Uma nova abordagem terapêutica anti-tumoral com menor cardiotoxicidade

A doxorubicina é um dos fármacos mais usados na terapia anti-tumoral. Apesar da sua elevada eficácia, a doxorubicina apresenta diversos efeitos secundários, nomeadamente cardiotoxicidade. Frequentemente, estes efeitos adversos ao nível cardiaco impedem a utilização desta abordagem terapêutica, inviabilizando o tratamento anti-tumoral. Desta forma, é fundamental encontrar novas formas de combate ao tumor, que não provoquem danos colaterias no coração. As vesículas extracelulares, uma espécie de pequenas partículas transportadoras, que permitem a comunicação entre células e órgaos, têm merecido, nos útimos tempos, uma grande atenção da comunidade científica, devido ao seu enorme potencial terapêutico, como veículos de fármacos. No nosso estudo demonstrámos que a incorporação de doxorubicina em vesículas extracelulares mantém as suas propriedades anti-tumorais, demonstrando que esta pode constituir uma estratégia inovadora de levar, de uma forma mais selectiva, o fármaco às celulas tumorais, diminuindo os efeitos secundários indesejados. O trabalho agora publicado demonstra ainda que o transporte de doxorubicina em vesículas extracelulares diminui o efeito tóxico para as células do coração. Este estudo abre assim novas perspectivas no que respeita ao desenvolvimento de estratégias inovadoras, usando vesículas extracelulares no combate ao cancro, diminuindo os efeitos colaterias, nomeadamente a nível cardíaco.

Autores e Afiliações:

Tania Martins-Marques ^1,2, Maria Joao Pinho ^1,2, Monica Zuzarte ^1,2, Carla Oliveira ^3,4,5, Paulo Pereira ⁶, Joost P. G. Sluijter ^7,8, Celia Gomes ^2,9,10, Henrique Girao ^1,2*

¹Institute of Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal;

²CNC.IBILI, University of Coimbra, Coimbra, Portugal; 

³Expression Regulation in Cancer Group, Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal; 

⁴Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal; 

⁵Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal; 

⁶Chronic Diseases Research Center (CEDOC), NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal; 

⁷Department of Cardiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands; 

⁸Interuniversity Cardiology Institute Netherlands (ICIN), Utrecht, The Netherlands; 

⁹Laboratory of Pharmacology and Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; 

¹⁰Center of Investigation in Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Coimbra, Portugal

Abstract:

Extracellular vesicles (EVs) are major conveyors of biological information, mediating local and systemic cell-to-cell communication under physiological and pathological conditions. These endogenous vesicles have been recognized as prominent drug delivery vehicles of several therapeutic cargoes, including doxorubicin (dox), presenting major advantages over the classical approaches. Although dox is one of the most effective anti-tumor agents in the clinical practice, its use is very often hindered by its consequent dramatic cardiotoxicity. Despite significant advances witnessed in the last few years, more comprehensive studies, supporting the therapeutic efficacy of EVs, with decreased side effects, are still scarce. The main objective of this study was to evaluate the role of the gap junction protein connexin43 (Cx43) in mediating the release of EV content into tumor cells. Moreover, we aimed to investigate whether Cx43 improves the efficiency of dox-based anti-tumor treatment, with a concomitant decrease of cardiotoxicity. In the present report, we demonstrate that the presence of Cx43 in EVs increases the release of luciferin from EVs into tumor cells in vitro and in vivo. Additionally, using cell-based approaches and a subcutaneous mouse tumor model, we show that the anti-tumor effect of dox incorporated into EVs is similar to the administration of the free drug, regardless the presence of Cx43. Strikingly, we demonstrate that the presence of Cx43 in dox-loaded EVs reduces the cardiotoxicity of the drug. Altogether, these results bring new insights into the concrete potential of EVs as therapeutic vehicles and open new avenues towards the development of new strategies that help to reduce unwanted side effects.

Revista: Journal of Extracellular Vesicles

Link: http://www.journalofextracellularvesicles.net/index.php/jev/article/view/32538