Xie, Liya; Ye, Shefang; Luo, Fanghong; Hou, Zhenqing

2015-04-01

258

Cancer Nanotheranostics: Improving Imaging and Therapy by Targeted Delivery across Biological Barriers  

PubMed Central

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

Kievit, Forrest M.; Zhang, Miqin

2012-01-01

259

Targeted Delivery of RNAi Therapeutics With Endogenous and Exogenous Ligand-Based Mechanisms  

PubMed Central

Lipid nanoparticles (LNPs) have proven to be highly efficient carriers of short-interfering RNAs (siRNAs) to hepatocytes in vivo; however, the precise mechanism by which this efficient delivery occurs has yet to be elucidated. We found that apolipoprotein E (apoE), which plays a major role in the clearance and hepatocellular uptake of physiological lipoproteins, also acts as an endogenous targeting ligand for ionizable LNPs (iLNPs), but not cationic LNPs (cLNPs). The role of apoE was investigated using both in vitro studies employing recombinant apoE and in vivo studies in wild-type and apoE?/? mice. Receptor dependence was explored in vitro and in vivo using low-density lipoprotein receptor (LDLR?/?)–deficient mice. As an alternative to endogenous apoE-based targeting, we developed a targeting approach using an exogenous ligand containing a multivalent N-acetylgalactosamine (GalNAc)-cluster, which binds with high affinity to the asialoglycoprotein receptor (ASGPR) expressed on hepatocytes. Both apoE-based endogenous and GalNAc-based exogenous targeting appear to be highly effective strategies for the delivery of iLNPs to liver. PMID:20461061

Akinc, Akin; Querbes, William; De, Soma; Qin, June; Frank-Kamenetsky, Maria; Jayaprakash, K. Narayanannair; Jayaraman, Muthusamy; Rajeev, Kallanthottathil G; Cantley, William L; Dorkin, J Robert; Butler, James S; Qin, LiuLiang; Racie, Timothy; Sprague, Andrew; Fava, Eugenio; Zeigerer, Anja; Hope, Michael J; Zerial, Marino; Sah, Dinah WY; Fitzgerald, Kevin; Tracy, Mark A; Manoharan, Muthiah; Koteliansky, Victor; Fougerolles, Antonin de; Maier, Martin A

2010-01-01

260

The Targeted Intracellular Delivery of Cytochrome-C Protein to Tumors Using Lipid-Apolipoprotein Nanoparticles  

PubMed Central

Intracellular-acting therapeutic proteins offer a promising clinical alternative to extracellular-acting agents, but are limited in efficacy by their low permeability into the cell cytoplasm. We have developed a nanoparticle (NP) composed of lipid (DOTAP/DOPE) and apolipoprotein (APO A-I) to mediate the targeted delivery of intracellular-acting protein drugs to non-small cell lung tumors. NPs were produced with either GFP, a fluorescent model protein, or cytochrome C (cytC), an inducer of apoptosis in cancer cells. GFP and cytC were separately conjugated with a membrane permeable sequence (MPS) peptide and were admixed with DOPE/DOTAP nanoparticle formulations (NPs) to enable successful protein loading. Protein-loaded NPs were modified with DSPE-PEG-Anisamide to enable specific NP targeting to the tumor site in a xenograft model. The resulting particle was 20–30 nm in size and exhibited a 64–75% loading efficiency. H460 cells treated with the PEGylated MPS-cytC-NPs exhibited massive apoptosis. When MPS-GFP-NPs or MPS-cytC-NPs were intravenously administered in H460 tumor bearing mice, a specific tumor targeting effect with low NP accumulation in the liver was observed. In addition, MPS-cytC-NP treatment provoked a tumor growth retardation effect in H460 xenograft mice. We conclude that our NP enables targeted, efficacious therapeutic protein delivery for the treatment of lung cancer. PMID:22365810

Kim, Sang Kyoon; Foote, Michael B.; Huang, Leaf

2012-01-01

261

Analytical methods for brain targeted delivery system in vivo: perspectives on imaging modalities and microdialysis.  

PubMed

Since the introduction of microdialysis in 1974, the semi-invasive analytical method has grown exponentially. Microdialysis is one of the most potential analysis technologies of pharmacological drug delivery to the brain. In recent decades, analysis of chemicals targeting the brain has led to many improvements. It seems likely that fluorescence imaging was limited to ex vivo and in vitro applications with the exception of several intravital microscopy and photographic imaging approaches. X-ray computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) have been commonly utilized for visualization of distribution and therapeutic effects of drugs. The efficient analytical methods for studies of brain-targeting delivery system is a major challenge in detecting the disposition as well as the variances of the factors that regulate the substances delivery into the brain. In this review, we highlight some of the ongoing trends in imaging modalities and the most recent developments in the field of microdialysis of live animals and present insights into exploiting brain disease for therapeutic and diagnostics purpose. PMID:22088476

Zhang, Xingguo; Liu, Lin; Zhang, Xiangyi; Ma, Kuifen; Rao, Yuefeng; Zhao, Qingwei; Li, Fanzhu

2012-02-01

262

Emulsomes Meet S-layer Proteins: An Emerging Targeted Drug Delivery System.  

PubMed

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

Ucisik, Mehmet H; Sleytr, Uwe B; Schuster, Bernhard

2015-01-01

263

Hepatocellular carcinoma dually-targeted nanoparticles for reduction triggered intracellular delivery of doxorubicin.  

PubMed

Hepatocellular carcinoma (HCC) dual targeted stimuli responsive nanoparticles (NPs) for intracellular delivery of doxorubicin (DOX) were developed based on a reduction cleavable hyaluronic acid-glycyrrhetinic acid conjugate (HA-Cyst-GA). HA-Cyst-GA conjugate readily formed NPs in aqueous milieu and exhibited a high drug loading capacity (33.9%). The NPs redox responsiveness evaluation showed a tendency to lose their structural integrity in response to a reductive stimulus while remaining stable at physiological conditions, and that drug release was dramatically accelerated in presence of an intracellular level of glutathione. Moreover, cellular uptake studies highlighted the affinity of hepatoma cells (HepG2) toward the NPs as compared to breast cancer cells (MDA-MB-231). HA-Cyst-GA DOX-NPs displayed an increased cytotoxic potency over their non-responsive counterparts and free DOX with IC50 of 5.75, 9.33 and 10.23?g/mL, respectively. CLSM observations showed that HA-Cyst-GA DOX-NPs mediated a faster intracellular release and nuclear delivery of DOX as compared to the insensitive control. In vivo imaging study performed on H22 tumor bearing mice revealed a selective accumulation of DiR labeled NPs in the tumor and liver upon systemic administration. The antitumor efficacy was evaluated in HepG2 tumor xenograft model. Overall HA-Cyst-GA NPs appear as a potential HCC targeted intracellular delivery platform for DOX. PMID:25455765

Mezghrani, Omar; Tang, Yue; Ke, Xue; Chen, Yi; Hu, Danrong; Tu, Jiasheng; Zhao, Li; Bourkaib, Nadia

2015-01-30

264

Chitosan-DNA nanoparticles delivered by intrabiliary infusion enhance liver-targeted gene delivery  

PubMed Central

The goal of this study was to examine the efficacy of liver-targeted gene delivery by chitosan-DNA nanoparticles through retrograde intrabiliary infusion (RII). The transfection efficiency of chitosan-DNA nanoparticles, as compared with PEI-DNA nanoparticles or naked DNA, was evaluated in Wistar rats by infusion into the common bile duct, portal vein, or tail vein. Chitosan-DNA nanoparticles administrated through the portal vein or tail vein did not produce detectable luciferase expression. In contrast, rats that received chitosan-DNA nanoparticles showed more than 500 times higher luciferase expression in the liver 3 days after RII; and transgene expression levels decreased gradually over 14 days. Luciferase expression in the kidney, lung, spleen, and heart was negligible compared with that in the liver. RII of chitosan-DNA nanoparticles did not yield significant toxicity and damage to the liver and biliary tree as evidenced by liver function analysis and histopathological examination. Luciferase expression by RII of PEI-DNA nanoparticles was 17-fold lower than that of chitosan-DNA nanoparticles on day 3, but it increased slightly over time. These results suggest that RII is a promising routine to achieve liver-targeted gene delivery by non-viral nanoparticles; and both gene carrier characteristics and mode of administration significantly influence gene delivery efficiency. PMID:17369870

Dai, Hui; Jiang, Xuan; Tan, Geoffrey CY; Chen, Yong; Torbenson, Michael; Leong, Kam W; Mao, Hai-Quan

2006-01-01

265

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

PubMed

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

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

2013-01-01

266

A multifunctional mesoporous silica nanocomposite for targeted delivery, controlled release of doxorubicin and bioimaging.  

PubMed

In this study, a targeting drug delivery system based on mesoporous silica nanoparticle (MSN) was successfully developed for anti-cancer drug delivery and bioimaging. Carboxyl functionalized MSN (MSN/COOH) was firstly prepared and then modified with folate as the cancer targeting moiety and a near infrared fluorescent dye as labeling segment. Folate was conjugated to MSN/COOH via functional polyethyleneglycol (PEG), constructing the vector MSN/COOH-PEG-FA. The functionalization with carboxyl caused the pore surface of the nanocarrier more negative than native MSN, which could provide attractive forces between the nanoparticles and positively charged doxorubicin hydrochloride (DOX). Meanwhile, the folate modification significantly enhanced the cellular uptake of the delivery system compared to unmodified counterparts. Furthermore, the introduction of PEG increased the water dispersibility. Besides, the modification with the near infrared fluorescent dye Cy5 made the system effective for live cell and in vivo imaging. Therefore, the Cy5-MSN/COOH-PEG-FA system could be a promising nanocarrier for simultaneous diagnosis and treatment of diseases. PMID:23711784

Xie, Meng; Shi, Hui; Li, Zhen; Shen, Haijun; Ma, Kun; Li, Bo; Shen, Song; Jin, Yi

2013-10-01

267

Mechanistic study of IR-780 dye as a potential tumor targeting and drug delivery agent.  

PubMed

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. PMID:24148240

Zhang, Erlong; Luo, Shenglin; Tan, Xu; Shi, Chunmeng

2014-01-01

268

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

PubMed Central

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

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

2014-01-01

269

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

NASA Astrophysics Data System (ADS)

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.

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

2012-12-01

270

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

NASA Astrophysics Data System (ADS)

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

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

2014-02-01

271

Synthesis and Characterization of Polymer Nanocarriers for the Targeted Delivery of Therapeutic Enzymes  

PubMed Central

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

Simone, Eric; Dziubla, Thomas; Shuvaev, Vladimir; Muzykantov, Vladimir R.

2011-01-01

272

Formulation/Preparation of Functionalized Nanoparticles for In Vivo Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

Targeted cancer therapy allows the delivery of therapeutic agents to cancer cells without incurring undesirable side effects on the neighboring healthy tissues. Over the past decade, there has been an increasing interest in the development of advanced cancer therapeutics using targeted nanoparticles. Here we describe the preparation of drug-encapsulated nanoparticles formulated with biocompatible and biodegradable poly( d, l-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2-fluoropyrimidine ribonucleic acid aptamers that recognize the extracellular domain of prostate-specific membrane antigen (PSMA), a well-characterized antigen expressed on the surface of prostate cancer cells. We show that the self-assembled nanoparticles can selectively bind to PSMA-targeted prostate cancer cells in vitro and in vivo. This formulation method may contribute to the development of highly selective and effective cancer therapeutic and diagnostic devices.

Gu, Frank; Langer, Robert; Farokhzad, Omid C.

273

Investigation of strategies for drug delivery by combination targeting of nanocarriers to multiple epitopes or receptors  

NASA Astrophysics Data System (ADS)

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 the same receptor (transferrin receptor epitopes 8D3 and R17). Binding to cells, endocytosis within cells, and biodistribution in mice were tested. Results indicate that combination targeting enhanced performance of nanocarriers with regard to these three parameters as compared to non-targeted nanocarriers and modulated their outcome relative to single-targeted nanocarriers. This modulation was observed as enhanced, intermediate, or diminished interaction with cells, accumulation in particular organs, and specificity for diseased sites relative to single-targeted nanocarriers. These results were general to strategies 1--3 and were difficult to foresee a priori due to the complex nature of said interactions. Importantly, outcomes depended on the multiplicity (dual- vs. triple-targeting) and/or combination of affinity moieties displayed on the nanocarrier surface, as well as the physiological/pathological state of cells and tissues. Modulation of the delivery of a model therapeutic cargo in mice relative to single-targeted nanocarriers demonstrated the potential of these strategies to control the biodistribution of therapeutic agents. Therefore, these findings illustrate that combination-targeting enables modulation over cellular interactions and biodistribution of nanocarriers, which may aid the development of nanocarriers tailored for particular therapeutic needs.

Papademetriou, Iason Titos

274

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

PubMed Central

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

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

2013-01-01

275

Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide  

PubMed Central

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

Li, Chong; Wang, Yixin; Zhang, Xiaolin; Deng, Li; Zhang, Yan; Chen, Zhangbao

2013-01-01

276

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

PubMed Central

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

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

2013-01-01

277

Functionalized Single-Walled Carbon Nanotubes as Rationally Designed Vehicles for Tumor-Targeted Drug Delivery  

SciTech Connect

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.

