Enzymatically Transformable Polymersome-Based Nanotherapeutics to Eliminate Minimal Relapsable Cancer
Enzymatically Transformable Polymersome-Based Nanotherapeutics to Eliminate Minimal Relapsable Cancer
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DOI：
10.1002/adma.202105254
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发表时间：
2021-10-07
影响因子：
29.4
通讯作者：
Kataoka, Kazunori
中科院分区：
文献类型：
--
作者：
Li, Junjie;Ge, Zhishen;Kataoka, Kazunori
预防手术后癌症的转移和局部复发仍然很困难。靶向手术后转移前小生境和微残留物提供了一个很好的前瞻性机会，但往往受到最小残留肿瘤治疗效果不佳的挑战。在这里，提出了一种基于酶促可转化聚合物的纳米管方法，该方法利用肿瘤相关组织中的基质金属蛋白酶（MMP）过度活化来指导秋水仙碱（微管破坏和抗炎剂）和马立马司他（MMP抑制剂）的共同递送。由MMP催化的聚合物囊泡的去聚乙二醇化不仅暴露胍部分以改善组织/细胞靶向/保留以增加生物利用度，而且差异性地释放马立马司他和秋水仙碱以分别接合其细胞外（MMP）和细胞内（微管）作用靶标。在原发性肿瘤/明显转移中，纳米治疗剂的血管特异性靶向可以与增强的渗透性和保留效应同步发挥作用，以阻止转移性乳腺癌的恶性进展。在手术切除大的原发性肿瘤后，纳米药物定位在转移前的小生境和手术后伤口的部位，破坏转移前的微环境并消除微残留物，这从根本上减少了转移和局部区域复发。研究结果表明，纳米治疗剂可以安全地扩大治疗窗口，以复苏秋水仙碱和MMP抑制剂用于其他炎症性疾病。
Prevention of metastatic and local-regional recurrence of cancer after surgery remains difficult. Targeting postsurgical premetastatic niche and microresiduals presents an excellent prospective opportunity but is often challenged by poor therapeutic delivery into minimal residual tumors. Here, an enzymatically transformable polymer-based nanotherapeutic approach is presented that exploits matrix metalloproteinase (MMP) overactivation in tumor-associated tissues to guide the codelivery of colchicine (microtubule-disrupting and anti-inflammatory agent) and marimastat (MMP inhibitor). The dePEGylation of polymersomes catalyzed by MMPs not only exposes the guanidine moiety to improve tissue/cell-targeting/retention to increase bioavailability, but also differentially releases marimastat and colchicine to engage their extracellular (MMPs) and intracellular (microtubules) targets of action, respectively. In primary tumors/overt metastases, the vasculature-specific targeting of nanotherapeutics can function synchronously with the enhanced permeability and retention effect to deter malignant progression of metastatic breast cancer. After the surgical removal of large primary tumors, nanotherapeutic agents are localized in the premetastatic niche and at the site of the postsurgical wound, disrupting the premetastatic microenvironment and eliminating microresiduals, which radically reduces metastatic and local-regional recurrence. The findings suggest that nanotherapeutics can safely widen the therapeutic window to resuscitate colchicine and MMP inhibitors for other inflammatory disorders.