ABSTRACT
Breast cancer is one of the most frequent and aggressive primary tumors among women of all races. Matrix metalloproteinase (MMPs), a family of zinc- and calcium-dependent secreted or membrane anchored endopeptidases, is overexpressed in varieties of diseases including breast cancer. Therefore, noninvasive visualization and quantification of MMP in vivo are of great interest in basic research and clinical application for breast cancer early diagnosis. Herein, we developed a 99mTc labeled membrane type I matrix metalloproteinase (MT1-MMP) specific binding peptide, [99mTc]-(HYNIC-AF7p)(tricine)(TPPTS), for in vivo detection of MDA-MB-231 breast tumor by single photon emission computed tomography (SPECT). [99mTc]-(HYNIC-AF7p)(tricine)(TPPTS) demonstrated nice biostability and high MT1-MMP binding affinity in vitro and in vivo. Tumor-to-muscle ratio was found to reach to the highest (4.17±0.49) at 2 hour after intravenously administration of [99mTc]-(HYNIC-AF7P)(tricine)(TPPTS) into MDA-MB-231 tumor bearing mice. Overall, [99mTc]-(HYNIC-AF7P)(tricine)(TPPTS) demonstrated great potential for MT1-MMP targeted detection in vivo and it would be a promising molecular imaging probe that are probably beneficial to breast cancer early diagnoses.
Subject(s)
Breast Neoplasms/enzymology , Matrix Metalloproteinase 14/analysis , Neoplasm Proteins/analysis , Neoplasms, Experimental/diagnostic imaging , Organotechnetium Compounds/analysis , Radiopharmaceuticals/analysis , Tomography, Emission-Computed, Single-Photon , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Heterografts , Humans , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Organotechnetium Compounds/chemical synthesis , Organotechnetium Compounds/pharmacokinetics , Organotechnetium Compounds/toxicity , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/toxicity , Tissue Distribution , Tomography, X-Ray Computed , Transplantation, Heterotopic , Tumor BurdenABSTRACT
BACKGROUND: Functional imaging can help clinicians assess the individual response of advanced nonsquamous non-small cell lung cancer (NSCLC) to chemoradiation therapy plus bevacizumab. Our purpose is to investigate the ability of (99m)Tc-3PRGD2 single photon emission computed tomography/computed tomography (SPECT/CT) in predicting the early response to treatment. METHODS: Patients with advanced nonsquamous NSCLC diagnosed by histological or cytological examination were imaged with (99m)Tc-3PRGD2 SPECT/CT at 3 time points: 1-3 days before the start of treatment (SPECT1), 40 Gy radiotherapy with 2 cycles of chemotherapy plus bevacizumab (SPECT2) and 4 weeks after chemoradiotherapy plus bevacizumab (SPECT3). The images were evaluated semiquantitatively by measuring the tumor to non-tumor ratio (T/N) and calculating the percentage change in T/N ratio. Short-term outcome was assessed by the treatment response evaluation according to the Response Evaluation Criteria in Solid Tumors criteria as: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Patients were divided two groups: responders (CR and PR) and nonresponders (SD and PD). To determine a threshold for percent reduction in T/N ratios, receiver-operating characteristic (ROC) curve analysis was used. Patients were grouped again based on the threshold of P1 (the change percentage from SPECT1 to SPECT2) and P2 (the change percentage from SPECT1 to SPECT3): P1 responders and P1 nonresponders; P2 responders and P2 nonresponders. Patients were followed up starting 4 weeks after completion of therapy and then every 3 months for the first 2 years and every 6 months after 2 years. OS of P1 responders, P1 nonresponders, P2 responders and P2 nonresponders was estimated and graphically illustrated using the Kaplan-Meier method and the log-rank test was used to test the null hypotheses of equal OS in subgroups of patients. RESULTS: A total of 28 patients completed all imaging and treatment. All primary lung tumors were well visualized on SPECT1. The mean T/N ratio of SPECT1 in responders and nonresponders was not statistically different (2.73 ± 0.59 vs. 2.59 ± 0.52, p > 0.05). At SPECT2 and SPECT3, the mean T/N ratios were both lower in the responders compared with the nonresponders and had statistical significance (p < 0.05). P1 and P2 in the responders was larger than the nonresponders with significant difference (P1: 34.18 ± 21.55 % vs. 9.02 ± 14.02 %, p < 0.05; P2: 53.02 ± 15.50 % vs. 7.74 ± 37.95 %, p < 0.05). The optimal threshold of P1 that can discriminate between P1 responders and P1 nonresponders was greater than 25.9 % reduction, and that of P2 that can discriminate between P2 responders and P2 nonresponders was 34.0 % reduction. The area under the ROC curve (AUC) of P1 and P2 for determining residual disease was 0.856 and 0.909, respectively; but there was no statistical significance between them (p > 0.05). There was a significant difference for OS between P1 responders and P1 nonresponders (p < 0.05), and also for OS between P2 responders and P2 nonresponders (p < 0.05). But there was no difference between the P1 responders and P2 responders (p > 0.05), or between the P1 nonresponders and P2 nonresponders (p > 0.05). CONCLUSION: A (99m)Tc-3PRGD2 SPECT/CT after two cycles of chemoradiotherapy plus bevacizumab can predict patients who will have a better response to treatment and survival.
