title: A pH-responsive prodrug delivery system of 10-HCPT for controlled release and tumor targeting.
abstract: We synthesized a pH-responsive conjugate of 10-hydroxycamptothecin-thiosemicarbazide-linear polyethylene glycol 2000 (PEG2000). The conjugate was confirmed by matrix-assisted laser desorption time of flight mass spectrometry,1H NMR, and13C NMR. The water solubility of the prodrug was increased by over 3,000 times; much longer body circulation time, higher tumor-targeting ability, and reduced toxicity were observed, compared with commercial 10-HCPT injection. The linker contains a pH-sensitive hydrazone bond, which breaks under low pH conditions in the tumor microenvironment. The conjugates showed good stability in phosphate-buffered saline (pH 7.4) and rat plasma. This amphiphilic conjugate could self-assemble into nanosized micelles of 80-100 nm. Cytotoxicity assay results indicate significantly higher efficacy of the conjugate (IC50[half maximal inhibitory concentration] =0.117 µM on SW180 cells) than 10-HCPT solution (IC50=0.241 µM on SW480 cells). Cellular uptake analysis suggested its rapid internalization and nuclear transport. Pharmacokinetic analysis of the conjugates demonstrated that the conjugate circulated for a longer time in the blood circulation system (T2/1=10.516±1.158 h) than did 10-HCPT solution (T2/1=1.859±1.385 h), and that it also enhanced the targeting and mean residence time (MRT0-inf=39.873±4.549 h) in the tumor site, compared with 10-HCPT (MRT0-inf=9.247±1.026 h). Finally, the conjugate demonstrated an increased tumor growth inhibition effect (TIR =82.66%±7.175%) in vivo and lower side effects than 10-HCPT (TIR =63.85%±5.233%). This prodrug holds great promise in improving therapeutic efficacy and overcoming multidrug resistance.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang; Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou; Department of Pharmaceutics, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan, Zhengzhou.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou.
authors.forename: Xinhong
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou.
authors.forename: Haiwei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Organic Chemistry, College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, People's Republic of China.
authors.forename: Chuanjun
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou.
authors.forename: Ruhan
authors.initials: R
authors.lastname: Fan
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang.
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008807:Mice, Inbred BALB C; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy; D051381:Rats; D012995:Solubility; D013050:Spectrometry, Fluorescence; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008823:Micelles; D011355:Prodrugs; C120029:homocamptothecin; D002166:Camptothecin
keywords: 10-hydroxycamptothecin; conjugate; controlled release; hydrazone; pH-responsive; prodrug