UC San Diego

Therapeutic Nanoparticles have shown significant impact in the field of medicine, particularly in anticancer drug delivery. Prolonged circulation time, functionalization with tumor-targeting ligands, and encapsulation of multiple drug types are among the key features of nanoparticles that make them desirable anticancer drug carriers. This dissertation will focus on these three major features of therapeutic nanoparticles and provide novel improvements in these areas. The first area of research is multi-drug coencapsulation, where precise control over drug-to-drug ratio has a major impact on the particles' therapeutic efficacy. A drug-polymer conjugate system is used to overcome the intrinsic differences in the physicochemical properties of different drug molecules. By adapting metal alkoxide chemistry, we synthesize highly hydrophobic drug-poly-l-lactide (drug- PLA) conjugates, of which the polymer has the same chain length while the drug may differ. These drug-polymer conjugates are then encapsulated into lipid-coated polymeric nanoparticles through a single-step nanoprecipitation method. Using doxorubicin (DOX) and camptothecin (CPT) as two model chemotherapy drugs, various ratios of DOX-PLA and CPT-PLA conjugates are loaded into the nanoparticles with over 90% loading efficiency. The resulting nanoparticles are uniform in size, size distribution and surface charge. The loading yield of DOX and CPT in the particles can be precisely controlled by simply adjusting the DOX-PLA:CPT-PLA molar ratio. Cellular cytotoxicity results show that the dual- drug loaded nanoparticles are superior to the corresponding cocktail mixtures of single-drug loaded nanoparticles. This dual-drug delivery approach offers a solution to the long-standing challenge in ratiometric control over the loading of different types of drugs onto the same drug delivery vehicle. The second area is nanoparticle functionalization for tumor-targeted delivery. we synthesize anti-CEA half-antibody conjugated lipid-polymer hybrid nanoparticles and characterize their ligand conjugation yields, physicochemical properties, and targeting ability against pancreatic cancer cells. Under the same drug loading, the half-antibody targeted nanoparticles show enhanced cancer killing effect compared to the corresponding non-targeted nanoparticles. The half- antibody approach offers the advantage of reduced ligand size, site-specific conjugation, and easy accessibility over existing functionalization approaches. The third area of research presented herein is a novel nature-inspired approach to camouflage nanoparticles for long systemic circulation. A top-down approach in coating biodegradable polymeric nanoparticles with natural erythrocyte membranes is reported. The structure, size and surface zeta potential, and protein contents of the erythrocyte membrane-coated nanoparticles were verified using transmission electron microscopy, dynamic light scattering, and gel electrophoresis respectively. Mice injections with fluorophore-loaded nanoparticles revealed superior circulation half-life by the erythrocyte-mimicking nanoparticles as compared to control particles coated with the state-of-the-art synthetic stealth materials. Biodistribution study revealed significant particle retention in the blood 72 hours following the particle injection. The translocation of natural cellular membranes, their associated proteins and the corresponding functionalities to the surface of synthetic particles represents a novel approach in nanoparticle functionalization. The developments on these three areas are compatible with one another and could be integrated as one multifunctional nanoparticle platform. Each of these features aims to target a distinctive barrier in cancer drug delivery