Liposome-Based Systemic Glioma-Targeted Drug Delivery Enabled by All‑d Peptides

As the most aggressive brain tumor, chemotherapy of malignant glioma remains to be extremely challenging in clinic. The blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) are physiological and pathological barriers preventing therapeutic drugs from reaching the glioma region. In addition, vasculogenic mimicry (VM) formed by invasive glioma cells instead of endothelial cells and angiogenesis are very common in glioma, leading to the poor prognosis and recurrence of glioma. An ideal drug delivery system for glioma chemotherapy needs to traverse the BBB and BBTB and then target VM, angiogenesis, and glioma cells. Herein we developed a liposome-based drug delivery system with the modification of proteolytically stable d-peptide ligands (^dCDX/^dA7R-LS). ^dCDX is a d-peptide ligand of nicotine acetylcholine receptors (nAChRs) capable of circumventing the BBB, and ^dA7R is a d-peptide ligand of vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) overexpressed on angiogenesis, VM, and glioma, presenting excellent glioma-homing property. ^dCDX/^dA7R-LS could efficiently internalize into the brain capillary endothelial cells, glioma cells, tumor neovascular endothelial cells, and tumor spheroids and cross the <i>in vitro</i> BBB and BBTB models. <i>Ex vivo</i> imaging and <i>in vivo</i> immunofluorescence assays confirmed the superiority of ^dCDX/^dA7R-LS in targeting intracranial glioma in comparison to plain liposomes or liposomes modified with an individual d-peptide ligand (either ^dCDX or ^dA7R). When loaded with doxorubicin, ^dCDX/^dA7R-LS achieved the best antiglioma, antiangiogenesis, and anti-VM effects among all tested formulations. These results suggested that systemic glioma-targeted drug delivery enabled by all-d peptide ligands was promising for the antiglioma therapy