| dc.description.abstract | Triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) are two of the most lethal and therapeutically challenging solid tumors. TNBC is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and Human epidermal growth factor receptor 2 (HER2) protein. This lack of common therapeutic targets makes it difficult to treat using conventional breast cancer therapies. TNBC is one subtype of breast cancer, accounting for approximately 15–20% of cases, and is associated with high recurrence rates and limited treatment options. Similarly, PDAC, the most common form of pancreatic cancer, remains one of the deadliest malignancies, with a five-year survival rate below 10%. Due to its aggressive nature, immune-suppressive tumor microenvironment, and poor response to standard chemotherapy, there is an urgent need to develop innovative therapeutic strategies for PDAC. Although TNBC and PDAC are distinct cancer types, they share several therapeutic barriers, including resistance to conventional therapies, a lack of actionable molecular targets, and an immunologically “cold” tumor microenvironment. These shared challenges highlight the need for therapeutic strategies that enhance drug delivery, remodel the tumor immune environment, and improve treatment response.
This dissertation applies nanoparticle (NP) engineering to address these clinical challenges by developing delivery platforms specifically designed for the unique limitations of two anticancer agents. The first project focuses on advancing copper diethyldithiocarbamate (Cu(DDC)2), a potent anticancer complex formed when the disulfiram metabolite diethyldithiocarbamate (DDC) chelates copper. Although Cu(DDC)2 exhibits vigorous cytotoxic activity against TNBC, systemic instability and inadequate formation limit its therapeutic application. To overcome these barriers, a library of amphiphilic PEG-lysine dendrimers was synthesized and screened to generate a stable, water-dispersible nanoparticle formulation. The optimized Cu(DDC)2 NPs exhibited high encapsulation efficiency, enhanced serum stability, and demonstrated significant antitumor activity in TNBC models. Mechanistic studies demonstrated robust induction of ER stress and hallmark signals of immunogenic cell death (ICD), including calreticulin exposure, ATP release, and HMGB1 secretion, leading to dendritic cell activation. These findings support the potential of Cu(DDC)2 NPs to convert poorly immunogenic TNBC into a more immune-responsive phenotype, offering translational promise for combination with immunotherapies.
The second project addresses the delivery limitations of ADT-007. This potent pan-RAS inhibitor binds the nucleotide-free state of RAS and suppresses downstream signaling in RAS-driven cancers such as PDAC. Despite its efficacy, ADT-007 is poorly water-soluble and rapidly metabolized by UDP-glucuronosyltransferases, restricting its systemic administration. To enable intravenous (IV) delivery and bypass first-pass metabolism, mixed-micelle NP formulations were developed and optimized for stability, encapsulation efficiency, and dispersion under physiological conditions. The resulting formulation, ADT-007 NP-2, retained cytotoxic potency in RAS-mutant pancreatic cancer cell lines and supported reproducible pharmacokinetic assessment in vivo without the need for harsh organic solvents.
Together, these studies demonstrate how NP design can overcome key pharmacological and biological limitations of anticancer agents, thereby improving the therapeutic potential in difficult-to-treat cancers. This work establishes NP-enabled strategies for stabilizing metal-organic complexes, enhancing immunogenic cell death, and enabling systemic administration of novel small-molecule inhibitors, offering translational pathways for future therapeutic development in TNBC and PDAC. | en_US |
