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ABSTRACT: Modification of carbon nanotubes (CNTs) with carboxyl group is one of the widely used strategies to increase their water dispersibility. Various molecules can be further coupled to the surface of carboxylated CNTs for the desired applications. However, the effect of carboxylation of CNTs on their cytotoxicity is far from being completely understood. In the present study, the impact of carboxylated multi-walled carbon nanotube (MWCNT-COOH) on human normal liver cell line L02 was studied and compared with pristine multi-walled carbon nanotube (p-MWCNT). The data accumulated in the current study revealed that modification with carboxyl group reduced the toxicity of MWCNT on L02 cells, probably due to the decreased activation of mitochondria mediated apoptotic pathway. Both p-MWCNT and MWCNT-COOH, when reaching to certain concentration, induced significant decrease in the mitochondrial membrane potential (MMP), enhanced release of cytochrome c (cyto-c) from the mitochondria to cytoplasm as well as activation of caspase-9, and -3. However, the changes induced by MWCNT-COOH were significantly milder than that by p-MWCNT. Our observation suggests that carboxylated MWCNTs might be safer for in vivo application as compared with p-MWCNT.
Journal of Biomedical Materials Research Part A 03/2013; · 2.63 Impact Factor
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DunWan Zhu,
HaiLing Zhang,
JinGen Bai,
WenGuang Liu,
XiGang Leng, CunXian Song,
Jian Yang,
XiaoWei Li,
Xu Jin,
LiPing Song,
LanXia Liu,
XiuLan Li,
Yang Zhang,
KangDe Yao
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ABSTRACT: Arginine-rich peptides have attracted considerable attention due to their distinct internalization mechanism. It was reported
that arginine and guanidino moieties were able to translocate through cell membranes and played a critical role in the process
of membrane permeation. In this work, arginine was conjugated to the backbone of chitosan to form a novel chitosan derivative,
arginine modified chitosan (Arg-CS). Arg-CS/DNA complexes were prepared according to the method of coacervation process. The
physicochemical properties of Arg-CS and Arg-CS/DNA complexes were characterized and the transfection activity and efficiency
mediated by Arg-CS/DNA complexes were investigated taking HeLa cells as target cells. Arg-CS was characterized by FTIR and
13C NMR. Arg-CS/DNA polyelectrolyte complexes were investigated by agarose gel retardation, dynamic light scattering (DLS) and
atomic force microscopy (AFM). The results revealed that the Arg-CS/DNA complexes started to form at N/P ratio of 2:1, and
the size of particles varied from 100 to 180 nm. The cytotoxicity of Arg-CS and their complexes with plasmid DNA were determined
by MTT assay for HeLa cells, and the results suggested that Arg-CS/DNA complexes were slightly less toxic than Arg-CS. Moreover,
the derivative alone and their complexes showed significantly lower toxicity than PEI and PEI/DNA complexes, respectively.
Taking HeLa cells as target cells and using pGL3-control as reporter gene, the luciferase expression mediated by Arg-CS was
greatly enhanced to about 100 folds compared with the luciferase expression mediated by chitosan at different pH media. These
results suggest that Arg-CS is a promising candidate as a safe and efficient vector for gene delivery and transfection.
Chinese Science Bulletin 04/2012; 52(23):3207-3215. · 1.32 Impact Factor
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ABSTRACT: Oral administration of insulin is a promising drug delivery system for diabetic patients as it is convenient and reduces pain, two of the major contributors to non-compliance.
In this study, insulin was encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) by using double-emulsion/solvent evaporation technique and analyses on its release kinetics were carried out using both in vitro and in vivo methods.
First, only by this simple methods, release speed of insulin from NPs can be controlled in different pH solution. The rate of release of insulin was found to be slower in acidic pH; about 90% of insulin was released in 11 days at pH 1.0. In alkaline conditions, the release was faster; about 90% release was observed to occur within 3 days at pH 7.8. The insulin-loaded poly (lactic-co-glycolic acid) nanoparticles (PINPs) were administered orally to diabetes mellitus-induced rats and the response of blood glucose and insulin levels was estimated. Blood glucose decreased and the concentration of insulin in animal blood increased. In diabetic animals which were administered intermittent insulin, every 8 h, blood glucose levels were maintained equivalently with those of healthy rats.
