Rational design of a poly-L-glutamic acid-based combination conjugate for hormone-responsive breast cancer treatment.

Autor: Boix-Montesinos P; Polymer Therapeutics Lab., Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain., Medel M; Polymer Therapeutics Lab., Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain; Centro de Investigación Biomédica en Red en Cancer, (CIBERONC), Instituto de Salud Carlos III, Spain., Malfanti A; Polymer Therapeutics Lab., Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy., Đorđević S; Polymer Therapeutics Lab., Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain; Centro de Investigación Biomédica en Red en Cancer, (CIBERONC), Instituto de Salud Carlos III, Spain., Masiá E; Polymer Therapeutics Lab., Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain; Centro de Investigación Biomédica en Red en Cancer, (CIBERONC), Instituto de Salud Carlos III, Spain; Screening Platform, Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain., Charbonnier D; Polymer Therapeutics Lab., Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain; Screening Platform, Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain; Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), IISCIII and CIEMAT, Madrid, Spain., Carrascosa-Marco P; Polymer Therapeutics Lab., Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain., Armiñán A; Polymer Therapeutics Lab., Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain; Centro de Investigación Biomédica en Red en Cancer, (CIBERONC), Instituto de Salud Carlos III, Spain. Electronic address: aarminan@cipf.es., Vicent MJ; Polymer Therapeutics Lab., Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain; Centro de Investigación Biomédica en Red en Cancer, (CIBERONC), Instituto de Salud Carlos III, Spain; Screening Platform, Príncipe Felipe Research Center, Av. Eduardo Primo Yúfera 3, 46012 Valencia, Spain. Electronic address: mjvicent@cipf.es.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2024 Nov; Vol. 375, pp. 193-208. Date of Electronic Publication: 2024 Sep 10.
DOI: 10.1016/j.jconrel.2024.09.002
Abstrakt: Breast cancer represents the most prevalent tumor type worldwide, with hormone-responsive breast cancer the most common subtype. Despite the effectiveness of endocrine therapy, advanced disease forms represent an unmet clinical need. While drug combination therapies remain promising, differences in pharmacokinetic profiles result in suboptimal ratios of free drugs reaching tumors. We identified a synergistic combination of bisdemethoxycurcumin and exemestane through drug screening and rationally designed star-shaped poly-L-glutamic acid-based combination conjugates carrying these drugs conjugated through pH-responsive linkers for hormone-responsive breast cancer treatment. We synthesized/characterized single and combination conjugates with synergistic drug ratios/loadings. Physicochemical characterization/drug release kinetics studies suggested that lower drug loading prompted a less compact conjugate conformation that supported optimal release. Screening in monolayer and spheroid breast cancer cell cultures revealed that combination conjugates possessed enhanced cytotoxicity/synergism compared to physical mixtures of single-drug conjugates/free drugs; moreover, a combination conjugate with the lowest drug loading outperformed remaining conjugates. This candidate inhibited proliferation-associated signaling, reduced inflammatory chemokine/exosome levels, and promoted autophagy in spheroids; furthermore, it outperformed a physical mixture of single-drug conjugates/free drugs regarding cytotoxicity in patient-derived breast cancer organoids. Our findings highlight the importance of rational design and advanced in vitro models for the selection of polypeptide-based combination conjugates.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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