High expression of integrin αvβ3 enables uptake of targeted fluorescent probes into ovarian cancer cells and tumors

Scott K Shaw; Cynthia L Schreiber; Felicia M Roland; Paul M Battles; Seamus P Brennan; Simon J Padanilam; Bradley D Smith

doi:10.1016/j.bmc.2018.03.007

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High expression of integrin αvβ3 enables uptake of targeted fluorescent probes into ovarian cancer cells and tumors

Journal article

Peer reviewed

High expression of integrin αvβ3 enables uptake of targeted fluorescent probes into ovarian cancer cells and tumors

Scott K Shaw, Cynthia L Schreiber, Felicia M Roland, Paul M Battles, Seamus P Brennan, Simon J Padanilam and Bradley D Smith

Bioorganic & medicinal chemistry, Vol.26(8), pp.2085-2091

05/01/2018

DOI: 10.1016/j.bmc.2018.03.007

PMCID: PMC5963687

PMID: 29548784

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Abstract

The cell line OVCAR-4 was recently ranked as one of the most representative cell lines for high grade serous ovarian cancer (HGSOC). However, little work has been done to assess the susceptibility of OVCAR-4 cells and tumors to the more common types of molecular targeting. Proteome profiles suggest OVCAR-4 express high levels of integrin αvβ3 receptors. Using flow cytometry with fluorescent antibodies we determined that OVCAR-4 cells have high number of integrin αvβ3 receptors ([9.8 ± 2.5] × 10 /cell) compared to the well-characterized cell line U87-MG ([5.2 ± 1.4] × 10 /cell). However, OVCAR-4 cells also have roughly three times the surface area of U87-MG cells, so the average αvβ3 receptor density is actually lower (11 ± 3 versus 18 ± 6 receptors/µm ). A series of new fluorescent molecular probes was prepared with structures comprised of a deep-red squaraine fluorophore (∼680 nm emission) covalently attached to zero, one, or two cyclic pentapeptide cRGD sequences for integrin targeting. Microscopy studies showed that uptake of the divalent probe into cultured OVCAR-4 cells was 2.2 ± 0.4 higher than the monovalent probe, which in turn was 2.2 ± 0.4 higher than the untargeted probe. This probe targeting trend was also seen in OVCAR-4 mouse tumor models. The results suggest that clinically relevant OVCAR-4 cells can be targeted using molecular probes based on αvβ3 integrin receptor antagonists such as the cRGD peptide. Furthermore, deep-red fluorescent cRGD-squaraine probes have potential as targeted stains of cancerous tissue associated with HGSOC in surgery and pathology settings.

Immunohistochemistry

Animals

Cell Line, Tumor

Cyclobutanes - chemistry

Female

Fluorescent Dyes - chemistry

Humans

Integrin alphaVbeta3 - metabolism

Mice

Mice, Nude

Microscopy, Fluorescence

Optical Imaging

Ovarian Neoplasms - diagnostic imaging

Ovarian Neoplasms - metabolism

Ovarian Neoplasms - pathology

Peptides, Cyclic - chemistry

Peptides, Cyclic - metabolism

Phenols - chemistry

Tissue Distribution

Transplantation, Heterologous

Details

Title: Subtitle: High expression of integrin αvβ3 enables uptake of targeted fluorescent probes into ovarian cancer cells and tumors
Creators: Scott K Shaw - University of Notre Dame, 236 Nieuwland Science Hall, Notre Dame, IN 46545, United States
Cynthia L Schreiber - University of Notre Dame, 236 Nieuwland Science Hall, Notre Dame, IN 46545, United States
Felicia M Roland - University of Notre Dame, 236 Nieuwland Science Hall, Notre Dame, IN 46545, United States
Paul M Battles - University of Notre Dame, 236 Nieuwland Science Hall, Notre Dame, IN 46545, United States
Seamus P Brennan - University of Notre Dame, 236 Nieuwland Science Hall, Notre Dame, IN 46545, United States
Simon J Padanilam - University of Notre Dame, 236 Nieuwland Science Hall, Notre Dame, IN 46545, United States
Bradley D Smith - University of Notre Dame, 236 Nieuwland Science Hall, Notre Dame, IN 46545, United States. Electronic address: author@university.edu
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry, Vol.26(8), pp.2085-2091
DOI: 10.1016/j.bmc.2018.03.007
PMID: 29548784
PMCID: PMC5963687
NLM abbreviation: Bioorg Med Chem
ISSN: 0968-0896
eISSN: 1464-3391
Grant note: R01 GM059078 / NIGMS NIH HHS T32 GM075762 / NIGMS NIH HHS
Language: English
Date published: 05/01/2018
Academic Unit: Chemistry
Record Identifier: 9984216600002771

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