Shanghai University of Medicine & Health Sciences Affiliated Sixth People's Hospital South Campus , Shanghai 201499, China.
Department of General Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University , No. 301, Yan-Chang Road, Shanghai 200072, China.
ACS Appl Mater Interfaces. 2017 Nov 22;9(46):40614-40627. doi: 10.1021/acsami.7b11614. Epub 2017 Nov 9.
Matrix metalloproteinases (MMPs), mostly abundant in the tumor extracellular matrix (ECM), tumor cells, and tumor vasculatures, are closely correlated with tumor progression and metastasis. In this case, making use of MMPs was supposed to achieve site-specific drug delivery and a satisfactory tumor treatment effect. Herein, we rationally developed a novel tumor microenvironment and tumor cell dual-targeting nanoparticle by integrating a chemotherapeutic-loaded drug-loaded carrier and a versatile polypeptide-LinTT1-PVGLIG-TAT (LPT) which is composed of a multitargeting peptide-LinTT1 and a cell-penetrating peptide-TAT. The functionalized nanoparticles exhibited a superior affinity to A549 lung-cancer cells and microenvironment including angiogenesis and tumor-associated macrophages (TAMs) in our study. In addition, cellular experiments demonstrated that the cell-penetrating ability of TAT was significantly shielded by the addition of LinTT1 to the fourth lysine of the TAT via an MMP cleavable linker PVGLIG and could be recovered under the catalysis of MMPs. This design was supposed to efficiently decrease the toxicological risk to normal tissues induced by the unselectivity of TAT. The finally treatment effect investigation showed that tumor-bearing mice treated with LPT-modified nanoparticles achieved an enhanced efficacy for inhibiting tumor growth and the longest survival time as compared to other groups. Collectively, this study provides a novel robust nanoplatform which could simultaneously target the tumor microenvironment and tumor cell drug delivery for increasing the efficacy of cancer therapy.
基质金属蛋白酶（MMPs）主要存在于肿瘤细胞外基质（ECM）、肿瘤细胞和肿瘤血管中，与肿瘤的进展和转移密切相关。在这种情况下，利用 MMPs 实现了肿瘤部位的特异性药物传递和令人满意的肿瘤治疗效果。在这里，我们通过整合载有化疗药物的载药载体和一种多功能多肽-LinTT1-PVGLIG-TAT（LPT），合理地开发了一种新型的肿瘤微环境和肿瘤细胞双重靶向纳米粒子，该多肽由一个多靶向肽-LinTT1 和一个细胞穿透肽-TAT 组成。在我们的研究中，功能化的纳米粒子表现出对 A549 肺癌细胞和微环境（包括血管生成和肿瘤相关巨噬细胞（TAMs））的优异亲和力。此外，细胞实验表明，TAT 的细胞穿透能力通过 MMP 可切割连接物 PVGLIG 被添加到 TAT 的第四个赖氨酸上的 LinTT1 显著屏蔽，并可以在 MMP 的催化下恢复。这种设计有望有效降低 TAT 的非选择性对正常组织造成的毒理学风险。最终的治疗效果研究表明，与其他组相比，用 LPT 修饰的纳米粒子治疗的荷瘤小鼠在抑制肿瘤生长方面取得了更好的疗效，并延长了生存时间。总的来说，这项研究提供了一种新型的强大纳米平台，可同时靶向肿瘤微环境和肿瘤细胞药物传递，以提高癌症治疗的疗效。
