École Polytechnique Fédérale de Lausanne (EPFL) , Institut des Matériaux et Institut des Sciences et Ingénierie Chimiques, Laboratoire des Polymères, Bâtiment MXD, Station 12, CH-1015 Lausanne, Switzerland.
Biomacromolecules. 2017 Jun 12;18(6):1855-1865. doi: 10.1021/acs.biomac.7b00291. Epub 2017 May 4.
Inhibition of P-glycoprotein (P-gp) transporter is an attractive approach for the reversion of cancer-associated multidrug resistance (MDR). Poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA)-based carriers that are able to release the anticancer drug doxorubicin in the lysosomes have shown promise to reduce P-gp mediated resistance. This is attributed to the release of the drug in close proximity to the nucleus and distant from the P-gp transporter. This work presents a strategy to maximize P-gp inhibition and enhance doxorubicin cytotoxicity in cancer cells by using a dual functional PHPMA conjugate carrying both the anticancer drug doxorubicin and the P-glycoprotein inhibitor zosuquidar (Zos). While doxorubicin was connected to the polymer backbone via a lysosomally cleavable spacer, the P-gp inhibitor Zos was attached by a hydrazone linker in order to promote release in the early stage of the endocytic process and maximize its cytosolic concentration in proximity of the P-gp transporter. Following Zos modification and determination of its ability to inhibit P-gp, conjugation to the PHPMA polymer backbone resulted in enhanced doxorubicin cytotoxicity in resistant A2780ADR ovarian carcinoma cells. Finally, the incorporation of both Dox and Zos in a single polymer carrier enhanced P-gp inhibition as compared to a control PHPMA conjugate containing only Dox.
抑制 P-糖蛋白（P-gp）转运体是逆转癌症相关多药耐药性（MDR）的一种有吸引力的方法。能够在溶酶体中释放阿霉素等抗癌药物的基于聚（N-（2-羟丙基）甲基丙烯酰胺）（PHPMA）的载体已显示出降低 P-gp 介导的耐药性的潜力。这归因于药物在靠近细胞核且远离 P-gp 转运体的位置释放。本工作提出了一种策略，通过使用同时携带抗癌药物阿霉素和 P-糖蛋白抑制剂唑来曲唑（Zos）的双重功能 PHPMA 缀合物，最大程度地抑制 P-gp 并增强癌细胞中阿霉素的细胞毒性。虽然阿霉素通过溶酶体可裂解间隔物连接到聚合物主链，但 P-gp 抑制剂 Zos 通过腙键连接，以促进在早期内吞过程中释放，并使其在靠近 P-gp 转运体的细胞质中具有更高的浓度。在对 Zos 进行修饰并确定其抑制 P-gp 的能力后，将其与 PHPMA 聚合物主链缀合可增强耐药性 A2780ADR 卵巢癌细胞中阿霉素的细胞毒性。最后，与仅包含 Dox 的对照 PHPMA 缀合物相比，将 Dox 和 Zos 同时包含在单个聚合物载体中可增强 P-gp 抑制作用。
