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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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID ![](/images/orcid_id_24x24.png) |
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Liu, X | | | | Lynn, BC | | | | Zhang, J | | | | Song, L | | | | Bom, D | | | | Du, W | | | | Curran, DP | curran@pitt.edu | CURRAN | | Burke, TG | | | |
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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: |
13 Jun 2021 01:55 |
URI: |
http://d-scholarship-dev.library.pitt.edu/id/eprint/20488 |
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