Matrix Metalloproteinases Cleavable Nanoparticles for Tumor Microenvironment and Tumor Cells Dual-Targeting Drug Delivery.

Matrix metalloproteinases (MMPs), mostly abundant in tumor extracellular matrix (ECM), tumor cells and tumor vasculatures, are closely correlated with tumor progression and metastasis. Therefore, making use of MMPs can readily achieve site-specific drug delivery and satisfactory tumor treatment effect. Herein, we rationally developed a novel tumor microenvironment and tumor cells dual-targeting nanoparticle by integrating a chemotherapeutics-loaded drug-loaded carrier and a versatile polypeptide-LinTT1-PVGLIG-TAT (LPT) which composed by a multi-targetingpeptide-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. Besides, cellular experiments demonstrated that transmembrane transport capacity of TAT was significantly shielded by the addition of LinTT1 to the fourth lysine of the TAT via a MMPs 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 unselectively of TAT. The finally pharmacodynamic investigation showed that tumor-bearing mice treated with LPT modified nanoparticles achieved an enhanced efficacy for inhibiting tumor growth and longest survival time than other groups. Collectively, this study provides a novel robust nanoplatform which could simultaneously target tumor microenvironment and tumor cells drug delivery for increasing the efficacy of cancer therapy.