title: Tumor priming using metronomic chemotherapy with neovasculature-targeted, nanoparticulate paclitaxel.
abstract: Normalization of the tumor microenvironment is a promising approach to render conventional chemotherapy more effective. Although passively targeted drug nanocarriers have been investigated to this end, actively targeted tumor priming remains to be explored. In this work, we demonstrate an effective tumor priming strategy using metronomic application of nanoparticles actively targeted to tumor neovasculature. F56 peptide-conjugated paclitaxel-loaded nanoparticles (F56-PTX-NP) were formulated from PEGylated polylactide using an oil in water emulsion approach. Metronomic F56-PTX-NP specifically targeted tumor vascular endothelial cells (ECs), pruned vessels with strong antiangiogenic activity and induced thrombospondin-1 (TSP-1) secretion from ECs. The treatment induced tumor vasculature normalization as evidenced by significantly increased coverage of basement membrane and pericytes. The tumor microenvironment was altered with enhanced pO2, lower interstitial fluid pressure, and enhanced vascular perfusion and doxorubicin delivery. A "normalization window" of at least 9 days was induced, which was longer than other approaches using antiangiogenic agents. Together, these results show that metronomic, actively-targeted nanomedicine can induce tumor vascular normalization and modulate the tumor microenvironment, opening a window of opportunity for effective combination chemotherapies.
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Luan
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China; Department of Pharmacy, Ruijin Hospital, SJTU-SM, 197 Rui Jin Er Road, Shanghai 200025, China.
authors.forename: Ying-Yun
authors.initials: YY
authors.lastname: Guan
authors.affiliation: Department of Biomedical Engineering, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
authors.forename: Jonathan F
authors.initials: JF
authors.lastname: Lovell
authors.affiliation: Department of Pharmacy, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Shanghai 201318, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Ya-Rong
authors.initials: YR
authors.lastname: Liu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Liu
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Yun-Ge
authors.initials: YG
authors.lastname: Gao
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Dong
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Si-Cong
authors.initials: SC
authors.lastname: Yang
authors.affiliation: Pathology Center, Shanghai First People's Hospital, SJTU-SM, 280 South Chongqing Road, Shanghai 200025, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of General Surgery, Shanghai Tongren Hospital, SJTU-SM, 1111 Xianxia Road, Shanghai 200336, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China. Electronic address: fangchao100@hotmail.com.
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
authors.affiliation: Hongqiao International Institute of Medicine, Shanghai Tongren Hospital and Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 South Chongqing Road, Shanghai 200025, China. Electronic address: hongzhuan_chen@hotmail.com.
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D059250:Administration, Metronomic; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D005260:Female; D064593:Heterografts; D006801:Humans; D007773:Lactates / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D059016:Tumor Microenvironment
chemical_list: D020533:Angiogenesis Inhibitors; D007773:Lactates; D009842:Oligopeptides; C488235:peptide F56; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D004317:Doxorubicin; D017239:Paclitaxel
keywords: Metronomic chemotherapy; Nanomedicine; Paclitaxel; Tumor priming; Tumor vascular normalization