Jian-Cheng Wang

Peking University, Peping, Beijing, China

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Publications (43)154.55 Total impact

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    ABSTRACT: A somatostatin analog, vapreotide (VAP), can be used as a ligand for targeting drug delivery based on its high affinity to somatostatin receptors (SSTRs), which is overexpressed in many tumor cells. RNA interference plays an important role on downregulation of vascular endothelial growth factor (VEGF), which is important for tumor growth, progression and metastasis. To improve tumor therapy efficacy, the vapreotide-modified core-shell type nanoparticles co-encapsulating VEGF targeted siRNA (siVEGF) and paclitaxel (PTX), termed as VAP-PLPC/siRNA NPs, were developed in this study. When targeted via somatostatin receptors to tumor cells, the VAP-PLPC/siRNA NPs could simultaneously delivery siVEGF and PTX into cells and achieve a synergistic inhibition of tumor growth. Interestingly, in vitro cell uptake and gene silencing experiments demonstrated that the targeted VAP-PLPC/siRNA NPs exhibited significant higher intracellular siRNA accumulation and VEGF downregulation in human breast cancer MCF-7 cells, compared to those of the non-targeted PEG-PLPC/siRNA NPs. More importantly, in vivo results further demonstrated that the targeted VAP-PLPC/siRNA NPs had significant stronger drug distribution in tumor tissues and tumor growth inhibition efficacy via receptor-mediated targeting delivery, accompany with an obvious inhibition of neovascularization induced by siVEGF silencing. These results suggested that the co-delivery of siRNA and paclitaxel via vapreotide-modified core-shell nanoparticles would be a promising approach for tumor targeted therapy.
    Biomaterials 03/2014; · 8.31 Impact Factor
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    ABSTRACT: Our previous study had reported that cholesterol-grafted poly(amidoamine) (rPAA-Chol polymer) was able to self-assemble into cationic nanoparticles and act as a potential carrier for siRNA transfection. In this study, the core-shell type lipid/rPAA-Chol hybrid nanoparticles (PEG-LP/siRNA NPs and T7-LP/siRNA NPs) were developed for improving in vivo siRNA delivery by modifying the surface of rPAA-Chol/siRNA nanoplex core with a lipid shell, followed by post-insertion of polyethylene glycol phospholipid (DSPE-PEG) and/or peptide (HAIYPRH, named as T7) modified DSPE-PEG-T7. The integrative hybrid nanostructures of LP/siRNA NPs were evidenced by dynamic light scattering (DLS), confocal laser scanning microscope (CLSM), cryo-transmission electron microscope (Cryo-TEM) and surface plasmon resonance (SPR) assay. It was demonstrated that the T7 peptide modified LP/siRNA NPs (T7-LP/siRNA NPs) exhibited uniform and spherical structures with particle size of 99.39 ± 0.65 nm and surface potential of 42.53 ± 1.03 mV, and showed high cellular uptake efficiency and rapid endosomal/lysosomal escape ability in MCF-7 cells. Importantly, in vitro gene silencing experiment demonstrated that both of pegylated and targeted LP/siEGFR NPs exhibited significantly stronger downregulation of EGFR protein expression level in MCF-7 cells, compared to that of the physical mixture of siRNA lipoplexes and rPAA-Chol/siRNA nanoplexes. In vivo tumor therapy on nude mice bearing MCF-7 tumors further confirmed that the targeted T7-LP/siEGFR NPs exhibited the greatest inhibition on tumor growth via transferrin receptor-mediated targeting delivery, without any activation of immune responses and significant body weight loss following systemic administration. These findings indicated that the core-shell type T7-LP/siRNA nanoparticles would be promising siRNA delivery systems for in vivo tumor-targeted therapy.
