Radiation-Induced Targeted Nanoparticle-Based Gene Delivery for Brain Tumor Therapy

###EgeUn###Targeted therapy against the programmed cell death ligand-1 (PD-L1) blockade holds considerable promise for the treatment of different tumor types; however, little effect has been observed against gliomas thus far. Effective glioma therapy requires a delivery vehicle that can reach tumor cells in the central nervous system, with limited systemic side effect. In this study, we developed a cyclic peptide iRGD (CCRGDKGPDC)-conjugated solid lipid nanoparticle (SLN) to deliver small interfering RNAs (siRNAs) against both epidermal growth factor receptor (EGFR) and PD-L1 for combined targeted and immunotherapy against glioblastoma, the most aggressive type of brain tumors. Building on recent studies showing that radiation therapy alters tumors for enhanced nanotherapeutic delivery in tumor associated macrophage-dependent fashion, we showed that low-dose radiation primes targeted SLN uptake into the brain tumor region, leading to enhanced downregulation of PD-L1 and EGFR Bioluminescence imaging revealed that radiation therapy followed by systemic administration of targeted SLN leads to a significant decrease in glioblastoma growth and prolonged mouse survival. This study combines radiation therapy to prime the tumor for nanoparticle uptake along with the targeting effect of iRGD-conjugated nanoparticles to yield a straightforward but effective approach for combined EGFR inhibition and immunotherapy against glioblastomas, which can be extended to other aggressive tumor types.NIH/NCIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P0ICA069246]; NIH/NINDSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [P30NS04776]; TUBITAK (The Scientific and Technological Research Council of Turkey) 2214/A scholarship; [1S1ORRO2S504]This work was supported by grant from NIH/NCI P0ICA069246 (B.A.T., E.A.C., and RW.) and NIH/NINDS P30NS04776 (B.A.T.). G.E.A. was supported by TUBITAK (The Scientific and Technological Research Council of Turkey) 2214/A scholarship. The authors would like to thank Michael F. Cuccarese from the Center for Systems Biology at the Massachusetts General Hospital for his help with DLS measurement experiments, the MGH Neuroscience Image Analysis Core (for confocal microscopy), and the MGH Vector Core (for producing the viral vector), and Ellen Sapp at the MGH EM core (supported by NIH/NINDS P30NS04776) as well as 1S1ORRO2S504 Shared Instrumentation Grant for the IVIS imaging system