Apoptosis imaging probe predicts early chemotherapy response in preclinical models: A comparative study with 18F-FDG...

Previously, we reported a small-molecular-weight peptide, single amino acid chelae((99m)Tc)-conjugated phosphatidylserine-binding peptide (SAAC((99m)Tc)-PSBP-6), with high binding affinity to phosphatidylserine on the surface of apoptotic cells. The purpose of this study was to determine the effectiveness of SAAC((99m)Tc)-PSBP-6 in detecting apoptosis induced by chemotherapy.

B16/F10 melanoma and 38C13 lymphoma tumor models were used in this study. For each type of tumor model, mice were divided into a group treated for imaging (treated group [TG]) and a control group that was not treated (nontreated group [N-TG]). In the TG, mice bearing murine B16/F10 melanoma received a single dose of intravenous polymeric paclitaxel (equivalent dose, 80 mg/kg), and mice bearing 38C13 xenografts received intraperitoneal cyclophosphamide (100 mg/kg). Mice in the N-TG were given the same volume of saline. γ-imaging 4 h after intravenous injection of SAAC((99m)Tc)-PSBP-6 and small-animal PET 1 h after intravenous injection of (18)F-FDG were performed before chemotherapy and at 1 d after chemotherapy. On day 1, immediately after the apoptosis imaging sessions, 3 mice each in the TGs and N-TGs were killed, and tumor tissues were excised for hematoxylin and eosin histology, autoradiography, and immunohistochemical staining using anti-active caspase 3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). The tumor volumes in the remaining mice (n = 5/group) were measured every other day for 7 d.

In both tumor models, the uptake of SAAC((99m)Tc)-PSBP-6 increased significantly on day 1 after treatment, whereas (18)F-FDG uptake decreased significantly during the same time. The mean tumor uptake values for SAAC((99m)Tc)-PSBP-6 increased 142.4% ± 36.9% and 112% ± 42.9% in 38C13 and B16/F10 tumors, respectively (both P < 0.05, pretreatment vs. day 1 after treatment). The mean tumor uptake value for (18)F-FDG decreased 67.36% ± 17.52% and 62.82% ± 4.53% in 38C13 and B16/F10 tumors, respectively. The uptake of SAAC((99m)Tc)-PSBP-6 negatively correlated with (18)F-FDG (r = -0.79, P < 0.05). Treated tumors had smaller volumes than untreated controls, treated tumors had significantly higher numbers of apoptotic cells, and tumor uptake of SAAC((99m)Tc)-PSBP-6 correlated with the number of TUNEL-positive cells.

SAAC((99m)Tc)-PSBP-6 γ-imaging is useful for the early assessment of treatment-induced apoptosis and, thus, may be used as a substitute for (18)F-FDG PET for assessing early treatment response.