title: A series of alpha-amino acid ester prodrugs of camptothecin: in vitro hydrolysis and A549 human lung carcinoma cell cytotoxicity.
abstract: The objective of the present study was to identify a camptothecin (CPT) prodrug with optimal release and cytotoxicity properties for immobilization on a passively targeted microparticle delivery system. A series of alpha-amino acid ester prodrugs of CPT were synthesized, characterized, and evaluated. Four CPT prodrugs were synthesized with increasing aliphatic chain length (glycine (Gly) (2a), alanine (Ala) (2b), aminobutyric acid (Abu) (2c), and norvaline (Nva) (2d)). Prodrug reconversion was studied at pH 6.6, 7.0, and 7.4 corresponding to tumor, lung, and extracellular/physiological pH, respectively. Cytotoxicity was evaluated in A549 human lung carcinoma cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The hydrolytic reconversion rate to parent CPT increased with decreasing side chain length as well as increasing pH. The Hill slope of 2d was significantly less than CPT and the other prodrugs tested, indicating a higher cell death rate at lower concentrations. These results suggest that 2d is the best candidate for a passively targeted sustained release lung delivery system.
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA.
authors.forename: Manjeet
authors.initials: M
authors.lastname: Deshmukh
authors.forename: Piyun
authors.initials: P
authors.lastname: Chao
authors.forename: Hilliard L
authors.initials: HL
authors.lastname: Kutscher
authors.forename: Dayuan
authors.initials: D
authors.lastname: Gao
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Sinko
mesh_terms: D000409:Alanine / Q000737:chemistry; D000613:Aminobutyrates / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002166:Camptothecin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival; D004952:Esters / Q000737:chemistry*; D005998:Glycine / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D008175:Lung Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D000613:Aminobutyrates; D000972:Antineoplastic Agents, Phytogenic; D004952:Esters; D011355:Prodrugs; C005313:norvaline; D014633:Valine; D000409:Alanine; D005998:Glycine; D002166:Camptothecin