Cancer heterogeneity and drug resistance limit the efficacy of cancer therapy. To address this issue, we have developed an integrated treatment protocol for effective treatment of heterogeneous ovarian cancer. Methods: An amphiphilic polymer coated magnetic iron oxide nanoparticle was conjugated with near infrared dye labeled HER2 affibody and chemotherapy drug cisplatin. The effects of the theranostic nanoparticle on targeted drug delivery, therapeutic efficacy, non-invasive magnetic resonance image (MRI)-guided therapy, and optical imaging detection of therapy resistant tumors were examined in an orthotopic human ovarian cancer xenograft model with highly heterogeneous levels of HER2 expression. Results: We found that systemic delivery of HER2-targeted magnetic iron oxide nanoparticles carrying cisplatin significantly inhibited the growth of primary tumor and peritoneal and lung metastases in the ovarian cancer xenograft model in nude mice. Differential delivery of theranostic nanoparticles into individual tumors with heterogeneous levels of HER2 expression and various responses to therapy were detectable by MRI. We further found a stronger therapeutic response in metastatic tumors compared to primary tumors, likely due to a higher level of HER2 expression and a larger number of proliferating cells in metastatic tumor cells. Relatively long-time retention of iron oxide nanoparticles in tumor tissues allowed interrogating the relationship between nanoparticle drug delivery and the presence of resistant residual tumors by in vivo molecular imaging and histological analysis of the tumor tissues. Following therapy, most of the remaining tumors were small, primary tumors that had low levels of HER2 expression and nanoparticle drug accumulation, thereby explaining their lack of therapeutic response. However, a few residual tumors had HER2-expressing tumor cells and detectable nanoparticle drug delivery but failed to respond, suggesting additional intrinsic resistant mechanisms. Nanoparticle retention in the small residual tumors, nevertheless, produced optical signals for detection by spectroscopic imaging. Conclusion: The inability to completely excise peritoneal metastatic tumors by debulking surgery as well as resistance to chemotherapy are the major clinical challenges for ovarian cancer treatment. This targeted cancer therapy has the potential for the development of effective treatment for metastatic ovarian cancer.

Development of sensitive and specific imaging approaches for the detection of ovarian cancer holds great promise for improving survival of ovarian cancer patients. Here we describe a dual-modality photoacoustic and fluorescence molecular tomography (PAT/FMT) approach in combination with a targeted imaging probe for three-dimensional imaging of ovarian tumors in mice. We found that the selective accumulation of the HER-2/neu targeted magnetic iron oxide nanoparticles (IONPs) led to about 5-fold contrast enhancements in the tumor for PAT, while near-infrared (NIR) dye labeled nanoparticles emitted strong optical signals for FMT. Both PAT and FMT were demonstrated to be able to detect ovarian tumors located deep in the peritoneal cavity in mice. The targeted nanoprobes allowed mapping tumors in high resolution via PAT, and high sensitivity and specificity via FMT. This study demonstrated the potential of the application of HER-2/neu-targeted PAT/FMT approach for non-invasive or intraoperative imaging of ovarian cancer.