Chen,J.; Wong,S.; Chen, S.; Zhao, X.; Kuznetsova, L.V.; and Ojima, I.

2008-11-14

278

Enhanced Endothelial Delivery and Biochemical Effects of ?-Galactosidase by ICAM-1-Targeted Nanocarriers for Fabry Disease  

PubMed Central

Fabry disease due to deficiency of ?-galactosidase A (?-Gal) causes lysosomal accumulation of globotriaosylceramide (Gb3) in multiple tissues and prominently in the vascular endothelium. Although enzyme replacement therapy (ERT) by injection of recombinant ?-Gal improves the disease outcome, effects on the vasculopathy associated to life-threatening cerebrovascular, cardiac and renal complications are still limited. We designed a strategy to enhance delivery of ?-Gal to organs and endothelial cells (ECs). We targeted ?-Gal to intercellular adhesion molecule 1 (ICAM-1), a protein expressed on ECs throughout the vasculature, by loading this enzyme on nanocarriers coated with anti-ICAM (anti-ICAM/?-Gal NCs). In vitro radioisotope tracing showed efficient loading of ?-Gal on anti-ICAM NCs, stability of this formulation under storage and in model physiological fluids, and enzyme release in response to lysosome environmental conditions. In mice, delivery of 125I-?-Gal was markedly enhanced by anti-ICAM/125I-?-Gal NCs in brain, kidney, heart, liver, lung, and spleen, and transmission electron microscopy showed anti-ICAM/?-Gal NCs attached to and internalized into the vascular endothelium. Fluorescence microscopy proved targeting, endocytosis and lysosomal transport of anti-ICAM/?-Gal NCs in macro- and micro-vascular ECs, and a marked enhancement of Gb3 degradation. Therefore, ICAM-1-targeting strategy may help improve the efficacy of therapeutic enzymes for Fabry disease. PMID:21047542

Hsu, Janet; Serrano, Daniel; Bhowmick, Tridib; Kumar, Kishan; Shen, Yang; Kuo, Yuan Chia; Garnacho, Carmen; Muro, Silvia

2010-01-01

279

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

PubMed

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

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

2013-07-01

280

Membrane domain formation—a key factor for targeted intracellular drug delivery  

PubMed Central

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

Popov-?eleketi?, Dušan; van Bergen en Henegouwen, Paul M. P.

2014-01-01

281

A double-targeted magnetic nanocarrier with potential application in hydrophobic drug delivery.  

PubMed

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 ?g/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. PMID:22088760

Ding, Guobin; Guo, Yi; Lv, Yanyun; Liu, Xiaofeng; Xu, Li; Zhang, Xuezhong

2012-03-01

282

Receptor binding peptides for target-selective delivery of nanoparticles encapsulated drugs  

PubMed Central

Active targeting by means of drug encapsulated nanoparticles decorated with targeting bioactive moieties represents the next frontier in drug delivery; it reduces drug side effects and increases the therapeutic index. Peptides, based on their chemical and biological properties, could have a prevalent role to direct drug encapsulated nanoparticles, such as liposomes, micelles, or hard nanoparticles, toward the tumor tissues. A considerable number of molecular targets for peptides are either exclusively expressed or overexpressed on both cancer vasculature and cancer cells. They can be classified into three wide categories: integrins; growth factor receptors (GFRs); and G-protein coupled receptors (GPCRs). Therapeutic agents based on nanovectors decorated with peptides targeting membrane receptors belonging to the GPCR family overexpressed by cancer cells are reviewed in this article. The most studied targeting membrane receptors are considered: somatostatin receptors; cholecystokinin receptors; receptors associated with the Bombesin like peptides family; luteinizing hormone-releasing hormone receptors; and neurotensin receptors. Nanovectors of different sizes and shapes (micelles, liposomes, or hard nanoparticles) loaded with doxorubicin or other cytotoxic drugs and externally functionalized with natural or synthetic peptides are able to target the overexpressed receptors and are described based on their formulation and in vitro and in vivo behaviors. PMID:24741304

Accardo, Antonella; Aloj, Luigi; Aurilio, Michela; Morelli, Giancarlo; Tesauro, Diego

2014-01-01

283

Urokinase Plasminogen Activator System Targeted Delivery of Nanobins as a Novel Ovarian Cancer Therapeutics  

PubMed Central

The urokinase system is overexpressed in epithelial ovarian cancer (OvCa) cells and is expressed at low levels in normal cells. To develop a platform for intracellular and targeted delivery of therapeutics in OvCa, we conjugated urokinase plasminogen activator (uPA) antibodies to liposomal nanobins. The arsenic trioxide loaded nanobins had favorable physicochemical properties and the ability to bind specifically to uPA. Confocal microscopy showed that the uPA targeted nanobins were internalized by OvCa cells, while both ICP-MS and FACS analyses confirmed >4-fold higher uptake of targeted nanobins when compared to untargeted nanobins. In a co-culture assay, the targeted nanobins showed efficient uptake in OvCa cells but not in the normal primary omental mesothelial cells. Moreover, this uptake could be blocked by either down-regulating uPA receptor expression in the OvCa cells using shRNA or by competition with free uPA or uPA antibody. In proof-of-concept experiments, mice bearing orthotopic ovarian tumors showed a greater reduction in tumor burden when treated with targeted nanobins than with untargeted nanobins (47% versus 27%; p<0.001). The targeted nanobins more effectively inhibited tumor cell growth both in vitro and in vivo compared to untargeted nanobins, inducing caspase-mediated apoptosis and impairing stem cell marker, ALDH1A1, expression. Ex vivo fluorescence imaging of tumors and organs corroborated these results, showing preferential localization of the targeted nanobins to the tumor. These findings suggest that uPA targeted nanobins capable of specifically and efficiently delivering payloads to cancer cells could serve as the foundation for a new targeted cancer therapy utilizing protease receptors. PMID:24061648

Zhang, Yilin; Kenny, Hilary A.; Swindell, Elden P.; Mitra, Anirban K.; Hankins, Patrick L.; Ahn, Richard W.; Gwin, Katja; Mazar, Andrew P.; O’Halloran, Thomas V.; Lengyel, Ernst

2013-01-01

284

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

E-print Network

GEN | News Highlights: Scientists Develop High-Capacity Nanoparticles for Targeted Delivery of Drug Cocktails http://www.genengnews.com/gen-news-highlights/scientists-develop-high-capacity-nanoparticles-for-targeted Magazine CurrentIssue View Larger Image Past Issues Adlink Subscription ADVERTISEMENT Comments Email

Brinker, C. Jeffrey

285

Synthetic Nano-Low Density Lipoprotein as Targeted Drug DeliveryVehicle for Glioblastoma Multiforme  

SciTech Connect

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.

Nikanjam, Mina; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Shu,Xiao; Budinger, Thomas F.; Forte, Trudy M.

2006-06-14

286

A pH-dependent colon targeted oral drug delivery system using methacrylic acid copolymers  

Microsoft Academic Search

Lactose-based placebo tablets were coated using various combinations of two methacrylic acid copolymers, Eudragit® L100-55 and Eudragit® S100, by spraying from aqueous systems. The Eudragit® L100-55–Eudragit® S100 combinations (w\\/w) studied were 1:0, 4:1, 3:2, 1:1, 2:3, 1:4, 1:5 and 0:1. The coated tablets were tested in vitro for their suitability for pH dependent colon targeted oral drug delivery. The same

M. Zahirul I Khan; Željko Prebeg; Nevenka Kurjakovi?

1999-01-01

287

Targeted Delivery of PSC-RANTES for HIV1 Prevention using Biodegradable Nanoparticles  

Microsoft Academic Search

Purpose  Nanoparticles formulated from the biodegradable co-polymer poly(lactic-co-glycolic acid) (PLGA), were investigated as a drug\\u000a delivery system to enhance tissue uptake, permeation, and targeting for PSC-RANTES anti-HIV-1 activity.\\u000a \\u000a \\u000a \\u000a Materials and Methods  PSC-RANTES nanoparticles formulated via a double emulsion process and characterized in both in vitro and ex vivo systems to determine PSC-RANTES release rate, nanoparticle tissue permeation, and anti-HIV bioactivity.\\u000a \\u000a \\u000a \\u000a Results  Spherical, monodisperse

Anthony S. Ham; Alexandra B. Sassi; Charlene S. Dezzutti; Lisa Cencia Rohan

2009-01-01

288

Second-generation aptamer-conjugated PSMA-targeted delivery system for prostate cancer therapy  

PubMed Central

Background: miR-15a and miR-16-1 have been identified as tumor suppressor genes in prostate cancer, but their safe and effective delivery to target cells is key to the successful use of this therapeutic strategy. RNA aptamer A10 has been used as a ligand, targeting prostate cancer cells that express prostate-specific membrane antigen (PSMA). Compared with A10, the binding of the second-generation RNA aptamer, A10-3.2, to PSMA is more efficient. Methods: A10-3.2 was investigated as a PSMA-targeting ligand in the design of a polyamidoamine (PAMAM)-based microRNA (miR-15a and miR-16-1) vector to prostate cancer cells. Using polyethyleneglycol (PEG) as a spacer, PAMAM was conjugated to aptamer (PAMAM-PEG-APT) and used as a vehicle for miRNA target delivery. Results: Luciferase assays of pGL-3 expression against PC3 (PSMA?) and LNCaP (PSMA+) cells demonstrated that the transfection efficiency of the synthesized DNA/PAMAM-PEG-APT complex was higher than that of the DNA/PAMAM-PEG complex. In addition, cell viability assays of LNCaP (PSMA+) cells showed that, with a N/P ratio of 15:1, the IC50 value of miRNA/PAMAM-PEG-APT was approximately 4.7-fold lower than that of miRNA/PAMAM-PEG. Conclusion: This PSMA-targeted system may prove useful in widening the therapeutic window and allow for selective killing of prostate cancer cells. PMID:21980237

Wu, Xin; Ding, Baoyue; Gao, Jing; Wang, Huanyun; Fan, Wei; Wang, Xiang; Zhang, Wei; Wang, Xiaoyu; Ye, Lihua; Zhang, Min; Ding, Xueying; Liu, Jiyong; Zhu, Quangang; Gao, Shen

2011-01-01

289

Odorranalectin Is a Small Peptide Lectin with Potential for Drug Delivery and Targeting  

PubMed Central

Background Lectins are sugar-binding proteins that specifically recognize sugar complexes. Based on the specificity of protein–sugar interactions, different lectins could be used as carrier molecules to target drugs specifically to different cells which express different glycan arrays. In spite of lectin's interesting biological potential for drug targeting and delivery, a potential disadvantage of natural lectins may be large size molecules that results in immunogenicity and toxicity. Smaller peptides which can mimic the function of lectins are promising candidates for drug targeting. Principal Findings Small peptide with lectin-like behavior was screened from amphibian skin secretions and its structure and function were studied by NMR, NMR-titration, SPR and mutant analysis. A lectin-like peptide named odorranalectin was identified from skin secretions of Odorrana grahami. It was composed of 17 aa with a sequence of YASPKCFRYPNGVLACT. L-fucose could specifically inhibit the haemagglutination induced by odorranalectin. 125I-odorranalectin was stable in mice plasma. In experimental mouse models, odorranalectin was proved to mainly conjugate to liver, spleen and lung after i.v. administration. Odorranalectin showed extremely low toxicity and immunogenicity in mice. The small size and single disulfide bridge of odorranalectin make it easy to manipulate for developing as a drug targeting system. The cyclic peptide of odorranalectin disclosed by solution NMR study adopts a ?-turn conformation stabilized by one intramolecular disulfide bond between Cys6-Cys16 and three hydrogen bonds between Phe7-Ala15, Tyr9-Val13, Tyr9-Gly12. Residues K5, C6, F7, C16 and T17 consist of the binding site of L-fucose on odorranalectin determined by NMR titration and mutant analysis. The structure of odorranalectin in bound form is more stable than in free form. Conclusion These findings identify the smallest lectin so far, and show the application potential of odorranalectin for drug delivery and targeting. It also disclosed a new strategy of amphibian anti-infection. PMID:18584053

Xu, Xueqing; Yang, Hailong; Wu, Bingxian; Wang, Yipeng; Zhu, Jianhua; Lai, Ren; Jiang, Xinguo; Lin, Donghai; Prescott, Mark C.; Rees, Huw H.

2008-01-01

290

Efficient Management of Fruit Pests by Pheromone Nanogels  

PubMed Central

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

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

2013-01-01

291

Nanogel Aerogel as Load Bearing Insulation for Cryogenic Systems  

NASA Astrophysics Data System (ADS)

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.

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

2010-04-01

292

Engineering RNA for Targeted siRNA Delivery and Medical Application  

PubMed Central

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

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

2010-01-01

293

PEI-derivatized fullerene drug delivery using folate as a homing device targeting to tumor.  

