Key Laboratory of Smart Drug Deliver, Ministry of Education and PLA Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
Biomaterials. 2012 Jun;33(19):4907-16. doi: 10.1016/j.biomaterials.2012.03.031. Epub 2012 Apr 7.
The combination of gene therapy and chemotherapy is a promising treatment strategy for brain gliomas. In this paper, we designed a co-delivery system (DGDPT/pORF-hTRAIL) loading chemotherapeutic drug doxorubicin and gene agent pORF-hTRAIL, and with functions of pH-trigger and cancer targeting. Peptide HAIYPRH (T7), a transferrin receptor-specific peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. T7-modified co-delivery system showed higher efficiency in cellular uptake and gene expression than unmodified co-delivery system in U87 MG cells, and accumulated in tumor more efficiently in vivo. DOX was covalently conjugated to carrier though pH-trigged hydrazone bond. In vitro incubation of the conjugates in buffers led to a fast DOX release at pH 5.0 (intracellular environment) while at pH 7.4 (blood) the conjugates are relatively stable. The combination treatment resulted in a synergistic growth inhibition (combination index, CI < 1) in U87 MG cells. The synergism effect of DGDPT/pORF-hTRAIL was verified in vitro and in vivo. In vivo anti-glioma efficacy study confirmed that DGDPT/pORF-hTRAIL displayed anti-glioma activity but was less toxic.
基因治疗与化疗相结合是脑胶质瘤有前途的治疗策略。本文设计了一种共递药系统（DGDPT/pORF-hTRAIL），装载化疗药物阿霉素和基因药物 pORF-hTRAIL，具有 pH 触发和癌症靶向功能。转铁蛋白受体特异性肽 HAIYPRH（T7）被选为配体，将共递药系统靶向表达转铁蛋白受体的肿瘤细胞。T7 修饰的共递药系统在 U87 MG 细胞中的细胞摄取和基因表达效率均高于未修饰的共递药系统，并且在体内更有效地聚集在肿瘤中。DOX 通过 pH 触发腙键共价连接到载体上。在 pH 5.0（细胞内环境）下缓冲液中孵育缀合物会导致 DOX 快速释放，而在 pH 7.4（血液）下缀合物相对稳定。在 U87 MG 细胞中，联合治疗导致协同生长抑制（组合指数，CI<1）。DGDPT/pORF-hTRAIL 的协同作用在体外和体内得到了验证。体内抗胶质瘤研究证实，DGDPT/pORF-hTRAIL 具有抗胶质瘤活性，但毒性较小。
