State Key Laboratory of Long Acting and Targeting Drug Delivery System

Yantai, China

State Key Laboratory of Long Acting and Targeting Drug Delivery System

Yantai, China
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Li X.,Jilin University | Li X.,State Key Laboratory of Long acting and Targeting Drug Delivery System | Wang C.,Jilin University | Liang R.,Jilin University | And 14 more authors.
Pharmaceutical Research | Year: 2015

Purpose: Exenatide, a potent insulinotropic agent, can be used for the treatment of non-insulin-dependent diabetes mellitus. However, the need for frequent injections seriously limits its therapeutic utility. The aim of present report was to develop an orally available exenatide formulation using goblet cell-targeting nanoparticles (NPs). Method: The exenatide-loaded nanoparticles were prepared with modified chitosan which was conjugated with a goblet cell-target peptide, CSKSSDYQC (CSK) peptide. Results: The CSK-chitosan nanoparticles shown reduced chitosan toxicity and enhanced the permeation of drugs across the Caco-2/HT-29 co-cultured cell monolayer, which simulated the intestinal epithelium. Following the oral administration of near-infrared fluorescent probe Cy-7-loaded NPs to mice, the distribution of the drugs was investigated with a near-infrared in vivo image system (FX Pro, Bruker, USA). The results showed that Cy-7 fluorescence disseminated from the oesophagus, then to stomach and small intestine and then was absorbed into hepatic, finally into the bladder; over time, Cy-7 was metabolized and excreted. The bioavailability of the modified nanoparticles was found to be 1.7-fold higher compared with the unmodified ones, and the hypoglycemic effect was also better. Conclusion: CSK peptide-modified chitosan nanoparticles could be a potential therapeutics for Type II diabetes patients. © 2014 Springer Science+Business Media New York.


Wang D.,Jilin University | Zhao J.,Jilin University | Liu X.,Jilin University | Sun F.,Jilin University | And 4 more authors.
European Journal of Pharmaceutical Sciences | Year: 2014

Novel biodegradable in situ forming organogel, obtained via the self-assembly of long chain fatty acid in pharmaceutical oil, was prepared and characterized. Different from traditional organogels, the use of organic solvent was avoided in this gel system, in consideration of its tissue irritation. Four kinds of fatty acids were employed as organogelators, which could successfully gel with injectable soybean oil. The gelation procedure was thermo-reversible. Phase transition temperature and time were depended on carbon chain length and concentration of gelators. Optimized formulations containing drug were then injected subcutaneously in rats for pharmacokinetic study. Results showed the steady drug release for one week with the well-controlled burst, which fitted well with the drug release mechanism of both drug diffusion and frame erosion. In vivo imaging of the organogel with fluorescence in live animals suggested that the organogel matrix was gradually absorbed and completely up-taken in nine days. Histopathological analysis of the surrounding tissues was carried out and revealed an overall good biocompatibility property of the implants over drug release period. This research demonstrates that this thermo-sensitive in situ forming organogel system represents a potentially promising platform for sustained drug delivery. © 2014 Elsevier Inc. All rights reserved.


Wang A.-P.,State Key Laboratory of Long acting and Targeting Drug Delivery System | Liu W.-H.,State Key Laboratory of Long acting and Targeting Drug Delivery System | Sun K.-X.,State Key Laboratory of Long acting and Targeting Drug Delivery System | Li Y.-X.,State Key Laboratory of Long acting and Targeting Drug Delivery System
Chinese Journal of New Drugs | Year: 2014

Rotigotine is a non-ergoline D3/D2/D1 dopamine agonist for the treatment of Parkinson's disease (PD). It showed significant antiparkinsonian and neuro-protective effects. This paper mainly describes the advance in the pharmaceutical preparations of rotigotine which can achieve continuous dopaminergic stimulation (CDS) for the treatment of PD. Rotigotine transdermal delivery system (NeuproⓇ) provided 24-h continuous drug levels that would improve efficacy and reduce motor complications. Rotigotine loaded microspheres (RoMS) displayed continuous-release characteristics of rotigotine in animals and the plasma drug level lasted for 2 weeks, indicating that RoMS could achieve CDS for the treatment of PD.


