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Prodrug polimérico autoeliminable sensible a ROS para la terapia del cáncer mediada por estrés nitrosativo

Anup Dey¹, Jeongjin Lee¹, Minsung Park²

¹School of Chemical Engineering, College of Engineering, Sungkyunkwan University (SKKU), Seobu-ro 2066, Jangan-gu, Suwon 16419, Republic of Korea.

Journal of controlled release : official journal of the Controlled Release Society

|January 19, 2026

Resumen

Este estudio presenta un nuevo profármaco polimérico que libera óxido nítrico (NO) y elimina el glutatión en los tumores. Este enfoque dirigido muestra potentes efectos anticancerígenos y una toxicidad mínima, ofreciendo una nueva terapia sensible a la oxidación-reducción.

Área de la Ciencia:

Ingeniería Biomédica
Terapias contra el Cáncer
Sistemas de Liberación de Fármacos

Sus antecedentes:

El óxido nítrico (NO) es un regulador redox prometedor para la terapia del cáncer.
Los donantes convencionales de NO enfrentan limitaciones debido a vidas medias cortas y mala especificidad tumoral.
Las especies reactivas de oxígeno (ROS) se elevan en el microambiente tumoral, presentando un objetivo terapéutico.

Objetivo del estudio:

Desarrollar un profármaco polimérico autoeliminable sensible a ROS (G-g-PSIP) para la terapia dirigida del cáncer.
Investigar el mecanismo de acción del profármaco, incluida la liberación de NO, el agotamiento de glutatión y la respuesta a ROS.
Evaluar la eficacia antitumoral y la seguridad de G-g-PSIP in vitro e in vivo.

Principales métodos:

Síntesis y caracterización del profármaco polimérico G-g-PSIP.
Ensayos de citotoxicidad in vitro utilizando células cancerosas CT26 y células normales L929.
Evaluación del agotamiento de glutatión intracelular, generación de NO y formación de peroxinitrito.
Estudios de eficacia antitumoral in vivo en ratones con tumores CT26.

Principales resultados:

G-g-PSIP demostró citotoxicidad dependiente de la dosis contra células cancerosas CT26 con toxicidad mínima para células normales.
El profármaco eliminó eficazmente el glutatión y generó NO en respuesta a ROS elevados.
La despolimerización amplificada en cascada condujo a la acumulación de peroxinitrito, induciendo estrés nitrosativo y muerte celular similar a la ferroptosis.
La administración sistémica de G-g-PSIP logró una eficacia antitumoral significativa in vivo.

Conclusiones:

G-g-PSIP es un potente profármaco polimérico sensible a ROS para la terapia dirigida del cáncer.
Los efectos sinérgicos del agotamiento de GSH y la generación de NO/peroxinitrito inducen muerte celular similar a la ferroptosis.
Esta plataforma sensible a la oxidación-reducción es prometedora para el desarrollo de nuevos tratamientos contra el cáncer.

Palabras clave:

agotamiento de glutatión óxido nítrico profármaco polimérico especies reactivas de oxígeno polímero autoeliminable tratamiento del cáncer

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