title: Tumor Microenvironment and Angiogenic Blood Vessels Dual-Targeting for Enhanced Anti-Glioma Therapy.
abstract: Advances in active targeting drug delivery system (DDS) have revolutionized glioma diagnosis and therapy. However, the lack of the sufficient targets on glioma cells and limited penetration capability of DDS have significantly compromised the treatment efficacy. In this study, by taking advantages of the abundant extracellular matrix-derived heparan sulfate proteoglycan (HSPG) and enhanced tumor penetration ability mediated by neuropilin-1 (NRP-1) protein, we reported the ATWLPPR and CGKRK peptide dual-decorated nanoparticulate DDS (designated AC-NP) to achieve angiogenic blood vessels and tumor microenvironment dual-targeting effect. The resulted AC-NP displayed the particle size of 123 ± 19.47 nm. Enhanced cellular association of AC-NP was achieved on HUVEC cells and U87MG cells. AC-NP was internalized via caveolin- and lipid raft-mediated mechanism with the involvement of energy and lysosome in HUVEC cells and via caveolin- and lipid raft-mediated pathway with the participation of energy, microtubulin, and lysosome in U87MG cells. After loading with anticancer drug, paclitaxel (PTX), the enhanced apoptosis induction and antiproliferative activity were achieved by AC-NP. Furthermore, in vitro U87MG tumor spheroids assays showed a deeper penetration and an enhanced inhibitory effect against the U87MG tumor spheroids achieved by AC-NP. In vivo animal experiment showed that decoration of AC peptide on the nanoparticulate DDS resulted in extensive accumulation at glioma site and improved anti-glioma efficacy. Collectively, the results suggested that AC-NP holds great promise to serve as an effective tumor blood vessel and tumor microenvironment dual-targeting DDS with enhanced penetration capability, holding great potential in improving anti-glioma efficacy.
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Lane 826, Zhangheng Road, Shanghai 201203, People's Republic of China.
authors: Quanyin
authors: Q
authors: Hu
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Lane 826, Zhangheng Road, Shanghai 201203, People's Republic of China.
authors: Ting
authors: T
authors: Kang
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Lane 826, Zhangheng Road, Shanghai 201203, People's Republic of China.
authors: Jingxian
authors: J
authors: Feng
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Lane 826, Zhangheng Road, Shanghai 201203, People's Republic of China.
authors: Qianqian
authors: Q
authors: Zhu
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Lane 826, Zhangheng Road, Shanghai 201203, People's Republic of China.
authors: Tianze
authors: T
authors: Jiang
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Lane 826, Zhangheng Road, Shanghai 201203, People's Republic of China.
authors: Jianhui
authors: J
authors: Yao
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Lane 826, Zhangheng Road, Shanghai 201203, People's Republic of China.
authors: Xinguo
authors: X
authors: Jiang
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Lane 826, Zhangheng Road, Shanghai 201203, People's Republic of China.
authors: Jun
authors: J
authors: Chen
mesh_terms: D000818:Animals; D001932:Brain Neoplasms; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005910:Glioma; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles; D017239:Paclitaxel; D059016:Tumor Microenvironment
chemical_list: D017239:Paclitaxel
keywords: dual-targeting; glioma; heparan sulfate; neuropilin-1; penetration; tumor microenvironment