    Biomaterials 12/2013; · 8.31 Impact Factor
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    ABSTRACT: In this study, a series of bioreducible poly(amidoamine)s grafting different percentages of cholesterol (rPAA-Ch14: 14%, rPAA-Ch29: 29%, rPAA-Ch57: 57% and rPAA-Ch87: 87%) was synthesized and used for siRNA delivery. These amphiphilic polymers were able to self-assemble into cationic nanoparticles in aqueous solution at low concentrations. The nanoparticle formation was evidenced via cryo-transmission electron microscope (Cryo-TEM) and dynamic light scattering analysis. The average hydrodynamic size of rPAA-Ch blank nanoparticles was about 80-160 nm with zeta potential of 50-60 mV. Also, the effects of different percentages of cholesterol grafted onto rPAA on physicochemical characteristics, in vitro cytotoxicity, cellular uptake, VEGF gene silencing efficacy and translocation mechanism of rPAA-Ch/siRNA complexes were investigated. The results showed that rPAA-Ch57 polymer was not only able to form stable nanocomplexes and possess high cell uptake, but also to exhibit the best in vitro VEGF gene silencing efficacy and the best in vivo tumor growth inhibition effect when it was formulated with VEGF-siRNA. Moreover, the observations of confocal laser scanning microscope (CLSM) and the study of cholesterol competitive inhibition demonstrated that endosomal/lysosomal escape and cytoplasmic dissociation of rPAA-Ch57/siRNA complexes were dependent on the "proton sponge effect" and disulfide cleavage, following internalization with cholesterol-related endocytosis pathway and subsequent transportion into endosomes/lysosomes. These findings indicated that the rPAA-Ch57 polymer should be a promising and potent carrier for siRNA delivery.
    Biomaterials 04/2013; · 8.31 Impact Factor
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    ABSTRACT: Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5-2.5 nm. The host-guest association constant K a was 1,639 M(-1) as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated β-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer.
    PLoS ONE 01/2013; 8(5):e62289. · 3.53 Impact Factor
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    ABSTRACT: Gemcitabine (GEM) is a nucleoside analog agent against a wide variety of tumors. To overcome its limitation of rapid metabolism in vivo that results in short circulation time and poor antitumor efficacy, a novel prodrug (CLA-GEM conjugate) has been developed through the covalent coupling of conjugated linoleic acid (CLA) to N(4)-amino group of GEM. The chemical structure of CLA-GEM conjugate was identified by NMR, FTIR and other methods. From in vitro tests, it was demonstrated that the linkage with CLA increased the plasma stability of GEM as well as the antitumor activity against human breast tumor cells (MCF-7). Importantly, it also altered the transport pattern of GEM across cell membrane (MCF-7 and MDA-MB-231), evidenced by the little effect of nucleoside transporter inhibitors (NBMPR and dipyridamole) on the IC(50) values of CLA-GEM, instead of the great effect on that of unmodified GEM. In vivo pharmacokinetic study showed that the CLA-GEM conjugate had a longer plasma half-life and a higher bioavailability compared to that of unmodified GEM. Significant stronger antitumor activity was observed in the nude mice xenografted MCF-7 breast tumor after treated with CLA-GEM than that of unmodified GEM, while no significant body weight loss was found in all treatments. In conclusion, the novel CLA-GEM conjugate prepared in this study would be a promising prodrug of gemcitabine for future clinical use.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 06/2012; 82(2):401-9. · 3.15 Impact Factor
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    ABSTRACT: Due to the absence of safe and effective carriers for in vivo delivery, the applications of small interference RNA (siRNA) in clinic for therapeutic purposes have been limited. In this study, a biodegradable amphiphilic tri-block copolymer (mPEG(2000)-PLA(3000)-b-R(15)) composed of monomethoxy poly(ethylene glycol), poly(d,l-lactide) and polyarginine was synthesized and further self-assembled to cationic polymeric nanomicelles for in vivo siRNA delivery, with an average diameter of 54.30 ± 3.48 nm and a zeta potential of approximately 34.8 ± 1.77 mV. The chemical structures of the copolymers were well characterized by (1)H NMR spectroscopy and FT-IR spectra. In vitro cytotoxicity and hemolysis assays demonstrated that the polymeric nanomicelles showed greater cell viability and haemocompatibility than those of polyethyleneimine (PEI) or R(15) peptide. In vitro experiments demonstrated that EGFR targeted siRNA formulated in micelleplexes exhibited approximately 65% inhibition of EGFR expression on MCF-7 cells in a sequence-specific manner, which was comparable to Lipofectamine™ 2000. The results of intravenous administration showed Micelleplex/EGFR-siRNA significantly inhibited tumor growth in nude mice xenografted MCF-7 tumors, with a remarkable inhibition of EGFR expression. Furthermore, no positive activation of the innate immune responses and no significant body weight loss was observed during treatment suggested that this polymeric micelle delivery system is non-toxic. In conclusion, the present nanomicelles based on cationic mPEG(2000)-PLA(3000)-b-R(15) copolymer would be a safe and efficient nanocarrier for in vivo delivery of therapeutic siRNA.
