| dc.description.abstract | Triple negative breast cancer (TNBC) is characterized by a lack of estrogen receptor, progesterone receptor, and HER2. Patients with TNBC therefore cannot benefit from treatment with one of the molecularly targeted therapies associated with these three markers and are instead relegated to treatment with neoadjuvant chemotherapy prior to surgical removal of the tumor. However, 70% of patients who undergo this standard of care have residual tumor in the tumor bed, making TNBC the deadliest subset of breast cancer. There is therefore a critical, unmet need for molecularly targeted therapeutics for triple negative breast cancer.
While small molecule drugs have revolutionized cancer treatment, their coverage is limited, leaving many tumor-driving genes “undruggable.” RNA interference using siRNA has the potential to silence any gene with high specificity but has historically been limited by in vivo obstacles including nuclease susceptibility, rapid renal clearance, and lack of cellular/cytoplasmic entry. To overcome these barriers, extensive efforts have been undertaken to encapsulate siRNA into lipid/polymer-based nanocarriers, but these formulations are relatively complex to create reproducibility and at clinical scale and can preferentially accumulate in clearance organs such as the liver and spleen. Liver accumulation of nanoparticles can be leveraged to block hepatocyte-driven diseases, as demonstrated by first-in-class siRNA nanomedicine patisiran. However, siRNA medicines that act on non-hepatic tissues, including tumors, remain unchartered clinically.
The focus of this dissertation work is the development of carrier-free siRNA conjugates that can achieve tumor gene silencing. Specifically, we report on the systematic optimization of siRNA conjugates for binding to serum albumin, the most abundant protein in the blood. Albumin exhibits an exceptional circulation half-life, natural cargo ferrying properties, and tumor tropism, making it a promising endogenous vehicle for delivering therapeutic cargo to cancer cells. We demonstrate the effects of stabilizing siRNAs to nucleases as well as optimization of structural features of our siRNA conjugates including linker length, lipid constraint, lipid chemistry, and linker degradability. We apply our lead siRNA construct to target oncogene Mcl-1, an antiapoptotic protein with well documented ties to chemoresistance and tumor growth. We show sustained, dose-dependent knockdown of Mcl-1 in tumor-bearing mouse models and reduction of tumor burden when used in combination with EGFR inhibitor erlotinib. We additionally compare our siRNA construct to small molecule inhibition of Mcl-1 as well as commercially available in vivo transfection reagents. This dissertation provides a promising platform for development in siRNA therapeutics for oncology and in other pathologies that benefit from use of albumin as a delivery vehicle. | |