These experimental results indicated that oral PINPs are able to deliver insulin effectively and decrease animal blood sugar; in conclusion, this may be a promising delivery system for the treatment of diabetes.
Diabetes Obesity and Metabolism 12/2011; 14(4):358-64. · 3.38 Impact Factor
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Journal of Controlled Release 11/2011; 152 Suppl 1:e114-6. · 5.73 Impact Factor
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Journal of Controlled Release 11/2011; 152 Suppl 1:e29-31. · 5.73 Impact Factor
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ABSTRACT: The present study describes a novel strategy to covalently immobilize genes onto inert PLGA films via -CONH-cross-links. PLGA with functional carboxylic acid groups was synthesized using free-radical grafting maleic anhydride (MA) groups onto the polymer backbone. Cationic PEI/DNA complexes were successfully immobilized onto the functional PLGA films and characterized by ATR-FTIR and SEM analysis. We conclude that robust PLGA with functional carboxylic groups is a suitable platform for localized gene delivery.
Journal of Controlled Release 11/2011; 152 Suppl 1:e161-3. · 5.73 Impact Factor
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ABSTRACT: A metal stent that could elute plasmid DNA (pDNA) for substrate-mediated gene transfection was fabricated by first coating with polyallylamine bisphosphonate (PAA-BP) and subsequent deposition of pDNA. To create a pDNA coating layer on the stent surface, anti-DNA antibody was chemically coupled on the PAA-BP coating. PAA-BP was conjugated to IgM by covalent cross-linking with N-succinimidyl-3(2-pyridyldithio) propionate (SPDP). In cell culture studies, green fluorescent protein (GFP)-transfected cells were only found on the stent, which demonstrated high localization and efficient gene delivery.
Journal of Controlled Release 11/2011; 152 Suppl 1:e173-4. · 5.73 Impact Factor
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ABSTRACT: The purpose of this study was to develop polymeric nanoscale drug-delivery system (nano-DDS) for paclitaxel (PTX) from poly(ɛ-caprolactone)-poly(ethylene glycol)-poly(ɛ-caprolactone) (PCL-PEG-PCL, PCEC) copolymers, intended to be intravenously administered, able to improve the therapeutic efficacy of the drug and devoid of the adverse effects of Cremophor EL. Both of the PTX-loaded polymeric micelles and polymersomes were successfully prepared from PCEC copolymers. The obtained PTX-loaded micelles exhibited core-shell morphology with satisfactory size (93 nm), and were favorable for intravenous injection. In vitro cytotoxicity demonstrated that the cytotoxic effect of PTX-loaded micelles was lower than that of Taxol (Bristol-Myers Squibb, Princeton, New Jersey). Pharmacokinetic results indicated that the PTX-loaded micelles had longer systemic circulation time and slower plasma elimination rate than those of Taxol. Furthermore, PTX-loaded micelles showed greater tumor growth-inhibition effect in vivo on EMT6 breast tumor, in comparison with Taxol. Therefore, the prepared polymeric micelles might be potential nano-DDS for PTX delivery in cancer chemotherapy.
