A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance
A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance
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DOI：
10.1007/s10637-007-9053-8
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发表时间：
2007-08-01
影响因子：
3.4
通讯作者：
Raucher, Drazen
中科院分区：
文献类型：
--
作者：
Bidwell, Gene L., III;Davis, Aisha N.;Raucher, Drazen
癌细胞同时对不同药物产生耐药性的能力（称为多药耐药性）仍然是成功抗癌治疗的主要障碍。耐药的一个主要机制涉及通过 P-糖蛋白 (P-gp) 的表达导致细胞药物流出，P-糖蛋白是一种具有多种底物的膜转运蛋白。蒽环类药物特别容易通过 P-gp 机制诱导耐药性。 P-gp 介导的耐药性通常通过使用 P-gp 抑制剂、合成新型类似物或将药物与大分子载体缀合以规避外排机制来解决。在本报告中，体外研究了游离和弹性蛋白样多肽（ELP）结合的阿霉素（Dox）对敏感（MES-SA和MCF-7）和多药耐药（MES-SA/Dx5和NCI/ADR-RES）人类癌细胞活力的影响。耐药性 MES-SA/Dx5 细胞对游离 Dox 的耐药性比敏感 MES-SA 细胞高约 70 倍，NCI/ADR-RES 细胞比 MCF-7 细胞高约 30 倍。然而，ELP 结合的 Dox 在敏感和耐药细胞系中具有同等的细胞毒性。 ELP 结合的 Dox 在 MES-SA/Dx5 细胞中积聚，而游离的 Dox 则被 P-gp 转运蛋白快速泵出。由于 ELP 是热响应载体，因此研究了高温对 ELP-Dox 缀合物细胞毒性的影响。 Dox 抗性细胞的细胞毒性和细胞凋亡均因高温而增强。结果表明，ELP-Dox 缀合物可能提供一种热靶向实体瘤并克服癌细胞耐药性的方法。
The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.