Course Content
Revolutionizing Solid Tumor Surgery with Fibroblast Activation Protein Targeted Imaging Probes for Precision Fluorescence-Guided Surgery
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Fluorescence Imaging of Triple Negative Breast Cancer targeting ROR1
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Fast-acting sprayable fluorogenic probe to visualize tumors for fluorescence-guided cytoreductive surgery
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PSMA-Targeted Novel Dual-functional Agent for Fluorescence Imaging-Guided Surgery and Photothermal Therapy for Prostate Cancer
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Fluorescence Image Guided Surgery and Adjuvant Photothermal Therapy Abolishes Tumor Regrowth, Delays/Eliminates Metastasis, and Improves Animal Survival in a 4T1 Breast Cancer Model.
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Canine Dose-Escalation Study of Fluorescently Labeled Nanobodies Targeting EGFR for Tumor Delineation in Head and Neck Cancer
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Evaluation of Fluorescence Lifetime-enhanced Tumor Imaging Using an Anti-CEA targeted Fluorescent Probe
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Illuminating Molecular Targets For Enhanced Surgical Precision
About Lesson
Abstract Body:

Introduction. Breast cancer (BCa) is the most common cancer in women. For 2023, breastcancer.org projected 297,790 new cases of invasive BCa and 55,720 new cases of non-invasive (in situ) BCa, projecting 43,700 deaths. Majority of US BCa surgeries are currently breast-conserving surgery (BCS)1. Among patients treated by BCS and radiation, positive margins are associated with a 2-fold increase in the risk of local recurrence when compared with negative margins2. Pathological analysis of post-operative specimens takes 3-5 days and if margins are positive requires patients to return for further surgery. Local disease recurrence is experienced by 5%-16% of patients with negative surgical margins, likely from false negatives due to under sampling during assessment. Thus, there remains a significant unmet clinical need to improve both surgical techniques and imaging probes for identifying tumor margins and complete removal of BCa during BCS.

Goal.  To expand on the utility  of a current fluorescence image guided surgery (FIGS) probe, AKRO-6qc3, as a theranostic photothermal therapy (PTT) agent. The AKRO-6qc (aka 6QC or 6qc-ICG), belongs to a well-characterized cathepsin-targeted family3,4 of ICG contrast5 imaging agents3,5-7 with excellent cellular retention leading to increased ICG signal strength and durability in solid tumors3. Here we test AKRO-6qc for FIGS followed by adjuvant PTT to ablate  any inoperative/non-detectable microscopic disease in a single surgical procedure.

Methods. Mouse BCa 4T1 cells were pretreated with AKRO-6qc for 24-h and then harvested, washed, and then irradiated (800-nm, up to 1-Watt) as pellets in tubes using a clinically approved ML7710-laser (Modulight) to record temperature changes in response to PTT. Nude female mice were inoculated with 4T1 luciferase-expressing cells in the flank. When tumor size reached 100-mm3 mice were divided into four groups: 1) intact control; 2) white light surgery (WLS); 3) FIGS; and 4) FIGS, followed by PTT (FIGS+PTT). AKRO-6qc was i.v. administered to the FIGS and FIGS+PTT mice and 24-hr later presence of both ICG fluorescence and/or bioluminescence in the tumor tissue was confirmed (IVIS-Spectrum). Then WLS, FIGS under live-image control (Curadel-FLARE), and FIGS followed by PTT (1.0-Watt once to the surgical cavities with 800-nm fiber-optic, Modulight) were provided under assessment of temperature kinetics using a photothermal camera (FLIR-One-PRO). Next, all surgical wounds were closed, and animals’ tumor size, lung metastasis, and survival were monitored for 90-days.

ResultsIn vitro data revealed: 1) Positive correlation between PTT-induced temperature changes and i) power of laser source, ii) distance from the optical fiber to the cell pellet for light, and iii) dose of AKRO-6qc; 2) PTT-induced temperature increase in BCa cells pre-treated with AKRO-6qc up to 550C (ΔT300C) in 5-min as compared to controls (no probe), leading to 100% killing after 10-min of irradiation. In vivo data showed that: 1) Tumor specific bio-luminescence signals correlate with AKRO-6qc fluorescence in tumor-bearing mice; 2) 24-36-hr after delivery of AKRO-6qc may be a suitable time-window for PTT; 3) PTT induced temperature increases only in the surgical cavities of AKRO-6qc-treated mice that had BCa surgically removed, demonstrating utility of combined FIGS+PTT; 4) Combination of FIGS and PTT may extend animal survival, abolish tumor recurrence, and delay/eliminate lung metastasis.

Conclusion. Combination of AKRO-6qc FIGS followed by PTT of the surgical cavity in this mouse model of 4T1 aggressive triple-negative BCa extended animal survival, abolished tumor regrowth, and delayed/abolished 4T1 metastasis to lungs in the host animals. AKRO-6qc probe has a potential to be a theranostic for solid cancers when it is used for FIGS and adjuvant PTT, and likely will improve the outcome of resection of tumor masses.

Author

Ethan Walker, PhD
Dr.
Case Western Reserve University
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