Nanomedicine: nanotechnology, biology, and medicine 11/2011; 8(6):925-34. · 5.44 Impact Factor
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ABSTRACT: Intra-articular drug delivery is the preferred approach for targeting pharmacologic treatment directly at the joints to reduce undesirable side effects associated with systemic drug delivery. In this study, a controlled delivery system of methotrexate (MTX) based on injectable thermosensitive poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PEP) hydrogels was developed for the intra-articular drug delivery. The thermosensitive PEP copolymers were prepared by ring-opening polymerization. The synthesized PEP copolymers were characterized for their structure, composition, and the sol-to-gel transition. The in vitro MTX release from the PEP hydrogels was studied. MTX plasma concentration following intra-articular injection into healthy rats was determined by HPLC. Biocompatibility was confirmed by histology analysis after the intra-articular injection. The synthesized PEP copolymers aqueous solutions formed in situ gel rapidly after the injection. PEP hydrogels showed the ability to control the release of incorporated MTX. Following intra-articular injection, the PEP hydrogels decreased the clearance rate of MTX in the joint cavity. The maximum plasma concentrations of MTX in rats injected with free MTX were threefold higher than that of the groups injected with MTX hydrogels. These results suggest that the intra-articular delivery of the PEP hydrogels may be a viable strategy for the controlled release of drugs for treating arthritis diseases. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Journal of Applied Polymer Science 06/2011; 122(3):2139 - 2145. · 1.29 Impact Factor
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Lin Mei,
Junbo Bao,
Lina Tang,
Chao Zhang,
Hai Wang,
Leilei Sun,
Guilei Ma,
Laiqiang Huang,
Jing Yang,
Linhua Zhang,
Kexin Liu, Cunxian Song,
Hongfan Sun
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ABSTRACT: The objective of this study was to prepare a novel mifepristone-loaded PCL/Pluronic F68 implant to achieve long-term treatment of endometriosis. PCL/Pluronic F68 compound (90/10, w/w) with viscosity average molecular weight of 65,000 was successfully synthesized. The end-capped Pluronic F68 was incorporated in PCL matrixes as molecular dispersion without forming a copolymer. The mifepristone-loaded implant made of PCL/Pluronic F68 compound was a cylindrical capsule with an outer diameter of 2.5mm and an inner diameter of 2.2mm. The surface of PCL/Pluronic F68 compound appears porous because Pluronic F68 which is water soluble could leach out due to the water phase. Drug loading of 0.75-, 1.5- and 3.0-cm length implants was 3.05+/-0.18, 6.06+/-0.41 and 11.87+/-0.39mg, respectively. A sustained mifepristone release rate without obvious initial burst and later decline over a period of 180d was observed. The cumulative drug release showed a linear relationship with time, indicating that mifepristone release from the implants followed zero-order kinetics (R(2)>0.99). The data showed that the C(max) and AUC(0-inf) were proportional to imlant length and dose, and all groups reached plasma C(max) at about the same time (approximately 7d) and had similar T(1/2) (approximately 150d) and MRT (approximately 220d). There were obvious inhibitory effects on the growth of endometrial explants in Wister rats in a dose-dependent manner after administration of mifepristone-loaded implants with implant length from 1.5 to 9.0cm for 1-3 months. However, mifepristone-loaded implants with implant length of 12.0cm had no better inhibitory effects on the growth of endometrium when compared with the implants with implant length of 9.0cm (P>0.05). In conclusion, subcutaneous implantation of mifepristone-loaded PCL/Pluronic F68 capsules was proven an effective means for long-term treatment of chronic endometriosis.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 03/2010; 39(5):421-7. · 2.61 Impact Factor
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ABSTRACT: In this work, a biodegradable and injectable in situ gel-forming controlled drug delivery system based on thermosensitive poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL) hydrogels was studied. A series of PCL-PEG-PCL triblock copolymers were synthesized and characterized by 1H-NMR and gel permeation chromatography (GPC). Thermosensitivity of the PCL-PEG-PCL triblock copolymers was tested using the tube inversion method. The in vitro release behaviors of two model proteins, including bovine serum albumin (BSA) and horseradish peroxidase (HRP), from PCL-PEG-PCL hydrogels were studied in detail. The in vivo gel formation and degradation of the PCL-PEG-PCL triblock copolymers were also investigated in this study. The results showed that aqueous solutions of the synthesized PCL-PEG-PCL copolymers can form in situ gel rapidly after injection under physiological conditions. The PCL-PEG-PCL hydrogels showed the ability to control the release of incorporated BSA and HRP. The released HRP was confirmed to conserve its biological activity by specific enzymatic activity assay. The in vivo gel formation and degradation studies indicated that PCL-PEG-PCL copolymers hydrogels can sustain at least 45 days by subcutaneous injection. Therefore, owing to great thermosensitivity and biodegradability of these copolymers, PCL-PEG-PCL copolymers hydrogels show promise as an in situ gel-forming controlled drug delivery system for therapeutic proteins. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010
Journal of Applied Polymer Science 01/2010; 116(4):1985 - 1993. · 1.29 Impact Factor
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ABSTRACT: A sterically stabilized, mitoxantrone-loaded liposome, tailored to target luteinizing hormone-releasing hormone (LHRH) receptor overexpressing cells, was developed to promote the efficiency of intracellular delivery of mitoxantrone through receptor-mediated endocytosis. Liposomes were prepared by lipid film hydration and an ultrasound dispersion process. Thiolated gonadorelin with affinity for the LHRH receptor was chemically coupled to N-[(3-maleimide-1-oxopropyl) aminopropyl polyethylene glycol-carbamyl] distearoyl-l-phosphatidyl-ethanolamine via a thioether bond and subsequently inserted into polyethylene glycol-grafted liposomes. The liposome was characterized in terms of its size, ligand density, drug loading, and leakage properties. The targeting nature and antitumor effects of the liposomes were evaluated in vitro using cultured MCF-7 breast cancer cells. A protein assay of ligand coupling to the liposomal surface indicated that more than 60% of the LHRH peptides were inserted into the liposome bilayer. Up to 1.0 mg/mL of stable liposomal mitoxantrone loading was achieved, with approximately 98% of this being entrapped within the liposomes. In vitro cell culture studies revealed that the gonadorelin-modified liposomes bound to their target cells had significantly higher affinity and better antitumor efficiency than generic drug-loaded liposomes. These events were presumed to occur through specific interactions of the LHRH with its cognate receptors on the cell surface. It was concluded that the targeting properties of the delivery system would potentially improve the therapeutic benefits of mitoxantrone, as compared with nontargeted liposomes.