    Biomaterials 06/2012; 33(28):6793-807. · 8.31 Impact Factor
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    ABSTRACT: In this study, a novel redox-responsive hyperbranched poly(amido amine) (named PCD) was synthesized and used as a cationic polymer to form a ternary complex with small interfering RNA (siRNA) and hyaluronic acid (HA) for siRNA delivery. Here, it is hypothesized that different mixing orders result in different assembly structures, which may affect the siRNA delivery efficiency. To investigate the effects of mixing orders on siRNA delivery efficiency in two human breast cancer cell lines, three ternary complexes with different mixing orders of siRNA/PCD/HA were prepared and characterized: mixing order I (initially prepared siRNA/PCD binary complex further coated by negatively charged HA), mixing order II ( initially prepared HA/PCD binary complex further incubated with siRNA), and mixing order III ( initially prepared siRNA/HA mixture further electrostatically compacted by positively charged PCD). With an optimized siRNA/PCD/HA charge ratio of 1/20/16, the particle sizes and zeta potentials of these ternary complexes were 124.8 nm and 27.3 mV (mixing order I), 147.5 nm and 29.9 mV (mixing order II), and 128.8 nm and 19.4 mV (mixing order III). Also, the effects on stability, cellular uptake, and gene silencing efficiency of siRNA formulated in ternary complexes with different mixing orders were investigated. The results showed that mixing orders I and III displayed better siRNA transfection and protection than mixing order II in human breast cancer MCF-7 and MDA-MB-231 cells. More interesting, at the siRNA/PCD/HA charge ratio of 1/20/16, the gene silencing effects on vascular endothelial growth factor expression in MDA-MB- 231 cells were as follows: mixing order III > mixing order I > mixing order II. Based on these results, a likely explanation for the difference in functionality dependent on mixing orders is the formation of different assembly structures. These results may help future optimization of siRNA ternary complexes for achieving better delivery efficiencies, especially for target-specific siRNA delivery to cells with HA receptor overexpression.
    International Journal of Nanomedicine 01/2012; 7:3837-49. · 4.20 Impact Factor
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    ABSTRACT: Paclitaxel and sorafenib loaded albumin nanoparticles (PTX-SRF-BSA-NPs) were prepared and studied here to avoid the toxicities from the excipients in the Taxol® and explore the effect of such combination on the antitumour efficacy and toxicity. PTX-BSA-NPs and so on were used as controls. The particle size, zeta potential, encapsulation efficiency and morphology were evaluated. Less than 70% of each drug released within 24 h. PTX and SRF existed as molecular or amorphous form in the PTX-SRF-BSA-NPs. The particle size did not change much after 2-month storage in freeze-dried form or 24 h in suspension. The treatment with PTX-SRF-BSA-NPs (7.5 mg kg(-1) PTX + 7.5 mg kg(-1) SRF) exhibited lower myelosuppression than PTX-BSA-NPs (15 mg kg(-1) PTX) while it remained or increased the antitumour effect in mice tumour models. Compared with the solution containing the same level of PTX and SRF, PTX-SRF-BSA-NPs demonstrated significantly lower haemolysis and myelosuppression effect.
