title: N-(2-hydroxypropyl)methacrylamide copolymer-6-(3-aminopropyl)-ellipticine conjugates. Synthesis, in vitro, and preliminary in vivo evaluation.
abstract: Ellipticine derivatives have potential as anticancer drugs. Their clinical use has been limited, however, by poor solubility and host toxicity. As N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-anticancer conjugates are showing promise in early clinical trials, a series of novel HPMA copolymer conjugates have been prepared containing the 6-(3-aminopropyl)-ellipticine derivative (APE, NSC176328). Drug was linked to the polymer via GFLG or GG peptide side chains. To optimize biological behavior, HPMA copolymer-GFLG-APE conjugates with different drug loading (total APE: 2.3-7% w/w; free APE: <0.1% w/w) were synthesized. Conjugation of APE to HPMA copolymers considerably increased its aqueous solubility (>10-fold). HPMA copolymer-GG-APE did not liberate drug in the presence of isolated lysosomal enzymes (tritosomes), but HPMA copolymer-GFLG-APE released APE to a maximum of 60% after 5 h. The rate of drug release was influenced by drug loading; lower loading led to greater release. Whereas free APE (35 microg/mL) caused significant hemolysis (50% after 1 h), HPMA copolymer-APE conjugates were not hemolytic up to 300 microg/mL (APE-equiv). As would be expected from its cellular pharmacokinetics, HPMA copolymer-GFLG-APE was >75 times less cytotoxic than free drug (IC(50) approximately 0.4 microg/mL) against B16F10 melanoma in vitro. However, in vivo when tested in mice bearing s.c. B16F10 melanoma, HPMA copolymer-GFLG-APE (1-10 mg/kg single dose, APE-equiv) given i.p. was somewhat more active (highest T/C value of 143%) than free APE (1 mg/kg) (T/C =127%). HPMA copolymer-APE conjugates warrant further evaluation as potential anticancer agents.
authors.affiliation: Centre for Polymer Therapeutics, School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, UK.
authors.forename: F
authors.initials: F
authors.lastname: Searle
authors.forename: S
authors.initials: S
authors.lastname: Gac-Breton
authors.forename: R
authors.initials: R
authors.lastname: Keane
authors.forename: S
authors.initials: S
authors.lastname: Dimitrijevic
authors.forename: S
authors.initials: S
authors.lastname: Brocchini
authors.forename: E A
authors.initials: EA
authors.lastname: Sausville
authors.forename: R
authors.initials: R
authors.lastname: Duncan
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002455:Cell Division / Q000187:drug effects; D004337:Drug Carriers / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D004611:Ellipticines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D008689:Methacrylates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011108:Polymers / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D012995:Solubility; D013810:Therapeutic Equivalency; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000637:transplantation
chemical_list: D000178:Acrylamides; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D004611:Ellipticines; D008689:Methacrylates; D011108:Polymers; C045985:methacrylamide; C032802:hydroxypropyl methacrylate