Molecular Beacon-Based Nanoparticles for TNBC Imaging and Targeted Therapy

? DESCRIPTION (provided by applicant): African American women are disproportionately affected by triple negative breast cancer (TNBC), a form of breast cancer that does not express the three widely used biomarkers and therapeutic targets namely Her-2, estrogen receptor and progesterone receptor. Consequently, these women do not benefit from the novel therapies (eg., Herceptin therapy) targeting the three biomarkers. TNBC are very aggressive resulting in higher mortality rate in African American women than women in other populations. Therefore, there is an urgent need for developing novel approaches for both diagnosis and therapy of TNBC. Combination of tumor chemotherapy and imaging in an `all-in-one system' provides a useful multi-modal approach in the battle against metastatic breast cancer. A promising imaging technique, time gated molecular beacon probes, is a noninvasive and painless method for detection and monitoring. Molecular beacon probe-based theranostic nanoparticles is a novel concept in next-generation medicine that combines simultaneous diagnostics and therapeutics to radically change the way we diagnose, image and treat breast cancer. The hypothesis of this proposal is that molecular beacon probe-based theranostic nanoparticles are effective for diagnosis and therapy of TNBC. The biodegradable polymeric nanoparticles (NP) containing molecular beacons specific to MMP-9 and an anticancer drug-NP conjugated to Annexin A2 peptide for targeting will enable visualization of the accumulated carriers together with therapy at the tumor site thereby provide an exciting new tool for breast cancer diagnosis and therapy. The Specific Aims are: Aim 1. Formulation of novel pH responsive PHis-PEG-PLLA-PEG multifunctional nanoparticles encapsulated with molecular beacons specific to MMP-9, along with docetaxel (anticancer agent) NP followed by surface conjugation of AnxA2 peptide for targeting. Aim 2. Characterization of the formulated multifunctional nanoparticles along with intracellular uptake studies in breast cancer cell lines. Aim 3. In vivo imaging and validation of the multi-model approach of these nanoparticles in metastatic breast cancer mouse model. This unique and innovative combinatorial theranostic strategy can improve the accuracy of diagnosis and therapy, provide better assessment of the severity of disease and even monitor the response to drug therapy. This innovative proposal of combining an imaging technique together with targeted delivery of anticancer drug at the tumor site will enhance their clinical potential for diagnosis and therapy in metastatic breast cancer therapy.