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学科主题: 药学
题名:
Novel cathepsin B-sensitive paclitaxel conjugate: Higher water solubility, better efficacy and lower toxicity
作者: Liang, Liang; Lin, Song-Wen; Dai, Wenbing; Lu, Jing-Kai; Yang, Ting-Yuan; Xiang, Yu; Zhang, Yang; Li, Run-Tao; Zhang, Qiang
关键词: Paclitaxel ; Pegylated ; Cathepsin B-sensitive ; Conjugate ; Anti-tumor effect
刊名: JOURNAL OF CONTROLLED RELEASE
发表日期: 2012-06-28
DOI: 10.1016/j.jconrel.2012.02.020
卷: 160, 期:3, 页:618-629
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
研究领域[WOS]: Chemistry ; Pharmacology & Pharmacy
关键词[WOS]: DRUG-DELIVERY ; CYSTEINE CATHEPSINS ; POLYETHYLENE-GLYCOL ; CANCER ; CHEMOTHERAPY ; DOXORUBICIN ; POLIGLUMEX ; RELEASE ; TAXOL ; BIODISTRIBUTION
英文摘要:

In order to realize the targeted delivery of paclitaxel (PTX) to tumor through an environment-sensitive mechanism, increase its solubility in water and reformulate without toxic excipients, a novel PTX conjugate, PEG-VC-PABC-PTX was designed and synthesized in this study, using p-aminobenzylcarbonyl (PABC), a spacer, and valine-citrulline (VC), a substrate of cathepsin B (C-B), to link polyethylene glycol (PEG) and PTX. Pegylated PTX (PEG-PTX) which was synthesized and Taxol formulation were prepared as controls. The conjugates were purified and characterized by melting points, H-1-NMR, ESI-MS or MALDI-TOF-MS. The two conjugates were similar in particle size, water solubility and their effects on MCF-7 cell line in vitro, and both of them induced no obvious toxicity in vivo. The release of PTX from PEG-PTX was faster due to its ester bond, while PEG-VC-PABC-PTX was proved to be C-B-sensitive in terms of PTX release and its effect on cell cycle. Additionally, PEG-VC-PABC-PTX exhibited significant effects of antitumor, anti-angiogenesis and anti-proliferation in vivo, while the control conjugate was almost inefficacious at the same in vivo test. On the other hand, PTX conjugates demonstrated a thousand-time or more improvement in water solubility compared to PTX, suggesting a very easy way in the preparation and use of its injection. Without involvement of Cremophore EL and ethanol, the PTX conjugate will guarantee less adverse effects as frequently reported for Taxol formulation. Taxol formulation had a higher cytoxicity in vitro than PEG-VC-PABC-PTX likely because of toxic additives. Importantly, the C-B-sensitive conjugate indicated a similar in vivo efficacy with the Taxol control, but much lower in vivo toxicity at the same doses evidenced by body weight, animal status, liver toxicity and blood count. Moreover, at the tolerant dose, this novel conjugate exhibited significantly better antitumor effect than that of Taxol formulation. In general, the PEG-VC-PABC-PTX conjugate designed in this study demonstrated significant advantages in terms of high water solubility, no toxic surfactant or organic solvent, tumor environment-sensitivity and high therapeutic index. (C) 2012 Elsevier B.V. All rights reserved.

语种: 英语
所属项目编号: 2009CB930300 ; 2009ZX09310-001 ; 81130059
项目资助者: Ministry of Science and Technology, PR China ; National Science Foundation
WOS记录号: WOS:000305789300025
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/50507
Appears in Collections:北京大学药学院_期刊论文

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作者单位: Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China

Recommended Citation:
Liang, Liang,Lin, Song-Wen,Dai, Wenbing,et al. Novel cathepsin B-sensitive paclitaxel conjugate: Higher water solubility, better efficacy and lower toxicity[J]. JOURNAL OF CONTROLLED RELEASE,2012,160(3):618-629.
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