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Dextrin-phospholipase A2: Synthesis and evaluation as a bioresponsive anticancer conjugate

Ferguson, Elaine Lesley ORCID: and Duncan, Ruth 2009. Dextrin-phospholipase A2: Synthesis and evaluation as a bioresponsive anticancer conjugate. Biomacromolecules 10 (6) , pp. 1358-1364. 10.1021/bm8013022

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There is still an urgent need for improved treatments for metastatic cancer. Although the phospholipase A2 (PLA2) crotoxin, an antitumor protein that appears to act by interaction with epidermal growth factor receptors (EGFR), has recently shown activity in breast cancer in phase I clinical trials, it also displayed nonspecific neurotoxicity. Therefore, the aim of this study was to apply a novel concept called polymer-masked-unmasked- protein therapy (PUMPT) to give a bioresponsive dextrin-PLA2 conjugate that would reduce PLA2 systemic toxicity but retain antitumor activity following α-amylase triggered degradation of dextrin in the tumor interstitium. Dextrin (Mw ∼ 60000 g/mol; ∼22 mol % succinoylation) and PLA2 (from honey bee venom) were chosen as models for these initial studies, and the conjugates synthesized contained 6.1 wt % PLA2, with <1% free enzyme. The conjugate showed decreased (∼36%) enzyme activity compared to native PLA2, but activity was restored to ∼100% following ncubation with α-amylase. Whereas dextrin conjugation caused a marked reduction in PLA2's hemolytic activity, the conjugate was cytotoxic toward MCF-7, HT29, and B16F10 cells at a level that was comparable to, or greater than, that seen for free PLA2. In these cell lines, cytotoxicity showed partial correlation with the level of EGFR expression. The reduced toxicity and α-amylase triggered activity of the dextrin-PLA2 conjugate confirmed the potential of this approach for further development as a novel anticancer treatment. © 2009 American Chemical Society.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Subjects: R Medicine > RM Therapeutics. Pharmacology
Publisher: ACS Publications
ISSN: 1525-7797
Last Modified: 18 Oct 2022 13:54

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