The intrinsic or acquired cisplatin resistance of cancer cells frequently limits the final therapeutic efficacy. Detoxification by the high level of intracellular glutathione (GSH) plays critical roles in the majority of cisplatin-resistant cancers. In this report, we designed an amphiphilic diblock copolymer composed of poly(ethylene glycol) (PEG) and polymerized phenylboronic ester-functionalized methacrylate (PBEMA), PEG-b-PBEMA, which can self-assemble into micelles in aqueous solutions to load hydrophobic cisplatin prodrug (Pt(IV)). Pt(IV)-loaded PEG-b-PBEMA micelles (PtBE-Micelle) reverse cisplatin-resistance of cancer cells through improving cellular uptake efficiency and reducing intracellular GSH level. We found that the cellular uptake amount of platinum from PtBE-Micelle was 6.1 times higher than that of free cisplatin in cisplatin-resistant human lung cancer cells (A549R). Meanwhile, GSH concentration of A549R cells was decreased to 32% upon treatment by PEG-b-PBEMA micelle at the phenyl borate-equivalent concentration of 100 μM. PtBE-Micelle displayed significantly higher cytotoxicity toward A549R cells with half maximal inhibitory concentration (IC₅₀) of cisplatin-equivalent 0.20 μM compared with free cisplatin of 33.15 μM and Pt(IV)-loaded PEG-b-poly(ε-caprolactone) micelles of cisplatin-equivalent 0.75 μM. PtBE-Micelle can inhibit the growth of A549R xenograft tumors effectively. Accordingly, PEG-b-PBEMA micelles show great potentials as drug delivery nanocarriers for platinum-based chemotherapy toward cisplatin-resistant cancers.

癌细胞固有的或获得的顺铂耐药性常常限制了最终的治疗效果。在大多数对顺铂耐药的癌症中，高水平的细胞内谷胱甘肽（GSH）排毒起着关键作用。在本报告中，我们设计了一种由聚（乙二醇）（PEG）和聚合的苯基硼酸酯官能化的甲基丙烯酸酯（PBEMA），PEG- b -PBEMA组成的两亲性二嵌段共聚物，该共聚物可以在水溶液中自组装成胶束以负载疏水性顺铂前药（Pt（IV））。载有Pt（IV）的PEG- b-PBEMA胶束（PtBE-Micelle）通过提高细胞摄取效率和降低细胞内GSH水平来逆转癌细胞的顺铂耐药性。我们发现在耐顺铂的人肺癌细胞（A549R）中，PtBE-Micelle对铂的细胞摄取量比游离顺铂的细胞摄取量高6.1倍。同时，在100μM的苯硼酸当量浓度下，通过PEG- b - PBEMA胶束处理，A549R细胞的GSH浓度降低至32％。PtBE-Micelle对A549R细胞表现出明显更高的细胞毒性，最大顺铂等效浓度（IC ₅₀）为一半，顺铂当量为0.20μM，而游离顺铂为33.15μM，且载有Pt（IV）的PEG- b -poly（ε）-己内酯）胶束的顺铂当量0.75μM。PtBE-Micelle可以有效抑制A549R异种移植肿瘤的生长。因此，PEG- b - PBEMA胶束显示出巨大的潜力，可作为铂类化学疗法对顺铂耐药性癌症的药物输送纳米载体。