Multimodal hybrid nanoparticles for the treatment of triple-negative breast cancer

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Abstract Breast cancer (BC) is the most frequently diagnosed cancer in women and remains one of the leading causes of cancer-related mortality of women in the United States. In 2021, the American Cancer Society estimated that 284,200 new cases of breast cancer (BC) were diagnosed for both women (281,550) and men (2,650), with an estimated death of 43,600 women and 530 men. Triple-negative breast cancer (TNBC) is a subtype of BC associated with younger age, African American and Hispanic ethnicity background, and BRCA gene-mutated populations. TNBC lacks expressions of ER/PR/HER2 and meaningful therapeutic targets, patients with TNBC are treated with conventional chemotherapy and radiation therapy. TNBC is characterized by intra-tumor heterogeneities, high proliferative activity, poor prognosis, high risk of relapse, and metastasis to lungs and brain. Approximately 50% of the patients diagnosed with early-stage TNBC experience recurrence, and 37% die within the first 5 years after surgery. Therefore, novel therapeutic alternatives to overcome resistance to chemotherapy and to prevent recurrence and metastasis are essential to significantly improve the clinical care of this deadly disease. The remarkable features of therapeutic nucleic acids (TNAs) and photodynamic therapy (PDT) such as low side-effects, targeting different cellular death mechanisms, and potential immunological effects make these treatment modalities a promising alternative for the treatment of TNBC. In this project, we are developing a combinational approach using two different silica-based platforms; polysilsesquioxane (PSilQ) and mesoporous silica nanoparticles (MSNs) carrying a photosensitizing agent (chlorin e6 (Ce6)), together with novel nanoparticle-based TNAs (RNA fibers, RNAfs). We are targeting the anti-apoptotic protein Bcl2, which is a relevant target to improve the treatment of TNBC. The main goal of this project is to develop a multimodal nanoparticulate platform for the efficient treatment of TNBC. To achieve this goal we will design, synthesize and characterize RNAfs-loaded PEG-Ce6-PSilQ and RNAfs-loaded PEG-Ce6-MSNs (Aim 1). We will study the therapeutic and silencing effect, impact on the cellular death and immune response of this platforms in vitro (Aim 2). The results obtained from Aim 2 will allow us to decide which one is the best platform to be evaluated in the next Aim. Finally, we will investigate and validate the therapeutic efficacy and effect on metastasis the selected system in an orthotopic model of TNBC (Aim 3).