    Journal of Microencapsulation 06/2011; 28(6):528-36. · 1.57 Impact Factor
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    ABSTRACT: To explore the possibility of the PEGylated liposome-protamine-hyaluronic acid nanoparticles (PEG-LPH-NP) loaded with siRNA (PEG-LPH-NP-S) in ARPE19 cells and a laser-induced rat model for the treatment of choroidal neovascularization (CNV). PEG-LPH-NP-S was characterized by dynamic light scattering and transmission electron microscopy (TEM). The encapsulation efficiency of siRNA in PEG-LPH-NP was analyzed by ultracentrifugation, whereas the protection of siRNA by PEG-LPH-NP was evaluated by electrophoresis. Human RPE cells (ARPE19) were used as the cell model for the studies of cellular uptake and the inhibition of VEGFR1 expression, visualized by a laser scanning confocal microscope. The area of CNV in the laser-induced rat model after intravitreous injection was measured. The distribution of the lipid nanoparticles in the retina after intravitreous administration was investigated by fluorescence microscopy. Finally, the TUNEL test and morphologic observation of the retina were conducted. It was indicated that PEG-LPH-NP-S was approximately 132 nm in particle size with a positive charge of approximately 20 mV, whereas the encapsulation efficiency of siRNA in PEG-LPH-NP was >95%. PEG-LPH-NP could protect the siRNA load and could facilitate the intracellular delivery of fluorescein-labeled siRNA to ARPE19 cells. VEGFR1 expression in ARPE19 cells could be inhibited, and the CNV area in the murine model could be reduced more effectively by PEG-LPH-NP-S compared with naked siRNA and by PEG-LPH-NP with negative siRNA. It seems that the toxicity of PEG-LPH-NP-S on the rat retina is low, based on the results of TUNEL testing and morphologic observation. PEG-LPH-NP may be a promising lipid nanoparticle system for the siRNA treatment of CNV.
    Investigative ophthalmology & visual science 04/2011; 52(7):4789-94. · 3.43 Impact Factor
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    ABSTRACT: As more and more oral formulations of nanoparticles are used in clinical contexts, a comprehensive study on the mechanisms of interaction between polymer nanoparticles and live cells seems merited. Such a study was conducted and the results were compared to the polymer itself in order to demonstrate different kinds of effects that are brought into the cell by polymer and its nanoparticles, especially the effects on the biomembrane. Several techniques, including surface plasmon resonance (SPR), Fourier transformed infrared spectroscopy (FTIR), Raman spectroscopy, fluorescence polarization spectroscopy (FP), flow cytometry (FCM) with quantitative analysis, and confocal images with antibody staining were employed toward this end. The cytotoxicity in vitro was also evaluated. Chitosan (CS), a polycationic polymer, was used to prepare the nanoparticles. We demonstrate that chitosan nanoparticles (CS-NP) induce strong alterations in the distribution of membrane proteins, fluidity of membrane lipids, and general membrane structure. Furthermore, the uptake of CS-NP into Caco-2 cells was found to have a similar mechanism to that of CS molecules, but the differences in degree were noted. These results indicate that positive charge and nanoscale size were the factors that most significantly affected the interactions between the nanoparticles of polycationic polymers and live cells. However, no difference in cytotoxicity toward the Caco-2 cells was found between CS and CS-NP. This supports the idea that CS-NP is an effective and safe carrier for oral drug delivery. KeywordsNanoparticles–Polycationic polymers–Thymopentin–Polymer interactions–Caco-2 Cells–C6 Cells–Nanomedicine
    Journal of Nanoparticle Research 01/2011; 13(10):4765-4776. · 2.18 Impact Factor
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    ABSTRACT: A sensitive and reliable reversed-phase liquid chromatography (RP-LC) with ultraviolet (UV) detection has been developed and validated for the quantification of Icariside II in rat plasma and tissues using Fermononetin as the internal standard. Protein precipitation and liquid–liquid extraction were utilized for plasma and tissue sample preparation, respectively. The analysis was successfully carried out on an Agilent SB-C18 column (5μm, 4.6×250mm) with the implementation of the following conditions: a mobile phase of phosphoric acid solution (0.1%, v/w)–Acetonitrile (55:45, v/v), a flow rate of 1mLmin−1, a column temperature of 25°C