Abstract 5482: Theranostic nanoparticles for targeted therapy of triple negative breast cancer and for monitoring therapeutic response by MRI

Abstract

Abstract Clinical Significance: Among 1 million cases of newly diagnosed breast cancer worldwide each year, over 170,000 cases will have a distinct type of triple-negative breast cancer (TNBC), which lacks expression of estrogen (ER), progesterone (PR) and human epidermal growth factor receptor 2 (Her-2/neu). The patients with TNBC are usually detected at the late stage, have an aggressive tumor type, an increased likelihood of local and distant recurrence, and a poorer prognosis compared to women with other types of breast cancer. TNBC patients usually receive neoadjuvant therapy to reduce local and distant recurrence. However, more than 50% of TNBC patients are resistant to conventional chemotherapy. Therefore, novel methods for effective therapy are an urgent need for improving survival of the TNBC patients. Methods: We have developed a targeted therapy for TNBC by systemic delivery of biodegradable theranostic magnetic iron oxide nanoparticles (IONPs) that combine targeted drug delivery and non-invasive tumor imaging capabilities. These theranostic IONPs are targeted to urokinase plasminogen activator receptor (uPAR) by conjugating to the amino-terminal fragment (ATF) of the high affinity receptor binding domain of uPA. Results: 1). Our results from analysis of the gene expressing profile of a cohort of 143 breast cancer tissues revealed that uPAR, a potential cell surface target for the development of targeted therapeutics in TNBC, is highly expressed in the TNBC tissues compared to the luminal type of breast cancer (p < 0.0001). The major advantage of targeting uPAR is that the receptor is highly expressed in tumor cells and angiogenic endothelial cells, which facilitates transporting nanoparticles across the endothelium lining tumor vessels. Internalization of ATF-nanoparticle complexes by tumor cells further increases intracellular drug concentration; 2). We demonstrated that systemic delivery of uPAR-targeted theranostic IONPs carrying a chemotherapy drug, doxorubicin, significantly inhibited the growth of primary tumors through anti-tumor and anti-angiogenesis effects, and delayed local and distant recurrence for 8 weeks as compared mice-treated with free doxorubicin in a TNBC-like 4T1 mouse mammary tumor model. The improved therapeutic effect using these targeted theranostic nanoparticles has also been demonstrated in a human breast cancer xenograft model; 3). Targeting theranostic nanoparticles into tumors allow for monitoring intratumoral drug delivery and therapeutic response in the tumors by MRI; and 4). Targeted delivery of doxorubicin using theranostic IONPs reduces systemic toxicity of the drug in normal organs, such as heart and liver. Conclusion: uPAR-targeted theranostic nanoparticles have potential for targeted therapy, timely assessment of therapeutic response of a given therapy, and ultimately, increased survival of TNBC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5482.