N-(2-Hydroxypropyl)methacrylamide Copolymer−6-(3-Aminopropyl)-ellipticine Conjugates. Synthesis, in Vitro, and Preliminary in Vivo Evaluation

Searle, F., Gac-Breton, S., Keane, R., Dimitrijevic, S., Brocchini, S., Sausville, E.A. and Duncan, R. (2001) N-(2-Hydroxypropyl)methacrylamide Copolymer−6-(3-Aminopropyl)-ellipticine Conjugates. Synthesis, in Vitro, and Preliminary in Vivo Evaluation. Bioconjugate Chemistry, 12 (5). pp. 711-718. 10.1021/bc0001544.

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DOI: 10.1021/bc0001544

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 μg/mL) caused significant hemolysis (50% after I h), HPMA copolymer-APE conjugates were not hemolytic up to 300 μg/mL (APE-equiv). As would be expected from its cellular pharmacokinetics, HPMA copolymer-GFLG-APE was >75 times less cytotoxic than free drug (IC50∼0.4 μg/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.

Item Type:Article
Departments, units and centres:Department of Pharmaceutics > Department of Pharmaceutics
ID Code:2868
Journal or Publication Title:Bioconjugate Chemistry
Deposited By:Library Staff
Deposited On:24 Feb 2012 16:48
Last Modified:24 Feb 2012 16:48

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