Therapeutic efficiency of folated poly(ethylene glycol)-chitosan-graft-polyethylenimine-Pdcd4 complexes in H-ras12V mice with liver cancer

Abstract

You-Kyoung Kim,1 Arash Minai-Tehrani,2 Jae-Ho Lee,2 Chong-Su Cho,3 Myung-Haing Cho,2–6 Hu-Lin Jiang1 1State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul, 3Department of Agricultural Biotechnology, Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, 4Department of Nano Fusion Technology, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, 5Graduate Group of Tumor Biology, Seoul National University, Seoul, 6Advanced Institute of Convergence Technology, Seoul National University, Suwon, Republic of Korea Background: Chitosan and chitosan derivatives have been proposed as alternative and biocompatible cationic polymers for nonviral gene delivery. However, the low transfection efficiency and low specificity of chitosan is an aspect of this approach that must be addressed prior to any clinical application. In the present study, folated poly(ethylene glycol)-chitosan-graft-polyethylenimine (FPCP) was investigated as a potential folate receptor-overexpressed cancer cell targeting gene carrier. Methods: The FPCP copolymer was synthesized in two steps. In the first step, folate-PEG was synthesized by an amide formation reaction between the activated carboxyl groups of folic acid and the amine groups of bifunctional poly(ethylene glycol) (PEG). In the second step, FPCP was synthesized by an amide formation reaction between the activated carboxyl groups of folate-PEG and amine groups of CHI-g-polyethyleneimine (PEI). The composition of FPCP was characterized by 1H nuclear magnetic resonance. Results: FPCP showed low cytotoxicity in various cell lines, and FPCP-DNA complexes showed good cancer cell specificity as well as good transfection efficiency in the presence of serum. Further, FPCP-Pdcd4 complexes reduced tumor numbers and progression more effectively than PEI 25 kDa in H-ras12V liver cancer mice after intravenous administration. Conclusion: Our data suggest that FPCP, which has improved transfection efficiency and cancer cell specificity, may be useful in gene therapy for liver cancer. Keywords: liver cancer, targeted gene therapy, folated poly(ethylene glycol)-chitosan-graft-polyethylenimine, safety, efficiency