Journal
MOLECULES
Volume 26, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/molecules26123687
Keywords
agonistic EphA2 peptides; streptavidin; pancreatic cancer; breast cancer; cancer imaging; orthotopic cancer models
Funding
- NIH [NS107479, CA168517, CA242620]
- City of Hope/UCR (CUBRI) research grant
- Division of Biomedical Sciences, School of Medicine at UCR
- 2017-2018 Pease Cancer Fellowship
- 2018-2019 Burden fellowship through the Division of Biomedical Sciences, School of Medicine at UCR
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The study demonstrated that multimerization of a synthetic agent targeting EphA2 could enhance agonistic activity towards the receptor, suggesting potential diagnostic and therapeutic applications in EphA2-expressing tumors.
We recently reported on a potent synthetic agent, 135H11, that selectively targets the receptor tyrosine kinase, EphA2. While 135H11 possesses a relatively high binding affinity for the ligand-binding domain of EphA2 (Kd similar to 130 nM), receptor activation in the cell required the synthesis of dimeric versions of such agent (namely 135H12). This was expected given that the natural ephrin ligands also need to be dimerized or clustered to elicit agonistic activity in cell. In the present report we investigated whether the agonistic activity of 135H11 could be enhanced by biotin conjugation followed by complex formation with streptavidin. Therefore, we measured the agonistic EphA2 activity of 135H11-biotin (147B5) at various agent/streptavidin ratios, side by side with 135H12, and a scrambled version of 147B5 in pancreatic- and breast-cancer cell lines. The (147B5)(n)-streptavidin complexes (when n = 2, 3, 4, but not when n = 1) induced a strong receptor degradation effect in both cell lines compared to 135H12 or the (scrambled-147B5)(4)-streptavidin complex as a control, indicating that multimerization of the targeting agent resulted in an increased ability to cause receptor clustering and internalization. Subsequently, we prepared an Alexa-Fluor-streptavidin conjugate to demonstrate that (147B5)(4)-AF-streptavidin, but not the scrambled equivalent complex, concentrates in pancreatic and breast cancers in orthotopic nude-mouse models. Hence, we conclude that these novel targeting agents, with proper derivatization with imaging reagents or chemotherapy, can be used as diagnostics, and/or to deliver chemotherapy selectively to EphA2-expressing tumors.
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