Desarrollo de conjugados polímericos para el tratamiento del cáncer de mama

Abstract

[EN] The medical application of nanotechnology holds a tremendous potential in the bettering of human health, particularly in grave chronic pathologies such as cancer. Within cancer many defective processes have been shown to be responsible of its deleterious characteristics; metastasis being one of those processes is the cause of the expansion of cancer in the body, through blood vessels and the lymphatic system, and responsible for most of the cancer-related deaths. fasudil, a ROCK inhibitor approved for clinical use, can have a substantial control over cell migration and ultimately over metastasis. In this project polymer therapeutics will be used; they are considered to be the first polymeric nanomedicines and their therapeutic worth in clinical stages has been demonstrated already. Nevertheless there are still challenges to overcome and opportunities to seize in the process to embetter this technologic platform. By using them, two advantages arise: (i) passive specificity due to the EPR effect (‘enhanced permeability and retention effect’) and as a consequence a lesser systemic toxicity; (ii) overcoming quimioresistant mechanisms by using endocytosis as a path for cellular internalization. Obtaining further knowledge on the specific cellular mechanisms responsible for internalization as well as the ones used by these low molecular weight molecules has become a key aspect to understand when developing new drug-delivery systems. The aim of this project in particular is to characterize at a biological level fasudil polymeric conjugates for the treatment of breast cancer as well as to study the effect of the drug on different breast cancer cell lines. To reach this goal carcinogenic cell line cultures will be used for evaluating the associated toxicity, the characteristics of the drug release of the polymeric conjugates and the mechanism responsible of the biological activity observed.

[ES] La aplicación médica de la nanotecnología posee un enorme potencial para mejorar la salud humana, sobretodo en patología crónicas graves como cáncer. En este trabajo se emplearán Polímeros Terapéuticos que han sido considerados las primeras nanomedicinas poliméricas y su valor terapéutico en clínica ya ha sido demostrado, sin embargo todavía existen retos y oportunidades para mejorar esta plataforma tecnológica. Su uso nos ofrece principalmente dos ventajas: (i) especificidad pasiva debido al efecto EPR (¿enhanced permeability and retention effect¿) y por tanto una menor toxicidad sistémica; (ii) superación de mecanismos quimioresistentes al utilizar la endocitosis como mecanismo de internalización celular. El conocimiento de los mecanismos de internalización celular específicos, así como el mecanismo de acción utilizado por estos nanofármacos en sistemas biológicos se ha convertido en una pieza clave para el desarrollo de nuevos sistemas de transporte de fármacos. En este trabajo concretamente se pretende caracterizar a nivel biológico un conjugado polimérico de fasudil para el tratamiento del cáncer de mama. Para ello se emplearan cultivos celulares de células cancerígenas en las cuales se evaluará la toxicidad celular asociada, los mecanismos de internalización celular empleados por los nanofármacos, así como el mecanismo responsable de la actividad biologica observada.