Evaluation of Cisplatin-Loaded Polymeric Micelles and Hybrid Nanoparticles Containing Poly(Ethylene Oxide)-Block-Poly(Methacrylic Acid) on Tumor Delivery

Particulate carriers such as polymeric micelles (PMs) and liposomes have been investigated to increase drug accumulation in tumors and reduce distribution to healthy tissues. In this study, we prepared PM and hybrid nanoparticles (HNPs) with poly(ethylene oxide)-block-poly(methacrylic acid) (PEO-b-PMAA) for loading cisplatin, and evaluated cisplatin release, cytotoxicity, and biodistribution in mice. PM composed of PEO-b-PMAA and HNPs composed of egg phosphatidylcholine (EPC)/PEO-b-PMAA at molar ratios of 50/2.8 (HNP-P5) and 50/50 (HNP-P50), respectively, were prepared by a nanoprecipitation method. The sizes of PM, HNP-P5, and HNP-P50 after inclusion of cisplatin were approximately 200, 100, and 55 nm, respectively, and their entrapment efficiencies were approximately 44% - 66%. In the drug-release study, HNP-P5 and HNP-P50 showed reduced release of cisplatin compared with PM. Regarding the cytotoxic assay, HNP-P5 exhibited lower cytotoxicity for mouse Lewis lung carcinoma (LLC) and mouse colon carcinoma Colon 26 cells than PM and HNP-P50. In terms of biodistribution, PM could significantly improve blood circulation and tumor accumulation after intravenous injection into Colon 26 tumor-bearing mice compared with free cisplatin, but HNP-P5 and HNP-P50 did not. EPC in HNPs might be destabilized in the circulation, although it could reduce release of cisplatin in in vitro experiments. This study suggested that polymeric micelles composed of PEO-b-PMAA are a better carrier for cisplatin than hybrid nanoparticles composed of PEO-b-PMAA and EPC.

Optimization of siRNA Delivery Method into the Liver by Sequential Injection of Polyglutamic Acid and Cationic Lipoplex

Previously, we developed a novel siRNA transfer method to the liver by sequential intravenous injection of poly-L-glutamic acid (PGA) and cationic liposome/siRNA complex (cationic lipoplex). In this study, we examined the effects of the charge ratio (+/-) of cationic liposome/siRNA, molecular weight of PGA and cationic lipid of cationic liposome on the biodistribution of siRNA after sequential injection of PGA plus cationic lipoplex. When 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/cholesterol (Chol) lipoplex was intravenously injected into mice, the accumulation of siRNA was mainly observed in the lungs. In contrast, when DOTAP/Chol lipoplex was intravenously injected at 1 min after intravenous injection of PGA, siRNA was largely accumulated in the liver. The charge ratio (+/-) of DOTAP/Chol liposome/siRNA did not affect the biodistribution of siRNA after sequential injection. As regards the molecular weight of PGA, the accumulation of siRNA was observed mainly in the liver after the sequential injection of PGA of 20.5, 38, 64 or 200 kDa plus DOTAP/Chol lipoplex. Furthermore, to examine the effect of cationic lipid of cationic liposome on the biodistribution of siRNA, we prepared other cationic liposomes composed of 1,2-di-O-octadecenyl-3-trimethylammonium propane chloride (DOTMA)/Chol, dimethyldioctade-cylammonium bromide (DDAB)/Chol and O,O’-ditetradecanoyl-N-(α-trimethylammonioacetyl)di-ethanolamine chloride (DC-6-14)/Chol. For the cationic liposomes, the accumulation of siRNA was observed mainly in the liver when their cationic lipoplexes were sequentially injected after injection of PGA into mice. From these findings, sequential injection of PGA plus cationic lipoplex could deliver siRNA efficiently into the liver regardless of the charge ratio (+/-) of lipoplex, lengths of PGA and cationic lipid of liposome.