ORCID ID
Graduation Date
Summer 8-14-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Pharmaceutical Sciences
First Advisor
Dr. Ram I. Mahato
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies because oncogenic KRAS signaling, dense desmoplasia, metabolic plasticity, and poor intratumoral drug delivery collectively sustain therapeutic resistance. This dissertation developed three mechanistically linked combination nanomedicine strategies that address both delivery failure and tumor-intrinsic escape mechanisms. Rather than representing independent approaches, Chapters 2–4 progressively target chemotherapy tolerance, oncogenic and adaptive signaling, and metabolic plasticity. Each chapter applies the same design principle, coordinating tumor exposure with suppression of a defined resistance mechanism using a carrier architecture matched to the physicochemical and intracellular-delivery requirements of its payloads. Chapter 1 defines the biological and biophysical basis of PDAC resistance, emphasizing stromal architecture, hypoxia, immune exclusion, and adaptive signaling as interconnected barriers to effective therapy. Chapter 2 introduces a MUC1-targeted liposomal platform co-delivering a redox-sensitive lipid-gemcitabine (L-GEM) conjugate and dordaviprone (ONC201). This formulation improved cellular uptake and tumor drug accumulation, enhanced apoptosis, reduced proliferation and metastatic markers, and suppressed AKT/ERK-associated resistance in orthotopic PDAC models. Chapter 3 advances this strategy to genotype-directed therapy using MUC4-targeted polymeric nanoparticles co-loaded with the KRAS G12D inhibitor MRTX1133 and the dual PI3K/BRD4 inhibitor MDP5. Coordinated inhibition of KRAS G12D and compensatory signaling reduced proliferation, migration, stem-like populations, immune-evasion markers, and stromal activation, while increasing cytotoxic immune features and producing marked tumor suppression without detectable systemic toxicity. Chapter 4 establishes a next-generation metabolic-resensitization approach combining L-GEM with siRNA-mediated PFKFB3 silencing. Preliminary studies showed strong PFKFB3 knockdown, cooperative cytotoxicity, reduced spheroid viability, clonogenic recovery, migration, glycolytic output, and adaptive signaling under normoxic and hypoxic conditions. MCIL-1-based lipid nanoparticles formed compact siRNA carriers, and MDC2-containing formulations increased early pancreas/tumor-associated accumulation, supporting further co-delivery optimization. Collectively, this work demonstrates that PDAC therapy can be strengthened by integrating tumor-targeted delivery with simultaneous suppression of chemoresistance, KRAS-driven signaling, adaptive survival pathways, and metabolic plasticity. These studies establish a modular, resistance-aware nanomedicine framework for improving the precision, durability, and translational potential of combination therapy in pancreatic cancer.
Rights
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Recommended Citation
Ghanwatkar, Yashwardhan, "Targeted Combination Nanomedicine to Overcome Oncogenic, Metabolic, and Microenvironmental Resistance in Pancreatic Ductal Adenocarcinoma" (2026). Theses & Dissertations. 1099.
https://digitalcommons.unmc.edu/etd/1099