Development of dual drug loaded PLGA based mesoporous silica nanoparticles and their conjugation with Angiopep-2 to treat glioma

Abstract

Chemotherapy most of the time fails in the treatment of glioma, because of blood-brain barrier (BBB) which prevents the penetration of drug molecules. This paper addresses the synthesis of mesoporous silica nanoparticles (MSNs) by suitably controlling the size of the particles. These nanoparticles were loaded with doxorubicin (DOX) as an anticancer drug and further modified with poly(lactic-co-glycolic acid) (PLGA) in order to incorporate paclitaxel (PTX) as another anticancer drug. The resulting drug-loaded nanoparticles were subsequently conjugated with Angiopep-2 (ANG) to bind selectively to low-density lipoprotein receptor-related protein 1 (LRP-1 receptors) to enable trans-endocytosis across BBB. The in-vitro cytotoxicity results revealed that a combined effect of DOX and PTX greatly enhanced the anticancer efficacy. The ANG-PTX-PLGA-DOX-MSNs-75 exhibited the significant IC50 value (0.0265 μg/mL) as compared to other nanoparticles. To mimic the transport mechanism of drugs across BBB, an in-vitro BBB model was developed using human brain microvascular endothelial (HBME) cells. Among the functionalized drugs loaded nanocarriers, ANG-PTX-PLGA-DOX-MSNs-75 recognized selectively and bound to LRP-1 receptors, and thereby enhanced the cellular uptake. From the results, we concluded that by tailoring the size of the MSNs and loading of dual drugs, one could effectively antagonize the glioblastoma by crossing the BBB.