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RGD and interleukin-13 peptide functionalized nanoparticles for enhanced glioblastoma cells and neovasculature dual targeting delivery and elevated tumor penetration.

As the most common malignant brain tumors, glioblastoma multiforme (GBM) was characterized by angiogenesis and tumor cells proliferation. Dual targeting to neovasculature and GBM cells could deliver cargoes to these two kinds of cells, leading to a combination treatment. In this study, polymeric nanoparticles were functionalized with RGD and interleukin-13 peptide (IRNPs) to construct a neovasculature and tumor cell dual targeting delivery system in which RGD could target αvβ3 on neovasculature and interleukin-13 peptide could target IL13Rα2 on GBM cells. In vitro, interleukin-13 peptide and RGD could enhance the uptake by corresponding cells (C6 and human umbilical vein endothelial cells). Due to the expression of both receptors on C6 cells, RGD also could enhance the uptake by C6 cells. Through receptor labeling, it clearly showed that αvβ3 could mediate the internalization of RGD modified nanoparticles and IL13Rα2 could mediate the internalization of interleukin-13 peptide modified nanoparticles. The ligand functionalization also resulted in a modification on endocytosis pathways, which changed the main endocytosis pathways from macropinocytosis for unmodified nanoparticles to clathrin-mediated endocytosis for IRNPs. IRNPs also displayed the strongest penetration ability according to tumor spheroid analysis. In vivo, IRNPs could effectively deliver cargoes to GBM with higher intensity than monomodified nanoparticles. After CD31-staining, it demonstrated IRNPs could target both neovasculature and GBM cells. In conclusion, IRNPs showed promising ability in dual targeting both neovasculature and GBM cells.