Multi-targeting Peptide-Functionalized Nanoparticles Recognized Vasculogenic Mimicry, Tumor Neovasculature, and Glioma Cells for Enhanced Anti-glioma Therapy

Chemotherapy failure of glioma, the most aggressive and devastating cancer, might be ascribed to the physiologic barriers of the tumor mainly including heterogeneous tumor perfusion and vascular permeability, which result in a limited penetration of chemotherapeutics. Besides, the vasculogenic mimicry (VM) channels, which are highly resistant to anti-angiogenic therapy and serve as a complement of angiogenesis, were abound in glioma and always associated with tumor recurrence. In order to enhance the therapy effect of anti-glioma, we developed a PEG-PLA-based nanodrug delivery system (nanoparticles, NP) in this study and modified its surface with CK peptide, which was composed of a human sonic hedgehog (SETH) targeting peptide (CVNHPAFAC) and a KDR targeting peptide (K237) through a GYG linker, for facilitating efficient VM channels, tumor neovasculature, and glioma cells multi-targeting delivery of paclitaxel. In vitro cellular assay showed that CK-NP-PTX not only exhibited the strongest antiproliferation effect on U87MG cells and HUVEC cells but also resulted in the most efficient destruction of VM channels when compared with CVNHPAFAC-NP, K237-NP, and the unmodified ones. Besides, CK-NP accumulated more selectively at the glioma site as demonstrated by in vivo and ex vivo imaging. As expected, the glioma-bearing mice treated with CK-NP-PTX achieved the longest median survival time compared to those treated with CVNHPAFAC-NP-PTX and K237-NP-PTX. These findings indicated that the multi-targeting therapy mediated by CK peptide might provide a promising way for glioblastoma therapy.