Journal Article

A dual-mediated liposomal drug delivery system targeting the brain: rational construction, integrity evaluation across the blood-brain barrier, and the transporting mechanism to glioma cells

Meng, Shuai, Xie, Ying, Liu, Xiao-Na, Hei, Yu, Yang, Ling-Fei, Wang, Gui-Ling, Yuan, Lan, Liu, Chang

2017

Overview

As the global population ages, cancer rates increase worldwide, and degenerative diseases of the central nervous system (CNS), brain tumors, and inflammation threaten human health more frequently. We designed a dual-mediated (receptor-mediated and adsorption-mediated) liposome, named transferrin-cell penetrating peptide-sterically stabilized liposome (TF-CPP-SSL), to improve therapy for gliomas through combining molecular recognition of transferrin receptors (TF-Rs) on the blood-brain barrier (BBB) and glioma cells with the internalization and lysosomal escaping ability of CPP. Based on the systematic investigation of structure-activity relations on the cellular level, we constructed TF-CPP-SSL rationally by conjugating TF and CPP moieties to the liposomes via PEG and PEG , respectively, and found the optimum densities of TF and CPP were 1.8% and 4%, respectively. These liposomes had the highest targeting efficacy for brain microvascular endothelial cell and C6 cell uptake but avoided capture by normal cells. Fluorescence resonance energy transfer technology and coculture models of BBB and glioma C6 cells indicated that TF-CPP-SSL was transported across the BBB without drug leakage, liposome breakup, or cleavage of ligand. TF-CPP-SSL offered advantages for crossing the BBB and entering into glioma C6 cells. Real-time confocal viewing revealed that TF-CPP-SSL was entrapped in endosomes of glioma C6 cells and then escaped from lysosomes successfully to release the liposomal contents into the cytosol. Entrapped contents, such as doxorubicin, could then enter the nucleus to exert pharmacological effects.

• Publisher: Dove Medical Press Limited,Dove Medical Press
• Subject: Animals / Blood-brain barrier / Blood-Brain Barrier - drug effects / Brain Neoplasms - drug therapy / Brain Neoplasms - pathology / Cell-penetrating peptide / Cell-Penetrating Peptides - administration & dosage / Cell-Penetrating Peptides - chemistry / Doxorubicin - administration & dosage / Drug delivery systems / Drug Delivery Systems - methods / Drug therapy / Dual-ligand modified liposomes / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Endothelium, Vascular - cytology / Endothelium, Vascular - drug effects / Fluorescence resonance energy transfer (FRET) / Glioma - drug therapy / Glioma - pathology / Gliomas / Liposomes / Liposomes - administration & dosage / Liposomes - chemistry / Liposomes - pharmacology / Mice, Inbred BALB C / Molecular Weight / Original Research / Physiological aspects / Polyethylene Glycols - chemistry / Properties / Rats / Real-time confocal / Transferrin / Transferrin - chemistry / Transferrin - metabolism / Tumor targeting