and a detection wavelength of 270nm. Good linear relationships of calibration curves were obtained (r 2>0.9906) over the investigated concentration range with plasma and tissue samples. The lower limit of quantification (LLOQ) and the limit of detection (LOD) were 0.1 and 0.02μgg−1, respectively (for plasma sample, they were 0.05 and 0.1μgmL−1, respectively). The developed method which was embodied with good precision, accuracy, recovery and stability was corroborated to satisfy the requirements for biomedical sample analysis. This method has been successfully applied to tissue distribution study of Icariside II in rats after a single intravenous dose at 12.5mgkg−1. Results suggested that Icariside II was distributed to rat tissues rapidly with greater initial concentrations in kidney, lung and liver. Moderate initial distributions were obtained in rat muscle, heart, bone, spleen and plasma. Low amount of Icariside II was detected in testes, and no Icariside II could be detected in the brain. KeywordsColumn liquid chromatography-ultraviolet detection–Icariside II–Flavonoids–Tissue distribution
    Chromatographia 01/2011; 74(3):251-258. · 1.44 Impact Factor
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    ABSTRACT: Tumor targeting drug delivery systems are being the ideal carriers of systemic administration for tumor therapy. We have reported previously that RGD peptide (arginine-glycine-aspartic acid)-modified liposomes containing drugs could increase targeting to tumor by binding with the integrin receptors overexpressed on tumor cells. RNA interference plays an important role on down-regulation of P-glycoprotein (P-gp), which is a drug efflux transporter overexpressed on multi-drug-resistant (MDR) tumor cells. To improve MDR tumor therapy, sequential treatment strategy with RGD-modified liposomes containing P-gp targeted small interference (siRNA) or doxorubicin (DOX) was reported in this study. When targeted via RGD to tumor-cell-surface and tumor neovasculature endothelial cell receptors, cationic liposomes could specifically deliver siRNAs to tumor cells and thus reverse drug resistance by down-regulation of P-gp, following administration of targeted liposomes containing DOX that inhibit formerly drug-resistant tumors. From the current results, the combination use of DOX and P-gp targeted siRNA showed significantly higher in vitro cytotoxicity in tumor cells than liposomal DOX alone. In vivo studies in a mouse model of drug-resistant MCF7/A tumor demonstrated significantly greater inhibition of tumor growth followed by the sequential treatment of RGD-modified liposomes containing siRNA or DOX when compared to liposomal DOX alone. Also, ex vivo tissue imaging studies have shown the accumulation of siRNA and DOX in tumors at same site-specific manner. These results suggested that the sequential treatment of P-gp gene silencing and cytotoxic drug with RGD-modified liposome drug delivery system could be a promising clinical treatment for drug-resistant tumors.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 10/2010; 76(2):170-8. · 3.15 Impact Factor
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    ABSTRACT: Arg-Gly-Asp (RGD) modified doxorubicin-loaded liposomes could improve anticancer effect, and vascular disrupting agents (VDAs) could induce a rapid and selective shutdown of the blood vessels of tumors. We propose that RGD-modified liposomes for co-encapsulation and sequential release of vascular disrupting agent combretastatin A-4 (CA-4) and cytotoxic agent doxorubicin (Dox) could enhance tumor inhibition responses. In this study, we encapsulated Dox and CA-4 in RGD-modified liposomes. The release rate of Dox was proved to be much slower than that of CA-4 in vitro. Flow cytometry and laser confocal scanning microscopy clearly showed that RGD-modification promoted intracellular uptake of liposomal drugs by B16/B16F10 melanoma tumor cells and human umbilical vein endothelial cells (HUVECs). Cytotoxicity assay showed that the IC(50) of RGD-modified liposomes was lower than that of the corresponding unmodified liposomes. Therapeutic benefits were examined on B16F10 melanoma tumors subcutaneously growing in C57BL/6 mice. In vivo study demonstrated that RGD-modified liposomes exhibited the most pronounced tumor regression effect when both CA-4 and Dox were co-encapsulated. These results suggest that the targeted drug delivery system for co-encapsulation of vascular disrupting agents and anticancer agents may be a promising strategy for cancer treatment.
