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Development of Silica Hollow Shells for Ultrasound Imaging and Cancer Immunotherapy

  • Author(s): Huang, Ching-Hsin
  • Advisor(s): Kummel, Andrew
  • et al.

Silica hollow shells have been developed as a convenient drug carrier and ultrasound imaging contrast agent because of their ease of modification and long imaging time. However, as an imaging contrast agent, hard silica shells possess the disadvantages of requiring a relatively high ultrasound insonation power for imaging and low biodegradability due to their structural and chemical stabilities. In order to ameliorate these disadvantages, non-spherical ultrathin silica microshells (with a diameter of 2 μm) doped with iron (III) were synthesized that can be imaged at low insonation power similar to commercial soft microbubble contrast agents and lasted for days. The amount of iron doping provides control over the silica shell thickness and structural morphology, which resulted in a 83% lower insonation power threshold compared to thick counterpart, as well as enhanced biodegradability. Besides using silica microshells to enhance the imaging contrast, nano-sized pure silica shells (NS, with a diameter of 100 nm) was engineered with a small molecule toll-like receptor 7 (TLR7) agonist, 1V209, to enhance the adjuvant activities in vitro and in vivo. TLR agonist (TLR7a) and silica NS combination triggered high level of IL-1β release while neither unconjugated TLR7a nor silica shells produced IL-1β. An immunization study demonstrated that silica nanoshell-conjugated TLR7a (NS-TLR7a) increased OVA-specific IgG antibodies a thousand-fold in mice sera and skewed response to a Th1-mediated immunity compared to unconjugated TLR7a. NS-TLR7a were administered intratumorally into mice and silica shells have a tendency to prolong the agonist accumulation time, leading to an increase of the T cell infiltration. When NS-TLR7a was used in combination with checkpoint inhibitors, a higher number of infiltrating lymphocytes were induced and the survival rate was improved compared to checkpoint inhibitors only. In a two-tumor bearing mouse model, the combination therapy (NS-TLR7a+checkpoint inhibitors) showed that not only can the injected tumor be induced into remission, but an uninjected contralateral tumor can also be induced into remission (abscopal effect). The results demonstrated that the NS-TLR7a+checkpoint inhibitors therapy is able to produce a systemic and tumor-specific immune response.

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