Smart chlorotoxin-functionalized liposomes for sunitinib targeted delivery into glioblastoma cells

Glioblastoma efficient drug delivery is hurdled by several pathophysiological barriers of the tumor microenvironment and the intrinsic limitations of chemotherapeutic agents. To overcome these drawbacks, we developed smart chlorotoxin (CTX)-functionalized liposomes (LS) for sunitinib (STB) targeted delivery into glioblastoma cells. The synthesized liposomes in terms of physicochemical parameters, drug encapsulation efficiency (EE%) and release profile, cytotoxicity, targeted cellular uptake by U87 and HEK293 cells, and their internalization mechanism were evaluated using dynamic light scattering, dialysis membrane, MTT cell viability, confocal microscopy, and flow cytometry. The qRT-PCR and scratch assays were used to evaluate VEGFR2, PECAM1, KI67, BCL2, BAX, CASP3, and BCLN1 gene expression levels and migration capacity in U87 cells in response to the CTX-LS-STB treatment. The CTX-LS-STB formula showed biocompatibility, suitable stability, small size, and high yield EE% of 97.34 ± 1.51% with a slow-controlled release pattern of STB. CTX-LS-STB liposomes were more efficiently internalized by U87 cells, while the cellular uptake of them was significantly reduced by non-tumor HEK293 cells compared to LS-STB liposomes. A mechanistic study demonstrated that CTX-LS-STB liposomes were internalized into studied cell lines via the receptor-mediated endocytosis. Treatment with CTX-LS-STB significantly inhibited cell viability and migration ability of U87 cells and suppressed KI67, VEGFR2, PECAM1 and BCL2 expressions. While, CTX-LS-STB treatment significantly upregulated BAX, CASP3 and BCLN1 expression levels. Furthermore, it led to the induction of apoptosis and autophagy-cell death simultaneously. The CTX-LS-STB formula can be used as an alternative nanoplatforms to enhance the targeted delivery of STB to achieve potential synergistic therapeutic efficacy on glioblastoma cells by modulating several different pathways governing glioblastoma tumorigenesis. [Display omitted]