Chen D.,Yantai University | Wang H.,Yantai University | Wang H.,State Key Laboratory of Long Acting and Targeting Drug Delivery System
Journal of Nanoscience and Nanotechnology | Year: 2014

This article reviews the recent developments on novel pH-sensitive ketal-based biodegradable polymeric drug delivery systems. Due to the degradation of ketal derivatives, neutral alcohols and ketones, ketal derivatives can be used to fabricate pH-degradable polymer with pH-degradable ketal linkages in new drug delivery systems by avoiding inflammatory problems. Due to the novelty of ketal polymers, there were few reports about ketal polymers. The review starts with a brief introduction to the pH-sensitive drug delivery system, followed by the structure, preparation and characterization techniques of ketal polymers. Thereafter, the promising applications in various diseases in relation to micro/nano drug carriers based on ketal polymers are summarized and discussed. Copyright © 2014 American Scientific Publishers All rights reserved.


Chen D.,Yantai University | Yu H.,Yantai University | Mu H.,Yantai University | Wei J.,Yantai University | And 8 more authors.
Carbohydrate Polymers | Year: 2013

In this study, a novel liposome-loaded microbubble gel based on N-cholesteryl hemisuccinate-O-sulfate chitosan (NCHOSC) was designed. The structure of the NCHOSC was characterized by FTIR and 1H NMR. The liposomal microbubble gel based on NCHOSC with a high encapsulation efficiency of curcumin was formed and improved the solubility of curcumin. The diameter of most liposomal microbubble was about 950 nm. The temperature-sensitive CS/GP gel could be formulated at room temperature and would form a gel at body temperature. Simultaneously, the ultrasound-sensitive induced release of curcumin was 85% applying ultrasound. The results of cytotoxicity assay indicated that encapsulated curcumin in Cur-LM or Cur-LM-G was less toxic. The anti-tumor efficacy in vivo suggested that Cur-LM-G by ultrasound suppressed tumor growth most efficiently. These findings have shed some light on the potential NCHOSC material used to liposome-loaded microbubble gel for temperature and ultrasound dual-sensitive drug delivery. © 2013 Elsevier Ltd. All rights reserved.


Wang W.-Y.,Yantai University | Wang W.-Y.,State Key Laboratory of Long acting and Targeting Drug Delivery System | Yao C.,Yantai University | Shao Y.-F.,Yantai University | And 3 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

To study pharmacokinetic properties of puerarin poly(amido amine) (PAMAM) dendrimer complex, a sensitive liquid chromatography tandem mass spectrometry method (LC-MS/MS) was developed and validated to determine puerarin in rabbit aqueous humor using microdialysis sampling. Astilbin was used as the internal standard. The linear range for puerarin was from 2 to 1000ng/mL (r=0.9986) based on 20μL of aqueous humor. The coefficients of variations for intra-day and inter-day precisions were less than 10.0%, and the relative error of accuracy was within ±6.3%. The mean extraction recovery of puerarin varied from 80.4% to 85.5%. Microdialysis provides a complete concentration versus time profile. A significant difference was observed in main pharmacokinetic parameters of C max, AUC and t 1/2 between puerarin solution and puerarin PAMAM dendrimer complex. Complex formation resulted in an obvious increase in bioavailability of puerarin after topical administration to rabbit according to the above LC-MS/MS assay method. © 2011 Elsevier B.V.


Ma P.,Yantai University | Zhang X.,Yantai University | Ni L.,State Key Laboratory of Long acting and Targeting Drug Delivery System | Li J.,State Key Laboratory of Long acting and Targeting Drug Delivery System | And 4 more authors.
International Journal of Nanomedicine | Year: 2015

Background: Antibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB), which binds to human epidermal growth factor receptor 2 (HER2), was used as a targeting agent in a TMAB-polyamidoamine (PAMAM) conjugate carrying paclitaxel (PTX) specifically to cells overexpressing HER2. Methods: TMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG). PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively. Results: Nuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was located in the cytoplasm. The in vitro cytotoxicity of TMAB-conjugated PAMAM was lower than free PTX due to the slow release of PTX from the conjugate. In vivo targeting further demonstrated that TMAB-conjugated PAMAM accumulated in the BT474 tumor model more efficiently than non-conjugated PAMAM. Conclusion: TMAB can serve as an effective targeting agent, and the TMAB-conjugated PAMAM can be exploited as a potential targeted chemotherapeutic drug delivery system for tumors that overexpress HER2. © 2015 Ma et al.


