Most chemotherapeutic drugs and their nanomedicine formulations exert anticancer activity by inducing cancer cell apoptosis. However, cancer cells inherently have and acquire many antiapoptosis mechanisms, causing cancer drug resistance and poor prognoses in patients. Herein, a potent paraptosis‐inducing nanomedicine is reported that causes quick nonapoptotic death of cancer cells, overcoming apoptosis‐based resistance and effectively inhibiting drug‐resistant tumor growth. The nanomedicine is composed of micelles made from an amphiphilic 8‐hydroxyquinoline (HQ)‐conjugate block copolymer with polyethylene glycol. Cu²⁺ can catalyze the hydrolysis of the HQ conjugation linker and liberate HQ, and these molecules can form the complex Cu(HQ)₂, a strong proteasome inhibitor effective at inducing cell paraptosis. In vivo, the Cu²⁺‐responsive HQ‐releasing micelles respond to elevated tumor Cu²⁺ levels or externally administered Cu²⁺ and effectively inhibit the growth of human breast adenocarcinoma doxorubicin‐resistant (MCF‐7/ADR) tumors. Compared with other nanomedicines that overcome drug resistance via delivering several agents or even siRNA, this paraptosis‐inducing nanomedicine provides a simple but potent approach to overcoming cancer drug resistance.

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截瘫诱导纳米药物克服了对有效癌症治疗方法的抗药性

大多数化学治疗药物及其纳米药物制剂通过诱导癌细胞凋亡来发挥抗癌活性。然而，癌细胞固有地具有并获得许多抗凋亡机制，从而引起癌症药物抗性和患者的不良预后。本文报道了一种有效的诱导麻痹病的纳米药物，可导致癌细胞快速非凋亡性死亡，克服了基于凋亡的耐药性并有效抑制了耐药性肿瘤的生长。纳米药物由两亲性8-羟基喹啉（HQ）-共轭嵌段共聚物与聚乙二醇制成的胶束组成。Cu ²⁺可以催化HQ共轭连接基的水解并释放HQ，这些分子可以形成复杂的Cu（HQ）₂，一种有效的蛋白酶体抑制剂，可有效诱导细胞麻痹。在体内，对Cu ^2+有反应的HQ释放胶束对升高的肿瘤Cu ²⁺水平或外部施用的Cu ^{2+有反应，}并有效抑制了人乳腺对阿霉素（MCF-7 / ADR）耐药的肿瘤的生长。与通过递送多种药物甚至siRNA克服耐药性的其他纳米药物相比，这种诱导麻痹的纳米药物为克服癌症的耐药性提供了一种简单而有效的方法。