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.