PubMed

Fullerene (C60) has shown great potential in drug delivery. In this study, firstly, amine-functionalized C60 (C60-NH(2)) was achieved by introducing ethylenediamine onto the surface of C60, and then PEI-derivatized C60 (C60-PEI) was performed via a cationic polymerization of aziridine on the surface of C60-NH(2); FT-IR and TGA results verified the structure of water-soluble C60-PEI. C60-PEI was encapsulated with folic acid (FA) through an amide linker, and then docetaxel (DTX) was conjugated to C60-PEI-FA and obtained a drug delivery system, C60-PEI-FA/DTX. Compared with free DTX, the tumor targeting drug delivery could efficiently cross cell membranes, lead to more apoptosis and afford higher antitumor efficacy in a cultured PC3 cells in vitro. Furthermore, compared with free DTX in an in vivo murine tumor model, C60-PEI-FA/DTX afforded higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 7.5-fold higher DTX uptake of tumor, demonstrating that C60-PEI-FA/DTX may be promising for high treatment efficacy with minimal side effects in future therapy. PMID:23069706

Shi, Jinjin; Zhang, Hongling; Wang, Lei; Li, Lulu; Wang, Honghong; Wang, Zhenzhen; Li, Zhi; Chen, Chengqun; Hou, Lin; Zhang, Chaofeng; Zhang, Zhenzhong

2013-01-01

294

Ultrasound Targeted Microbubble Destruction Stimulates Cellular Endocytosis in Facilitation of Adeno-Associated Virus Delivery  

PubMed Central

The generally accepted mechanism for ultrasound targeted microbubble destruction (UTMD) to enhance drug and gene delivery is through sonoporation. However, passive uptake of adeno-associated virus (AAV) into cells following sonoporation does not adequately explain observations of enhanced transduction by UTMD. This study investigated alternative mechanisms of UTMD enhancement in AAV delivery. UTMD significantly enhanced transduction efficiency of AAV in a dose-dependent manner. UTMD stimulated a persistent uptake of AAV into the cytoplasm and nucleus. This phenomenon occurred over several hours, suggesting that some viral particles are endocytosed by cells rather than exclusively passing through pores created by sonoporation. Additionally, UTMD enhanced clathrin expression and accumulation at the plasma membrane suggesting greater clathrin-mediated endocytosis following UTMD. Transmission electron microscopy (TEM) revealed that UTMD stimulated formation of clathrin-coated pits (CPs) and uncoated pits (nCPs). Furthermore, inhibition of clathrin-mediated endocytosis partially blocked the enhancement of AAV uptake following UTMD. The results of this study implicate endocytosis as a mechanism that contributes to UTMD-enhanced AAV delivery. PMID:23652832

Jin, Li-Fang; Li, Fan; Wang, Hui-Ping; Wei, Fang; Qin, Peng; Du, Lian-Fang

2013-01-01

295

Biomaterials-based nanofiber scaffold: targeted and controlled carrier for cell and drug delivery.  

PubMed

Abstract Nanofiber scaffold formulations (diameter less than 1000?nm) were successfully used to deliver the drug/cell/gene into the body organs through different routes for an effective treatment of various diseases. Various fabrication methods like drawing, template synthesis, fiber-mesh, phase separation, fiber-bonding, self-assembly, melt-blown, and electrospinning are successfully used for fabrication of nanofibers. These formulations are widely used in various fields such as tissue engineering, drug delivery, cosmetics, as filter media, protective clothing, wound dressing, homeostatic, sensor devices, etc. The present review gives a detailed account on the need of the nanofiber scaffold formulation development along with the biomaterials and techniques implemented for fabrication of the same against innumerable diseases. At present, there is a huge extent of research being performed worldwide on all aspects of biomolecules delivery. The unique characteristics of nanofibers such as higher loading efficiency, superior mechanical performance (stiffness and tensile strength), controlled release behavior, and excellent stability helps in the delivery of plasmid DNA, large protein drugs, genetic materials, and autologous stem-cell to the target site in the future. PMID:25539071

Garg, Tarun; Rath, Goutam; Goyal, Amit K

2015-04-01

296

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

PubMed Central

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

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

2012-01-01

297

Hyaluronic acid-modified multiwalled carbon nanotubes for targeted delivery of doxorubicin into cancer cells.  

PubMed

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. PMID:25500334

Cao, Xueyan; Tao, Lei; Wen, Shihui; Hou, Wenxiu; Shi, Xiangyang

2015-03-20

298

Brain-targeting delivery for RNAi neuroprotection against cerebral ischemia reperfusion injury.  

PubMed

Nanoparticles (NPs) with modification of brain-targeting molecules have been extensively exploited for therapeutic gene delivery across the blood-brain barrier (BBB). As one of the effective RNA interference (RNAi) approaches, short hairpin RNA (shRNA) has been proved to be promising in the field of gene therapy. Apoptosis signal-regulating kinase 1 (Ask1) has been reported to be an important target for gene therapy against cerebral ischemia reperfusion injury. In this study, dendrigraft poly-l-lysine (DGL) was decorated by dermorphin (a ?-opiate receptor agonist) through PEG for efficient brain-targeting, then complexed with anti-Ask1 shRNA plasmid DNA, yielding the DGL-PEG-dermorphin/shRNA NPs. The DGL-PEG-dermorphin/shRNA NPs were characterized and estimated the brain-targeting ability. In vitro, increased cellular uptake and transfection efficiency were explored; in vivo, preferable accumulation and gene transfection in brain were showed in images. The DGL-PEG-dermorphin/shRNA NPs also revealed high efficiency of neuroprotection. As a result of RNAi, corresponding mRNA was distinctly degraded, expression of Ask1 protein was obviously suppressed, apoptotic cell death was apparently decreased and cerebral infarct area was significantly reduced. Above all, DGL-PEG-dermorphin/shRNA NPs were proved to be efficient and safe for brain-targeting RNAi neuroprotection against cerebral ischemia reperfusion injury. PMID:23968852

An, Sai; Kuang, Yuyang; Shen, Teng; Li, Jianfeng; Ma, Haojun; Guo, Yubo; He, Xi; Jiang, Chen

2013-11-01

299

Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery  

PubMed Central

The poor aqueous solubility and low bioavailability of curcumin restrict its clinical application for cancer treatment. In this study, a novel tumor-targeting nanofiber carrier was developed to improve the solubility and tumor-targeting ability of curcumin using a self-assembled Nap-GFFYG-RGD peptide. The morphologies of the peptide nanofiber and the curcumin-encapsulated nanofiber were visualized by transmission electron microscopy. The tumor-targeting activity of the curcumin-encapsulated Nap-GFFYG-RGD peptide nanofiber (f-RGD-Cur) was studied in vitro and in vivo, using Nap-GFFYG-RGE peptide nanofiber (f-RGE-Cur) as the control. Curcumin was encapsulated into the peptide nanofiber, which had a diameter of approximately 10–20 nm. Curcumin showed sustained-release behavior from the nanofibers in vitro. f-RGD-Cur showed much higher cellular uptake in ?v?3 integrin-positive HepG2 liver carcinoma cells than did non-targeted f-RGE-Cur, thereby leading to significantly higher cytotoxicity. Ex vivo studies further demonstrated that curcumin could accumulate markedly in mouse tumors after administration of f-RGD-Cur via the tail vein. These results indicate that Nap-GFFYG-RGD peptide self-assembled nanofibers are a promising hydrophobic drug delivery system for targeted treatment of cancer. PMID:24399876

Liu, Jianfeng; Liu, Jinjian; Xu, Hongyan; Zhang, Yumin; Chu, Liping; Liu, Qingfen; Song, Naling; Yang, Cuihong

2014-01-01

300

Folated Synperonic-Cholesteryl Hemisuccinate Polymeric Micelles for the Targeted Delivery of Docetaxel in Melanoma  

PubMed Central

The objective of this study was the synthesis of folic acid- (FA-) targeted polymeric micelles of Synperonic PE/F 127-cholesteryl hemisuccinate (PF127-Chol) for specific delivery of docetaxel (DTX). Targeted or nontargeted micelles loaded with DTX were prepared via dialysis method. The effects of processing variables on the physicochemical properties of targeted micelles were evaluated using a full factorial design. After the optimization of the polymer/drug ratio, the organic solvent type used for the preparation of the micelles, and the temperature of dialyzing medium, the in vitro cytotoxicity and cellular uptake of the optimized micelles were studied on B16F10 melanoma cells by flow cytometry and fluorescent microscopy. The anticancer efficacy of DTX-loaded FA-PF127-Chol was evaluated in mice bearing melanoma tumor. Optimized targeted micelles had the particle size of 171.3?nm, zeta potential of ?7.8?mV, PDI of 0.325, and a high encapsulation efficiency that released the drug within 144?h. The MTT assay indicated that targeted micelles carrying DTX were significantly more cytotoxic, had higher cellular uptake, and reduced the tumor volume significantly more than the nontargeted micelles and the free drug. FA-PF127-Chol could be, therefore, a promising biomaterial for tumors overexpressing folate receptors.

Varshosaz, Jaleh; Taymouri, Somayeh; Hassanzadeh, Farshid; Haghjooy Javanmard, Shaghayegh; Rostami, Mahboobeh

2015-01-01

301

Insights into EPR effect versus lectin-mediated targeted delivery: biodegradable polycarbonate micellar nanoparticles with and without galactose surface decoration.  

PubMed

Polymeric micelles with and without galactose are synthesized to study liver targeting ability in an orthotopic HCC rat model. Micelles with galactose accumulate more in the healthy liver tissue instead of HCC, while micelles without galactose amass in HCC by the EPR effect. These micelles show great potential as drug delivery carriers to target either the liver or HCC. PMID:25091699

Ebrahim Attia, Amalina Binte; Oh, Pamela; Yang, Chuan; Tan, Jeremy Pang Kern; Rao, Nithya; Hedrick, James L; Yang, Yi Yan; Ge, Ruowen

2014-11-12

302

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

E-print Network

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

Summa, Christopher M.

303

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

PubMed Central

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

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

2009-01-01

304

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

PubMed

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

Zeng, Junyan; Qu, Qiumin

2013-06-01

305

Homing of mesenchymal stem cells: mechanistic or stochastic? Implications for targeted delivery in arthritis.  

PubMed

Mesenchymal stem cells (MSCs) are multipotent cells with the capacity to undergo chondrogenic differentiation. Systemically administered MSCs have been shown to preferentially accumulate at sites of tissue damage and inflammation, thus MSC-based therapy holds great promise for the treatment of inflammatory diseases such as RA. Modulation of MSC homing may allow targeted delivery of systemically administered MSCs to damaged articular cartilage, where they can suppress immune-mediated cartilage destruction and contribute to cartilage repair via a combination of chondrogenic differentiation and paracrine stimulation of intrinsic residual repair. To harness the potential of MSC homing, a thorough understanding of the mechanism is key. This review discusses current knowledge of the mechanism of MSC homing to injured/inflamed tissue and its implications for targeted MSC-based therapy in arthritis. PMID:25288785

Eseonu, Onyedikachi I; De Bari, Cosimo

2015-02-01

306

Targeted delivery of peptide-conjugated biocompatible gold nanoparticles into cancer cell nucleus  

NASA Astrophysics Data System (ADS)

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.

Qian, Wei; Curry, Taeyjuana; Che, Yong; Kopelman, Raoul

2013-02-01

307

Chitosan nanoparticles for targeting and sustaining minoxidil sulphate delivery to hair follicles.  

PubMed

This work developed minoxidil sulphate-loaded chitosan nanoparticles (MXS-NP) for targeted delivery to hair follicles, which could sustain drug release and improve the topical treatment of alopecia. Chitosan nanoparticles were obtained using low-molecular weight chitosan and tripolyphosphate as crosslink agent. MXS-NP presented a monomodal distribution with hydrodynamic diameter of 235.5±99.9nm (PDI of 0.31±0.01) and positive zeta potential (+38.6±6.0mV). SEM analysis confirmed nanoparticles average size and spherical shape. A drug loading efficiency of 73.0±0.3% was obtained with polymer:drug ratio of 1:1 (w/w). Drug release through cellulose acetate membranes from MXS-NP was sustained in about 5 times in comparison to the diffusion rate of MXS from the solution (188.9±6.0?g/cm(2)/h and 35.4±1.8?g/cm(2)/h). Drug permeation studies through the skin in vitro, followed by selective recovery of MXS from the hair follicles, showed that MXS-NP application resulted in a two-fold MXS increase into hair follicles after 6h in comparison to the control solution (5.9±0.6?g/cm(2) and 2.9±0.8?g/cm(2)). MXS-loading in nanoparticles appears as a promising and easy strategy to target and sustain drug delivery to hair follicles, which may improve the topical treatment of alopecia. PMID:25647618

Matos, Breno Noronha; Reis, Thaiene Avila; Gratieri, Taís; Gelfuso, Guilherme Martins

2015-04-01

308

Nanoparticle-based biocompatible and targeted drug delivery: characterization and in vitro studies.  

