Engineering Composite Particles Based on Synthetic Functionalized Biodegradable Materials for Cancer Diagnostics and Targeted Therapeutics

Cancer remains one of the leading causes of morbidity and mortality worldwide, and both earlier detection and durable therapeutic strategies are essential for improving patient outcomes. However, current diagnostic and therapeutic approaches face significant limitations. Multiplex immunoassays, although powerful for detecting tumor- and immune-related biomarkers, are often constrained by high per-test costs, reliance on proprietary reagents and instruments, and complex workflows that hinder widespread clinical adoption. Similarly, cytokine therapies, while uniquely positioned to reprogram the tumor–immune interface, have been limited by short systemic half-lives, poor selectivity, and dose-limiting toxicities.

This thesis addresses these challenges by developing dextran-based solutions that bridge the domains of diagnostics and immunotherapy. For diagnostics, a dextran microsphere-based multiplex immunoassay was designed to simplify fabrication and reduce reagent and consumable costs. By enabling the simultaneous quantification of multiple immune biomarkers from microliter-scale specimens, this platform improves sensitivity and specificity, reduces false positives and negatives, and provides richer information than single-analyte tests. The approach is sample-sparing, cost-efficient, and amenable to both clinical research and population-level surveillance, while also offering scalability for large-scale manufacturing.

For therapy, this work focuses on interleukin-18 (IL-18), a cytokine with strong potential to enhance Th1 polarization, natural killer (NK) cell cytotoxicity, and CD8⁺ T-cell responses. Although nanoplatforms have been widely explored for cytokine delivery, their clinical translation re-mains hampered primarily by the low encapsulation/loading efficiency of fragile protein cargos and by weak, poorly tuned enzyme-responsiveness, which together reduce spatial precision and complicate pharmacokinetic control, high-lighting the need for improved strategies. In this study, to directly address these two bottlenecks, a dextran-based, enzyme-responsive nanoparticle for IL-18 was built using azido-functionalized dextran and copper-free click chemistry to covalently display IL-18 on the particle surface, circumventing low encapsulation and enabling high, uniform loading, while a rationally selected protease-cleavable linker was incorporated directly at the particle–solvent inter-face so that disease-associated enzymes can access it im-mediately, thereby accelerating activation kinetics and achieving faster responsiveness. Poly (ethylene glycol) conjugation (PEGylation) was installed via the protease-cleavable linker to both stabilize systemic circulation and act as a reversible steric blocker of IL-18 activity. Upon enzymatic cleavage, the PEG blocker is shed to restore cytokine function, and in vitro assays have accordingly shown strong and fast protease-responsiveness. Biodistribution and pharmacokinetic studies in healthy mice further demonstrated prolonged systemic circulation with PEGylation. However, the capacity of this platform to achieve tumor-specific activation and therapeutic efficacy in vivo remains to be validated in tumor-bearing models.

Dextran serves as the unifying platform across these two research directions. Its natural biocompatibility, chemical addressability, and scalable processing enable versatile modification strategies and robust formulation methods. From stable microsphere surfaces for biomarker detection to responsive nanoparticles for cytokine delivery, dextran provides a practical chassis that supports both diagnostic innovation and therapeutic translation.

Overall, this dissertation demonstrates how dextran-based engineering can be leveraged to lower barriers in cancer diagnostics and unlock the therapeutic potential of cytokines. By integrating cost-conscious multiplex immunoas-says with tumor microenvironment (TME) -responsive cytokine delivery, the work advances complementary strategies that contribute to both earlier detection and more durable disease control, thereby addressing critical gaps in cancer management.