Advancing polymeric nanotechnology for functional improvements: from particles to purpose

Nanomedicine has emerged as a powerful paradigm in modern healthcare, enabling targeted drug delivery, advanced diagnostic imaging, and the development of multifunctional and personalized therapeutic strategies. Despite substantial academic progress, however, clinical translation remains limited, largely due to challenges in reproducibility, long-term stability, scalable manufacturing, and safety validation. Addressing these barriers is essential to enable the reliable clinical implementation of nanoscale systems.

This thesis focuses on polymeric nanoparticles (NPs), with particular emphasis on poly(lactic-co-glycolic acid) (PLGA), a biodegradable and biocompatible polymer with established regulatory acceptance. The overarching aim was to advance PLGA-based nanoplatforms toward multifunctional imaging, active targeting, and gene delivery within a translational framework. Perfluorocarbon (PFC)-loaded PLGA NPs were employed as a central model system, serving both as quantitative probes for fluorine-19 magnetic resonance imaging (19F MRI) and as a sensitive platform for evaluating formulation stability and process-dependent variability.

Perfluoro-15-crown-5-ether (PFCE)-loaded PLGA NPs were shown to exhibit exceptional long-term colloidal stability, maintaining particle size, morphology, polydispersity, and encapsulation efficiency over storage periods exceeding six years. This finding addresses a major translational bottleneck in nanomedicine, where instability frequently limits clinical progress. Building on this robust formulation, multifunctional imaging capabilities were introduced through co-encapsulation of gadolinium chelates, yielding dual-mode proton/19F MRI nanoprobes. The results demonstrate that magnetic relaxation enhancement is strongly governed by nanoparticle ultrastructure, highlighting how internal nanoscale organization directly shapes imaging performance.

Building on this structure-function relationship, the work enabled the development of pH-responsive MRI probes. The system displayed a reversible “on–off” 19F signal, with suppression at physiological pH and recovery under acidic conditions characteristic of tumor microenvironments and intracellular lysosomes, establishing a strategy for activatable 19F MRI based on architectural responsiveness. In parallel, bio-orthogonal click-chemistry approaches were developed to enable PD-L1-targeted surface functionalization while preserving formulation integrity.

Beyond imaging, the thesis extends PLGA NP technology to gene delivery within a collaborative effort aimed at non-viral therapies for hereditary anemias. Finally, reproducibility was systematically investigated for PLGA-PFCE NPs by assessing the impact of subtle variations in materials, handling, and equipment. The findings highlight that consistent nanoparticle performance requires standardized workflows, transparent reporting, and rigorous operator training.

Overall, this work demonstrates how robust and reproducible PLGA-based nanoplatforms can integrate imaging and therapy, contributing practical strategies toward more reliable and translatable nanomedicine.