Bioengineered exosomes based approaches for the effective treatment of non-small cell lung cancer

Descripción del proyecto

Reclutamiento de exosomas para la administración de fármacos en los pulmones

Los exosomas son vesículas extracelulares que se generan en casi todas las células y que llevan diversas biomoléculas, como ADN, lípidos y proteínas. Su origen endógeno los ayuda a evitar el reconocimiento inmunológico y su capacidad para llevar cargas a órganos diana concretos hace que sean ideales para la administración de fármacos. El proyecto financiado con fondos europeos BESG creará exosomas a partir de células madre mesenquimales para que se dirijan al carcinoma pulmonar no microcítico (CPNM). Los exosomas llevarán un inhibidor del receptor del factor de crecimiento epidérmico y un ARN interferente pequeño contra el CPNM y la metástasis. Mediante el uso de técnicas de imagenología avanzada, los científicos evaluarán la farmacodinámica, la biodistribución y la actividad antineoplásica de los exosomas en un modelo murino de la enfermedad. Los resultados del proyecto servirán de base para el ensayo clínico de exosomas diseñados por bioingeniería como opción de tratamiento del cáncer de pulmón.

Objetivo

ABSTRACT: Lung cancer is the principal cause of cancer-related death around the world and has become more predominant among former than current smokers. Smoking, alcoholism, air pollution, occupational exposure are among the main causes of non-small cell lung cancer (NSCLCs). It is difficult to simultaneously deliver therapeutics and nucleic acid to the target site. With the advancement of nanotechnology, a delivery system composing of cellular proteins which can bypass the reticuloendothelial system (RES) and have the ability to release payload at the specific target site is the necessity of the current era. Exosomes (Exo) are clinically acceptable, having protein membrane composition and the ability to deliver payload at specific target sites. Having endogenous origin, Exo evade immune recognition and clearance compared to exogenous nanovesicles. Exo are natural carriers of nucleic acids and they can be engineered to deliver siRNA as well as anti-cancer drugs. In this we propose the conjugation or covering of mesenchymal stromal cells (MSCs) derived exosomes with HSP4 peptide (target specific to NSCLCs) and loading them with Gefitinib (GEF), an EGFR inhibitor and SPC24 siRNA (target for NSCLCs and metastasis). The delivery of GEF and SPC24 siRNA using bioengineered exosomes (BESG) will reduce their dosage; improve patient compliance and life expectancy of patients. BESG will be evaluated for their uptake mechanisms and their mechanism of action in cell culture models of NSCLCs. BESG will specifically target the NSCLCs and release its payloads at cancer site. The underlying mechanisms, pharmacokinetics, biodistribution and anti-cancer activity will be evaluated in xenograft model of NSCLCs using advance imaging technologies. The BESG developed during this program will have a clinical potential and the trainings obtained through this program will help in career advancement in the area of drug delivery and precision medicine.