Hypoxia-Responsive Stereocomplex Polymeric Micelles with Improved Drug Loading Inhibit Breast Cancer Metastasis in an Orthotopic Murine Model
Hypoxia-Responsive Stereocomplex Polymeric Micelles with Improved Drug Loading Inhibit Breast Cancer Metastasis in an Orthotopic Murine Model
复制标题
具有改进的药物负载量的缺氧响应性立体复合物聚合物胶束在原位小鼠模型中抑制乳腺癌转移
DOI：
10.1021/acsami.1c23737
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发表时间：
2022-05-11
影响因子：
9.5
通讯作者：
Chen, Zhongping
中科院分区：
文献类型：
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作者：
Lu, Min;Huang, Xu;Chen, Zhongping
肿瘤转移是乳腺癌相关死亡的主要原因。紫杉烷负载的聚合物制剂，如Genexol PM和Nanoxel M，使用聚乙二醇-聚（D， l -丙交酯）（PEG-PLA）胶束作为药物载体，已被批准用于治疗转移性乳腺癌。不幸的是，PEG-PLA胶束的物理不稳定性导致药物装载不良，药物过早泄漏，从而限制了药物向肿瘤的递送，这在很大程度上阻碍了它们的治疗效果。受聚乳酸对映体性质的启发，本研究通过对映体聚乳酸的立体选择相互作用，开发了立体复合物PEG-PLA胶束，并进一步与缺氧反应片段结合，作为聚乙二醇和聚乳酸的缺氧可切割连接物，以最大限度地提高治疗效果。结果表明，获得的胶束具有较高的结构稳定性，可以提高药物负载，从而有效地将药物输送到肿瘤和其他组织。特别是，它们能够敏感地响应低氧肿瘤环境以释放药物，逆转低氧诱导的耐药和低氧促进的细胞迁移，从而提高低氧下的生物利用度。体内实验结果进一步表明，特别是在高剂量时，胶束可以抑制原发肿瘤的生长，改善肿瘤病理状况，从而显著抑制其向肺和肝脏的转移，而不会引起任何全身毒性。因此，低氧反应立体复合物胶束成为治疗乳腺癌转移的可靠药物传递系统。
Tumor metastasis is a leading cause of breast cancer-related death. Taxane-loaded polymeric formulations, such as Genexol PM and Nanoxel M using poly(ethylene glycol)-poly(D,L-lactide) (PEG-PLA) micelles as drug carriers, have been approved for the treatment of metastatic breast cancer. Unfortunately, the physical instability of PEG-PLA micelles, leading to poor drug loading, premature drug leakage, and consequently limited drug delivery to tumors, largely hinders their therapeutic outcome. Inspired by the enantiomeric nature of PLA, this work developed stereocomplex PEG-PLA micelles through stereoselective interactions of enantiomeric PLA, which are further incorporated with a hypoxia-responsive moiety used as a hypoxia-cleavable linker of PEG and PLA, to maximize therapeutic outcomes. The results showed that the obtained micelles had high structural stability, showing improved drug loading for effective drug delivery to tumors as well as other tissues. Especially, they were capable of sensitively responding to the hypoxic tumor environment for drug release, reversing hypoxia-induced drug resistance and hypoxia-promoted cell migration for enhanced bioavailability under hypoxia. In vivo results further showed that the micelles, especially at a high dose, inhibited the growth of the primary tumor and improved tumor pathological conditions, consequently remarkably inhibiting its metastasis to the lungs and liver, while not causing any systemic toxicity. Hypoxia-responsive stereocomplex micelles thus emerge as a reliable drug delivery system to treat breast cancer metastasis.