Novel Biodegradable and pH-sensitive Nanocarriers based on Self-assembling Polypeptides for Active Targeted Drug Delivery

L-W Wang, L-H Chen, S. Wu, T-W Wang
National Tsing Hua University,

Keywords: nanoparticles, drug delivery, polypeptides, pH sensitivity, active targeting


Polymeric nanoparticles have shown promising potential as carriers for drug delivery. The structural stability of delivery vehicle and effective release of encapsulated therapeutic drugs are crucial for drug delivery system. In this study, the biodegradable pH-sensitive nanoparticles composed of natural polypeptides and calcium phosphate (CaP), have been developed. We utilized two different amphiphilic sequences, poly(ethylene glycol)3400-aconityl linkage- poly(L-glutamic acid)- poly(L-histidine)-poly(L-leucine) and LyP1-poly(ethylene glycol) 1100-poly(L-glutamic acid)- poly(L-histidine)-poly(L-leucine), to self-assemble into nanoparticles in aqueous phase. The biostable nanoparticles provide three distinct functional domains: the hydrated PEG outer corona for prolonging circulation time, the anionic PGlu shell for CaP mineralization, and the protonation of PHis shell for facilitating anticancer drug release at target site. The active targeting ligand, LyP-1, is served to bind to lymphatic endothelial cells in tumor for the reduction rate of metastasis. The resulting mineralized Dox-loaded particles (M-DOX NPs) with negative charge (-21.9 ± 1.6 mV) have a smaller size 179.4 ±33.9 nm at pH 7.4, but particles at pH 5.0 have a doubled size (291.2 ±25.1 nm) and positive charged (21.7 ± 2.1 mV), implying the protonation of poly-histidine. From the release profile, M-DOX NPs effectively reduce the leakage at physiological pH value comparing to DOX NPs, and both nanoparticles facilitate the encapsulated drug release at acidic condition. The inhibition effect on cell proliferation of M-DOX NPs with LyP1 enhanced with time, which was comparable with free drug. The biocompatible pH-sensitive drug carriers can effectively release anti-cancer drug in acidic condition to obtain sustained controlled release as promising carriers for anti-tumor drug delivery.