PubMed

Paclitaxel nanoparticles (PAX NPs) prepared with the size of 110 ± 10 nm and ? potential of -40 ± 3 mV were encapsulated in synthetic/biomacromolecule shell chitosan, dextran-sulfate using a layer-by-layer self-assembly technique. Zeta potential measurements, analysis of X-ray photoelectron spectroscopy, and scanning electron microscopy confirmed the successful adsorption of each layer. Surface modifications of these core-shell NPs were performed by covalently conjugating with poly(ethylene glycol) (H(2)N-PEG-carboxymethyl, M(w) 3400) and fluorescence labeled wheat germ agglutinin (F-WGA) to build a biocompatible and targeted drug delivery system. 32% of PAX was released from four bilayers of biomacromolecule assembled NPs within 8 h as compared with >85% of the drug released from the bare NPs. Moreover, high cell viability with PEG conjugation and high binding capacity of WGA-modified NPs with Caco-2 cells were observed. This biocompatible and targeted NP-based drug delivery system, therefore, may be considered as a potential candidate for the treatment of colonic cancer and other diseases. PMID:21786828

Yu, Xiao; Pishko, Michael V

2011-09-12

309

Formulation, Evaluation and Optimization of Pectin- Bora Rice Beads for Colon Targeted Drug Delivery System  

PubMed Central

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

Ramteke, Kuldeep Hemraj; Nath, Lilakant

2014-01-01

310

Preparation, characterization and targeted delivery of serratiopeptidase immobilized on amino-functionalized magnetic nanoparticles.  

PubMed

Targeted delivery of serratiopeptidase enzyme immobilized on magnetic nanoparticles (MNPs) of Fe3O4 has been reported for the treatment using this enzyme. The enzyme was immobilized by covalent bonding through glutaraldehyde after amino functionalization of MNPs and parameters was studied. The enzyme bound MNPs (EMNPs) were characterized for size, crystallographic identity, phase purity, zeta potential and magnetic properties along with elemental and thermal analysis. The binding of enzyme had little effect on sizes (~10-17 nm) and on magnetic properties, but the zeta potential increased from -25 mV to +14.5 mV with surface amino groups up to 350 ?moles g(-1) MNPs, to stabilize its suspensions. In the molecular level, maximum of 17 molecules of enzyme could bind to each particle of MNPs that showed residual activity 67%, decreased KM and Vmax, good storage stability. Magnetic targeting of EMNPs increased the delivery (permeation) of drug through the membrane in in vitro study and enhanced the anti-inflammatory effect on carrageenan induced paw oedema in rats in in vivo study at much lower doses of enzyme than the doses required for treatment with free enzyme. PMID:23851102

Kumar, Sandeep; Jana, Asim K; Dhamija, Isha; Singla, Yashpaul; Maiti, Mithu

2013-11-01

311

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

PubMed

The aim of this study was to synthesize green chemistry based gold nanoparticles using liver specific biopolymer and to develop a liver cancer targeted drug delivery system with enhanced efficacy and minimal side effects. Pullulan stabilized gold nanoparticles (PAuNPs) were coupled with 5-Fluorouracil (5-Fu) and folic acid (Fa) which could be used as a tool for targeted drug delivery and imaging of cancer. The toxicity of 5-Fu, 5-Fu adsorbed gold nanoparticles (5-Fu@AuNPs), Fa-coupled 5-Fu adsorbed gold nanoparticles (5-Fu@AuNPs-Fa), was studied using zebrafish embryo as an in vivo model. The in vitro cytotoxicity of free 5-Fu, 5-Fu@AuNPs, 5-Fu@AuNPs-Fa against HepG2 cells was studied and found that the amount of 5-Fu required to achieve 50% of growth of inhibition (Ic50) was much lower in 5-Fu@AuNP-Fa than in free 5-Fu, 5-Fu@AuNPs. The in vivo biodistribution of PAuNPs showed that higher amount of gold had been accumulated in liver (54.42±5.96 ?g) than in other organs. PMID:24762575

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

2014-09-15

312

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

NASA Astrophysics Data System (ADS)

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

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

2014-09-01

313

Tumor-targeted polydiacetylene micelles for in vivo imaging and drug delivery.  

PubMed

In vivo tumor targeting and drug delivery properties of small polymerized polydiacetylene (PDA) micelles (?10 nm) is investigated in a murine MDA-MB-231 xenograft model of breast cancer. Three micelles with different surface coatings are synthesized and tested for their ability to passively target tumor through the enhanced permeability and retention effect. After injection (24 h), fluorescence diffuse optical tomographic imaging indicates a tumor uptake of nearly 3% of the injected dose for the micelles with a 2 kDa poly(ethylene glycol) (PEG)-coating (PDA-PEG2000). The uptake of PDA micelles in tumors is confirmed by co-localization with [(18) F]-fluorodeoxyglucose (FDG) positron emission tomography. Although FDG has a higher diffusion rate in tumors, 40 ± 19% of the retained micelles is co-registered with the tumor volume visualized by FDG. Finally, PDA-PEG2000 micelles are loaded with the hydrophobic anticancer drug paclitaxel and used in vivo to inhibit tumor growth. These findings demonstrate the potential of PDA-PEG2000 micelles for both in vivo tumor imaging and drug delivery applications. PMID:21837631

Mackiewicz, Nicolas; Gravel, Edmond; Garofalakis, Anikitos; Ogier, Julien; John, Jubi; Dupont, Daniel Miotto; Gombert, Karine; Tavitian, Bertrand; Doris, Eric; Ducongé, Frédéric

2011-10-01

314

P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery  

PubMed Central

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

Davis, Thomas P.; Sanchez-Covarubias, Lucy; Tome, Margaret E.

2014-01-01

315

Feasibility of targeted drug delivery to selective areas of the retina  

SciTech Connect

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

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

1991-07-01

316

A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting  

PubMed Central

Background The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells. Methods Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol) used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research. Results The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor® EL, 32.5% Transcutol® HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the folate receptors on the surface of positive folate receptors cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells. Conclusion FSMEDDS-filled colon-targeted capsules are a potential carrier for colon delivery of curcumin. PMID:22275831

Zhang, Lin; Zhu, Weiwei; Yang, Chunfen; Guo, Hongxia; Yu, Aihua; Ji, Jianbo; Gao, Yan; Sun, Min; Zhai, Guangxi

2012-01-01

317

In vivo tumor targeting and image-guided drug delivery with antibody-conjugated, radiolabeled mesoporous silica nanoparticles.  

PubMed

Since the first use of biocompatible mesoporous silica (mSiO2) nanoparticles as drug delivery vehicles, in vivo tumor targeted imaging and enhanced anticancer drug delivery has remained a major challenge. In this work, we describe the development of functionalized mSiO2 nanoparticles for actively targeted positron emission tomography (PET) imaging and drug delivery in 4T1 murine breast tumor-bearing mice. Our structural design involves the synthesis, surface functionalization with thiol groups, PEGylation, TRC105 antibody (specific for CD105/endoglin) conjugation, and (64)Cu-labeling of uniform 80 nm sized mSiO2 nanoparticles. Systematic in vivo tumor targeting studies clearly demonstrated that (64)Cu-NOTA-mSiO2-PEG-TRC105 could accumulate prominently at the 4T1 tumor site via both the enhanced permeability and retention effect and TRC105-mediated binding to tumor vasculature CD105. As a proof-of-concept, we also demonstrated successful enhanced tumor targeted delivery of doxorubicin (DOX) in 4T1 tumor-bearing mice after intravenous injection of DOX-loaded NOTA-mSiO2-PEG-TRC105, which holds great potential for future image-guided drug delivery and targeted cancer therapy. PMID:24083623

Chen, Feng; Hong, Hao; Zhang, Yin; Valdovinos, Hector F; Shi, Sixiang; Kwon, Glen S; Theuer, Charles P; Barnhart, Todd E; Cai, Weibo

2013-10-22

318

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

PubMed Central

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

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

2014-01-01

319

Preparation of quantum dot/drug nanoparticle formulations for traceable targeted delivery and therapy.  

PubMed

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

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

2012-01-01

320

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

PubMed Central

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

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

2012-01-01

321

Targeted delivery of a sialic acid-blocking glycomimetic to cancer cells inhibits metastatic spread.  

PubMed

Sialic acid sugars are overexpressed by cancer cells and contribute to the metastatic cascade at multiple levels. Therapeutic interference of sialic acids, however, has been difficult to pursue because of the absence of dedicated tools. Here we show that a rationally designed sialic acid-blocking glycomimetic (P-3F(ax)-Neu5Ac) successfully prevents cancer metastasis. Formulation of P-3F(ax)--Neu5Ac into poly(lactic-co-glycolic acid nanoparticles coated with antityrosinase-related protein-1 antibodies allowed targeted delivery of P-3F(ax)--Neu5Ac into melanoma cells, slow release, and long-term sialic acid blockade. Most importantly, intravenous injections of melanoma-targeting P-3F(ax)--Neu5Ac nanoparticles prevented metastasis formation in a murine lung metastasis model. These findings stress the importance of sialoglycans in cancer metastasis and advocate that sialic acid blockade using rationally designed glycomimetics targeted to cancer cells can effectively prevent cancer metastases. This targeting strategy to interfere with sialic acid-dependent processes is broadly applicable not only for different types of cancer but also in infection and inflammation. PMID:25575241

Büll, Christian; Boltje, Thomas Jan; van Dinther, Eric A W; Peters, Timo; de Graaf, Annemarie M A; Leusen, Jeanette H W; Kreutz, Martin; Figdor, Carl G; den Brok, Martijn H; Adema, Gosse J

2015-01-27

322

The Targeted Delivery of Multicomponent Cargos to Cancer Cells via Nanoporous Particle-Supported Lipid Bilayers  

PubMed Central

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability, and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma (HCC) exhibit a 10,000-fold greater affinity for HCC than for hepatocytes, endothelial cells, and immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, siRNA, and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer allow a single protocell loaded with a drug cocktail to kill a drug-resistant HCC cell, representing a 106-fold improvement over comparable liposomes. PMID:21499315

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

2011-01-01

323

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

PubMed

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

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

2014-09-01

324

A strategy for precision engineering of nanoparticles of biodegradable copolymers for quantitative control of targeted drug delivery  

Microsoft Academic Search

Research on quantitative control of targeting effect for the drug delivery system of ligand-conjugated nanoparticles of biodegradable polymers is at the cutting edge in the design of drug delivery device. In this work, we developed a post-conjugation strategy, which makes the ligand conjugation after the preparation of the drug-loaded nanoparticles of two copolymers blend. We synthesized the PLGA-PEG copolymer with

Yutao Liu; Kai Li; Bin Liu; Si-Shen Feng

2010-01-01

325

Targeted Drug Delivery with Focused Ultrasound-Induced Blood-Brain Barrier Opening Using Acoustically-Activated Nanodroplets  

PubMed Central

Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. More homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature. PMID:24096019

Chen, Cherry C.; Sheeran, Paul S.; Wu, Shih-Ying; Olumolade, Oluyemi O.; Dayton, Paul A.; Konofagou, Elisa E.

2013-01-01

326

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

PubMed

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

Zhang, Ziqiang; Yao, Jing

2012-09-01

327

Characterization of lactoferrin as a targeting ligand for nonviral gene delivery to airway epithelial cells.  

PubMed

In this study lactoferrin (Lf) was investigated as a targeting ligand for receptor-mediated gene delivery to human bronchial epithelial cells. A high number of lactoferrin receptors (LfRs) were detected on bronchial epithelial (BEAS-2B), but not on alveolar epithelial (A549) cells by fluorescence microscopy and FACS measurements, suggesting potential targeting selectivity for bronchial epithelial cells. Molecular conjugates with ratios of Lf to branched polyethylenimine 25 kDa (PEI) ranging from 4:1 to 1:40 (mol/mol) were synthesized and analyzed for complexation of plasmid DNA (pDNA), transfection efficiency, and cytotoxicity. Whereas particle size increased with the degree of Lf coupling from 45 to 225 nm, surface charge was not significantly influenced. Transfection studies on BEAS-2B cells revealed that Lf-PEI 1:20 exhibited the highest luciferase gene expression which was 5-fold higher at an N/P ratio (molar ratio of PEI nitrogen to pDNA phosphate) of 4 than PEI and could be inhibited by an excess of free Lf. With A549 cells, no significant enhancement in transfection efficiency between Lf-PEI/pDNA and PEI/pDNA complexes could be observed. Increasing the degree of Lf coupling to PEI resulted in reduced transfection efficiency in both alveolar and bronchial epithelial cells. Cell viability assays resulted in significantly lower cellular toxicity of Lf-PEI/pDNA compared with PEI/pDNA complexes. We suggest that Lf represents a potent targeting ligand for receptor-mediated gene delivery to bronchial epithelial cells and might be a promising candidate for lung gene transfer in vivo. PMID:17475321

Elfinger, Markus; Maucksch, Christof; Rudolph, Carsten

2007-08-01

328

A biocleavable pullulan-based vector via ATRP for liver cell-targeting gene delivery.  

