title: PEG-PLA nanoparticles modified with APTEDB peptide for enhanced anti-angiogenic and anti-glioma therapy.
abstract: Tumor neovasculature and tumor cells dual-targeting chemotherapy can not only destroy the tumor neovasculature, cut off the supply of nutrition and starve the tumor cells, but also directly kill tumor cells, holding great potential in overcoming the drawbacks of anti-angiogenic therapy only and improving the anti-glioma efficacy. In the present study, by taking advantage of the specific expression of fibronectin extra domain B (EDB) on both glioma neovasculature endothelial cells and glioma cells, we constructed EDB-targeted peptide APTEDB-modified PEG-PLA nanoparticles (APT-NP) for paclitaxel (PTX) loading to enable tumor neovasculature and tumor cells dual-targeting chemotherapy. PTX-loaded APT-NP showed satisfactory encapsulated efficiency, loading capacity and size distribution. In human umbilical vein endothelial cells, APT-NP exhibited significantly elevated cellular accumulation via energy-dependent, caveolae and lipid raft-involved endocytosis, and improved PTX-induced apoptosis therein. Both in vitro tube formation assay and in vivo matrigel angiogenesis analysis confirmed that APT-NP significantly improved the antiangiogenic ability of PTX. In U87MG cells, APT-NP showed elevated cellular internalization and also enhanced the cytotoxicity of the loaded PTX. Following intravenous administration, as shown by both in vivo live animal imaging and tissue distribution analysis, APT-NP achieved a much higher and specific accumulation within the glioma. As a result, APT-NP-PTX exhibited improved anti-glioma efficacy over unmodified nanoparticles and Taxol(®) in both subcutaneous and intracranial U87MG xenograft models. These findings collectively indicated that APTEDB-modified nanoparticles might serve as a promising nanocarrier for tumor cells and neovasculature dual-targeting chemotherapy and hold great potential in improving the efficacy anti-glioma therapy.
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China; Shanghai Institute for Food and Drug Control (SIFDC), 479 Futexi First Road, Shanghai 200131, PR China.
authors: Guangzhi
authors: G
authors: Gu
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR 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, PR China.
authors: Xingye
authors: X
authors: Feng
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
authors: Xiaoling
authors: X
authors: Gao
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China.
authors: Jiang
authors: J
authors: Menglin
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR 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, PR China.
authors: Di
authors: D
authors: Jiang
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
authors: Qingxiang
authors: Q
authors: Song
authors: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiaotong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, PR China.
authors: Hongzhuan
authors: H
authors: Chen
authors: Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Lane 826, Zhangheng Road, Shanghai 201203, PR China. Electronic address: chenjun@fudan.edu.cn.
authors: Jun
authors: J
authors: Chen
mesh_terms: D061605:Administration, Intravenous; D020533:Angiogenesis Inhibitors / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy*; D021941:Caveolae / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D004705:Endocytosis; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007797:Laminin / Q000737:chemistry; D021962:Membrane Microdomains / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000737:chemistry; D010316:Particle Size; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry; D013696:Temperature
chemical_list: C000601127:APT(EDB) peptide; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D010455:Peptides; D011509:Proteoglycans; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; C059485:matrigel; D011092:Polyethylene Glycols; D003094:Collagen; D017239:Paclitaxel
keywords: APTEDB peptide; Dual-targeting; Glioma therapy; Nanoparticles; Paclitaxel