Targeting delivery of synergistic dual drugs with elastic PEG-modified multi-functional nanoparticles for hepatocellular carcinoma therapy

Integration of multiple advantages in one system has been leveraged to overcome multiple biological barriers in anti-tumor therapeutic strategies. In this study, multi-functional nanoparticles (MFNPs) are constructed by layer-by-layer method. MFNPs are modified with pH-responsive elastic PEG-GPC3MAb (glypican-3 monoclonal antibody), which draws back into PEG layer in blood and normal tissues; and stretches out of MFNPs surface in the acidic tumor microenvironment. It is proved that blank MFNPs have good biocompatibility by MTT and acute toxicity assays. Elastic PEG chains are able to respond sensitively in different pH environments (6.8 and 7.4), which is demonstrated by transmission electron microscope (TEM) and ¹H nuclear magnetic resonance (¹H NMR). In vitro experiments show that MFNPs have better specificity to Hepa 1-6 cells, can escape from lysosomes, and are able to increase the nuclear delivery of dual drugs for synergistic therapy, which are proved by flow cytometry, MTT, confocal laser scanning microscopy, and western blot studies. In vivo experiments indicate that MFNPs show extending circulation half-life in blood, promoting localization into tumor tissues, improving the therapeutic efficacy of BAL b/c nude mice with subcutaneous tumors. Overall, the results indicate that FMNPs are a potential candidate for hepatocellular carcinoma therapy.