Reference

Self-Assembling ELR-Based Nanoparticles as Smart Drug-Delivery Systems Modulating Cellular Growth via Akt.
Juan Gonzalez-Valdivieso, Alessandra Girotti, Raquel Muñoz, J. Carlos Rodriguez-Cabello, and F. Javier Arias
Biomacromolecules 2019 20 (5), 1996-2007. DOI: 10.1021/acs.biomac.9b00206.Portada Biomacromolecules

Authors

Juan González-Valdivieso, Alessandra Girotti, Raquel Muñoz, Jose Carlos Rodríguez-Cabello y Francisco Javier Arias Vallejo.

Abstract

This work investigates the physicochemical properties and in vitro accuracy of a genetically engineered drug delivery system based on elastin-like block recombinamers. The DNA recombinant technics allowed us to create this smart complex polymer containing bioactive sequences for internalization, lysosome activation under acidic pH and blockage of cellular growth by a small peptide inhibitor. The recombinant polymer reversibly self-assembled, when temperature was increased above 15°C, into nanoparticles with a diameter of 72 nm and negative surface charge. Furthermore, smart nanoparticles were showed to enter in the cells via clathrin-dependent endocytosis, and properly blocked phosphorylation and consequent activation of Akt kinase. This system provoked apoptosis-mediated cell death in breast and colorectal cancer cells, which possess higher expression levels of Akt, whereas non-cancerous cells, such as endothelial cells, fibroblasts and mesenchymal stem cells, were not affected. Hence, we conclude that the conformational complexity of this smart elastin-like recombinamer leads to achieve successful drug delivery in targeted cells and could be a promising approach as nanocarriers with bioactive peptides in order to modulate multiple cellular processes involved in different diseases.

Description

Una de las limitaciones principales de la quimioterapia actual es la falta de especificidad, dando lugar a efectos adversos en tejidos sanos del organismo. En este artículo hemos desarrollado nanopartículas poliméricas dirigidas a la inhibición de la proteína Akt, sobreexpresada en células cancerígenas y responsable de su proliferación descontrolada. Gracias a la ingeniería genética se han incorporado diversas secuencias bioactivas y hemos conseguido que las nanopartículas liberen un inhibidor peptídico de la proteína Akt únicamente en las células tumorales en las condiciones requeridas. Los resultados han demostrado que nuestras nanopartículas presentan un efecto selectivo sobre la viabilidad de las células cancerígenas y podrían considerarse una herramienta prometedora para la liberación controlada de fármacos.

 

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REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de investigación BIOFORGE, perteneciente a la Universidad de Valladolid y miembro del CIBER-BBN, está liderado por los catedráticos Francisco Javier Arias, Jose Carlos Rodríguez-Cabello y Matilde Alonso y estudia el desarrollo de nuevos biomateriales para diversas aplicaciones biomédicas como la dosificación controlada de fármacos e ingeniería de tejidos. Para ello, diseñamos y producimos polímeros recombinantes basados en la secuencia proteica de la elastina, que se caracterizan por su biocompatibilidad, biodegradabilidad y respuesta a múltiples estímulos. Además, caracterizamos estos biomateriales y estudiamos su aplicación en cultivos celulares in vitro y modelos animales de distintas enfermedades.

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