International Journal of Nanomedicine 01/2010; 5:697-705. · 3.13 Impact Factor
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ABSTRACT: Development of efficacious therapeutic strategies to prevent and inhibit the occurrences of restenosis after percutaneous transluminal coronary angioplasty is critical for the treatment of cardiovascular diseases. In this study, the feasibility and efficiency of stents coated with dodecylated chitosan-plasmid DNA nanoparticles (DCDNPs) were evaluated as scaffolds for localized and prolonged delivery of reporter genes into the diseased blood vessel wall. Dodecylated chitosan-plasmid DNA complexes formed stable positive charged nanospheres with mean diameter of approximately 90-180 nm and zeta potential of +28 ± 3 mV. As prepared DCDNPs were spray-coated on stents, a thin layer of dense DCDNPs was successfully distributed onto the metal struts of the endovascular stents as demonstrated by scanning electron microscopy. The DCDNP stents were characterized for the release kinetics of plasmid DNA, and further evaluated for gene delivery and expression both in vitro and in vivo. In cell culture, DCDNP stents containing plasmid EGFP-C1 exhibited high level of GFP expression in cells grown on the stent surface and along the adjacent area. In animal studies, reporter gene activity was observed in the region of the artery in contact with the DCDNP stents, but not in adjacent arterial segments or distal organs. The DCDNP stent provides a very promising strategy for cardiovascular gene therapy.
International Journal of Nanomedicine 01/2010; 5:1095-102. · 3.13 Impact Factor
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Yangqing Zhang,
Lina Tang,
Leilei Sun,
Junbo Bao, Cunxian Song,
Laiqiang Huang,
Kexin Liu,
Yan Tian,
Ge Tian,
Zhen Li,
Hongfan Sun,
Lin Mei
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ABSTRACT: Multidrug resistance (MDR) of tumor cells is a major obstacle to the success of cancer chemotherapy. Poloxamers have been used in cancer therapy to overcome MDR. The objective of this research is to test the feasibility of paclitaxel-loaded poly(epsilon-caprolactone)/Poloxamer 188 (PCL/Poloxamer 188) nanoparticles to overcome MDR in a paclitaxel-resistant human breast cancer cell line. Paclitaxel-loaded nanoparticles were prepared by a water-acetone solvent displacement method using commercial PCL and self-synthesized PCL/Poloxamer 188 compound, respectively. PCL/Poloxamer 188 nanoparticles were found to be of spherical shape and tended to have a rough and porous surface. The nanoparticles had an average size of around 220nm, with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a clear biphasic release pattern. There was an increased level of uptake of PCL/Poloxamer 188 nanoparticles (PPNP) in the paclitaxel-resistant human breast cancer cell line MCF-7/TAX, in comparison with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxol in the MCF-7/TAX cell culture, but the differences were not significant. However, the PCL/Poloxamer 188 nanoparticles achieved a significantly higher level of cytotoxicity than both of PCL nanoparticle formulation and Taxol(R), indicating that paclitaxel-loaded PCL/Poloxamer 188 nanoparticles could overcome MDR in human breast cancer cells and therefore could have considerable therapeutic potential for breast cancer.
