Reduction-Degradable Polymeric Micelles Decorated with PArg for Improving Anticancer Drug Delivery Efficacy

In this study, five kinds of reduction-degradable polyamide amine-<i>g</i>-polyethylene glycol/polyarginine (PAA-<i>g</i>-PEG/PArg) micelles with different proportions of hydrophilic and hydrophobic segments were synthesized as novel drug delivery vehicles. Polyarginine not only acted as a hydrophilic segment but also possessed a cell-penetrating function to carry out a rapid transduction into target cells. Polyamide amine-<i>g</i>-polyethylene glycol (PAA-<i>g</i>-PEG) was prepared for comparison. The characterization and antitumor effect of the DOX-incorporated PAA-<i>g</i>-PEG/PArg cationic polymeric micelles were investigated <i>in vitro</i> and <i>in vivo</i>. The cytotoxicity experiments demonstrated that the PAA-<i>g</i>-PEG/PArg micelles have good biocompatibility. Compared with DOX-incorporated PAA-<i>g</i>-PEG micelles, the DOX-incorporated PAA-<i>g</i>-PEG/PArg micelles were more efficiently internalized into human hepatocellular carcinoma (HepG2) cells and more rapidly released DOX into the cytoplasm to inhibit cell proliferation. In the 4T1-bearing nude mouse tumor models, the DOX-incorporated PAA-<i>g</i>-PEG/PArg micelles could efficiently accumulate in the tumor site and had a longer accumulation time and more significant aggregation concentration than those of PAA-<i>g</i>-PEG micelles. Meanwhile, it excellently inhibited the solid tumor growth and extended the survival period of the tumor-bearing Balb/c mice. These results could be attributed to their appropriate nanosize and the cell-penetrating peculiarity of polyarginine as a surface layer. The PAA-<i>g</i>-PEG/PArg polymeric micelles as a safe and high efficiency drug delivery system were expected to be a promising delivery carrier that targeted hydrophobic chemotherapy drugs to tumors and significantly enhanced antitumor effects