title: Polymeric nanomedicine for tumor-targeted combination therapy to elicit synergistic genotoxicity against prostate cancer.
abstract: To improve the therapeutic efficacy of anticancer combination therapy, we designed a nanoplatform based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers that allows covalent bonding of two chemotherapeutics acting via different anticancer mechanisms and that can enter target cells by receptor-mediated endocytosis. Doxorubicin (DOX) was covalently conjugated to a nanosized HPMA copolymer using a pH-sensitive hydrazone bond and 5-fluorouracil (5-Fu) was conjugated to the same backbone using an enzymatically degradable oligopeptide Gly-Phe-Leu-Gly sequence. Then, the conjugate was decorated with galectin-3 targeting peptide G3-C12 [P-(G3-C12)-DOX-Fu]. The two drugs showed similar in vitro release profiles, suggesting that they may be able to work synergistically in the codelivery system. In galectin-3 overexpressed PC-3 human prostate carcinoma cells, P-(G3-C12)-DOX-Fu surprisingly exhibited comparable cytotoxicity to free DOX at high concentration by increasing cell internalization and exerting synergistic genotoxic effects of cell cycle arrest, caspase-3 activation, and DNA damage. In mice bearing PC-3 tumor xenografts, the use of tumor-targeting ligand substantially enhanced the intracellular delivery of P-(G3-C12)-DOX-Fu in tumors. The targeted dual drug-loaded conjugate inhibited tumor growth to a greater extent (tumor inhibition of 81.6%) than did nontargeted P-DOX-Fu (71.2%), P-DOX (63%), DOX·HCl (40.5%), P-Fu (32.0%), or 5-Fu (14.6%), without inducing any obvious side effects. These results demonstrate the potential of synergistic combination therapy using targeted nanocarriers for efficient treatment of prostate cancer.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
authors.forename: Lian
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D005472:Fluorouracil / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D051379:Mice; D050997:Nanomedicine; D049329:Nanostructures / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008689:Methacrylates; D004317:Doxorubicin; D005472:Fluorouracil; C032802:hydroxypropyl methacrylate
keywords: G3-C12; HPMA copolymer; combination therapy; prostate cancer; synergistic genotoxicity