An EPR strategy for bio-responsive fluorescence guided surgery with simulation of the benefit for imaging

A successful matching of a PEG group size with the EPR effect for an off-to-on responsive NIR-fluorophore conjugate has been accomplished which allows two distinct in vivo tumor imaging periods, the first being the switch on during the initial tumor uptake via enhanced permeability into the ROI (as background is suppressed) and a second, later, due to enhanced retention within the tumor. Methods: Software simulation (https://mihaitodor.github.io/particle_simulation/index.html), synthetic chemistry, with in vitro and in vivo imaging have been synergistically employed to identify an optimal PEG conjugate of a bio-responsive NIR-AZA fluorophore for in vivo tumor imaging. Results: A bio-responsive NIR-AZA fluorophore conjugated to a 10 kDa PEG group has shown excellent in vivo imaging performance with sustained high tumor to background ratios and peak tumor emission within 24 h. Analysis of fluorescence profiles over 7 days has provided evidence for the EPR effect playing a positive role. Conclusion: Preclinical results show that exploiting the EPR effect by utilizing an optimized PEG substituent on a bio-responsive fluorophore may offer a means for intraoperative tumor margin delineation. The off-to-on responsive nature of the fluorophore makes tumor imaging achievable without waiting for clearance from normal tissue.</p

Additional file 1: Table S1. of Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies

Non-synonymous somatic mutations in PIK3CA and ERBB family genes. (DOCX 15 kb

Additional file 2: Table S2. of Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies

Specific somatic mutations in PIK3CA, EGFR, ERBB3, ERBB4 and PIK3CA detected in our patient cohort. (DOCX 13 kb

Supplementary_material – Supplemental material for Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer

<p>Supplemental material, Supplementary_material for Frequency, impact and a preclinical study of novel ERBB gene family mutations in HER2-positive breast cancer by Naomi Elster, Sinead Toomey, Yue Fan, Mattia Cremona, Clare Morgan, Karolina Weiner Gorzel, Una Bhreathnach, Malgorzata Milewska, Madeline Murphy, Stephen Madden, Jarushka Naidoo, Joanna Fay, Elaine Kay, Aoife Carr, Sean Kennedy, Simon Furney, Janusz Mezynski, Oscar Breathhnach, Patrick Morris, Liam Grogan, Arnold Hill, Susan Kennedy, John Crown, William Gallagher, Bryan Hennessy and Alex Eustace in Therapeutic Advances in Medical Oncology</p