Author: David Alcorta, Joseph Farina, Timothy Haystead, Yiping He, Philip Hughes, David Loiselle, Marybeth Nedrud, Victoria J. P. Radosova, Jianpeng Yu 👨🔬
Affiliation: Duke University Department of Pharmacology and Cancer Biology, Medical Physics Graduate Program, Duke University, Duke University Department of Medicine, Duke University, Duke University Pharmacology and Cancer Biology, Duke University School of Medicine, Duke Cancer Institute 🌍
Purpose: Targeted radiopharmaceuticals have become of widespread interest in the scientific community given their ability to detect and treat metastatic disease. We aim to validate the use of novel chelate-tethered eHSP-90 inhibitors as potential agents for detection of aggressive cancers regardless of site of origin.
Methods: Novel chelate-tethered eHSP-90 inhibitors (HS530 and HS559) were synthesized and radiolabeled with pharmaceutical-grade Ga-68. Intracellular accumulation was evaluated in breast (MDA-MB-231) and prostate (TrampC2, PC3, LNCaP) cancer cell lines in-vitro using PET imaging, with PSMA-11 serving as the benchmark for prostate cancer comparison. In-vivo biodistribution was assessed in healthy C57BL/6J mice. SCID mice bearing MDA-MB-231 and TrampC2 flank tumors analyzed in-vivo tumor-specific uptake. Mice received ~100 µCi of radiopharmaceutical via tail vein injection, followed by PET imaging at 20-minute intervals over 60 minutes using a Sedecal SuperArgus microPET/CT system. Pharmacokinetic analyses using Imalytics software revealed radiotracer distribution, with organ-specific uptake confirmed by scintillation counting and mass spectrometry.
Results: In MDA-MB-231, maximum cellular uptake (7.6±1.6 %ID/mL) was achieved within 50 minutes. Novel chelate-tethered eHSP-90 inhibitors and the positive control PSMA-11 showed similar uptake to the PSMA+ prostate cancer cell lines LNCaP and TrampC2 (p > 0.7 and p > 0.6, respectively). Small animal PET imaging of novel chelates demonstrates physiologic uptake in the liver and heart with renal excretion over 90 minutes. Quantitative assessments and scintillation counting confirm increased tumor localization relative to normal liver, heart and kidneys for the novel eHSP90 chelated inhibitors.
Conclusion: Experimental methods were effective in demonstrating the potential of chelate-tethered eHSP90 inhibitors for detecting aggressive cancers, showing enhanced tumor localization relative to normal tissues. These findings highlight the promise of eHSP90 inhibitors for cancer detection, with future studies focused on comparing their efficacy to currently used clinical agents.