UC San Diego

Silica micro and nanomaterials have been widely used in the biomedical field due to its chemical stability and flexibility, biocompatibility and ease of functionalization. Herein, silica micro and nanoshells were synthesized as a multifunctional theranostic tool in cancer imaging and therapy. Templated sol-gel method was employed to synthesize monodispersed silica hollow shells with thickness tunable by modulating the composition of silica precursors and organically modified alkoxysilanes. When ultrathin silica shells were filled with perfluorocarbon, a decreased acoustic threshold was observed when compared to silica shells synthesized with pure tetramethyl orthosilicate as a precursor. Furthermore, an increased ultrasound signal lifetime was achieved when compared to commercial microbubble based ultrasound contrast agents. Ultrathin silica shells with liquid perfluoropentane filled core were shown to exhibit a bimodal acoustic excitation profile where low acoustic power resulted in bubble oscillation and high acoustic power promoted bubble cavitation. Liquid filled ultrathin silica shells were chemically and physically stable, acting as a long-term ultrasound tumor marking agent when intravenously injected into mice that were subcutaneously grafted with tumor. When intratumorally injected into tumor, liquid filled silica shells act as effect acoustic enhancer for high intensity focused ultrasound ablation. The presence of silica stabilized liquid perfluorocarbon resulted in generation of ultrasound signal in the form of cavitation clouds and decreased ultrasound intensity to generate mechanical ablation of tumor tissue and promote release of tumor neo-antigens. With concomitant administration of checkpoint blockade immunotherapy, three quarters of mice grafted with glioblastoma were induced into remission along with acquired immunity. These mice were characterized by increased tumor-infiltrating lymphocytes and T-cell activation. Silica hollow particles have been demonstrated as a flexible theranostic platform that can be used with ultrasound imaging and tumor ablation. When combined with current immunotherapies, silica hollow particles provide a myriad of opportunities to enhance efficacy without increasing potential drug burden.