title: Tumor angiogenesis therapy using targeted delivery of Paclitaxel to the vasculature of breast cancer metastases.
abstract: Breast cancer aberrantly expresses tissue factor (TF) in cancer tissues and cancer vascular endothelial cells (VECs). TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa). We have coupled PTX (paclitaxel, also named Taxol) with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01-0.05) compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Road, NE, Atlanta, GA 30322, USA.
authors.forename: Shijun
authors.identifier: 0000-0003-1257-6528
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Kisiel
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Road, NE, Atlanta, GA 30322, USA.
authors.forename: Yang J
authors.initials: YJ
authors.lastname: Lu
authors.affiliation: Biopharmaceuticals Research Unit, Novo Nordisk A/S, 2760 Måløv, Denmark.
authors.forename: Lars C
authors.initials: LC
authors.lastname: Petersen
authors.affiliation: Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Ndungu
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy and UIC Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Terry W
authors.initials: TW
authors.lastname: Moore
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Road, NE, Atlanta, GA 30322, USA.
authors.forename: Ernest T
authors.initials: ET
authors.lastname: Parker
authors.affiliation: Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA.
authors.forename: Aiming
authors.initials: A
authors.lastname: Sun
authors.affiliation: Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Road, NE, Atlanta, GA 30322, USA.
authors.forename: Bassel F
authors.initials: BF
authors.lastname: El-Rayes
authors.affiliation: Department of Pathology, Winship Cancer Institute, Emory University, 1365 Clifton Road, NE, Atlanta, GA 30322, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.affiliation: Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, 1365 Clifton Road, NE, Atlanta, GA 30322, USA.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Shoji