Acta biomaterialia 12/2009; 6(6):2045-52. · 3.98 Impact Factor
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ABSTRACT: A paclitaxel-loaded poly (epsilon]-caprolactone)(PCL)/pluronic F68 (F68) nanoparticle formulation was prepared as an intratumoral delivery system to assess its potential for future neoadjuvant chemotherapy application in the treatment of breast cancer. Paclitaxel-loaded nanoparticles were prepared by a solvent evaporation method using the self-synthesized PCL/F68 compound. Prepared nanoparticles were spherical with a rough, porous surface. As described in our earlier study, F68 was incorporated into the PCL matrix as both a pore-forming agent and to enhance drug release from the particles. A murine breast cancer model has shown that when using equivalent paclitaxel doses, paclitaxel-loaded PCL/F68 nanoparticles administered by a single intratumoral injection were more efficient in impeding tumor development than conventional paclitaxel injections administered by multiple intraperitoneal injections. In conclusion, paclitaxel-loaded PCL/F68 nanoparticles can be delivered intratumorally and they effectively prevent tumor cell growth and establishment in a localized area. This treatment shows promise as a future neoadjuvant chemotherapy application in the treatment of breast cancer.
Anti-cancer drugs 12/2009; 21(3):261-9. · 2.23 Impact Factor
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ABSTRACT: The aim of this work was to investigate the effect of triblock copolymer poloxamer 188 on nanoparticle morphology, size, cancer cell uptake, and cytotoxicity. Docetaxel-loaded nanoparticles were prepared by oil-in-water emulsion/solvent evaporation technique using biodegradable poly(lactic-co-glycolic acid) (PLGA) with or without addition of poloxamer 188, respectively. The resulting nanoparticles were found to be spherical with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug-release profile of both nanoparticle formulations showed a biphasic release pattern. An increased level of uptake of PLGA/poloxamer 188 nanoparticles in the docetaxel-resistant MCF-7 TAX30 human breast cancer cell line could be found in comparison with that of PLGA nanoparticles. In addition, the docetaxel-loaded PLGA/poloxamer 188 nanoparticles achieved a significantly higher level of cytotoxicity than that of docetaxel-loaded PLGA nanoparticles and Taxotere (P < .05). In conclusion, the results showed advantages of docetaxel-loaded PLGA nanoparticles incorporated with poloxamer 188 compared with the nanoparticles without incorporation of poloxamer 188 in terms of sustainable release and efficacy in breast cancer chemotherapy. FROM THE CLINICAL EDITOR: The effects of poloxamer 188, a triblock copolymer were studied on nanoparticle morphology, size, cancer cell uptake and cytotoxicity. An increased level of uptake of PLGA/poloxamer 188 nanoparticles in resistant human breast cancer cell line was demonstrated, resulting in a significantly higher level of cytotoxicity.
Nanomedicine: nanotechnology, biology, and medicine 06/2009; 6(1):170-8. · 5.44 Impact Factor
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Lin Mei,
Yangqing Zhang,
Yi Zheng,
Ge Tian, Cunxian Song,
Dongye Yang,
Hongli Chen,
Hongfan Sun,
Yan Tian,
Kexin Liu,
Zhen Li,
Laiqiang Huang
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ABSTRACT: Multidrug resistance (MDR) in tumor cells is a significant obstacle to the success of chemotherapy in many cancers. The purpose of this research is to test the possibility of docetaxel-loaded poly (ε-caprolactone)/Pluronic F68 (PCL/Pluronic F68) nanoparticles to overcome MDR in docetaxel-resistance human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial PCL and self-synthesized PCL/Pluronic F68, respectively. PCL/Pluronic F68 nanoparticles were found to be of spherical shape with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere®in the MCF-7 TAX30 cell culture, but the differences were not significant (p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere®(p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer.
