Development and Applications of a Cisplatin-containing Hydrogel Nanoparticle

The interdependence of size, shape, deformability, and surface chemistry of micro- and nanoparticles is of interest to many research communities. Oncologists, pharmaceutical scientists, and toxicologists are examples of the wide community of professionals who would benefit from establishing optimal particle properties for the treatment of tumors. Cisplatin is a cytotoxic drug used as a first-line therapy for a wide variety of cancers. However, significant renal and neurological toxicities limits it clinical use. It has been documented that drug toxicities can be mitigated through nanoparticle formulation, while simultaneously increasing tumor accumulation through the enhanced permeation and retention effect. Circulation persistence is a key tenet for exploiting this effect, and there is general consensus in the literature for particle characteristics -- such as charge, stealthing, and size - that will yield long circulating particles. Utilizing Particle Replication in Non-wetting Templates (PRINT), monodisperse shape specific particles with highly tunable physical characteristics can be fabricated. The capacity of PRINT to independently and systematically vary parameters is a crucial advantage in elucidating their role on particle behavior in a biological setting. By holding all parameters for long circulation constant, a series of filamentous particles (80 nm x 180 nm, 80 nm x 320 nm, 80 nm x 5000 nm) was made to evaluate the effect of shape on circulation. The optimal particle was then selected for drug loading and delivery studies using cisplatin as a model therapeutic. Scale-up and optimization of the PRINT process using roll-to-roll technology allowed for fabrication of the large quantities of particles needed for pre-clinical studies.;Grafting of polyethylene glycol to the surface of a nanoparticle (PEGylation) is a common tactic used to minimize opsonization and macrophage uptake, consequently improving circulation parameters. Development of a tunable surface PEGylation density on 80 nm x 320 nm PRINT hydrogels resulted in prolonged circulation times for PEG Brush and Mushroom conformations compared to a non-PEGylated surface. Another major contributor to particle circulation profiles is shape, a characteristic that has been less explored due to the inherent difficulties in control using common particle fabrication techniques. Utilizing PRINT, previously unrivaled control over shape was demonstrated through calibration-quality fabrication of various aspect ratio hydrogel particles. Observation of biological interactions---specifically macrophage association, circulation profile, and biodistribution--- with the particles revealed different trends with respect to macrophage association and circulation profile. While macrophages appear to have frustrated interaction with the filamentous 80 nm x 5000 nm particles, the worm-like geometry was ineffective at delaying in vivo clearance.;Cisplatin was complexed into the long-circulating, PEGylated, polymeric 80 nm x 320 nm hydrogels for therapeutic applications. Sustained release was demonstrated, and drug loading correlated to surface PEG density. A PEG Mushroom conformation showed the optimal compromise between pharmacokinetic (PK) parameters and drug loading. Particles displayed comparable cytotoxicity to cisplatin in several cancer cell lines and had a higher maximum tolerated dose in mice. Additionally, the PK profiles of drug in plasma, tumor, and kidney indicate improved exposure in the blood and tumor accumulation for the particulate form, with concurrent renal protection. A comparison of PK in healthy versus tumored mice revealed a tumor-induced modulation of particle behavior. A shift in cell population behavior was responsible for a rapid clearance of particles from circulation and an increased rate of accumulation in the liver and spleen. Upon further investigation by flow cytommetry, macrophages in the lung, spleen, and liver were polarized toward an M2-like phenotype by the presence of a tumor. Furthermore, these M2-like polarized macrophages were more proficient in particle recognition compared to an M1 phenotype. Overall, this work paves the way for future applications in cancer chemotherapy and immunotherapy.