    European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 03/2010; 74(3):467-73. · 3.15 Impact Factor
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    ABSTRACT: To investigate the effect of different enteric polymers on the characteristics of pH-sensitive nanoparticles, Rhodamine 6G (Rho) was incorporated in various pH-sensitive nanoparticles. The different patterns of pH-dependent release profiles were observed, although some polymers have the same dissolving pH. The distribution, adhesion and transition of different nanoparticles in rat gut showed significant difference, closely related to the release characteristics of nanoparticles, and their release behaviour are dependent on the dissolving pH and the structure of the polymers, as well as the drug property.Most nanoparticle formulations decreased the distribution and adhesion of Rho in the stomach but increased these values in the intestine. The nanocarriers also control the drug release sites and release rate in the GI tract. In conclusion, pH-sensitive nanoparticles seem favourable for drug absorption and it is important to choose the proper materials to obtain the suitable characteristics for the oral pH-sensitive nanoparticles.
    Journal of Microencapsulation 08/2009; 27(3):205-17. · 1.57 Impact Factor
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    ABSTRACT: The objective of this study was to develop an efficient vasculature-targeted liposomal combretastatin A4 (CA4), by the modification of the sterically stabilized liposomes (SSL) with a ligand of integrins and to explore the possibility of such system for the treatment of choroidal neovascularization (CNV). CA4-loaded liposomes were prepared by thin-film dispersion method. The linear arginine-glycine-aspartic acid tripeptide (RGD) with affinity for integrins such as alphavbeta3 expressed on rapidly proliferative vascular endothelial cells was coupled to the distal end of polyethylene glycol (PEG) connected on the surface of SSL. The liposome delivery system was characterized in terms of size and size distribution profiles by dynamic light scattering method, entrapment efficiency, and leakage properties by high-performance liquid chromatography (HPLC). The uptake efficiency by human umbilical vein endothelial cells (HUVECs) was evaluated by confocal microscopy. The therapeutic efficacy was quantitatively assessed by choroidal flat mounts. CA4-loaded RGD-SSL (RGD-SSL-CA4) was obtained with an entrapment efficiency over 70% and an average diameter of approximately 120 nm. The leakage property of RGD-SSL-CA4 was similar with SSL-CA4, both were slower than CA4 ethanol solution. Confocal microscopy studies revealed that RGD-SSL could facilitate the liposomes' uptake into HUVECs. Rats treated with two intravenous injections of 7 mg/kg RGD-SSL-CA4 resulted in a significant reduction in the area of CNV compared with control group (P < 0.05). RGD-modified SSL loaded with CA4 can be successfully prepared, and the vasculature-targeted liposome system would increase the uptake of HUVECs and improve the therapeutic efficacy of CA4 on CNV compared with the control formulations.
    Journal of ocular pharmacology and therapeutics: the official journal of the Association for Ocular Pharmacology and Therapeutics 07/2009; 25(3):195-200. · 1.46 Impact Factor
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    ABSTRACT: Chemotherapy of brain tumors remains a big challenge owing to the low drug transport across the blood-brain barrier (BBB), multidrug resistance (MDR), and poor penetration into the tumor tissue. We developed a novel dual-targeting liposomal carrier that enabled drug to transport across the BBB and then target the brain tumor. In the dual-targeting liposomal carrier, tamoxifen (TAM) was incorporated into the lipid bilayer membrane of liposomes and wheat germ agglutinin (WGA) was conjugated to the liposomes' surface. Topotecan was then loaded into the above liposomes. In vitro, topotecan liposomes modified with TAM and WGA were applied to the glioma cells, BBB model, and avascular C6 glioma spheroids, respectively. In vivo, they were systemically administered via vein to brain C6 glioma-bearing rats. In view of the microtiter tetrazolium (MTT) results, topotecan liposomes modified with TAM and WGA exhibited a significant inhibitory effect compared to unmodified topotecan liposomes, suggesting that TAM plus WGA contributed strong drug delivery effects into the brain tumor cells after direct drug exposure. In the experiments of drug transport across the BBB model following drug exposure to tumor cells, topotecan liposomes modified with TAM and WGA exhibited the most robust dual-targeting effects: crossing the BBB and then targeting brain tumor cells. Similar strong activity was found in the reduction of C6 glioma tumor spheroid volume and in the apoptosis of the spheroids. In the brain tumor-bearing rats, the dual-targeting effects of topotecan liposomes modified with TAM and WGA could be evidently observed, resulting in a significant improvement in the overall survival of the brain tumor-bearing rats compared with free topotecan and topotecan liposomes. Moreover, results from an extended treatment group indicated that the survival could be further significantly enhanced, indicating that an extended chemotherapy with topotecan liposomes modified with TAM and WGA would be beneficial for treatment. The dual-targeting effects in vivo of topotecan liposomes modified with TAM and WGA could be related to an enhanced effect by TAM via inhibiting efflux of MDR proteins in the BBB and the brain tumor, and an enhanced effect by WGA via endocytosis in the BBB and in the brain tumor. In conclusion, topotecan liposomes modified with TAM and WGA significantly improve topotecan transport across the blood-brain barrier and the survival of brain tumor-bearing animals, showing dual-targeting effects. These findings would encourage further developments of noninvasive therapy for brain tumor.
