Huo Meirong, Zhu Qinnv, Wu Qu, Yin Tingjie, Wang Lei, Yin Lifang, Zhou Jianping
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University Nanjing 210009 China.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University Nanjing 210009 China.
J Pharm Sci. 2015 Jun;104(6):2018-2028. doi: 10.1002/jps.24438. Epub 2015 Mar 27.
In this study, a novel PTX prodrug, octreotide(Phe)-polyethene glycol-paclitaxel [OCT(Phe)-PEG-PTX], was successfully synthesized and used for targeted cancer therapy. A nontargeting conjugate, mPEG-PTX, was also synthesized and used as a control. Chemical structures of OCT(Phe)-PEG-PTX and mPEG-PTX were confirmed using (1) H nuclear magnetic resonance and circular dichroism. The drug contents in both the conjugates were 12.0% and 14.0%, respectively. Compared with the parent drug (PTX), OCT(Phe)-PEG-PTX, and mPEG-PTX prodrugs showed a 20,000- and 30,000-fold increase in water solubility, respectively. PTX release from mPEG-PTX and OCT(Phe)-PEG-PTX exhibited a pH-dependent profile. Moreover, compared with mPEG-PTX, OCT(Phe)-PEG-PTX exhibited significantly stronger cytotoxicity against NCI-H446 cells (SSTR overexpression) but comparable cytotoxicity against WI-38 cells (no SSTR expression). Results of confocal laser scanning microscopy revealed that the targeting prodrug labeled with fluorescence probe was selectively taken into tumor cells via SSTR-mediated endocytosis. In vivo investigation of prodrugs in nude mice bearing NCI-H446 cancer xenografts confirmed that OCT(Phe)-PEG-PTX prodrug exhibited stronger antitumor efficacy and lower systemic toxicity than mPEG-PTX and commercial Taxol. These results suggested that OCT(Phe)-PEG-PTX is a promising anticancer drug delivery system for targeted cancer therapy.
在本研究中，一种新型的紫杉醇前药，奥曲肽（苯丙氨酸）-聚乙二醇-紫杉醇[OCT（苯丙氨酸）-PEG-PTX]成功合成并用于靶向癌症治疗。还合成了一种非靶向缀合物mPEG-PTX并用作对照。使用氢核磁共振和圆二色性确认了OCT（苯丙氨酸）-PEG-PTX和mPEG-PTX的化学结构。两种缀合物中的药物含量分别为12.0%和14.0%。与母体药物（紫杉醇）相比，OCT（苯丙氨酸）-PEG-PTX和mPEG-PTX前药的水溶性分别增加了20000倍和30000倍。mPEG-PTX和OCT（苯丙氨酸）-PEG-PTX的紫杉醇释放呈现pH依赖性。此外，与mPEG-PTX相比，OCT（苯丙氨酸）-PEG-PTX对NCI-H446细胞（生长抑素受体过表达）表现出明显更强的细胞毒性，但对WI-38细胞（无生长抑素受体表达）的细胞毒性相当。共聚焦激光扫描显微镜结果显示，用荧光探针标记的靶向前药通过生长抑素受体介导的内吞作用被选择性地摄取到肿瘤细胞中。在携带NCI-H446癌异种移植瘤的裸鼠体内对前药进行的研究证实，OCT（苯丙氨酸）-PEG-PTX前药比mPEG-PTX和市售紫杉醇表现出更强的抗肿瘤疗效和更低的全身毒性。这些结果表明，OCT（苯丙氨酸）-PEG-PTX是一种有前途的用于靶向癌症治疗的抗癌药物递送系统。