PubMed

Pullulan due to its specificity for liver has been widely exploited for biomedical applications. In this work, a tailor-made biocleavable pullulan-based gene vector (PuPGEA) with good hemocompatibility was successfully proposed via atom transfer radical polymerization (ATRP) for efficient liver cell-targeting gene delivery. A two-step method involving the reaction of hydroxyl groups of pullulan with cystamine was developed to introduce reduction-sensitive disulfide-linked initiation sites of ATRP onto pullulan. The poly(glycidyl methacrylate) (PGMA) side chains prepared subsequently via ATRP were functionalized with ethanolamine (EA) to produce the resultant biocleavable comb-shaped PuPGEA vectors consisting of nonionic pullulan backbones and disulfide-linked cationic EA-functionalized PGMA (PGEA) side chains with plentiful secondary amine and nonionic hydroxyl units. The cationic PGEA side chains can be readily cleavable from the pullulan backbones of PuPGEA under reducible conditions. Due to the liver targeting performance of pullulan backbones, such PuPGEA vectors exhibited much higher gene transfection efficiency and cellular uptake rates in HepG2 cell lines than in Hella cell lines. In addition, in vitro transfection efficiency and uptake mechanism of polyplex in HepG2 cells were evaluated in the presence of different endocytosis inhibitors, indicating that the asialoglycoprotein receptor was involved in transfection process of hepatocytes. More importantly, in comparison with gold standard polyethylenimine (PEI, ?25 kDa), PuPGEA vectors possessed excellent hemocompatibility without causing undesirable hemolysis. Properly grafting short bioreducible PGEA polycation side chains from a liver cell-targeting pullulan backbone is an effective means to produce new hemocompatible polysaccharide-based gene delivery vectors. PMID:24485791

Yang, Xin-Chao; Niu, Yan-Lan; Zhao, Na-Na; Mao, Chun; Xu, Fu-Jian

2014-04-01

329

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

PubMed Central

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

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

2012-01-01

330

Superparamagnetic iron oxide nanoparticles (SPIONs)-loaded Trojan microparticles for targeted aerosol delivery to the lung.  

PubMed

Targeted aerosol delivery to specific regions of the lung may improve therapeutic efficiency and minimise unwanted side effects. Targeted delivery could potentially be achieved with porous microparticles loaded with superparamagnetic iron oxide nanoparticles (SPIONs)-in combination with a target-directed magnetic gradient field. The aim of this study was to formulate and evaluate the aerodynamic properties of SPIONs-loaded Trojan microparticles after delivery from a dry powder inhaler. Microparticles made of SPIONs, PEG and hydroxypropyl-?-cyclodextrin (HP?CD) were formulated by spray drying and characterised by various physicochemical methods. Aerodynamic properties were evaluated using a next generation cascade impactor (NGI), with or without a magnet positioned at stage 2. Mixing appropriate proportions of SPIONs, PEG and HP?CD allowed Trojan microparticle to be formulated. These particles had a median geometric diameter of 2.8±0.3?m and were shown to be sensitive to the magnetic field induced by a magnet having a maximum energy product of 413.8kJ/m(3). However, these particles, characterised by a mass median aerodynamic diameter (MMAD) of 10.2±2.0?m, were considered to be not inhalable. The poor aerodynamic properties resulted from aggregation of the particles. The addition of (NH4)2CO3 and magnesium stearate (MgST) to the formulation improved the aerodynamic properties of the Trojan particles and resulted in a MMAD of 2.2±0.8?m. In the presence of a magnetic field on stage 2 of the NGI, the amount of particles deposited at this stage increased 4-fold from 4.8±0.7% to 19.5±3.3%. These Trojan particles appeared highly sensitive to the magnetic field and their deposition on most of the stages of the NGI was changed in the presence compared to the absence of the magnet. If loaded with a pharmaceutical active ingredient, these particles may be useful for treating localised lung disease such as cancer nodules or bacterial infectious foci. PMID:24055690

Tewes, Frederic; Ehrhardt, Carsten; Healy, Anne Marie

2014-01-01

331

Localized increase of tissue oxygen tension by magnetic targeted drug delivery  

NASA Astrophysics Data System (ADS)

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

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

2014-07-01

332

Localized Increase of Tissue Oxygen Tension by Magnetic Targeted Drug Delivery  

PubMed Central

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

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

2014-01-01

333

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

PubMed Central

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

Burke, Caitlin W.; Price, Richard J.

2010-01-01

334

Enzyme/pH dual sensitive polymeric nanoparticles for targeted drug delivery to the inflamed colon.  

PubMed

Novel nanoparticles whose drug release profiles are controlled by both enzyme and pH were prepared for the colon-specific drug delivery using a polymeric mixture of enzyme-sensitive azo-polyurethane and pH-sensitive Eudragit S100 (ES-Azo.pu). The enzyme/pH dual sensitive nanoparticles were designed to release a drug based on a two-fold approach which specifically aimed to target drug delivery to the inflamed colon while preventing the burst release of drugs in the stomach and small intestine. Single pH-sensitive (ES) and dual sensitive (ES-Azo.pu) nanoparticles were prepared using an oil-in-water emulsion solvent evaporation method and coumarin-6 (C-6) was used as a model drug. The successful formation of ES and ES-azo.pu nanoparticles that have 214 nm and 244 nm in mean particle size, respectively, was confirmed by scanning electron microscopy and qNano. ES nanoparticles showed almost 100% of burst drug release at pH 7.4, whereas ES-Azo.pu nanoparticles prevented the burst drug release at pH 7.4, followed by a sustained release phase thereafter. Furthermore, ES-Azo.pu nanoparticles exhibited enzyme-triggered drug release in the presence of rat cecal contents obtained from a rat model of colitis. An in vivo localization study in rat gastrointestinal tract demonstrated that ES-Azo.pu nanoparticles were selectively distributed in the inflamed colon, showing 5.5-fold higher C-6 than ES nanoparticles. In conclusion, the enzyme/pH dual sensitive nanoparticles presented in this study can serve as a promising strategy for colon-specific drug delivery against inflammatory bowel disease and other colon disorders. PMID:25266978

Naeem, Muhammad; Kim, Wooseong; Cao, Jiafu; Jung, Yunjin; Yoo, Jin-Wook

2014-11-01

335

Photoactive metal carbonyl complexes as potential agents for targeted CO delivery.  

PubMed

The surprising discovery of carbon monoxide (CO) as a signaling molecule in mammalian physiology has recently raised interest in this toxic gas among researchers in biochemical and pharmaceutical community. CO is endogenously produced mainly from catabolism of heme by the enzyme heme oxygenase (HO) and participates in a myriad of anti-inflammatory, anti-proliferative, and vasoregulatory pathways. In animal models, low doses of CO have exhibited beneficial effects in suppression of organ graft rejection and safeguarding the heart during reperfusion after cardiopulmonary bypass surgery. The salutary effects of CO have naturally drawn attention of the pharmaceutical industry for its use as a cytoprotective agent. Safety-related concerns of the use of this noxious gas have prompted research in the area of syntheses of CO-releasing molecules (CORMs) and to date, several metal carbonyls (metal complexes of CO) have been employed as CORMs in promoting prolonged (and safe) delivery of low doses of CO to cellular targets. Because many carbonyl complexes release CO upon illumination, investigators have recently began to explore the possibility of "controlled CO delivery" through the use of light. During the past few years, a number of photoactive CORMs or "photoCORMs" have been synthesized that release CO upon illumination with UV or visible light. The utility of these photoCORMs in CO delivery has also been confirmed. Novel design principles for isolation of photoCORMs have started to appear in recent reports. Scrutiny of the literature reveals the emergence of a new exciting area of drug development in such efforts. The potential of photoCORMs as CO-donating pharmaceuticals along with a brief overview of the physiological roles of CO is presented in this review. PMID:24287103

Gonzales, Margarita A; Mascharak, Pradip K

2014-04-01

336

A Study of Shrinkage Stress Reduction and Mechanical Properties of Nanogel-Modified Resin Systems  

PubMed Central

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

Liu, JianCheng; Howard, Gregory D.; Lewis, Steven H.; Barros, Matthew D.; Stansbury, Jeffrey W.

2012-01-01

337

On the scattered light by dilute aqueous dispersions of nanogel particles.  

PubMed

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(-)(?). The value of exponent ? 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(?)(-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. PMID:25837408

Callejas-Fernández, J; Ramos, J; Forcada, J; Moncho-Jordá, A

2015-07-15

338

Soluble T-Cell Receptors Produced in Human Cells for Targeted Delivery  

PubMed Central

Recently, technology has become available to generate soluble T-cell receptors (sTCRs) that contain the antigen recognition part. In contrast to antibodies, sTCRs recognize intracellular in addition to extracellular epitopes, potentially increasing the number of applications as reagents for target detection and immunotherapy. Moreover, recent data show that they can be used for identification of their natural peptide ligands in disease. Here we describe a new and simplified expression method for sTCRs in human cells and show that these sTCRs can be used for antigen-specific labeling and elimination of human target cells. Four different TCRs were solubilized by expression of constructs encoding the TCR alpha (?) and beta (?) chains lacking the transmembrane and intracellular domains, linked by a ribosomal skipping 2A sequence that facilitates equimolar production of the chains. Cell supernatants containing sTCRs labeled target cells directly in a peptide (p)-human leukocyte antigen (HLA)-specific manner. We demonstrated that a MART-1p/HLA-A*02:01-specific sTCR fused to a fluorescent protein, or multimerized onto magnetic nanoparticles, could be internalized. Moreover, we showed that this sTCR and two sTCRs recognizing CD20p/HLA-A*02:01 could mediate selective elimination of target cells expressing the relevant pHLA complex when tetramerized to streptavidin-conjugated toxin, demonstrating the potential for specific delivery of cargo. This simple and efficient method can be utilized to generate a wide range of minimally modified sTCRs from the naturally occurring TCR repertoire for antigen-specific detection and targeting. PMID:25875651

Fallang, Lars-Egil; Yang, Weiwen; Vefferstad, Anette; Areffard, Ali; Olweus, Johanna

2015-01-01

339

Inorganic nanovehicle for potential targeted drug delivery to tumor cells, tumor optical imaging.  

PubMed

In this work, an inorganic multifunctional nanovehicle was tailored as a carrier to deliver anticancer drug for tumor optical imaging and therapy. The nanovehicle could be used as a dually targeted drug nanovehicle by bonded magnetical (passive) and folic acid (active) targeting capabilities. In addition, it was developed using rhodamine 6G (R6G) as a fluorescence reagent, and an ?-zirconium phosphate nanoplatform (Zr(HPO4)2·H2O, abbreviated as ?-ZrP) as the anticancer drug nanovehicle. The novel drug-release system was designed and fabricated by intercalation of ?-ZrP with magnetic Fe3O4 nanoparticles and anticancer drug 5-fluorouracil (5-FU), followed by reacting with a folate acid-chitosan-rhodamine6G (FA-CHI-R6G) complex, and then ?-ZrP intercalated with Fe3O4 nanoparticles and 5-fluorouracil (5-FU) was successfully encapsulated into chitosan (CHI). The resultant multifunctional drug delivery system was characterized by scanning electron microscopy, X-ray diffraction, energy-dispersive X-ray analysis, photoluminescence spectra, magnetometry, fluorescence microscopy imaging studies and other characterization methods. Simultaneously, the drug release in vitro on the obtained nanocomposites that exhibited a sustained release behavior was carried out in buffer solution at 37 °C, which demonstrated clearly that the nanocomposites shown a sustained release behavior. Meanwhile, cell culture experiments also indicated that the drug-release system had the potential to be used as an dually targeted drug nanovehicle into the tumor cells. PMID:25693506

Yu, Shiyong; Gao, Xuechuan; Baigude, Huricha; Hai, Xiao; Zhang, Renfei; Gao, Xiaolong; Shen, Beibei; Li, Zhao; Tan, Zhibing; Su, Haiquan

2015-03-11

340

Prodrug strategy for PSMA-targeted delivery of TGX-221 to prostate cancer cells.  

PubMed

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110? catalytic subunit. Recent studies showed that TGX-221 has antiproliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles was significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than that of the naked drug, and the drug clearance rate was 6.16-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment. PMID:22494444

Zhao, Yunqi; Duan, Shaofeng; Zeng, Xing; Liu, Chunjing; Davies, Neal M; Li, Benyi; Forrest, M Laird

2012-06-01

341

Multifunctional polymer-capped mesoporous silica nanoparticles for pH-responsive targeted drug delivery.  

PubMed

A highly stable modular platform, based on the sequential covalent attachment of different functionalities to the surface of core-shell mesoporous silica nanoparticles (MSNs) for targeted drug delivery is presented. A reversible pH-responsive cap system based on covalently attached poly(2-vinylpyridine) (PVP) was developed as drug release mechanism. Our platform offers (i) tuneable interactions and release kinetics with the cargo drug in the mesopores based on chemically orthogonal core-shell design, (ii) an extremely robust and reversible closure and release mechanism based on endosomal acidification of the covalently attached PVP polymer block, (iii) high colloidal stability due to a covalently coupled PEG shell, and (iv) the ability to covalently attach a wide variety of dyes, targeting ligands and other functionalities at the outer periphery of the PEG shell. The functionality of the system was demonstrated in several cell studies, showing pH-triggered release in the endosome, light-triggered endosomal escape with an on-board photosensitizer, and efficient folic acid-based cell targeting. PMID:25865957

Niedermayer, Stefan; Weiss, Veronika; Herrmann, Annika; Schmidt, Alexandra; Datz, Stefan; Müller, Katharina; Wagner, Ernst; Bein, Thomas; Bräuchle, Christoph

2015-04-24

342

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

NASA Astrophysics Data System (ADS)

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

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

2012-02-01

343

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

SciTech Connect

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

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

1994-12-31

344

Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery  

PubMed Central

The rational design of a nanoplatform in drug delivery plays a crucial role in determining its targeting specificity and efficacy in vivo. A conventional approach relies on the surface conjugation of a nanometer-sized particle with two functionally distinct types of molecules, one as a targeting ligand, and the other as a therapeutic agent to be delivered to the diseased cell. However, an alternative simplified approach can be used, in which a single type of molecule displaying dual function as both a targeting ligand and therapeutic agent is conjugated to the nanoparticle. In this review, we evaluate the validity of this new strategy by using methotrexate, which displays multifunctional mechanisms of action. Methotrexate binds to the folate receptor, a surface biomarker frequently overexpressed in tumor cells, and also inhibits dihydrofolate reductase, an enzyme critical for cell survival and division. Thus we describe a series of fifth generation poly(amido amine) dendrimers conjugated with methotrexate, and discuss several lines of evidence supporting the efficacy of this new platform strategy based on surface plasmon resonance spectroscopy, enzyme activity assays, and cell-based studies with folate receptor (+) KB cancer cells. PMID:25590303

Wong, Pamela T.; Choi, Seok Ki

2015-01-01

345

Prodrug Strategy for PSMA-targeted Delivery of TGX-221 to Prostate Cancer Cells  

PubMed Central

TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110? catalytic subunit. Recent studies showed that TGX-221 has anti-proliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles were significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than the naked drug, and the drug clearance rate was 17.5-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment. PMID:22494444

Zhao, Yunqi; Duan, Shaofeng; Zeng, Xing; Liu, Chunjing; Davies, Neal M.; Li, Benyi; Forrest, M. Laird

2013-01-01

346

Methotrexate transport mechanisms: the basis for targeted drug delivery and ß-folate-receptor-specific treatment.  

