^99mTc-Duramycin SPECT Imaging of Early Tumor Response to Targeted Therapy: A Comparison with¹⁸F-FDG PET

Abstract

Molecular imaging of cell death may provide a detailed readout of the cellular response to novel therapies and prognostic information on tumor treatment efficacy, assisting in the design of individualized therapy. We compared the predictive power of cell death imaging using Tc-duramycin with the current gold standardF-FDG for treatment response evaluation after targeted therapy. Early therapy response evaluation was assessed byTc-duramycin SPECT and F-FDG PET imaging in treatment-sensitive COLO205 and treatment-resistant HT29 human colorectal cancer xenografts 24 h after a single dose of conatumumab or IgG1 control. The specificity ofTc-duramycin for apoptosis was assessed using Tc-linear duramycin control radiotracer. Radiotracer uptake was validated ex vivo by γ-counting and autoradiography and compared with cleaved caspase-3 (CC3) activation and DNA fragmentation (TdT-mediated dUTP nick-end labeling [TUNEL]). Data were analyzed with the Student test and Pearson correlation. All statistical tests were 2-sided. COLO205 tumor uptake ofTc-duramycin was increased 7-fold from baseline in conatumumab- versus IgG1-treated control mice ( < 0.001), in good correlation with histologic analysis of apoptosis (CC3, = 0.842, and TUNEL, = 0.894; < 0.001). No response was detected in HT29 tumors. No change in Tc-linear duramycin uptake could be detected in COLO205 tumors after treatment, indicating specificity of theTc-duramycin tumor signal. F-FDG uptake was not significantly increased from baseline in conatumumab- versus IgG1-treated COLO205 and HT29 tumor-bearing mice ( = 0.104 and 0.779, respectively) and did not correlate with immunohistochemical evidence of apoptosis. We have demonstrated thatTc-duramycin specifically accumulates in apoptotic tumors in which F-FDG was not able to differentiate responding from nonresponding tumors early after treatment.Tc-duramycin holds promise as a noninvasive imaging radiotracer for early treatment evaluation in the clinic.

SPECT/CT imaging of chemotherapy-induced tumor apoptosis using 99mTc-labeled dendrimer-entrapped gold nanoparticles

“…In contrast, the normal C6 cells treated with the duramycin-Au DENPs exhibit similar fluorescence intensity to those treated with Au DENPs ( Figure S3(d) ). These data confirm that the duramycin-modified Au DENPs are able to specifically target apoptotic cancer cells presumably through specific PE interaction, in agreement with the literature (Elvas et al., 2016 , 2017 ). Confocal microscopy was also used to further demonstrate the targeting specificity of the formed duramycin-Au DENPs ( Figure 2 ).…”

“…The previous successes of dendrimer-based multifunctional NPs inspire us to speculate that PAMAM dendrimers are also able to be explored as a nanoplatform to develop SPECT/CT dual mode nanoprobes for early detection of apoptosis in tumors. Duramycin, an important peptide with high affinity and selectivity for phosphatidylethanolamine (PE) that externalizes to cell surface during apoptosis, has been developed as a targeting ligand for SPECT imaging of cell apoptosis in vivo (Elvas et al., 2016 ; Luo et al., 2016 ; Elvas et al., 2017 ).…”

Magnetic Resonance Imaging Is More Sensitive Than PET for Detecting Treatment-Induced Cell Death–Dependent Changes in Glycolysis

“…However, the hyperpolarized [1-13 C]pyruvate/[1-13 C]lactate ratio, in which pyruvate delivery is accounted for, may be a more practical clinical approach than kinetic analysis of [ 18 F]FDG uptake, which requires prolonged dynamic image acquisition and arterial blood sampling. 13 The failure of [ 18 F]FDG to detect treatment response has frequently been attributed to activation of phagocytic cells and to a lesser extent other immune cells, resulting in a paradoxical increase in tumor [ 18 F]FDG uptake (12,14,46,47). Here, [ 18 F]FDG uptake per cell was quantified by sorting labeled cell populations using FACS.…”

SPECT/CT: Standing on the Shoulders of Giants, It Is Time to Reach for the Sky!

“…A promising example is the development of 99m Tc-duramycin as a SPECT tracer for apoptosis, enabling imaging of the induction of cell death early after chemotherapy and radiotherapy. Providing a very early readout of treatment effect, it could potentially be used to tailor cancer treatments more quickly, sparing toxicity and cost in nonresponding patients (53). Another interesting target in oncology and cardiovascular medicine is angiogenesis, with 99m Tc-HYNIC-L(arginine-glycine-aspartate) or 99m Tc-maraciclatide integrin a v b 3 imaging demonstrating the ability to visualize tumors and treatment response in cancer models (54).…”