A polypeptide based podophyllotoxin conjugate for the treatment of multi drug resistant breast cancer with enhanced efficiency and minimal toxicity
A polypeptide based podophyllotoxin conjugate for the treatment of multi drug resistant breast cancer with enhanced efficiency and minimal toxicity
复制标题
基于多肽的鬼臼毒素缀合物，用于治疗多重耐药乳腺癌，具有更高的效率和最小的毒性
DOI：
10.1016/j.actbio.2018.04.016
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发表时间：
2018
影响因子：
9.7
通讯作者：
Tang ZH
中科院分区：
文献类型：
--
作者：
Zhou Huicong;Zhang Xuefei;Zhou Huicong;Zhang Xuefei;Zhou Huicong;Lv Shixian;Zhang Dawei;Tang Zhaohui;Chen Xuesi;Deng Mingxiao;Zhang XF;Zhang XF;Tang ZH
鬼臼毒素（PPT）是一种对P-糖蛋白（P-gp）介导的多药耐药癌细胞具有显著活性的化疗药物。但PPT水溶性差、毒性大，不能用于临床肿瘤治疗。为了提高PPT的疗效和减少副作用，我们研制了一种基于多肽的PPT偶联物PLG-g-mPEG-PPT，并用于治疗多药耐药乳腺癌。PLG-g-mPEG-PPT是通过酯键将PPT与聚（1-谷氨酸）-g-甲氧基聚（乙二醇）（PLG-g-mPEG）偶联制备的。PPT偶联物在水溶液中自组装成平均粒径约为100 nm的纳米粒子。Western blotting实验表明，PLG-g-mPEG-PPT能有效抑制MCF-7/ADR多药耐药细胞P-gp的表达，体外细胞毒实验表明，PLG-g-mPEG-PPT对不同耐药细胞系的耐药指数（RI）值较传统微管抑制剂化疗药物PTX或DTX降低57-270倍。溶血实验表明，偶联物大大降低了游离PPT的溶血活性。PLG-g-mPEG-PPT的最大耐受剂量（MTD）显著增加体内研究表明，PLG-g-mPEG-PPT缀合物显著增强了对MCF-7/ADR异种移植瘤的抗肿瘤功效，肿瘤抑制率（TSR）为82.5%，与游离PPT相比，（TSR = 37.1%），当两种制剂均以MTD使用时毒性最小。化疗失败的主要原因是肿瘤细胞的耐多药（MDR）。P-糖蛋白（P-gp）的过度表达是肿瘤多药耐药的重要原因。鬼臼毒素（Podophyllotoxin，PPT）是一种抗多药耐药的化疗药物，它能同时抑制P-gp的过度表达和肿瘤细胞的生长。但PPT水溶性差、毒性大，不能用于临床肿瘤治疗。本文中，我们通过将PPT缀合至聚（l-谷氨酸）-g-甲氧基聚（乙二醇）开发了基于多肽的PPT缀合物PLG-g-mPEG-PPT。与游离PPT相比，PLG-g-mPEG-PPT显示出显著降低的溶血活性、极大提高的最大耐受剂量和显著增强的抗MCF-7/ADR异种移植肿瘤的抗肿瘤功效。
Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown significant activity against P-glycoprotein (P-gp) mediated multi drug resistant cancer cells. However, because of the poor aqueous solubility and high toxicity, PPT cannot be used in clinical cancer therapy. In order to enhance the efficiency and reduce side effect of PPT, a polypeptide based PPT conjugate PLG-g-mPEG-PPT was developed and used for the treatment of multi drug resistant breast cancer. The PLG-g-mPEG-PPT was prepared by conjugating PPT to poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG)viaester bonds. The PPT conjugates self-assembled into nanoparticles with average sizes about 100 nm in aqueous solution. Western blotting assay showed that the PLG-g-mPEG-PPT could effectively inhibit the expression of P-gp in the multiple drug resistant MCF-7/ADR cells.In vitrocytotoxicity assay indicated that the resistance index (RI) values of PLG-g-mPEG-PPT on different drug-resistant cancer cell lines exhibited 57–270 folds reduction than of traditional microtubule inhibitor chemotherapeutic drug PTX or DTX. Hemolysis assay demonstrated that the conjugation greatly decreased the hemolytic activity of free PPT. Maximum tolerated dose (MTD) of PLG-g-mPEG-PPT increased greatly (13.3 folds) as compared to that of free PPT.In vivostudy showed that the PLG-g-mPEG-PPT conjugate remarkably enhanced the antitumor efficacy against MCF-7/ADR xenograft tumors with a tumor suppression rate (TSR) of 82.5%, displayed significantly improved anticancer efficacy as compared to free PPT (TSR = 37.1%) with minimal toxicity when both of the two formulations were used in MTD.Statement of SignificanceThe development of multiple drug resistance (MDR) of cancer cells is the main cause of chemotherapy failure. The over-expression of P-glycoprotein (P-gp) has been recognized to be the most important cause of MDR in cancer. Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown strong activity against P-gp mediated multidrug resistant cancer cells by simultaneously inhibiting the over-expression of P-gp and the growth of cancer cells. However, PPT can not be used in clinical cancer treatment due to its poor aqueous solubility and high toxicity. Herein, we developed a polypeptide based PPT conjugate PLG-g-mPEG-PPT by conjugating PPT to poly(l-glutamic acid)-g-methoxy poly(ethylene glycol). The PLG-g-mPEG-PPT shows significantly decreased hemolytic activity, greatly improved maximum tolerated dose and remarkably enhanced antitumor efficacy against MCF-7/ADR xenograft tumors as compared to free PPT.