UMMS Affiliation
Department of Radiology
Publication Date
2016-01-16
Document Type
Article
Disciplines
Medicinal and Pharmaceutical Chemistry | Medicinal Chemistry and Pharmaceutics | Neoplasms | Radiology | Therapeutics
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.
Keywords
177Lu, Breast cancer, Metastases, Targeted radiopharmaceutical, VEGF receptors
Rights and Permissions
© Rusckowski et al. 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
DOI of Published Version
10.1186/s13550-016-0163-1
Source
EJNMMI Res. 2016 Dec;6(1):4. doi: 10.1186/s13550-016-0163-1. Epub 2016 Jan 16. Link to article on publisher's site
Journal/Book/Conference Title
EJNMMI research
Related Resources
PubMed ID
26780081
Repository Citation
Rusckowski, Mary; Wang, Yuzhen; Blankenberg, Francis G.; Levashova, Zoia; Backer, Marina V.; and Backer, Joseph M., "Targeted scVEGF/(177)Lu radiopharmaceutical inhibits growth of metastases and can be effectively combined with chemotherapy" (2016). Radiology Publications and Presentations. 137.
https://escholarship.umassmed.edu/radiology_pubs/137
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Medicinal and Pharmaceutical Chemistry Commons, Medicinal Chemistry and Pharmaceutics Commons, Neoplasms Commons, Radiology Commons, Therapeutics Commons