title: Targeted scVEGF/(177)Lu radiopharmaceutical inhibits growth of metastases and can be effectively combined with chemotherapy.
abstract: BACKGROUND
  scVEGF/(177)Lu is a novel radiopharmaceutical targeted by recombinant single-chain (sc) derivative of vascular endothelial growth factor (VEGF) that binds to and is internalized by vascular endothelial growth factor receptors (VEGFR). scVEGF/(177)Lu potential as adjuvant and neoadjuvant anti-angiogenic therapy was assessed in metastatic and orthotopic mouse models of triple-negative breast cancer.
  
  
  METHODS
  Metastatic lesions in Balb/c mice were established by intracardiac injection of luciferase-expressing 4T1luc mouse breast carcinoma cells. Mice with metastatic lesions received single intravenous (i.v.) injection of well-tolerated dose of scVEGF/(177)Lu (7.4 MBq/mouse) at day 8 after 4T1luc cell injection. Primary orthotopic breast tumors in immunodeficient mice were established by injecting luciferase-expressing MDA231luc human breast carcinoma cells into mammary fat pad. Tumor-bearing mice were treated with single injections of scVEGF/(177)Lu (7.4 MBq/mouse, i.v), or liposomal doxorubicin (Doxil, 1 mg doxorubicin per kg, i.v.), or with a combination of Doxil and scVEGF/(177)Lu given at the same doses, but two hours apart. "Cold" scVEGF-targeting conjugate was included in controls and in Doxil alone group. The effects of treatments were defined by bioluminescent imaging (BLI), computed tomography (CT), computed microtomography (microCT), measurements of primary tumor growth, and immunohistochemical analysis.
  
  
  RESULTS
  In metastatic model, adjuvant treatment with scVEGF/(177)Lu decreased overall metastatic burden and improved survival. In orthotopic primary tumor model, a combination of Doxil and scVEGF/(177)Lu was more efficient in tumor growth inhibition than each treatment alone. scVEGF/(177)Lu treatment decreased immunostaining for VEGFR-1, VEGFR-2, and pro-tumorigenic M2-type macrophage marker CD206.
  
  
  CONCLUSIONS
  Selective targeting of VEGFR with well-tolerated doses of scVEGF/(177)Lu is effective in metastatic and primary breast cancer models and can be combined with chemotherapy. As high level of VEGFR expression is a common feature in a variety of cancers, targeted delivery of (177)Lu for specific receptor-mediated uptake warrants further exploration.
authors.affiliation: Department of Radiology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Rusckowski
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Radiology/MIPS, Stanford University, Palo Alto, CA, 94305, USA.
authors.forename: Francis G
authors.initials: FG
authors.lastname: Blankenberg
authors.affiliation: Department of Radiology/MIPS, Stanford University, Palo Alto, CA, 94305, USA.|Current address: Igenica Biotherapeutics, Inc., Burlingame, CA, 94010, USA.
authors.forename: Zoia
authors.initials: Z
authors.lastname: Levashova
authors.affiliation: Sibtech, Inc., Brookfield, CT, 06804, USA.
authors.forename: Marina V
authors.initials: MV
authors.lastname: Backer
authors.affiliation: Sibtech, Inc., Brookfield, CT, 06804, USA. jbacker@sibtech.com.
authors.forename: Joseph M
authors.identifier: http://orcid.org/0000-0002-2044-4819
authors.initials: JM
authors.lastname: Backer
keywords: 177Lu; Breast cancer; Metastases; Targeted radiopharmaceutical; VEGF receptors