多功能肽修饰的基质金属蛋白酶2响应性表面可变脂质体通过增强靶向性和渗透性克服三阴性乳腺癌的耐药性,ACS Biomaterials Science & Engineering

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多功能肽修饰的基质金属蛋白酶2响应性表面可变脂质体通过增强靶向性和渗透性克服三阴性乳腺癌的耐药性
ACS Biomaterials Science & Engineering ( IF 5.4 ) Pub Date : 2022-06-06 , DOI: 10.1021/acsbiomaterials.2c00295
Changliang Liu ₁ , Zijian Zhao ₂ , Rui Gao ₁ , Xueying Zhang ₁ , Yalan Sun ₁ , Jiahui Wu ₁ , Jin Liu ₁ , Chan Chen ₁

Affiliation

尽管纳米药物在对抗耐药性方面显示出巨大的潜力，但其对恶性细胞的识别不佳和跨多个生物障碍的有限转运严重阻碍了药物在肿瘤病灶中的有效积累，这极大地限制了其在耐药三联药物的临床治疗中的应用。阴性乳腺癌（TNBC）。因此，在这项工作中制造了一种基于用多功能肽（命名为 EMC）修饰脂质体的表面可变药物递送载体，并用于封装阿霉素和 p-糖蛋白抑制剂 tariquidar。该 EMC 肽包含一个 EGFR 靶向子弹，该子弹是从“单珠单化合物”组合文库、MMP-2 切割底物和细胞穿透片段中筛选出来的。EGFR 靶向序列已被验证在细胞和分子水平上对 EGFR 具有出色的特异性和亲和力，并且可以在肿瘤微环境中通过 MMP-2 从 EMC 肽中卸载。这种多柔比星/tariquidar 共载和肽功能化脂质体 (DT-pLip) 在肿瘤生长抑制方面表现出优于耐药 TNBC 的功效在体外和体内通过 EGFR 靶向、响应 MMP-2 的渗透增强、可控释放和抑制外排。因此，我们的系统研究表明，这种基于脂质体的纳米平台通过靶向作用和肿瘤微环境触发的渗透增强在治疗耐药 TNBC 中的潜力。

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Matrix Metalloproteinase-2-Responsive Surface-Changeable Liposomes Decorated by Multifunctional Peptides to Overcome the Drug Resistance of Triple-Negative Breast Cancer through Enhanced Targeting and Penetrability

Although nanomedicine has demonstrated great potential for combating drug resistance, its suboptimal recognition of malignant cells and limited transport across multiple biological obstacles seriously impede the efficacious accumulation of drugs in tumor lesions, which strikingly limits its application in the clinical therapy of drug-resistant triple-negative breast cancer (TNBC). Hence, a surface-variable drug delivery vehicle based on the modification of liposomes with a multifunctional peptide (named EMC) was fabricated in this work and used for encapsulating doxorubicin and the p-glycoprotein inhibitor tariquidar. This EMC peptide contains an EGFR-targeting bullet that was screened from a “one-bead one-compound” combinatorial library, an MMP-2-cleaved substrate, and a cell-penetrating segment. The EGFR-targeting sequence has been validated to possess excellent specificity and affinity for EGFR at both the cellular and molecular levels and could be unloaded from the EMC peptide by MMP-2 in the tumor microenvironment. This doxorubicin/tariquidar-coloaded and peptide-functionalized liposome (DT-pLip) exhibited superior efficacy in tumor growth inhibition to drug-resistant TNBC both in vitro and in vivo through EGFR targeting, osmotic enhancement in response to MMP-2, controllable release, and inhibited efflux. Consequently, our systematic studies indicated the potential of this liposome-based nanoplatform in the therapy of drug-resistant TNBC through targeting effects and tumor microenvironment-triggered penetration enhancement.

更新日期：2022-06-06

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