Preliminary efficacy evaluation of ⁶⁴Cu-labeled disintegrin in tracking response to docetaxel treatment in prostate tumor-bearing mice

Objectives: A new sequence-engineered vicrostatin (VCN) displays high binding affinity to a broad range of human integrins. In this study, we preliminarily evaluated the efficacy of a ⁶⁴Cu-labeled VCN PET probe in quantitatively measuring response to chemotherapeutic agent docetaxel ‒ a standard therapy in castrate-resistant metastatic prostate cancer (PC). Methods: Macrocyclic chelating agent 1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosine (DiAmSar) was modified with a PEG unit, and followed by conjugation with VCN. The precursor was then radiolabeled with positron emitter ⁶⁴Cu (t_1/2 = 12.7h) in ammonium acetate buffer to provide ⁶⁴Cu-Sar-PEG-VCN, which was subsequently subject to animal studies in an intracardiac metastatic model of PC. For ease of monitoring tumor growth and spread, PC-3-luc cells were injected into the left ventricle of the mouse under ultrasound guidance. After 10-14 days of injection, the metastatic model was validated by bioluminescence imaging (BLI), and then used for docetaxel treatment at 6 mg/kg IV injection twice per week for 25 days. MicroPET-CT imaging with ⁶⁴Cu-Sar-PEG-VCN was performed before and after docetaxel treatment. Results: The preparation of ⁶⁴Cu-Sar-PEG-VCN was achieved in 75% yield (decay-corrected) with radiochemical purity of >98%. The specific activity of ⁶⁴Cu-Sar-PEG-VCN was estimated to be 37 MBq/nmol. The BLI data demonstrated successful establishment of the intracardiac metastatic model of PC. Before docetaxel treatment, microPET-CT imaging results showed that ⁶⁴Cu-Sar-PEG-VCN has preferential tumor uptake and good tumor retention in the metastatic model, producing high tumor-to-muscle (T/M) imaging contrast ratio (2.59±0.71) and good tumor-to-liver (T/L) ratio (0.28±0.08) at 2 h post-injection. After docetaxel treatment, insignificant change of T/M uptake ratio of ⁶⁴Cu-Sar-PEG-VCN was observed (3.07±0.75).

Conclusions: ⁶⁴Cu-Sar-PEG-VCN has the potential for in vivo imaging of metastatic PC with PET, which may provide a non-invasive method to quantitatively localize and characterize metastatic PC. The optimization of docetaxel dose in the animal treatment model is underway. It is hoped that ⁶⁴Cu-Sar-PEG-VCN could be used for measuring response to chemotherapeutic treatment in experimental metastatic PC models and as an imaging theranostic companion with therapeutic VCN component. Research Support: This project was supported by a grant to H. Jadvar from an NIH award to Southern California Clinical and Translational Science Institute at USC.