PubMed

Methotrexate (MTX) plays a pivotal role in the treatment of rheumatoid arthritis (RA). The transport mechanisms with which MTX reaches is target after application are an important part of MTX pharmacology and its concentration in target tissue such as RA synovial membrane might strongly influence the effectiveness of the drug. Physiological plasma protein binding of MTX to albumin is important for the distribution of MTX in the body and relative high concentrations of the drug are found in the liver. However, targeted drug delivery into inflamed joints and increased anti-arthritic efficiency can be obtained by covalent coupling of MTX ex-vivo to human serum albumin (MTX-HSA) or in-vivo to endogenous albumin mediated through the MTX-pro-drug AWO54. High expression of the folate receptor ? (FR-?) on synovial macrophages of RA patients and its capacity to mediate binding and uptake of MTX has been demonstrated. To further improve drug treatment of RA, FR-? specific drugs have been developed and were characterised for their therapeutic potency in synovial inflammation. Therefore, different approaches to improve folate inhibitory and FR-? specific therapy of RA beyond MTX are in development and will be described. PMID:21044432

Fiehn, C

2010-01-01

347

Targeted Drug Delivery to Intestinal Macrophages by Bioactive Nanovesicles Released from Grapefruit  

PubMed Central

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

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

2014-01-01

348

Tumor Angiogenesis Therapy Using Targeted Delivery of Paclitaxel to the Vasculature of Breast Cancer Metastases  

PubMed Central

Breast cancer aberrantly expresses tissue factor (TF) in cancer tissues and cancer vascular endothelial cells (VECs). TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa). We have coupled PTX (paclitaxel, also named Taxol) with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01–0.05) compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis. PMID:25574399

Kisiel, Walter; Lu, Yang J.; Petersen, Lars C.; Ndungu, John M.; Moore, Terry W.; Parker, Ernest T.; Sun, Aiming; Liotta, Dennis C.; El-Rayes, Bassel F.; Brat, Daniel J.; Snyder, James P.; Shoji, Mamoru

2014-01-01

349

Fabrication of high specificity hollow mesoporous silica nanoparticles assisted by Eudragit for targeted drug delivery.  

PubMed

Hollow mesoporous silica nanoparticles (HMSNs) are one of the most promising carriers for effective drug delivery due to their large surface area, high volume for drug loading and excellent biocompatibility. However, the non-ionic surfactant templated HMSNs often have a broad size distribution and a defective mesoporous structure because of the difficulties involved in controlling the formation and organization of micelles for the growth of silica framework. In this paper, a novel "Eudragit assisted" strategy has been developed to fabricate HMSNs by utilising the Eudragit nanoparticles as cores and to assist in the self-assembly of micelle organisation. Highly dispersed mesoporous silica spheres with intact hollow interiors and through pores on the shell were fabricated. The HMSNs have a high surface area (670m(2)/g), small diameter (120nm) and uniform pore size (2.5nm) that facilitated the effective encapsulation of 5-fluorouracil within HMSNs, achieving a high loading capacity of 194.5mg(5-FU)/g(HMSNs). The HMSNs were non-cytotoxic to colorectal cancer cells SW480 and can be bioconjugated with Epidermal Growth Factor (EGF) for efficient and specific cell internalization. The high specificity and excellent targeting performance of EGF grafted HMSNs have demonstrated that they can become potential intracellular drug delivery vehicles for colorectal cancers via EGF-EGFR interaction. PMID:25617610

She, Xiaodong; Chen, Lijue; Velleman, Leonora; Li, Chengpeng; Zhu, Haijin; He, Canzhong; Wang, Tao; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

2015-05-01

350

PMMA/polysaccharides nanofilm loaded with adenosine deaminase inhibitor for targeted anti-inflammatory drug delivery.  

PubMed

A novel drug delivery vector, a free-standing polymeric ultrathin film (nanofilm) composed of PMMA and a polysaccharides multilayer, is presented. Chitosan and sodium alginate are alternatively deposited by spin-assisted LbL assembly onto a plasma-treated PMMA thin film. Hydrophobic anti-inflammatory drugs, an adenosine deaminase inhibitor (APP) and its fluorescent dansyl derivate (APP-Dns), are encapsulated inside the LbL multilayer using a simple casting deposition procedure. The resulting drug loaded nanofilm can be suspended in water upon dissolution of a PVA sacrificial layer. Morphological characterization of the nanofilm shows that PMMA/LbL nanofilms possess nanometric thickness (<200 nm) and very low surface roughness (1-2 nm for drug loaded nanofilms and <1 nm for blank nanofilm). Drug loaded films exhibit a diffusion controlled release mechanism following the Korsmayer-Peppas release model, confirmed by the fit of release data with a characteristic power law. Drug release is impaired through the PMMA layer, which acts effectively as a barrier for drug transport. This ultrathin polymer film can find application as a nanopatch for targeted inflammatory drug delivery to treat localized pathologies as inflammatory bowel disease. PMID:24073802

Redolfi Riva, Eugenio; Desii, Andrea; Sartini, Stefania; La Motta, Concettina; Mazzolai, Barbara; Mattoli, Virgilio

2013-10-29

351

Systemic delivery of small interfering RNA by use of targeted polycation liposomes for cancer therapy.  

PubMed

Novel polycation liposomes decorated with cyclic(Cys-Arg-Gly-Asp-D-Phe) peptide (cyclicRGD)-polyethylene glycol (PEG) (RGD-PEG-polycation liposomes (PCL)) were previously developed for cancer therapy based on RNA interference. Here, we demonstrate the in vivo delivery of small interfering RNA (siRNA) to tumors by use of RGD-PEG-PCL in B16F10 melanoma-bearing mice. Pharmacokinetic data obtained by positron emission tomography showed that cholesterol-conjugated siRNA formulated in RGD-PEG-PCL markedly accumulated in the tumors. Delivered by RGD-PEG-PCL, a therapeutic cocktail of siRNAs composed of cholesterol-conjugated siRNAs for c-myc, MDM2, and vascular endothelial growth factor (VEGF) were able to significantly inhibit the growth of B16F10 melanoma both in vitro and in vivo. These data suggest that targeted delivery of siRNAs by use of RGD-PEG-PCL has considerable potential for cancer treatment. PMID:23370357

Kenjo, Eriya; Asai, Tomohiro; Yonenaga, Norihito; Ando, Hidenori; Ishii, Takayuki; Hatanaka, Kentaro; Shimizu, Kosuke; Urita, Yugo; Dewa, Takehisa; Nango, Mamoru; Tsukada, Hideo; Oku, Naoto

2013-01-01

352

Development of colon targeted multiparticulate pulsatile drug delivery system for treating nocturnal asthma.  

PubMed

The aim of the present study was to develop theophylline fast release enteric-coated pellets as a pulsatile drug delivery to the colon. The novelty of this work is the combination of pH and time-dependant enteric polymers as a single coating for the development of multiparticulate formulation. Theophylline pellets were optimized by applying a 2-factors 3-levels full factorial design. Continuous dissolution studies were carried out in simulated gastric, intestinal, and colonic fluid with pH 1.2 (0.1 N HCl), pH 7.4 and pH 6.8 (phosphate buffer), respectively. The lag time prior to the drug release was highly affected by combination of two factors, i.e. the percentage of Eudragit RL100 in polymer mixture and coating level. The formulation containing Eudragit RL100 and Eudragit S100 with a ratio of 4:1 and coating level of 12%w/w was found to be optimum. The results of serum study in New Zealand rabbits showed that the developed formulation provided a significant lag phase of 5 h. The present study demonstrates that the theophylline enteric-coated pellets could be successfully colon targeted by the design of pH- and time-dependant modified chronopharmaceutical formulation. In conclusion, pulsatile drug release over a period of 3-12 h is consistent with the requirements for chronopharmaceutical drug delivery. PMID:20429842

Kadam, Vinayak D; Gattani, Surendra G

2010-07-01

353

Plasmid pORF-hTRAIL and doxorubicin co-delivery targeting to tumor using peptide-conjugated polyamidoamine dendrimer  

Microsoft Academic Search

A combination cancer therapy was investigated via co-delivery of therapeutic gene encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL) and doxorubicin (DOX) using a tumor-targeting carrier, peptide HAIYPRH (T7)-conjugated polyethylene glycol-modified polyamidoamine dendrimer (PAMAM-PEG-T7). T7, a transferrin receptor-specific peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. The result of fluorescence

Liang Han; Rongqin Huang; Jianfeng Li; Shuhuan Liu; Shixian Huang; Chen Jiang

2011-01-01

354

A photochemical approach for controlled drug release in targeted drug delivery  

PubMed Central

Photochemistry provides a unique mechanism that enables the active control of drug release in cancer-targeting drug delivery. This study investigates the light-mediated release of methotrexate, an anticancer drug, using a photocleavable linker strategy based on o-nitrobenzyl protection. We evaluated two types of the o-nitrobenzyl-linked methotrexate for the drug release study and further extended the study to a fifth-generation poly(amidoamine) dendrimer carrier covalently conjugated with methotrexate via the o-nitrobenzyl linker. We performed the drug release studies by using a combination of three standard analytical methods that include UV/vis spectrometry, 1H NMR spectroscopy, and anal. HPLC. This article reports that methotrexate is released by the photochemical mechanism in an actively controlled manner. The rate of the drug release varies in response to multiple control parameters, including linker design, light wavelength, exposure time, and the pH of the medium where the drug release occurs. PMID:22225916

Choi, Seok Ki; Verma, Manisha; Silpe, Justin; Moody, Ryan E.; Tang, Kenny; Hanson, Jeffrey J.; Baker, James R.

2012-01-01

355

Targeted drug delivery to flow-obstructed blood vessels using mechanically activated nanotherapeutics.  

PubMed

Obstruction of normal blood flow, which occurs in a variety of diseases, including thromboembolism in stroke and atherosclerosis, is a leading cause of death and long-term adult disability in the Western world. This review focuses on a novel nanotherapeutic drug-delivery platform that is mechanically activated within blood vessels by high-fluid shear stresses to selectively target drugs to sites of vascular obstruction. In vitro and in vivo studies have shown that this approach can be used to efficiently lyse clots using a significantly lower amount of thrombolytic drug than is required when administered in a soluble formulation. This nanotherapeutic strategy can potentially improve both the efficacy and safety of thrombolytic drugs, particularly in patients who are at high risk for brain hemorrhage, and thus provide a new approach for the treatment of many life-threatening and debilitating vascular disorders. PMID:25365638

Korin, Netanel; Gounis, Matthew J; Wakhloo, Ajay K; Ingber, Donald E

2015-01-01

356

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

NASA Astrophysics Data System (ADS)

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

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

2010-12-01

357

Multi-ligand nanoparticles for targeted drug delivery to the injured vascular wall  

NASA Astrophysics Data System (ADS)

