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Proceedings Paper

MFLI-FRET as an analytical tool to monitor drug distribution and penetration in tumor xenografts, liver and bladder in intact, live animals (Conference Presentation)
Author(s): Margarida Barroso; Alena Rudkouskaya; Nattawut Sinsuebphon; Xavier Intes

Paper Abstract

There is a great unmet need to non-invasively quantify the active versus passive delivery of drugs in preclinical studies. Quantifying probe-receptor interactions, or target engagement in living systems, is critical as it directly correlates with drug efficacy. We selected the transferrin receptor (TfR) as a target, since TfR is overexpressed in breast cancer cells. MFLI-FRET enables the quantification of transferrin (Tf) internalization into the cells by measuring FRET between receptor-bound Tf donor and acceptor near infrared (NIR) fluorophore pairs, based on the reduction of donor fluorophore lifetime in live intact mice. In this study we compared FRET levels in aggressively growing triple negative MDA-MB-231 breast cancer tumors to estrogen receptor positive T47D tumors, which are less dense and slowly growing. Unlike in T47D xenografts, in MDA-MB-231 tumors FRET donor fraction (FD%) was very low or undetectable in first few hours post injection. Only by 24-48 h p.i. FD% reached comparable to T47D FD% levels. Immunohistochemical analysis of excised tumors showed that TfR density levels were similar in both types of tumors. This suggests that ligand penetration inside the MDA-MB-231 tumors is impaired due to microenvironment features, such as the perfusion defects, elevated stroma stiffness and interstitial fluid pressure. We plan to measure functional blood flow using contrast-enhanced Doppler Ultrasound imaging in tumors to further validate MFLI-FRET data. Overall, MFLI-FRET is well suited for guiding the development of targeted drug therapy in preclinical studies as analytical tool to monitor and quantify drug penetration in heterogeneous breast cancer xenografts.

Paper Details

Date Published: 4 March 2019
Proc. SPIE 10859, Visualizing and Quantifying Drug Distribution in Tissue III, 108590D (4 March 2019); doi: 10.1117/12.2507523
Show Author Affiliations
Margarida Barroso, Albany Medical College (United States)
Alena Rudkouskaya, Albany Medical College (United States)
Nattawut Sinsuebphon, Rensselaer Polytechnic Institute (United States)
Xavier Intes, Rensselaer Polytechnic Institute (United States)

Published in SPIE Proceedings Vol. 10859:
Visualizing and Quantifying Drug Distribution in Tissue III
Kin Foong Chan; Conor L. Evans, Editor(s)

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