Yang Wu1, Wei Zhang2, Tinghan Li3, Rong Ma1, Dan Chen1, Junying Zhang1, Jianzhong Wu1, Jinhai Tang4. 1. Research Center of Clinical Oncology, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China. 2. Collaborative Innovation Center of Suzhou Nano Science and Technology, Southeast University, Nanjing, China. 3. Jiangsu Key Laboratory of Drug Design and Optimization and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China. 4. Department of General Surgery, the First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
Abstract
BACKGROUND: Cationic polymers are outstanding representatives of the most efficient small interfering RNA (siRNA) vectors. Low cytotoxicity and siRNA protecting effect can be obtained with these cationic polymers via a variety of structural modifications. Nevertheless, the gap between their efficiency and the requirement for therapeutic processes is still noticeable. METHODS: A cationic polymer vector was synthesized via the copolymerization of N-(1,3-dihydroxy propan-2-yl)methacrylamide (DHPMA) and N-(3-aminopropyl)methacrylamide (APMA). RESULTS: APMA provides amine functionality that allows the conjugation of guanidine and methionine groups. Attributed to the hydroxy groups of DHPMA, the synthesized guanidine and methionine grafted DHPMA-b-APMA block copolymer (mDG) is water soluble and has good biocompatibility. The obtained mDG has high zeta potential, narrow molecular weight distribution, better membrane-penetrating ability, high transfection efficiency, tumor cell targeting ability and high stability. CONCLUSIONS: The synthesized polymer vector can deliver siRNA molecules into tumor cells and then reverse drug resistance by down regulation of P-glycoprotein mRNA expression.
BACKGROUND: Cationic polymers are outstanding representatives of the most efficient small interfering RNA (siRNA) vectors. Low cytotoxicity and siRNA protecting effect can be obtained with these cationic polymers via a variety of structural modifications. Nevertheless, the gap between their efficiency and the requirement for therapeutic processes is still noticeable. METHODS: A cationic polymer vector was synthesized via the copolymerization of N-(1,3-dihydroxy propan-2-yl)methacrylamide (DHPMA) and N-(3-aminopropyl)methacrylamide (APMA). RESULTS:APMA provides amine functionality that allows the conjugation of guanidine and methionine groups. Attributed to the hydroxy groups of DHPMA, the synthesized guanidine and methionine grafted DHPMA-b-APMA block copolymer (mDG) is water soluble and has good biocompatibility. The obtained mDG has high zeta potential, narrow molecular weight distribution, better membrane-penetrating ability, high transfection efficiency, tumor cell targeting ability and high stability. CONCLUSIONS: The synthesized polymer vector can deliver siRNA molecules into tumor cells and then reverse drug resistance by down regulation of P-glycoprotein mRNA expression.