Chen D.,Yantai University | Yu H.,Yantai University | Yu H.,State Key Laboratory of Long acting and Targeting Drug Delivery System | Sun K.,Yantai University | And 5 more authors.
Drug Delivery | Year: 2014

In this article, we prepared a dual thermoresponsive and pH-responsive self-assembled micellar nanogel for anticancer drug delivery by using a degradable pH-responsive ketal derivative, mPEG2000-Isopropylideneglycerol (mPEG-IS, PI) polymer. The purpose of this study is to develop an injectable dual-responsive micellar nanogel system which has a sol-gel phase transition by the stimulation of body temperature with improved stability and biocompatibility as a controlled drug delivery carrier for cancer therapy. The pH-responsive PI was designed with pH-responsive ketal group as hydrophobic moieties and PEG group as hydrophilic moieties. The PI micelles encapsulated paclitaxel (PTX) was fabricated. Then, the PI micelles were formed in a thermo-nanogel. The micellar nanogel could improve the solubility and stability of PTX. The physiochemical properties of PI micelles and micellar nanogel were characterized. The results showed that dual-responsive micellar nanogel could carry out sol-gel transition at 37 °C. The PI polymer can spontaneously self-assemble into micellar structure with size of 100-200 nm. The dual-responsive micellar nanogel could be degraded under lower pH condition. The test in vitro PTX release showed that dual-responsive micellar nanogel could release about 70% for 70 h under pH 5.0 while about 10% release at pH 7.4 and pH 9.0. The dual-responsive micellar nanogel was of lower cytotoxicity and suppressed tumor growth most efficiently. The micellar nanogel will be a new potential dual-responsive drug delivery system for cancer therapy. © 2014 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted.


Yan Z.,Tianjin Medical University | Zhu Z.-L.,Tianjin Medical University | Qian Z.-Z.,Tianjin Medical University | Hu G.,Tianjin Medical University | And 3 more authors.
Acta Pharmacologica Sinica | Year: 2012

Aim: To evaluate the single- and multiple-dose pharmacokinetics of vincristine sulfate liposomes (VSLI) in patients with advanced solid tumors. Methods: In single-dose pharmacokinetic study, 16 patients were administered VSLI (1.5, 2.0, or 2.3 mg·m -2) through intravenous infusion. Another 6 patients receiving vincristine sulfate (VCR, 2.0 mg) were taken as the control. In multiple-dose pharmacokinetic study, 12 patients were administered VSLI (1.5 or 1.8 mg·m -2) through intravenous infusion weekly for 4 consecutive weeks. The plasma concentration of VSLI was determined using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Results: After intravenous infusion of the single dose of VSLI, the plasma concentrations were characterized by bi-exponential decline curves. No statistically significant differences were observed between the main pharmacokinetic parameters in the 3 dose groups. Compared with the patients receiving VCR, the patients treated with VSLI displayed an increase in the area under the plasma concentration vs time curve (AUC), and a decrease in plasma clearance rates. On the 4th cycle in the multiple-dose study, the plasma concentration of VCR in all subjects prior to the weekly administration was below the lower limit of quantification (LLOQ). The calculated pharmacokinetic parameters from the subjects in the multiple- and single-dose (1.5 mg·m -2) groups had no significant differences. Although the administration of liposomal VCR may significantly elevate the plasma concentration of VCR, VSLI-associated adverse events were similar to those associated with conventional VCR. Conclusion: VSLI exhibits a lower clearance and a higher AUC compared with conventional VCR. No accumulation was observed in patients exposed to VSLI for 4 consecutive weeks. VSLI was generally tolerated in the subjects. The phase II dose of VSLI may be recommended as 4 doses of 1.5 mg·m -2 for treatment of patients with advanced solid tumors. © 2012 CPS and SIMM All rights reserved.


PubMed | Yantai University and State Key Laboratory of Long acting and Targeting Drug Delivery System
Type: | Journal: International journal of nanomedicine | Year: 2015

Antibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB), which binds to human epidermal growth factor receptor 2 (HER2), was used as a targeting agent in a TMAB-polyamidoamine (PAMAM) conjugate carrying paclitaxel (PTX) specifically to cells overexpressing HER2.TMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG). PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively.Nuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was located in the cytoplasm. The in vitro cytotoxicity of TMAB-conjugated PAMAM was lower than free PTX due to the slow release of PTX from the conjugate. In vivo targeting further demonstrated that TMAB-conjugated PAMAM accumulated in the BT474 tumor model more efficiently than non-conjugated PAMAM.TMAB can serve as an effective targeting agent, and the TMAB-conjugated PAMAM can be exploited as a potential targeted chemotherapeutic drug delivery system for tumors that overexpress HER2.

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