Dissertation
ADVANCES IN TARGETED DRUG DELIVERY FOR CANCER: OVERCOMING RESISTANCE AND ENHANCING THERAPEUTIC EFFICACY
Doctor of Philosophy (PhD), Washington State University
12/2025
DOI:
https://doi.org/10.7273/000008362
Abstract
Conventional chemotherapy remains a cornerstone of cancer treatment but is hindered by poor tumor selectivity, dose-limiting toxicity, and the development of multidrug resistance. These challenges, coupled with the complexity of the tumor microenvironment, underscore the need for the development of targeted drug delivery platforms that improve therapeutic index and reduce off-target effects. This dissertation explores the design and evaluation of targeted and resistance-responsive delivery platforms through a progression of mechanistic and translational studies. The first chapter provides a comprehensive overview of current strategies in targeted drug delivery, highlighting advances in prodrug design, efflux modulation, and nanocarrier systems aimed at overcoming intrinsic and acquired resistance. Subsequent chapters present experimental work investigating efflux-mediated resistance and transporter-guided drug activation using imidazoquinoline-based immunostimulants and small-molecule prodrugs. These studies establish the mechanistic basis for exploiting efflux transporters such as P-glycoprotein to enhance immune signaling and therapeutic selectivity. Dendrimer-based drug delivery systems were designed to improve solubility, stability, and intracellular release of potent chemotherapeutics. In triple-negative breast cancer, a non-targeted dendrimer-camptothecin conjugate exhibited strong cytotoxic and apoptotic activity through controlled release and synergistic interactions with DNA damage repair inhibitors. In parallel, PSMA-targeted dendrimer conjugates for prostate cancer achieved receptor-mediated uptake, enhanced cytotoxicity, and inhibition of angiogenic and hypoxia-associated resistance mechanisms. Collectively, these studies integrate enzyme-activated and efflux-modulated prodrug design with receptor-targeted dendrimer therapeutics, establishing complementary strategies to overcome major barriers in cancer treatment. The findings demonstrate how rationally engineered delivery systems can improve solubility, selectivity, and intracellular activation while mitigating efflux-driven resistance. By combining mechanistic insight with translational relevance, this work provides a framework for developing next-generation targeted therapeutics that achieve durable and selective responses across diverse cancer models.
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Details
- Title
- ADVANCES IN TARGETED DRUG DELIVERY FOR CANCER
- Creators
- Anunay James Pulukuri
- Contributors
- Clifford E Berkman (Chair)Anjali Sharma (Committee Member)Alan G Goodman (Committee Member)Ming Xian (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Department of Chemistry
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 562
- Identifiers
- 99901356972201842
- Language
- English
- Resource Type
- Dissertation