F3-targeted cisplatin-hydrogel nanoparticles as an effective therapeutic that targets both murine and human ovarian tumor endothelial cells in vivo.
Recent studies indicate that ovarian cancer may be highly responsive to antivascular therapeutics. We have developed an antivascular tumor therapeutic using the F3 peptide to target cisplatin-loaded nanoparticles (F3-Cis-Np) to tumor vessels. We show that although F3-Cis-Np bind with high specificity to both human ovarian tumor cells and tumor endothelial cells in vitro, they only show cytotoxic activity against the tumor endothelial cells. In vivo these nanoparticles bind primarily to tumor endothelial cells. Therapeutic studies in both flank and orthotopic i.p. murine ovarian tumor models, as well as human tumor xenograft models, show rapid tumor regression with treatment. Treatment was associated with significant vascular necrosis consistent with an antivascular effect. Furthermore, treatment was active in both platinum-sensitive and platinum-resistant cell lines. Importantly, we show that F3-Cis-Np bind to human tumor endothelial cells in vitro and to human tumor vessels in vivo. Therapy targeting human vasculature in vivo with F3-Cis-Np led to near complete loss of all human tumor vessels in a murine model of human tumor vasculature. Our studies indicate that F3-targeted vascular therapeutics may be an effective treatment modality in human ovarian cancer.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Medical Center, Ann Arbor, Michigan 20892, USA.
Ira
I
Winer
Shouyan
S
Wang
Yong-Eun Koo
YE
Lee
Youg-Eun Koo
YE
Lee
Wenzhe
W
Fan
Yusong
Y
Gong
Daniela
D
Burgos-Ojeda
Greg
G
Spahlinger
R
R
Kopelman
Ronald J
RJ
Buckanovich
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D053758:Nanoparticles; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D010446:Peptide Fragments / Q000008:administration & dosage*; D015996:Survival Rate; D013724:Teratoma / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D002945:Cisplatin