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

Abstract

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 (CDX/A7R-LS). CDX is a d-peptide ligand of nicotine acetylcholine receptors (nAChRs) capable of circumventing the BBB, andA7R 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. CDX/A7R-LS could efficiently internalize into the brain capillary endothelial cells, glioma cells, tumor neovascular endothelial cells, and tumor spheroids and cross the in vitro BBB and BBTB models. Ex vivo imaging and in vivo immunofluorescence assays confirmed the superiority of CDX/A7R-LS in targeting intracranial glioma in comparison to plain liposomes or liposomes modified with an individual d-peptide ligand (either CDX orA7R). When loaded with doxorubicin, CDX/A7R-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.

Long Non-Coding RNA HOXA-AS2 Regulates Malignant Glioma Behaviors and Vasculogenic Mimicry Formation via the MiR-373/EGFR Axis

“…Liu et al [5] demonstrated that VM-positive glioma patients have a poorer prognosis than patients with VM-negative gliomas. Ju et al [9], Huang et al [33], and Ying et al [34] proved that liposomes containing VM-targeting drugs improve anti-glioma therapy in orthotopic glioma-bearing nude mice. In agreement with the above findings, our in vitro and in vivo results showed that the destruction of VM formation by HOXA-AS2 knockdown impaired glioma malignancy.…”

Enhanced immunocompatibility of ligand-targeted liposomes by attenuating natural IgM absorption

“…3 ). The disappear of the characteristic peak of maleimide group at 6.8 ppm in the 1H-NMR spectra of all peptide-PEG3400-DSPE indicated the successful reaction 58 , 59 . Liposomes were prepared by the thin film hydration and extrusion method 60 .…”

Effects of Micro-environmental pH of Liposome on Chemical Stability of Loaded Drug

“…Due to this structure, liposome is able to solubilize the insoluble drug molecules and prevent the loaded drug from the harsh physiological environment [8][9][10]. In addition, the surface of liposome can be modified to prolong the blood circulation time and/or target specific tissues [11][12][13][14][15]. With these abovementioned advantages, various liposome systems have been clinically approved [8,9,16].…”