Graduation Date

Fall 12-19-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupicky

Abstract

Effective targeted drug delivery is a critical unmet need in the management of both ulcerative colitis and metastatic colorectal cancer, where conventional systemic therapies may be hindered by suboptimal efficacy and significant side effects. This thesis explores the development and preclinical assessment of polymeric chloroquine (PCQ)-based nanotherapeutics, leveraging stimuli-responsive designs for disease-specific delivery and action.

For ulcerative colitis, a reactive oxygen species (ROS)-responsive nanogel system was engineered to release PCQ, a macromolecular derivative of hydroxychloroquine, specifically in the inflamed areas within the colon. Nanogels with well-defined size and positive surface charge were synthesized via reversible fragmentation chain transfer (RAFT) polymerization using a thioketal dimethacrylate crosslinker. The nanogels demonstrated ROS-triggered disintegration, stability in gastrointestinal environments, and preferential accumulation in inflamed colon. In a Citrobacter rodentium (C.rodentium)-induced murine model of colitis, the PCQ nanogels conferred superior local therapeutic effects, including restoration of epithelial integrity, reduction in immune cell infiltration, and modulation of inflammatory signaling, while minimizing systemic toxicity compared to free hydroxychloroquine. Evaluation of nanogel variants further revealed that optimizing particle size and surface charge can fine-tune the balance between local and systemic immunomodulatory responses, underscoring the need for careful formulation design in targeted colitis therapy.

In parallel, this work addresses the challenge of peritoneal metastasis in colorectal cancer, a clinical scenario marked by poor prognosis and limited treatment options. A reduction-responsive PCQ-gemcitabine (PCQ-SS-GEM) conjugate was developed, employing disulfide linkages to achieve glutathione-triggered, tumor-selective release of gemcitabine. In an aggressive CT26-Luc murine peritoneal metastasis model, PCQ-SS-GEM displayed approximately 40-fold enhanced in vitro cytotoxicity versus 5-fluorouracil and achieved near-complete suppression of peritoneal tumor growth and ascites accumulation in vivo. Notably, animals treated with PCQ-SS-GEM exhibited a near absence of peritoneal metastases on histopathological evaluation, far outperforming reference chemotherapy and vehicle controls. These results highlight the advantages of stimulus-responsive polymeric carriers for maximizing efficacy and minimizing systemic adverse effects in cancer therapy.

Collectively, this body of work establishes PCQ-based, stimuli-responsive nanotherapeutics as versatile platforms for disease-targeted treatment in both ulcerative colitis and metastatic colorectal cancer. The findings support further development and translational studies of these next-generation, controlled-release polymeric drug systems, with the ultimate goal of improving local disease control and clinical outcomes in patients suffering from inflammatory and metastatic disease of the colon.

Comments

2025 Copyright, the authors

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