Nanoparticle-based prodrugs offer an effective strategy to improve the safety and delivery of small-molecule therapeutics while reducing the risk of drug resistance. Here, we conjugated a maleimide-functionalized cisplatin prodrug containing Pt(IV) to the internal and/or external surface of virus-like particles (VLPs) derived from Physalis mottle virus (PhMV) to develop a pH-sensitive drug delivery system. The internally loaded and PEGylated VLPs (Pt-PhMVCy5.5-PEG) were taken up efficiently by cancer cells where they released platinum, presumably as a reduced, DNA-reactive Pt(II) complex, rapidly under acidic conditions in vitro (>80% in 30 h). The efficacy of the VLP-based drug delivery system was demonstrated against a panel of cancer cell lines, including cell lines resistant to platinum therapy. Furthermore, Pt-PhMVCy5.5-PEG successfully inhibited the growth of xenograft MDA-MB-231 breast tumors in vivo and significantly prolonged the survival of mice compared to free cisplatin and cisplatin-maleimide. Pt-PhMVCy5.5-PEG therefore appears promising as a prodrug to overcome the limitations of conventional platinum-based drugs for cancer therapy.

中文翻译：

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基于酸浆斑驳病毒的顺铂前药纳米颗粒用于癌症治疗

基于纳米颗粒的前药提供了一种有效的策略，可以提高小分子疗法的安全性和递送，同时降低耐药风险。在这里，我们将含有 Pt(IV) 的马来酰亚胺功能化顺铂前药偶联到源自酸浆斑驳病毒 (PhMV) 的病毒样颗粒 (VLP) 的内部和/或外部表面，以开发 pH 敏感的药物递送系统。内部负载和聚乙二醇化的 VLP（Pt-PhMVCy5.5-PEG）被癌细胞有效吸收，在体外酸性条件下，它们释放铂，可能是还原的 DNA 反应性 Pt(II) 复合物（30 小时内 >80%）。基于 VLP 的药物递送系统对一组癌细胞系的功效得到了证明，包括对铂疗法有抗性的细胞系。此外，与游离顺铂和顺铂-马来酰亚胺相比，Pt-PhMVCy5.5-PEG 成功地抑制了体内异种移植物 MDA-MB-231 乳腺肿瘤的生长，并显着延长了小鼠的存活率。因此，Pt-PhMVCy5.5-PEG 作为前药似乎很有前景，可以克服传统铂类药物在癌症治疗中的局限性。