UC San Diego

Advancements in nanomedicines have enabled breakthroughs in both disease diagnosis and treatment, including ultrasound bioimaging and cancer immunotherapy. On the one hand, nanomedicines of various formulations have been used as ultrasound contrast and greatly improved the ultrasound imaging quality. However, an ideal ultrasound contrast agent— that has tunable, modifiable surface, biodegradability, biocompatibility, and sufficient stability (half-life) for transient ultrasound imaging— is yet to be explored. On the other hand, to overcome the limitations of immune checkpoint blockage therapy,— immune-related toxicity and inefficacy in immune-suppressive tumors— nanomedicines have been rationally designed to trigger immunogenic cell death (ICD) of tumor cells. However, further work is necessary to develop ICD-inducing nanomedicines that are biodegradable, biocompatible, and intrinsically potent in inducing ICD. In this dissertation, I will discuss how creating novel nanomedicines can benefit both ultrasound imaging and cancer immunotherapy.First chapter reviews applications of nanomedicines in both ultrasound imaging and ICD-based cancer immunotherapy, with a highlight of successes and limitations of existing nanomedicines. Second chapter describes how sol-gel reaction combined with electrospray can generate biodegradable calcium phosphate micro/nano particles. Effects of synthetic parameters on the particle size and morphology are discussed in detail. The biodegradability of these particles was validated. Third chapter illustrates a bio-inspired, facile, mild, and solution-based synthetic method for creating calcium phosphate micro/nano particles. Systematic investigations on synthetic parameters led to calcium phosphate particles with versatile sizes (396±128 nm to 63±8 µm) and morphologies (hexagonal micro-disc, micro-flower, micro-leaf, nano-butterfly, and nano-ribbon). A “phosphate sponge” mechanism was found to be the key for regulating the particle sizes and morphologies. These calcium phosphate micro/nano particles are proven to be biodegradable, non-toxic, and efficient in creating transient ultrasound contrast. Fourth chapter studies the building of proton sponge nano-assembly (PSNA) optimized for imaging and triggering ICD of cancer cells. By carefully tuning the hydrophilic and hydrophobic components, the self-assembly tendency of PSNA was optimized. In turn, the PSNA with the highest fluorescence, positive surface charge density, intracellular fluorescence, and cancer cell cytotoxicity was achieved. The lysosome rupturing-regulated pyroptosis and necroptosis were triggered by PSNA, suggesting the great potential of the PSNA for anticancer immunity.