    Molecular Pharmaceutics 05/2009; 6(3):905-17. · 4.57 Impact Factor
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    ABSTRACT: The current 'fixed-dosage strategy' approach to medicine, means there is much inter-individual variation in drug response. Pharmacogenetics is the study of how inter-individual variations in the DNA sequence of specific genes affect drug responses. This article will highlight current pharmacogenetic knowledge on important drug metabolizing enzymes, drug transporters and drug targets to understand interindividual variability in drug clearance and responses in clinical practice and potential use in personalized medicine. Polymorphisms in the cytochrome P450 (CYP) family may have had the most impact on the fate of pharmaceutical drugs. CYP2D6, CYP2C19 and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in phase I metabolism of drugs since nearly 80% of drugs in use today are metabolised by these enzymes. Approximately 5% of Europeans and 1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant drug metabolising enzyme that demonstrates genetic variants. Studies into CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and CYP2C9*3 alleles. Extensive polymorphism also occurs in a majority of Phase II drug metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyl transferases (TPMT) that catalyzes the S-methylation of thiopurine drugs. With respect to drug transport polymorphism, the most extensively studied drug transporter is P-glycoprotein (P-gp/MDR1), but the current data on the clinical impact is limited. Polymorphisms in drug transporters may change drug's distribution, excretion and response. Recent advances in molecular research have revealed many of the genes that encode drug targets demonstrate genetic polymorphism. These variations, in many cases, have altered the targets sensitivity to the specific drug molecule and thus have a profound effect on drug efficacy and toxicity. For example, the beta (2)-adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically significant genetic variation in drug targets. The variable number tandem repeat polymorphisms in serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. The distribution of the common variant alleles of genes that encode drug metabolizing enzymes, drug transporters and drug targets has been found to vary among different populations. The promise of pharmacogenetics lies in its potential to identify the right drug at the right dose for the right individual. Drugs with a narrow therapeutic index are thought to benefit more from pharmacogenetic studies. For example, warfarin serves as a good practical example of how pharmacogenetics can be utilized prior to commencement of therapy in order to achieve maximum efficacy and minimum toxicity. As such, pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and licensed drugs.
    Current Drug Metabolism 11/2008; 9(8):738-84. · 4.41 Impact Factor
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    ABSTRACT: Tumor-targeting drug delivery systems are being the ideal carrier for systemic administration of antiproliferative drugs. RGD peptide (arginine-glycine-aspartic acid) modified liposomes containing paclitaxel (RGD-SSL-PTX). The arginine-glycine-aspartic acid tripeptide (RGD) modified sterically stabilized liposomes (SSL) containing paclitaxel (PTX) (RGD-SSL-PTX), which could increase targeting to tumor by binding with the integrin receptors overexpressed on tumor cells. The encapsulation efficiency was more than 90% and the mean particle size was of 120 nm with a narrow size distribution. It was indicated that significant cytotoxicity (3.5 times lower IC(50)) was found in the SKOV-3 human ovarian cancer cells treated with RGD-SSL-PTX preparation, as well as the intracellular uptake of liposomes (a 6.21-fold increase in fluorescence intensity), when compared to those of non-targeted liposomes (SSL). For in vivo antitumor activity, it was shown in the present study that RGD-SSL-PTX preparation had the strongest tumor growth inhibition among the test formulations (P < 0.05) in BALB/c nude mice xenografted with SKOV-3 solid tumor. Meanwhile, there was no significant change in the body weight of the animals treated with RGD-SSL-PTX for intravenous injection at a dose of 12.5 mg/kg. It was suggested that the RGD-SSL-PTX preparation might have a great advantage over present-day chemotherapy with Taxol in curing those tumors overexpressing integrin receptors.
