Formulation of a Thermosensitive Imaging Hydrogel for Topical Application and Rapid Visualization of Tumor Margins in the Surgical Cavity

Ethan Walker; Daan G J Linders; Eric Abenojar; Xinning Wang; Hans Marten Hazelbag; Marieke E Straver; Okker D Bijlstra; Taryn L March; Alexander L Vahrmeijer; Agata Exner; Matthew Bogyo; James P Basilion; Brian Straight

doi:10.3390/cancers14143459

Formulation of a Thermosensitive Imaging Hydrogel for Topical Application and Rapid Visualization of Tumor Margins in the Surgical Cavity

Cancers (Basel). 2022 Jul 16;14(14):3459. doi: 10.3390/cancers14143459.

Authors

Ethan Walker¹, Daan G J Linders², Eric Abenojar³, Xinning Wang¹, Hans Marten Hazelbag⁴, Marieke E Straver⁵, Okker D Bijlstra², Taryn L March⁶, Alexander L Vahrmeijer², Agata Exner^{1

3}, Matthew Bogyo^{7

8}, James P Basilion^{1

3

9}, Brian Straight⁹

Affiliations

¹ Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA.
² Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
³ Department of Radiology, Case Western Reserve University, Cleveland, OH 44106, USA.
⁴ Department of Pathology, Haaglanden Medical Center, 2512 VA The Hague, The Netherlands.
⁵ Department of Surgery, Haaglanden Medical Center, 2512 VA The Hague, The Netherlands.
⁶ Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
⁷ Department of Pathology, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
⁹ Akrotome Imaging Inc., Charlotte, NC 28205, USA.

Abstract

Background: Tumor-positive surgical margins during primary breast cancer (BCa) surgery are associated with a two-fold increase in the risk of local recurrence when compared with tumor-negative margins. Pathological microscopic evaluation of the samples only assesses about 1/10 of 1% of the entire volume of the removed BCa specimens, leading to margin under-sampling and potential local recurrence in patients with pathologically clean margins, i.e., false negative margins. In the case of tumor-positive margins, patients need to undergo re-excision and/or radiation therapy, resulting in increases in complications, morbidity, and healthcare costs. Development of a simple real-time imaging technique to identify residual BCa in the surgical cavity rapidly and precisely could significantly improve the quality of care.

Methods: A small-molecule, fluorescently quenched protease-substrate probe, AKRO-QC-ICG, was tested as part of a thermosensitive imaging gel formulated for topical application and imaging of the BCa surgical cavity.

Results: More than forty formulations of gel mixtures were investigated to enable easy fluid application and subsequent solidification once applied, preventing dripping and pooling in the surgical cavity. The final formulation was tested using human BCa orthotopic implants in nude and NSG patient-derived xenografts (PDX) mice. This formulation of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel was found to be a good solvent for the probe, with a desirable thermo-reversible solid-gel transition and mechanical strength for distribution of AKRO-QC-ICG on the surfaces of tissue. It demonstrated excellent ability to detect BCa tissue after 10 min exposure, with a high signal-to-noise ratio both in mouse xenografts and freshly excised human lumpectomy tissue. The in vivo efficacy of the AKRO-QC-ICG imaging gel to detect BCa revealed the levels of sensitivity/specificity = 0.92/1 in 12 nude mice, which was corroborated with the sensitivity/specificity = 0.94/1 in 10 PDX mice.

Conclusions: Utilization of Pluronic F-127/DMSO/AKRO-QC-ICG imaging gel for topical application to detect BCa in the surgical cavity during surgery has the potential to reduce re-excisions, with consequent savings in healthcare costs and enhancement in patient quality of life.

Keywords: human breast cancer; optical imaging; surgical cavity; tumor margins.

Abstract

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