Myristic Acid-Modified DA7R Peptide for Whole-Process Glioma-Targeted Drug Delivery.

The clinical treatment of aggressive glioma has been a great challenge, mainly because of the complexity of the glioma microenvironment and the existence of the blood-brain tumor barrier (BBTB)/blood-brain barrier (BBB), which severely hampers the effective accumulation of most therapeutic agents in the glioma region. Additionally, vasculogenic mimicry (VM), angiogenesis, and glioma stem cells (GSC) in malignant glioma also lead to the failure of clinical therapy. To address the aforementioned issues, a whole-process glioma-targeted drug delivery strategy was proposed. The DA7R peptide has effective BBTB-penetrating and notable glioma-, angiogenesis-, and VM-targeting abilities. Herein, we designed a myristic acid modified DA7R ligand (MC-DA7R), which combines tumor-homing DA7R with BBB-penetrable MC. MC-DA7R was then immobilized to PEGylated liposomes (MC-DA7R-LS) to form a whole-process glioma-targeting system. MC-DA7R-LS exhibited exceptional internalization in glioma, tumor neovascular, and brain capillary endothelial cells. Enhanced BBTB- and BBB-traversing efficiencies were also observed on MC-DA7R-LS. Ex vivo imaging on brain tumors also demonstrated the feasibility of MC-DA7R-LS in intracranial glioma-homing, whereas the immunofluorescence studies demonstrated its GSC and angiogenesis homing. Furthermore, doxorubicin-loaded MC-DA7R-LS accomplished a remarkable therapeutic outcome, as a result of a synergistic improvement on the glioma microenvironment. Our study highlights the potential of the MC-modified DA7R peptide as a great candidate for the whole-process glioma-targeted drug delivery.