POLYESTER-PAMAM “JANUS-TYPE” LINEAR-DENDRITIC BLOCKOPOLYMERS (LDBCS) AS NEXT GENERATION BIOMATERIALS
Date of Award
Ph.D. in Chemistry
Chemistry and Biochemistry
Davita L. Watkins
James V. Cizdziel
Nanomedicine is defined as the application of knowledge and tools of nanotechnology for disease treatment, diagnosis, monitoring, delivery, and sensing. Rapid advances in polymer chemistry and nanotechnology have led to an extensive development of polymeric-based therapeutic systems for nanomedical applications. Compared to traditional molecular-based therapies, polymers facilitate a higher level of versatility and functionality, such as simultaneous imaging and delivery. In particular, amphiphilic diblock copolymers and their self-assemblies have shown apparent success in nanomedicine owing to their ability to provide narrow molar mass distributions and highly ordered nanoscale multimolecular aggregates, including micelles and vesicles. However, engineering these polymeric materials to form nanoaggregates with the desired size and morphology remains a challenge. Furthermore, conventional diblock copolymeric nanoaggregates fail to provide expected in-vivo efficacy due to the insufficient mechanical stability and adverse interactions with bloodstream components. Herein is presented a novel approach taken to produce next-generation biomaterials polyesters (polylactides (PLA) and polycaprolactones (PCL)) and polyamidoamine (PAMAM). Rather than using conventional block copolymeric architectures, a linear dendritic architecture was developed. A feasible and robust synthetic strategy was used to synthesize a library of amphiphilic linear dendritic block copolymers (LDBCs) with well-controlled hydrophobic to hydrophilic weight ratios. Systems with hydrophobic weight ratios higher than 70% formed nanoparticles in aqueous media exhibiting morphologies, hydrodynamic diameters, and surface properties suitable for enhanced permeability retention effect (EPR) mediated therapeutic delivery. Aiming to apply these materials towards theranostics, hydrophobic imaging and photothermal agents were successfully loaded and trafficked into the endosomal and lysosomal compartments of human embryonic kidney (HEK) cells and Schneider 2 (S2) cells without inducing significant cell death. Photothermally induced cell death was observed, confirming the potential of these LDBCs as promising candidates in nanomedicine. To enhance the stability and hydrophobic loading, the hydrophobic core-forming polymer chains of the nanoparticle were crosslinked. Core-crosslinked LDBC nanoparticles demonstrated increased stability and hydrophobic loading efficiencies relative to the non-crosslinked systems. Such insights provide a pathway toward nanomaterials with enhanced stability, unique morphologies, and tunable properties deemed relevant in developing next-generation biomaterials.
Chandrasiri, Indika, "POLYESTER-PAMAM “JANUS-TYPE” LINEAR-DENDRITIC BLOCKOPOLYMERS (LDBCS) AS NEXT GENERATION BIOMATERIALS" (2021). Electronic Theses and Dissertations. 1991.