Targeted delivery of irinotecan and SLP2 shRNA with GRP-conjugated magnetic graphene oxide for glioblastoma treatment.

Abstract

Magnetic nanoparticles (MNPs) are useful for magnetic targeted drug delivery while ligand-mediated active targeting is another common delivery strategy for cancer therapy. In this work, we intend to prepare magnetic graphene oxide (mGO) by chemical co-precipitation of MNPs on the GO surface, followed by conjugation of the gastrin releasing peptide (GRP) as a targeting ligand, for dual targeted drug/gene delivery in invasive brain glioma treatment. mGO was grafted with chitosan, complexed with shRNA plasmid DNA for stomatin-like protein 2 (SLP2) gene silencing, modified with urocanic acid for plasmid DNA endosomal escape, PEGylated for GRP conjugation, and loaded with the chemotherapeutic drug irinotecan (CPT-11) by π-π interaction for pH-responsive drug release (mGOCUG/CPT-11/shRNA). In addition to the in depth characterization of the physico-chemical and biological properties during each preparation step, we also study the loading/pH-responsive release behavior of CPT-11 and the shRNA plasmid loading/cell transfection efficiency. The targeting and antitumor efficacies of the nanocomposite were studied with U87 human glioblastoma cells in vitro. An in vivo study revealed that intravenous administration followed by magnetic guidance results in the efficient targeted delivery of mGOCUG/CPT-11/shRNA to orthotopic brain tumors in nude mice, and it exhibits excellent antitumor efficacy with a reduced tumor growth rate and prolonged animal survival time. Our work thus highlights a multifunctional mGO-based drug/gene delivery platform for effective combination cancer therapy in glioblastoma treatment.