Pathological conditions like coronary artery disease, acute myocardial infarction, stroke, and peripheral artery diseases as well as cardiovascular interventions used in the treatment of coronary artery diseases such as angioplasty and stenting damage/injure the blood vessel wall, leading to inflamed or activated endothelial cells that have been implicated in events leading to thrombosis, inflammation, and restenosis. Oral administration of anti-coagulant and anti-inflammatory drugs causes systemic toxicity, bleeding, patient incompliance, and inadequate amounts of drugs at the injured area. Though drug-eluting stents have shown therapeutic benefits, complications such as in-stent restenosis and late thrombosis still remain and are a cause for concern. Rapid growth in the field of nanotechnology and nanoscience in recent years has paved the way for new targeted and controlled drug delivery strategies. In this perspective, the development of biodegradable nanoparticles for targeted intracellular drug delivery to the inflamed endothelial cells may offer an improved avenue for treatment of cardiovascular diseases. The major objective of this research was to develop "novel multi-ligand nanoparticles," as drug carriers that can efficiently target and deliver therapeutic agents to the injured/inflamed vascular cells under dynamic flow conditions. Our approach mimics the natural binding ability of platelets to injured/activated endothelial cells through glycoprotein Ib (GPIb) bound to P-selectin expressed on inflamed endothelial cells and to the subendothelium through GPIb binding to von Willebrand factor (vWF) deposited onto the injured vascular wall. Our design also exploits the natural cell membrane translocation ability of the internalizing cell peptide - trans-activating transcriptor (TAT) to enhance the nanoparticle uptake by the targeted cells. Our hypothesis is that these multi-ligand nanoparticles would show an increased accumulation at the injury site since GPIb specially binds to both P-selectin expressed on damaged endothelial cells and vWF deposited on injured subendothelium while the cell penetrating peptide -- TAT would facilitate enhanced uptake of these nanoparticles by the damaged vascular cells. To test this hypothesis, fluorescent drug loaded poly (D, L-lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) nanoparticles (PLGA-PEG NPs) were formulated using a standard double emulsion method. We further conjugated GPIb and TAT via carbodiimide and avidin-biotin chemistry to the PLGA-PEG nanoparticles. Characterization of these nanoparticles indicated the average size to be about 200nm. Endothelial cell uptake studies indicated an optimal nanoparticle incubation time of one hour and optimal dose of 400 mug/ml. Biocompatibility results showed these particles to be non-toxic to endothelial cells. Moreover, dexamethasone release profiles from the nanoparticles demonstrated their ability to provide a sustained drug release over four weeks. Static and dynamic uptake studies of control, GPIb-conjugated, and GPIb-TAT-conjugated PLGA-PEG nanoparticles on activated endothelial cells exhibited an increased adhesion and uptake of GPIb-TAT conjugated PLGA-PEG nanoparticles compared to control nanoparticles. A similar trend of significantly higher adhesion of GPIb-TAT conjugated PLGA-PEG nanoparticles to the injured vessel wall was also observed in preliminary ex-vivo studies using the rat carotid injury model. These results suggest that "our novel multi-ligand NPs" would provide a unique active targeting strategy. This system would rapidly target and deliver therapeutic agents to the injured vascular wall under flow conditions. It could also serve as an effective therapeutic delivery system to treat the complications associated with cardiovascular diseases.

Kona, Soujanya

358

Combination of antibody targeting and PTD-mediated intracellular toxin delivery for colorectal cancer therapy.  

PubMed

The bottlenecks of current chemotherapy in the treatment of colorectal cancer lie in the ineffectiveness of the existing anti-cancer small molecule drugs as well as the dose-limiting toxicity caused by the nonselective action on normal tissues by such drugs. To address these problems, we introduce a novel therapeutic strategy based on tumor targeting using a non-internalizing anti-carcinoembryonic antigen (CEA) monoclonal antibody (mAb) and intracellular delivery of the extremely potent yet cell-impermeable protein toxin gelonin via the aid of a cell-penetrating peptide (also termed as protein transduction domain; PTD). A chimeric TAT-gelonin fusion protein was genetically engineered, and it displayed remarkably enhanced anti-cancer activity against human colorectal cancer cells, with IC50 values being several orders of magnitude lower than the unmodified gelonin. On the other hand, a chemically synthesized conjugate of heparin and a murine anti-CEA mAb, T84.66 (termed T84.66-Hep) was found able to bind highly specifically to CEA over-expressing LS174T colorectal cancer cells. When mixing together, TAT-gelonin and T84.66-Hep could associate tightly and automatically through an electrostatic interaction between the cationic TAT and anionic heparin. In preliminary in vivo studies using LS174T s.c. xenograft tumor bearing mouse, selective and significantly augmented (58-fold) delivery of TAT-gelonin to the tumor target was observed, when compared with administration of TAT-gelonin alone. More importantly, efficacy studies also revealed that only the TAT-gelonin/T84.66-Hep complex yielded a significant inhibition of tumor growth (46%) without causing gelonin-induced systemic toxicity. Overall, this study suggested a generic strategy to effectively yet safely deliver potent PTD-modified protein toxins to the tumor. PMID:25204286

Shin, Meong Cheol; Zhang, Jian; Min, Kyoung Ah; Lee, Kyuri; Moon, Cheol; Balthasar, Joseph P; Yang, Victor C

2014-11-28

359

Poly(NIPAm-AMPS) nanoparticles for targeted delivery of anti-inflammatory cell penetrating peptides  

NASA Astrophysics Data System (ADS)

Inflammatory diseases such as osteoarthritis and rheumatoid arthritis cause $127.8 billion in US healthcare expenditures each year and are the cause of disability for 27% of disabled persons in the United States. Current treatment options rarely halt disease progression and often result in significant unwanted and debilitating side effects. Our laboratory has previously developed a family of cell penetrating peptides (CPPs) which inhibit the activity of mitogen activated protein kinase activate protein kinase 2 (MK2). MK2 mediates the inflammatory response by activating Tristetraprline (TTP). Once activated, TTP rapidly stabilizes AU rich regions of pro-inflammatory cytokine mRNA which allows translation of pro-inflammatory cytokines to occur. Blocking MK2 with our labs CPPs yields a decrease in inflammatory activity but CPPs by are highly non specific and prone to rapid enzymatic degradation in vivo.. In order to increase the potency of MK2 inhibiting CPPs we have developed a novel nanoparticle drug carrier composed of poly(N-isopropylacrylamide-co-2-acrylamido-2-methyl-1-propanesulfonic acid). This drug carrier has been shown to have preliminary efficacy in vitro and ex vivo for suppressing pro-inflammatory cytokine production when releasing CPPs. This thesis will present progress made on three aims: Specific Aim 1) Create and validate a NIPAm based drug delivery system that mimics the binding and release previously observed between cell penetrating peptides and glycosaminoglycans. Specific Aim 2) Engineer degradability into poly(NIPAm-AMPS) nanoparticles to enable more drug to be released and qualify that system in vitro. Specific Aim 3) Validate poly(NIPAm-AMPS) nanoparticles for targeted drug delivery in an ex vivo inflammatory model. Overall we have developed a novel anionic nanoparticle system that is biocompatible and efficient at loading and releasing cell penetrating peptides to inflamed tissue. Once loaded with a CPP the nanoparticle drug complex is capable of targeting diseased tissue and preventing the production of pro-inflammatory cytokines in both in vitro and ex vivo models.

Bartlett, Rush Lloyd, II

360

Locally targeted delivery of a micron-size radiation therapy source using temperature-sensitive hydrogel  

PubMed Central

Purpose To propose a novel radiotherapy (RT) delivery modality—locally targeted delivery of micro-size level RT sources using temperature-sensitive hydroGEL (RT-GEL) as an injectable vehicle. Methods and Materials Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two FDA-approved polymers were synthesized. Indium-111 (In-111) was used as a radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-Saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and three with RT-Saline. A SPECT and a CT scan were performed on each mouse at 0, 24, and 48 hours after injection. The efficacy of RT-GEL over the control datasets was determined by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. Results RT-GEL was successfully injected to the tumor using 30-gauge needles. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-Saline. The residual tumor activities of In-111 were 49% (44%) at 24 hours (48 hour) for RT-GEL and 29% (22%) for RT-Saline. SPECT-CT fused images of RT-Saline show considerable kidney accumulation of In-111 (2,886%, 261% and 262% of RT-GEL at the 0, 24 and 48 hour marks, respectively). Conclusion RT-GEL was successfully injected and showed much higher residual tumor activity 170% (200%) than that of RT-Saline 24 hour (48 hour) after injection with a minimal accumulation of In-111 to the kidneys. The preliminary data of RT-GEL as a delivery modality of a radiation source to a local tumor is promising. PMID:24495593

Kim, Y; Seol, DR; Mohapatra, S; Sunderland, JJ; Schultz, MK; Domann, FE; Lim, TH

2014-01-01

361

Templateless Synthesis of Polyacrylamide-Based Nanogels via RAFT Dispersion Polymerization.  

PubMed

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. PMID:25684634

Ma, Kai; Xu, Yuanyuan; An, Zesheng

2015-03-01

362

Aerosol fabrication of thermosensitive nanogels and in situ hybridization with iron nanoparticles  

NASA Astrophysics Data System (ADS)

Collison atomized n-isopropylacrylamide (NIPAM) droplets were thermally treated with different furnace wall temperatures to form nanogels in an aerosol state. The size of the aerosol nanogels decreased from 40.3 nm to 32.8 nm by increasing the temperature from 40 °C to 90 °C due to the coil-to-globule transition of the NIPAM. A serial reactor consisting of a spark generator coupled to a collison atomizer was further employed to efficiently (>90% in production yield) fabricate biocompatible (78.8% in cell viability)-magnetic (30.3 emu g-1 in saturation magnetization) hybrid nanogels of NIPAM and iron nanoparticles.

Byeon, Jeong Hoon; Kim, Jang-Woo

2012-07-01

363

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

PubMed Central

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

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

2013-01-01

364

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery  

PubMed Central

Background Modular nanotransporters (MNT) are recombinant multifunctional polypeptides created to exploit a cascade of cellular processes, initiated with membrane receptor recognition to deliver selective short-range and highly cytotoxic therapeutics to the cell nucleus. This research was designed for in vivo concept testing for this drug delivery platform using two modular nanotransporters, one targeted to the ?-melanocyte-stimulating hormone (?MSH) receptor overexpressed on melanoma cells and the other to the epidermal growth factor (EGF) receptor overexpressed on several cancers, including glioblastoma, and head-and-neck and breast carcinoma cells. Methods In vivo targeting of the modular nanotransporter was determined by immuno-fluorescence confocal laser scanning microscopy and by accumulation of 125I-labeled modular nanotransporters. The in vivo therapeutic effects of the modular nanotransporters were assessed by photodynamic therapy studies, given that the cytotoxicity of photosensitizers is critically dependent on their delivery to the cell nucleus. Results Immunohistochemical analyses of tumor and neighboring normal tissues of mice injected with multifunctional nanotransporters demonstrated preferential uptake in tumor tissue, particularly in cell nuclei. With 125I-labeled MNT{?MSH}, optimal tumor:muscle and tumor:skin ratios of 8:1 and 9.8:1, respectively, were observed 3 hours after injection in B16-F1 melanoma-bearing mice. Treatment with bacteriochlorin p-MNT{?MSH} yielded 89%–98% tumor growth inhibition and a two-fold increase in survival for mice with B16-F1 and Cloudman S91 melanomas. Likewise, treatment of A431 human epidermoid carcinoma-bearing mice with chlorin e6- MNT{EGF} resulted in 94% tumor growth inhibition compared with free chlorin e6, with 75% of animals surviving at 3 months compared with 0% and 20% for untreated and free chlorin e6-treated groups, respectively. Conclusion The multifunctional nanotransporter approach provides a new in vivo functional platform for drug development that could, in principle, be applicable to any combination of cell surface receptor and agent (photosensitizers, oligonucleotides, radionuclides) requiring nuclear delivery to achieve maximum effectiveness. PMID:22346349

Slastnikova, Tatiana A; Rosenkranz, Andrey A; Gulak, Pavel V; Schiffelers, Raymond M; Lupanova, Tatiana N; Khramtsov, Yuri V; Zalutsky, Michael R; Sobolev, Alexander S

2012-01-01

365

Heparin-folate-retinoic acid bioconjugates for targeted delivery of hydrophobic photosensitizers.  

PubMed

Amphiphilic heparin-retinoic acid (HR) and heparin-folate-retinoic acid bioconjugates (HFR) were synthesized by chemical conjugation of a hydrophobic anticancer agent all-trans-retinoic acid (RA) and a targeting ligand, folic acid (FA), to the high molecular weight heparin backbone. The HR and HFR bioconjugates had a high RA content (22%, w/w) and could self-assemble into nanoparticles with efficient encapsulation of a hydrophobic photosensitizer, pheophorbide a (PhA). The HFR bioconjugate demonstrated higher PhA loading content and loading efficiency compared to HR bioconjugate. The PhA-loaded HR and HFR nanoparticles had an average diameter of about 70 nm, a negatively charged surface, a sustained release pattern and self-quenching effect in a buffered solution. Furthermore, the cellular uptake of PhA-loaded HFR nanoparticles in folate receptor-positive HeLa cells was higher than that of PhA-loaded HR nanoparticles. Upon irradiation, HFR nanoparticles selectively enhanced the phototoxicity of PhA in HeLa cells while the dark-toxicity of the nanoparticles was minimal without light treatment. HFR nanoparticles also demonstrated targeted anti-cancer effect, improving the cytotoxicity of RA in HeLa cells compared to HR nanoparticles at RA concentration ?50 ?g/mL. The targeting effect of HFR and PhA-loaded HFR nanoparticles was not observed in folate receptor-negative HT-29 cells. The results indicated that HFR nanoparticles may be useful for targeted delivery of hydrophobic PDT agents and as a potential nanocarrier for dual chemo-and photodynamic therapies. PMID:23399198

Tran, Thanh Huyen; Bae, Byoung-chan; Lee, Yong-kyu; Na, Kun; Huh, Kang Moo

2013-02-15

366

Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors  

PubMed Central

Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and “bridging” interactions. “Bridging” interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of “bridging interactions” such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated “stealth” vectors which avoid these interactions. Simultaneous retargeting and detargeting can be achieved by combining multiple genetic and/or chemical modifications. PMID:21994621

Coughlan, Lynda; Alba, Raul; Parker, Alan L.; Bradshaw, Angela C.; McNeish, Iain A.; Nicklin, Stuart A.; Baker, Andrew H.