    Journal of Drug Targeting 11/2008; 17(1):10-8. · 2.77 Impact Factor
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    ABSTRACT: The multi-drug resistance (MDR) could be caused by the over-expression of adenosine triphosphate binding cassette transporters such as p-glycoprotein, thereby resulting in the efflux of anti-cancer drugs from the cells. An anti-resistant stealthy liposomal vincristine plus quinacrine was defined in this study. Human chronic myelogenous leukemia K562 and MDR K562 cells were included for comparisons. Anti-tumor activity studies were performed on female BALB/c nude mice with MDR K562 cell xenografts. Results showed that quinacrine was effective in reversing the resistance in the MDR K562 cells, and enhanced the anti-tumor effect of vincristine in K562 cells. The caspase-9 and -3 activities in the MDR K562 and K562 cells were increased with the dose rise of quinacrine. In the MDR K562 cell xenografts in mice, the anti-resistant tumor effect of the stealthy liposomal vincristine plus quinacrine was evidently observed. The enhanced anti-tumor effects of vincristine by quinacrine in the resistant/non-resistant K562 cells could be because of the direct injury and the potentiating apoptotic effect of vincristine via activating the initiator caspase-9 and subsequently the effector caspase-3, and the long circulatory effect of stealthy liposomes. The stealthy liposomal encapsulation of vincristine plus quinacrine could be a potential therapeutic approach for resistant human leukemia.
    Fundamental and Clinical Pharmacology 09/2008; 22(4):429-37. · 1.99 Impact Factor
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    ABSTRACT: Earthworm fibrinolytic enzyme (EFE-d, Mr 24177), a water-soluble protein, is clinically used for the management of cardiovascular diseases. However, this protein drug has a very low oral bioavailability because of its low oil/water partitioning, low membrane permeability and unstable nature in harsh gastric juice. This study explored the possibility of absorption and efficacy enhancement for EFE-d through the delivery of the water-in-oil (w/o) microemulsions. The w/o microemulsion consisting of Labrafac CC, Labrasol, Plurol Oleique CC 497 and saline (54/18/18/10, % w/w) was developed and characterized, including conductivity, viscosity, particle size and in vitro membrane permeability. The w/o microemulsion and the control solution of EFE-d were administered intraduodenally (or orally) to rats. The w/o microemulsion possessed a higher intestinal membrane permeability in vitro as well as a higher absorption and efficacy in vivo, when compared to control solution. The intraduodenal bioavailability of EFE-d for microemulsions was 208-fold higher than that of control solution and the absolute bioavailability was 17.55%. Meanwhile, there was no tissue damage of the intestinal mucosa found after oral multiple-dose administration of the EFE-d microemulsion to rats. These findings indicated that the w/o microemulsion may represent a safe and effective oral delivery system for hydrophilic bioactivity macromolecules.
    Journal of Controlled Release 08/2008; 129(1):41-8. · 7.63 Impact Factor

Publication Stats

492 Citations
154.55 Total Impact Points

Institutions

  • 2005–2014
    • Peking University
      • School of Pharmaceutical Sciences
      Peping, Beijing, China
  • 2013
    • University of South Florida
      Tampa, Florida, United States
  • 2012
    • Shenyang Pharmaceutical University
      • School of Pharmaceutics
      Feng-t’ien, Liaoning, China
  • 2006–2011
    • Peking University Third Hospital
      Peping, Beijing, China
    • National University of Singapore
      • Department of Pharmacy
      Singapore, Singapore
  • 2006–2010
    • Peking University Health Science Center
      Peping, Beijing, China