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A versatile prodrug approach for liposomal core-loading of water-insoluble camptothecin anticancer drugs

Liu, X and Lynn, BC and Zhang, J and Song, L and Bom, D and Du, W and Curran, DP and Burke, TG (2002) A versatile prodrug approach for liposomal core-loading of water-insoluble camptothecin anticancer drugs. Journal of the American Chemical Society, 124 (26). 7650 - 7651. ISSN 0002-7863

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Abstract

We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR ω-aminoalkanoanic ester prodrug in which R = CO[CH2]nNH2 and n = 1-3. The basic amino group of the prodrug serves three roles. First, at pH ranges of 3-5, the amine enhances aqueous solubility. Second, it enhances responsiveness to a transmembrane ammonium sulfate gradient across the liposomal bilayer, thereby facilitating active loading of the agent into the liposomal aqueous core. Third, at a physiological pH of 7 or above (the pH to be encountered following drug release at the tumor site), the nucleophilicity of the amine manifests itself and cyclization to the C-21 carbonyl carbon occurs. This cyclization triggers a rapid and convenient nonenzymatic decomposition process that releases active camptothecin. Accordingly, this novel liposomal approach offers a potential system for tumor-targeting prodrugs of many water-insoluble camptothecins, including the highly lipophilic and clinically attractive analogues SN-38, 9-nitrocamptothecin and DB-67. The rate of formation of the active agent at the tumor site can be controlled through the selection of n (the length of the alkyl spacer group). Copyright © 2002 American Chemical Society.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Liu, X
Lynn, BC
Zhang, J
Song, L
Bom, D
Du, W
Curran, DPcurran@pitt.eduCURRAN
Burke, TG
Date: 3 July 2002
Date Type: Publication
Journal or Publication Title: Journal of the American Chemical Society
Volume: 124
Number: 26
Page Range: 7650 - 7651
DOI or Unique Handle: 10.1021/ja0256212
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0002-7863
MeSH Headings: Antineoplastic Agents, Phytogenic--administration & dosage; Antineoplastic Agents, Phytogenic--chemistry; Camptothecin--administration & dosage; Camptothecin--analogs & derivatives; Camptothecin--chemistry; Drug Carriers--chemistry; Liposomes--chemistry; Prodrugs--administration & dosage; Prodrugs--chemistry; Solubility; Water--chemistry
PubMed ID: 12083906
Date Deposited: 07 Feb 2014 00:01
Last Modified: 02 Feb 2019 16:58
URI: http://d-scholarship.pitt.edu/id/eprint/20488

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