Abstract
BackgroundscVEGF/177Lu 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/177Lu potential as adjuvant and neoadjuvant anti-angiogenic therapy was assessed in metastatic and orthotopic mouse models of triple-negative breast cancer.MethodsMetastatic 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/177Lu (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/177Lu (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/177Lu 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.ResultsIn metastatic model, adjuvant treatment with scVEGF/177Lu decreased overall metastatic burden and improved survival. In orthotopic primary tumor model, a combination of Doxil and scVEGF/177Lu was more efficient in tumor growth inhibition than each treatment alone. scVEGF/177Lu treatment decreased immunostaining for VEGFR-1, VEGFR-2, and pro-tumorigenic M2-type macrophage marker CD206.ConclusionsSelective targeting of VEGFR with well-tolerated doses of scVEGF/177Lu 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 177Lu for specific receptor-mediated uptake warrants further exploration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0163-1) contains supplementary material, which is available to authorized users.
Highlights
ScVEGF/177Lu is a novel radiopharmaceutical targeted by recombinant single-chain derivative of vascular endothelial growth factor (VEGF) that binds to and is internalized by vascular endothelial growth factor receptors (VEGFR). scVEGF/177Lu potential as adjuvant and neoadjuvant anti-angiogenic therapy was assessed in metastatic and orthotopic mouse models of triple-negative breast cancer
Two mechanisms are involved in vascular rebound: (1) so-called evasive resistance of endothelial cells, which allows them to use pathways other than VEGF/VEGFR for growth and survival, and (2) only recently appreciated systemic pro-angiogenic/pro-inflammatory/pro-tumorigenic host responses induced by inhibition of VEGF/VEGFR signaling in VEGFR-positive cell populations, including endothelial, immune, progenitor, and stem cells [10,11,12,13,14,15,16,17,18,19,20,21]
High levels of VEGFRs are found in tumor endothelial cells that are positioned at the tips of growing angiogenic vascular sprouts [23], making them the primary targets for scVEGF/177Lu
Summary
ScVEGF/177Lu 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/177Lu potential as adjuvant and neoadjuvant anti-angiogenic therapy was assessed in metastatic and orthotopic mouse models of triple-negative breast cancer. Two mechanisms are involved in vascular rebound: (1) so-called evasive resistance of endothelial cells, which allows them to use pathways other than VEGF/VEGFR for growth and survival, and (2) only recently appreciated systemic pro-angiogenic/pro-inflammatory/pro-tumorigenic host responses induced by inhibition of VEGF/VEGFR signaling in VEGFR-positive cell populations, including endothelial, immune, progenitor, and stem cells [10,11,12,13,14,15,16,17,18,19,20,21]. We reasoned that since such a radiopharmaceutical is not an inhibitor of VEGFR signaling, it would not lead to either evasive resistance of endothelial cells or to systemic responses associated with inhibition of this pathway in various host cells. High levels of VEGFRs are found in tumor endothelial cells that are positioned at the tips of growing angiogenic vascular sprouts [23], making them the primary targets for scVEGF/177Lu
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
