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Anticancer activity driven by drug linker modification in a polyglutamic acid-based combination-drug conjugate

Arroyo-Crespo, Juan J., Deladriere, Coralie, Nebot, Vicent J., Charbonnier, David, Masiá, Esther, Paul, Alison, James, Craig, Armiñán, Ana and Vicent, María J. 2018. Anticancer activity driven by drug linker modification in a polyglutamic acid-based combination-drug conjugate. Advanced Functional Materials 28 (22) , 1800931. 10.1002/adfm.201800931

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Abstract

Combination nanotherapies for the treatment of breast cancer permits synergistic drug targeting of multiple pathways. However, poor carrier degradability, poor synergism of the combined drugs, low drug release regulation, and a lack of control on final macromolecule solution conformation (which drives the biological fate) limit the application of this strategy. The present study describes the development of a family of drug delivery systems composed of chemotherapeutic (doxorubicin) and endocrine therapy (aromatase inhibitor aminoglutethimide) agents conjugated to a biodegradable poly‐l‐glutamic acid backbone via various linking moieties. Data from in vitro cytotoxicity and drug release assessments and animal model validation select a conjugate family member with optimal biological performance. Exhaustive physicochemical characterization in relevant media (including the study of secondary structure, size measurements, and detailed small‐angle neutron scattering analysis) correlates biological data with the intrinsic supramolecular characteristics of the conjugate. Overall, this study demonstrates how a small flexible Gly linker can modify the spatial conformation of the entire polymer–drug conjugate, promote the synergistic release of both drugs, and significantly improve biological activity. These findings highlight the need for a deeper understanding of polymer–drug conjugates at supramolecular level to allow the design of more effective polymer–drug conjugates.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Wiley
ISSN: 1616-301X
Date of First Compliant Deposit: 15 May 2018
Date of Acceptance: 16 April 2018
Last Modified: 31 Jul 2018 21:43
URI: http://orca-mwe.cf.ac.uk/id/eprint/111452

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