title: Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model.
abstract: Fumagillin, an unstable anti-angiogenesis mycotoxin, was synthesized into a stable lipase-labile prodrug and incorporated into integrin-targeted lipid-encapsulated nanoparticles (αvβ3-Fum-PD NP). Dual anti-angiogenic therapy combining αvβ3-Fum-PD NP with zoledronic acid (ZA), a long-acting osteoclast inhibitor with proposed anti-angiogenic effects, was evaluated. In vitro, αvβ3-Fum-PD NP reduced (P<0.05) endothelial cell viability without impacting macrophage viability. ZA suppressed (P<0.05) macrophage viability at high dosages but not endothelial cell proliferation. 3D MR neovascular imaging of rabbit Vx2 tumors showed no effect with ZA, whereas αvβ3-Fum-PD NP alone and with ZA decreased angiogenesis (P<0.05). Immunohistochemistry revealed decreased (P<0.05) microvascularity with αvβ3-Fum-PD NP and ZA and further microvascular reduction (P<0.05) with dual-therapy. In vivo, ZA did not decrease tumor macrophage numbers nor cancer cell proliferation, whereas αvβ3-Fum-PD-NPs reduced both measures. Dual-therapy with ZA and αvβ3-Fum-PD-NP may provide enhanced neo-adjuvant utility if macrophage ZA uptake is increased. From the Clinical Editor: Although anti-angiogenesis is one of the treatment modalities in the fight against cancer, many cancers become resistant to VEGF pathway inhibitors. In this article, the authors investigated the use of dual therapy using fumagillin, integrin-targeted lipid-encapsulated nanoparticles (αvβ3- Fum-PD NP) and zoledronic acid (ZA), in both in-vitro and in-vivo experiments. This combination approach may provide an insight to the design of future drugs against cancers.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Alison K
authors.initials: AK
authors.lastname: Esser
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Anne H
authors.initials: AH
authors.lastname: Schmieder
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ross
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Xinming
authors.initials: X
authors.lastname: Su
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Cui
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Huiying
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Allen
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Williams
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wickline
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana, Urbana, IL, USA.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Pan
authors.affiliation: Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: greg.lanza@mac.com.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lanza
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: kweilbae@wustl.edu.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000493:pharmacokinetics*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D004058:Diffusion; D004164:Diphosphonates / Q000008:administration & dosage* / Q000737:chemistry; D007093:Imidazoles / Q000008:administration & dosage* / Q000737:chemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008297:Male; D058990:Molecular Targeted Therapy / Q000379:methods; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D011817:Rabbits; D016896:Treatment Outcome; D000077211:Zoledronic Acid
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D020533:Angiogenesis Inhibitors; D004164:Diphosphonates; D007093:Imidazoles; D039302:Integrin alphaVbeta3; D053769:Nanocapsules; D011355:Prodrugs; C424137:SLC38A5 protein, human; D000077211:Zoledronic Acid
keywords: Cancer; Fumagillin; MRI; Molecular imaging; Nanoparticle; Zoledronic acid