Nanoscale Research Letters 01/2009; 4(12):1530-9. · 2.73 Impact Factor
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ABSTRACT: The aim of the study was to investigate the tolerance and pharmacokinetics of dexamethasone (DEX)-loaded poly(lactic acid-co-glycolic acid) nanoparticles (DEX-NPs) in rabbits after intravitreal injection. The DEX-NPs were prepared and characterized in terms of morphology, particle size and size distribution, encapsulation efficiency, and in vitro release. Ophthalmic investigations were performed, including fundus observation and photography, intraocular pressure measurement, and B-scan ocular ultrasonography. There were no abnormalities up to 50 days after administration of DEX-NPs in rabbits. The DEX concentrations in plasma and the ocular tissues such as the cornea, aqueous humor, lens, iris, vitreous humor, and chorioretina were determined by high-pressure liquid chromatography. The DEX-NPs maintained a sustained release of DEX for about 50 days in vitreous and provided relatively constant DEX levels for more than 30 days with a mean concentration of 3.85 mg/L(-1). Based on the areas under the curve, the bioavailability of DEX in the experimental group was significantly higher than that in the control group injected with regular DEX. These results suggest that intravitreal injection of DEX-NPs lead to a sustained release of DEX with a high bioavailability, providing a basis for a novel approach to the treatment of posterior segment diseases.
International Journal of Nanomedicine 01/2009; 4:175-83. · 3.13 Impact Factor
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ABSTRACT: The purpose of this research is to test the possibility of localized intravascular infusion of didodecyldimethylammonium bromide (DMAB)-modified paclitaxel-loaded poly(epsilon-caprolactone)/Pluronic F68 (PCL/F68) nanoparticles to achieve long-term inhibition of hyperplasia in a balloon-injured rabbit carotid artery model. Paclitaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial poly(lactide-co-glycolide) (PLGA) and self-synthesized PCL/F68, respectively. DMAB was adsorbed on the nanoparticle surface by electrostatic attraction between positive and negative charges to enhance arterial retention. Nanoparticles were found to be of spherical shape with a mean size of around 300 nm and polydispersity of less than 0.150. The surface charge was changed to positive values after the DMAB modification. The in vitro drug release profile of all nanoparticle formulation showed a biphasic release pattern. Drug release from DMAB-modified PCL/F68 nanoparticles (DPNP) was significantly slower than DMAB-modified PLGA nanoparticles (PGNP). After 90 days, DPNP group showed very significant inhibition of neointimal proliferation (p < 0.01), and PGNP group yielded significant inhibition of neointimal proliferation (p < 0.05), when compared with drug-free nanoparticles group. In conclusion, local delivery of paclitaxel-loaded DMAB-modified PCL/F68 nanoparticles was proven an effective means of long-term inhibition of hyperplasia in the rabbits.
Journal of Pharmaceutical Sciences 10/2008; 98(6):2040-50. · 3.06 Impact Factor
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ABSTRACT: Polymeric nanoparticles (NPs) have been implicated as potential gene carriers in the treatment of various genetic and acquired diseases. In this work we investigated the efficacy of NPs as gene carrier for intravascular gene therapy in animal models of restenosis.
A therapeutic antisense against the monocyte chemotactic protein-1 (anti-MCP-1) was encapsulated into the poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) using double-emulsion/solvent evaporation technology. Laser defractometer was used to assess size distribution of NPs. Particle morphology was assessed by scanning electron microscopy (SEM). DNA content in NPs was determined by DNA extraction using TE buffer from a chloroform solution dissolved a known amount of NPs. DNA concentration was assayed by spectrophotometer. In vitro DNA release was performed in the TE buffer at 37 degrees C utilizing double-chamber diffusion cell. NPs loaded with pEGFP and anti-MCP-1 gene were tested in SMC cell culture for transduction efficiency. The anti-MCP-1 NPs were further evaluated in rabbit vein grafting and carotid artery injury models for their potential in inhibition of restenosis.
The NPs demonstrated a steady in vitro release of DNA with approximately 95% of total enclosed DNA released within 30 days. Anti-sense MCP-1 expression was confirmed in arterial tissues with single infusion of the therapeutic NPs into the injured rabbit carotid arteries. The intima/media ratio of arteries treated with the anti-MCP-1 NP was reduced by 43% compared with control groups following a 2-week treatment. In a rabbit jugular vein-to-artery-bypass grafting model, animals with local-infusion of anti-MCP-1 NPs also demonstrated a significantly lower intimal hyperplasia than that of control groups with no or free antisense treatment.
Collectively, our data revealed that local delivered anti-MCP-1 NPs effectively inhibited experimental restenosis.
European Journal of Pharmaceutical Sciences 10/2008; 35(5):427-34. · 3.21 Impact Factor
