Evaluation of tumor response to paclitaxel treatment in breast cancer xenograft with 99mTc-labeled duramycin

Objectives Duramycin binds PE with high affinity and specificity. the goal was to investigate 99mTc-labeled duramycin for monitoring tumor response to Paclitaxel treatment in breast cancer xenograft.

Methods Duramycin is covalently modified with succinimidyl 6-hydrazinonicotinate acetone hydrazone (HYNIC) and labeled with 99mTc using a coordination chemistry . The binding of 99mTc-Duramycin toward apoptosis was validated in vitro using pactaxel-induced MDB-MA-231 tumor cells. MDB-MA-231 xenografts were divided into two groups randomly, one group receive single dose of paclitaxel (40mg/kg) treatment, the control receive the same volume of saline . After injection of 99mTc-duramycinby tail vein, micro SPECT/CTwere performed at 1,2h,respectively. Radioactivity in different tissues was determined after imaging. Apoptotic cells were measured with flow cytometry. Morphological changes ofapoptosis were observed by transmission electron microscopies. The data were analyzed by SPSS 19.0.

Results The radiochemical purity of 99mTc-Duramycin was > 95%. The predominant uptake was found in kidney, rapid clearance was observed in the blood and kidney. The ratio of tumor to muscle (T/NT) in treated group was 4.21±0.06, significantly higher than that of control (1.57±0.67,p<0.05,). Regarding the retention percentages of radioactivity (%ID/g) in tumor tissue at 48 hours later in treatment group was 4.82±0.54, significant higher than that of control (1.44±0.38). The tumor uptake of 99mTc-hynic-Duramycin of treatment correlated well with Annexin V/PI-positive cells in the tumor. Histopathology and ultrastructural changes further confirmed that the tumor radiouptake was caused by tumor apoptosis induced by chemotherapy , not by nonspecific uptake.

Conclusions Our data demonstrate the feasibility of 99mTc-duramycin for the early detection of apoptosis after pactaxel chemotherapy in breast xenografts. 99mTc-duramycin which derived with lantibiotics with low molecular weight ,unique three dimensional structure , might serve as a potential probe to detect cell death.