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Effective Tumor Targeting by EphA2-Agonist-Biotin-Streptavidin Conjugates
- Source :
- Molecules, Vol 26, Iss 3687, p 3687 (2021), Molecules, Volume 26, Issue 12
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- 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~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.
- Subjects :
- Agonist
Streptavidin
medicine.drug_class
media_common.quotation_subject
pancreatic cancer
Pharmaceutical Science
Biotin
Organic chemistry
Breast Neoplasms
agonistic EphA2 peptides
Ligands
Article
Receptor tyrosine kinase
Analytical Chemistry
cancer imaging
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
breast cancer
QD241-441
Cell Line, Tumor
Drug Discovery
medicine
streptavidin
Ephrin
Animals
Humans
Physical and Theoretical Chemistry
Internalization
030304 developmental biology
media_common
0303 health sciences
Binding Sites
biology
Chemistry
Receptor, EphA2
Cell biology
Pancreatic Neoplasms
Chemistry (miscellaneous)
030220 oncology & carcinogenesis
orthotopic cancer models
biology.protein
Molecular Medicine
Female
Receptor clustering
Conjugate
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 26
- Issue :
- 3687
- Database :
- OpenAIRE
- Journal :
- Molecules
- Accession number :
- edsair.doi.dedup.....9c280439a5f9f1f59400112362c7b122