Activatable Cell Penetrating Peptide-Conjugated Nanoparticles with Enhanced Permeability for Site-Specific Targeting Delivery of Anticancer Drug

摘要

Based on the powerful cell-penetrating ability of low molecular weight protamine (LMVVP) and the over-expression of matrix metalloproteinases in the tumor sites, we constructed an activatable low molecular weight protamine (ALMWP) and modified it onto the surface of poly(ethylene glycol)-poly(lactic acid) nanoparticles to develop a "smart" drug delivery system with enhanced permeability for facilitating site-specific targeting delivery of anticancer drug. The obtained ALMWP-functionalized nanoparticles (ALMWP-NP) with a particle size of 134.0 ± 4.59 nm and a zeta potential of -34.4 ± 2.7 mV, exhibited an enhanced MMP-dependent accumulation in HT-1080 cells via both energy-independent direct translocation and clathrin-mediated, cytoskeleton-dependent endocytosis. Pharmacokinetic and biodistribution study in HT-1080 tumor-bearing mice showed that ALMWP-NP significantly increased the accumulation of paclitaxel (PTX) in the tumor site but not the nontarget tissues. In addition, intratumor distribution analysis demonstrated that more ALMWP-NP penetrated deeply into the tumor parenchyma. As a result, PTX loaded by ALMWP-NP exhibited improved antitumor efficacy over that by unmodified nanoparticles and LMWP-functionalized nanoparticles. The findings suggested that ALMWP-NP could be used as a safe and effective tumor-targeting drug delivery system and opened a new gateway to the application of cell-penetrating peptides for targeted antitumor therapy.