2010-01-01

367

Tropism-modification strategies for targeted gene delivery using adenoviral vectors.  

PubMed

Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e. CAR/integrins/heparan sulfate proteoglycans) and "bridging" interactions. "Bridging" interactions refer to coagulation factor binding, namely coagulation factor X (FX), which bridges hepatocyte transduction in vivo through engagement with surface expressed heparan sulfate proteoglycans (HSPGs). These interactions can contribute to the off-target sequestration of Ad5 in the liver and its characteristic dose-limiting hepatotoxicity, thereby significantly limiting the in vivo targeting efficiency and clinical potential of Ad5-based therapeutics. To date, various approaches to retargeting adenoviruses (Ad) have been described. These include genetic modification strategies to incorporate peptide ligands (within fiber knob domain, fiber shaft, penton base, pIX or hexon), pseudotyping of capsid proteins to include whole fiber substitutions or fiber knob chimeras, pseudotyping with non-human Ad species or with capsid proteins derived from other viral families, hexon hypervariable region (HVR) substitutions and adapter-based conjugation/crosslinking of scFv, growth factors or monoclonal antibodies directed against surface-expressed target antigens. In order to maximize retargeting, strategies which permit detargeting from undesirable interactions between the Ad capsid and components of the circulatory system (e.g. coagulation factors, erythrocytes, pre-existing neutralizing antibodies), can be employed simultaneously. Detargeting can be achieved by genetic ablation of native receptor-binding determinants, ablation of "bridging interactions" such as those which occur between the hexon of Ad5 and coagulation factor X (FX), or alternatively, through the use of polymer-coated "stealth" vectors which avoid these interactions. Simultaneous retargeting and detargeting can be achieved by combining multiple genetic and/or chemical modifications. PMID:21994621

Coughlan, Lynda; Alba, Raul; Parker, Alan L; Bradshaw, Angela C; McNeish, Iain A; Nicklin, Stuart A; Baker, Andrew H

2010-10-01

368

Delivery of lipid micelles into infarcted myocardium using a lipid-linked matrix metalloproteinase targeting Peptide.  

PubMed

There is a great need for delivery strategies capable of efficiently localizing drugs to the damaged myocardium that do not require direct intramyocardial injection of therapeutic molecules. In the work discussed here, we exploited the myocardium-specific upregulation of matrix metalloproteinases (MMPs) that occurs during myocardium remodeling by designing a micellar vehicle containing an MMP-targeting peptide (MMP-TP). The binding of MMP-TP to MMP was evaluated with purified MMP-2 protein and U-937 cells induced to overexpress MMP. Inhibition of MMP-2 activity was not observed in the presence of unmodified micelles but was pronounced at a 5 mol % MMP-TP ligand density. In a FACS analysis, MMP-TP micelles containing 5 mol % of the MMP-targeting peptide showed ?10-fold higher binding to activated U937 cells than plain micelles and micelles containing a control peptide with two amino acid replacements. MMP-TP-micelles and plain micelles were injected intravenously into C57BL/6 mice 1, 3, and 7 days after the induction of a myocardial infarction (MI). Immunohistochemistry performed on heart tissue sections revealed that MMP-TP-micelles colocalize with both MMP and infiltrating macrophages. MMP-TP micelles showed significantly enhanced accumulation to the necrotic area of the heart after MI on days 3 and 7 when compared to plain micelles and negative control peptide micelles. This is coincident with the measured temporal profile of MMP gene expression in the heart after MI. These results suggest that MMP-TP micelles are candidates for the development of targeted regenerative heart therapeutics because of their ability to target the infarcted myocardium in a MMP dependent manner. PMID:25642730

Nguyen, Juliane; Sievers, Richard; Motion, J P Michael; Kivimäe, Saul; Fang, Qizhi; Lee, Randall J

2015-04-01

369

Folate-modified lipid–polymer hybrid nanoparticles for targeted paclitaxel delivery  

PubMed Central

The purpose of this study was to develop a novel lipid–polymer hybrid drug carrier comprised of folate (FA) modified lipid-shell and polymer-core nanoparticles (FLPNPs) for sustained, controlled, and targeted delivery of paclitaxel (PTX). The core-shell NPs consist of 1) a poly(?-caprolactone) hydrophobic core based on self-assembly of poly(?-caprolactone)–poly(ethylene glycol)–poly(?-caprolactone) (PCL-PEG-PCL) amphiphilic copolymers, 2) a lipid monolayer formed with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000), 3) a targeting ligand (FA) on the surface, and were prepared using a thin-film hydration and ultrasonic dispersion method. Transmission electron microscopy and dynamic light scattering analysis confirmed the coating of the lipid monolayer on the hydrophobic polymer core. Physicochemical characterizations of PTX-loaded FLPNPs, such as particle size and size distribution, zeta potential, morphology, drug loading content, encapsulation efficiency, and in vitro drug release, were also evaluated. Fluorescent microscopy proved the internalization efficiency and targeting ability of the folate conjugated on the lipid monolayer for the EMT6 cancer cells which overexpress folate receptor. In vitro cytotoxicity assay demonstrated that the cytotoxic effect of PTX-loaded FLPNPs was lower than that of Taxol®, but higher than that of PTX-loaded LPNPs (without folate conjugation). In EMT6 breast tumor model, intratumoral administration of PTX-loaded FLPNPs showed similar antitumor efficacy but low toxicity compared to Taxol®. More importantly, PTX-loaded FLPNPs showed greater tumor growth inhibition (65.78%) than the nontargeted PTX-loaded LPNPs (48.38%) (P<0.05). These findings indicated that the PTX loaded-FLPNPs with mixed lipid monolayer shell and biodegradable polymer core would be a promising nanosized drug formulation for tumor-targeted therapy.

Zhang, Linhua; Zhu, Dunwan; Dong, Xia; Sun, Hongfan; Song, Cunxian; Wang, Chun; Kong, Deling

2015-01-01

370

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

NASA Astrophysics Data System (ADS)

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

D'Addio, Suzanne M.

371

Nanogel-quantum dot hybrid nanoparticles for live cell imaging  

SciTech Connect

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.

Hasegawa, Urara [Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan); Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, 2-3-10, Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan); Nomura, Shin-ichiro M. [Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan); Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, 2-3-10, Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan); Kaul, Sunil C. [National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562 (Japan); Hirano, Takashi [National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8562 (Japan); Akiyoshi, Kazunari [Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10, Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan); Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, 2-3-10, Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062 (Japan); E-mail: akiyoshi.org@tmd.ac.jp

2005-06-17

372

Aptamer-Mediated Up-conversion Core/MOF Shell Nanocomposites for Targeted Drug Delivery and Cell Imaging  

PubMed Central

Multifunctional nanocarriers for targeted bioimaging and drug delivery have attracted much attention in early diagnosis and therapy of cancer. In this work, we develop a novel aptamer-guided nanocarrier based on the mesoporous metal-organic framework (MOF) shell and up-conversion luminescent NaYF4:Yb3+/Er3+ nanoparticles (UCNPs) core for the first time to achieve these goals. These UCNPs, chosen as optical labels in biological assays and medical imaging, could emit strong green emission under 980?nm laser. The MOF structure based on iron (III) carboxylate materials [MIL-100 (Fe)] possesses high porosity and non-toxicity, which is of great value as nanocarriers for drug storage/delivery. As a unique nanoplatform, the hybrid inorganic-organic drug delivery vehicles show great promising for simultaneous targeted labeling and therapy of cancer cells. PMID:25597762

Deng, Kerong; Hou, Zhiyao; Li, Xuejiao; Li, Chunxia; Zhang, Yuanxin; Deng, Xiaoran; Cheng, Ziyong; Lin, Jun

2015-01-01

373

Delivery.  

PubMed

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

Miller, Thomas A

2013-11-01

374

Delivery  

PubMed Central

Enthusiasm greeted the development of synthetic organic insecticides in the mid-twentieth century, only to see this give way to dismay and eventually scepticism and outright opposition by some. Regardless of how anyone feels about this issue, insecticides and other pesticides have become indispensable, which creates something of a dilemma. Possibly as a result of the shift in public attitude towards insecticides, genetic engineering of microbes was first met with scepticism and caution among scientists. Later, the development of genetically modified crop plants was met with an attitude that hardened into both acceptance and hard-core resistance. Transgenic insects, which came along at the dawn of the twenty-first century, encountered an entrenched opposition. Those of us responsible for studying the protection of crops have been affected more or less by these protagonist and antagonistic positions, and the experiences have often left one thoughtfully mystified as decisions are made by non-participants. Most of the issues boil down to concerns over delivery mechanisms. © 2013 Society of Chemical Industry PMID:23852646

Miller, Thomas A

2013-01-01

375

Efficient gene delivery targeted to the brain using a transferrin-conjugated polyethyleneglycol-modified polyamidoamine dendrimer  

Microsoft Academic Search

The blood-brain barrier (BBB) poses great difficulties for gene delivery to the brain. To circumvent the BBB, we investigated a novel brain-targeting gene vector based on the nanoscopic high-branching den- drimer, polyamidoamine (PAMAM), in vitro and in vivo. Transferrin (Tf) was selected as a brain-targeting ligand conjugated to PAMAM via bifunctional polyethylenegly- col (PEG), yielding PAMAM-PEG-Tf. UV and nuclear magnetic

Rong-Qin Huang; Ying-Hua Qu; Wei-Lun Ke; Jian-Hua Zhu; Yuan-Ying Pei; Chen Jiang

2007-01-01

376

Expression and characterization of myristoylated preS1-conjugated nanocages for targeted cell delivery.  

PubMed

Lipid modification of proteins plays key roles in cellular signaling pathways. We describe the development of myristoylated preS1-nanocages (myr-preS1-nanocages) that specifically target human hepatocyte-like HepaRG cells in which a specific receptor-binding peptide (preS1) is joined to the surface of naturally occurring ferritin cages. Using a genetic engineering approach, the preS1 peptide was joined to the N-terminal regions of the ferritin cage via flexible linker moieties. Myristoylation of the preS1 peptide was achieved by co-expression with yeast N-myristoyltransferase-1 in the presence of myristic acid in Escherichia coli cells. The myristoylated preS1-nanocages exhibited significantly greater specificity for human hepatocyte-like HepaRG cells than the unmyristoylated preS1-nanocages. These results suggest that the lipid-modified nanocages have great potential for effective targeted delivery to specific cells. PMID:25497224

Murata, Masaharu; Piao, Jing Shu; Narahara, Sayoko; Kawano, Takahito; Hamano, Nobuhito; Kang, Jeong-Hun; Asai, Daisuke; Ugawa, Ryo; Hashizume, Makoto

2015-06-01

377

Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors.  

PubMed

Exosomes, the endogenous nanocarriers that can deliver biological information between cells, were recently introduced as new kind of drug delivery system. However, mammalian cells release relatively low quantities of exosomes, and purification of exosomes is difficult. Here, we developed bioinspired exosome-mimetic nanovesicles that deliver chemotherapeutics to the tumor tissue after systemic administration. The chemotherapeutics-loaded nanovesicles were produced by the breakdown of monocytes or macrophages using a serial extrusion through filters with diminishing pore sizes (10, 5, and 1 ?m). These cell-derived nanovesicles have similar characteristics with the exosomes but have 100-fold higher production yield. Furthermore, the nanovesicles have natural targeting ability of cells by maintaining the topology of plasma membrane proteins. In vitro, chemotherapeutic drug-loaded nanovesicles induced TNF-?-stimulated endothelial cell death in a dose-dependent manner. In vivo, experiments in mice showed that the chemotherapeutic drug-loaded nanovesicles traffic to tumor tissue and reduce tumor growth without the adverse effects observed with equipotent free drug. Furthermore, compared with doxorubicin-loaded exosomes, doxorubicin-loaded nanovesicles showed similar in vivo antitumor activity. However, doxorubicin-loaded liposomes that did not carry targeting proteins were inefficient in reducing tumor growth. Importantly, removal of the plasma membrane proteins by trypsinization eliminated the therapeutic effects of the nanovesicles both in vitro and in vivo. Taken together, these studies suggest that the bioengineered nanovesicles can serve as novel exosome-mimetics to effectively deliver chemotherapeutics to treat malignant tumors. PMID:24004438

Jang, Su Chul; Kim, Oh Youn; Yoon, Chang Min; Choi, Dong-Sic; Roh, Tae-Young; Park, Jaesung; Nilsson, Jonas; Lötvall, Jan; Kim, Yoon-Keun; Gho, Yong Song

2013-09-24

378

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

PubMed

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

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

2012-02-28

379

Dual targeted polymeric nanoparticles based on tumor endothelium and tumor cells for enhanced antitumor drug delivery.  

PubMed

Some specific types of tumor cells and tumor endothelial cells represented CD13 proteins and act as receptors for Asn-Gly-Arg (NGR) motifs containing peptide. These CD13 receptors can be speci