A d-Peptide Ligand of Integrins for Simultaneously Targeting Angiogenic Blood Vasculature and Glioma Cells

The current prognosis of glioma patients remains poor after intensive multimodal treatments, which is partially due to the existence of the blood-brain tumor barrier (BBTB). In the present study, a novel "bifunctional ligand" (termed (VS)-V-D) was developed by retro-inverso isomerization. (VS)-V-D is a ligand of integrins highly expressed on glioma cells and tumor neo-vasculature. (VS)-V-D exhibited exceptional stability in serum and demonstrated significantly higher targeting efficiency for glioma and HUVEC cells compared with the parent L-peptide. As a result, (VS)-V-D modified micelles ((VS)-V-D-MS) exhibited high encapsulation efficiency of doxorubicin, ideal size distribution, and sustained release behavior of the payload. In vivo studies showed that (VS)-V-D-MS could target and efficiently deliver fluorescence to tumor cells and tumor vasculature not only in the mice bearing subcutaneous. tumors but also in those bearing intracranial tumors. Moreover, doxorubicin loaded (VS)-V-D modified micelles exerted potent tumor growth inhibitory activity against subcutaneous and intracranial human glioma in comparison to drug loaded plain micelles and (VS)-V-L modified micelles. Therefore, (VS)-V-D appears to be a suitable targeting ligand with potential applications for glioma targeted drug delivery.