title: Sigma receptor-mediated targeted delivery of anti-angiogenic multifunctional nanodrugs for combination tumor therapy.
abstract: The potential of low molecular weight heparin (LMWH) in anti-angiogenic therapy has been tempered by poor in vivo delivery to the tumor cell and potentially harmful side effects, such as the risk of bleeding due to heparin's anticoagulant activity. In order to overcome these limitations and further improve the therapeutic effect of LMWH, we designed a novel combination nanosystem of LMWH and ursolic acid (UA), which is also an angiogenesis inhibitor for tumor therapy. In this system, an amphiphilic LMWH-UA (LHU) conjugate was synthesized and self-assembled into core/shell nanodrugs with combined anti-angiogenic activity and significantly reduced anticoagulant activity. Furthermore, DSPE-PEG-AA-modified LHU nanodrugs (A-LHU) were developed to facilitate the delivery of nanodrugs to the tumor. The anti-angiogenic activity of A-LHU was investigated both in vitro and in vivo. It was found that A-LHU significantly inhibited the tubular formation of human umbilical vein endothelial cells (HUVECs) (p<0.01) and the angiogenesis induced by basic fibroblast growth factor (bFGF) in a Matrigel plug assay (p<0.001). More importantly, A-LHU displayed significant inhibition on the tumor growth in B16F10-bearing mice in vivo. The level of CD31 and p-VEGFR-2 expression has demonstrated that the excellent efficacy of antitumor was associated with a decrease in angiogenesis. In conclusion, A-LHU nanodrugs are a promising multifunctional antitumor drug delivery system.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yuanke
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill 27599, USA.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill 27599, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Miao
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill 27599, USA; University of North Carolina and North Carolina State University Joint Department of Biomedical Engineering, Chapel Hill, NC 27599, USA.
authors.forename: Andrew Benson
authors.initials: AB
authors.lastname: Satterlee
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: yaojing@cpu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D049329:Nanostructures / Q000737:chemistry / Q000648:ultrastructure; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism*; D014315:Triterpenes / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000378:metabolism; D000097245:Ursolic Acid
chemical_list: D020533:Angiogenesis Inhibitors; D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017480:Receptors, sigma; D014315:Triterpenes; D040301:Vascular Endothelial Growth Factor Receptor-2; D000097245:Ursolic Acid
keywords: Anti-angiogenesis; Combination therapy; Low molecular weight heparin; Nanodrugs; Sigma receptor; Ursolic acid