Journal Article

A Dual Receptor Targeting- and BBB Penetrating- Peptide Functionalized Polyethyleneimine Nanocomplex for Secretory Endostatin Gene Delivery to Malignant Glioma

Lu, Lu, Wang, Longkun, Wang, Fengshan, Zhao, Lin, Chen, Hongyuan, Wang, Aijun, Cheng, Yanna, Zhang, Xinke

2020

Overview

Vascular endothelial growth factor receptor 2 (VEGFR-2) and neuropilin-1 (NRP-1) are two prominent synergistic receptors overexpressed on new blood vessels in glioma and may be promising targets for antiglioma therapy. The aim of this study was to design a dual receptor targeting and blood-brain barrier (BBB) penetrating peptide-modified polyethyleneimine (PEI) nanocomplex that can efficiently deliver the angiogenesis-inhibiting secretory endostatin gene (pVAXI-En) to treat glioma. We first constructed the tandem peptide TAT-AT7 by conjugating AT7 to TAT and evaluated its binding affinity to VEGFR-2 and NRP-1, vasculature-targeting ability and BBB crossing capacity. Then, TAT-AT7-modified PEI polymer (PPTA) was synthesized, and a pVAXI-En-loaded PPTA nanocomplex (PPTA/pVAXI-En) was prepared. The physicochemical properties, cytotoxicity, transfection efficiency, capacities to cross the BBB and BTB (blood-tumor barrier) and glioma-targeting properties of PPTA/pVAXI-En were investigated. Moreover, the in vivo anti-angiogenic behaviors and anti-glioma effects of PPTA/pVAXI-En were evaluated in nude mice. The binding affinity of TAT-AT7 to VEGFR-2 and NRP-1 was approximately 3 to 10 times greater than that of AT7 or TAT. The cellular uptake of TAT-AT7 in endothelial cells was 5-fold and 119-fold greater than that of TAT and AT7 alone, respectively. TAT-AT7 also displayed remarkable efficiency in penetrating the BBB and glioma tissue in vivo. PPTA/pVAXI-En exhibited lower cytotoxicity, stronger BBB and BTB traversing abilities, higher selective glioma targeting and better gene transfection efficiency than PEI/pVAXI-En. More importantly, PPTA/pVAXI-En significantly suppressed the tube formation and migration of endothelial cells, inhibited glioma growth, and reduced the microvasculature in orthotopic U87 glioma-bearing nude mice. Our study demonstrates that PPTA/pVAXI-En can be exploited as an efficient dual-targeting nanocomplex to cross the BBB and BTB, and hence it represents a feasible and promising nonviral gene delivery system for effective glioma therapy.

• Publisher: Dove Medical Press Limited,Taylor & Francis Ltd,Dove,Dove Medical Press
• Subject: Angiogenesis / Angiogenesis inhibitors / Animals / anti-angiogenesis / Antibodies / Blood-Brain Barrier - metabolism / Brain cancer / Brain Neoplasms - genetics / Brain Neoplasms - pathology / Brain Neoplasms - therapy / Cancer / Cell Line, Tumor / Cytomegalovirus / Drug Carriers - chemistry / Efficiency / Endostatins - chemistry / Endostatins - genetics / Endothelium / gene delivery system / Gene therapy / Genes / Genetic aspects / Genetic Therapy / Glioma / Glioma - genetics / Glioma - pathology / Glioma - therapy / glioma penetration / Gliomas / Humans / Medical research / Mice / Mice, Nude / Molecular Targeted Therapy / multifunctional peptide / Nanostructures - chemistry / Neuropilin-1 - metabolism / Original Research / Peptides / Peptides - chemistry / Permeability / Physicochemical properties / Plasmids / Polyethyleneimine - chemistry / Proteins / Transfection / Vascular endothelial growth factor / Vascular Endothelial Growth Factor Receptor-2 - metabolism / vegfr-2 and nrp-1 receptor targeting