Multiparametric Monitoring of Tumor Response to Chemotherapy by Noninvasive Imaging

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]

Optical imaging-guided cancer therapy with fluorescent nanoparticles

“…In 2006, the same group demonstrated that the dual-modal imaging probe could not only detect orthotopically implanted preclinical models of adenocarcinomas but could also track tumour response to 5-fluorouracil, a clinically used chemotherapeutic agent, in vivo in real time (Medarova et al 2006). More recently, they further proved that tumour delta-T2 was significantly reduced after treatment with DOX drug, indicating a lower accumulation of probe and reflecting the reduced expression of uMUC-1 in orthotopic human breast tumour (Medarova et al 2009). This dual-modality approach delivers information not only about change in tumour size but also about target antigen expression in vivo.…”

Pharmacokinetics of contrast agents targeted to the tumor vasculature in molecular magnetic resonance imaging

“…This would provide direct information on whether the drugs reach their target and on tissue retention time, which would be valuable for the development and evaluation of pharmaceutical products. Third, the presented method can be adapted to study the pharmacokinetics of other contrast agents targeted to, for instance, the Her-2/Neu receptor (27), tumor transglutaminase (28) or the underglycosylated mucin-1 tumor antigen (29). However, differences in extravasation and cellular uptake of probes should be carefully investigated.…”

Imaging applications of nanotechnology in cancer

“…Medarova et al [62] have recently designed a particle capable of monitoring a patient's response to chemotherapy with MRI. It is not only tumor size that is monitored but also target antigen expression.…”