title: In vitro cytotoxicity, in vivo biodistribution and antitumor activity of HPMA copolymer-5-fluorouracil conjugates.
abstract: 5-Fluorouracil (5-FU) is an antimetabolite with a broad-spectrum activity against solid tumors. However, its very short half-life in plasma circulation greatly limited the in vivo antitumor efficacy and clinical application. The current work aimed to solve this problem as well as to increase 5-FU biodistribution to tumor by covalently conjugating 5-FU to a biocompatible, non-toxic and non-immunogenic drug carrier -N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer. The in vitro cytotoxicity, in vivo biodistribution and therapeutic efficacy of HPMA copolymer-5-FU conjugates (P-FU) were reported. Cytotoxicity was evaluated by using a serial of tumor cells (A549, CT-26, Hela, HepG(2) cells and 5-FU resistant HepG(2) cells). In vivo biodistribution and therapeutic efficacy were investigated in Kunming mice-bearing hepatoma 22 (H(22)). Results indicated that P-FU could increase the cytotoxicity of 5-FU in Hela, HepG(2) and 5-FU resistant HepG(2) cells, while it decreases the cytotoxicity of 5-FU in A549 and CT-26. Both in vitro release profile in plasma and biodistribution study showed that P-FU significantly prolonged the drug plasma circulation time. P-FU also showed an over 3-fold larger area under the concentration-time curve (AUC) in tumor when compared with free drug. Therapeutic evaluation also demonstrated that the treatment with P-FU displayed stronger inhibition of the tumor growth when compared with that of control group (physiologic saline) or 5-FU group at the same dose. All the results suggested that P-FU could increase cytotoxicity of 5-FU in certain cancer cell lines, prolong 5-FU circulation time in vivo, enhance 5-FU distribution to tumor and improve therapeutic efficacy. Therefore, HPMA copolymer is a potential carrier for 5-FU for the effective treatment of cancer.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.forename: Xuan
authors.initials: X
authors.lastname: Qin
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Xiang
authors.forename: Min-Ting
authors.initials: MT
authors.lastname: Wang
authors.forename: Zhi-Rong
authors.initials: ZR
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D005260:Female; D005472:Fluorouracil / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D013997:Time Factors
chemical_list: D000178:Acrylamides; D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; C032976:N-(2-hydroxypropyl)methacrylamide; D005472:Fluorouracil