Multiparametric Monitoring of Tumor Response to Chemotherapy by Noninvasive Imaging

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Abstract
With the emerging concept of individualized cancer therapy, it becomes crucial to develop methods for the noninvasive assessment of treatment outcome. With this in mind, we designed a novel approach for the comprehensive evaluation of response to chemotherapy with the established agent doxorubicin in a preclinical breast cancer model. This approach delivers information not only about change in tumor size but also about target antigen expression. Our strategy relies on a tumor-specific contrast agent (MN-EPPT) targeting the underglycosylated MUC-1 (uMUC-1) tumor antigen, found on more than 90% of breast cancers and predictive of chemotherapeutic response. MN-EPPT consists of superparamagnetic iron oxide nanoparticles (MN) for magnetic resonance imaging, modified with Cy5.5 dye (for near-IR fluorescence optical imaging), and conjugated to peptides (EPPT), specifically recognizing uMUC-1. In vivo, treatment of mice bearing orthotopic human breast carcinomas with doxorubicin led to a reduction in tumor mass and resulted in down-regulation of uMUC-1. The tumor-specific accumulation of MN-EPPT allowed the assessment of change in tumor volume by noninvasive imaging. Furthermore, in mice injected with MN-EPPT, tumor delta-T2 was significantly reduced after treatment with doxorubicin, indicating a lower accumulation of MN-EPPT and reflecting the reduced expression of uMUC-1. With these studies, we have shown the utility of magnetic resonance imaging for the multiparametric characterization of breast tumor response to chemotherapy. This approach has the potential of significantly advancing our ability to better direct the development of molecularly targeted individualized therapy protocols because it permits the monitoring of therapy on a molecular scale. [Cancer Res 2009;69(3):1182–9]