Paper BI+AS-MoA9
Targeted Ultrathin Silica Nanoshells as HIFU Sensitizing Agents for In Vivo LnCAP Prostate Tumor Removal

Monday, October 19, 2015, 5:00 pm, Room 211D

Diagnostic ultrasound (US) is a prevalent medical imaging modality due to its low-cost, high resolution, and therapeutic capability when coupled with high intensity focused ultrasound (HIFU) systems. 500 nm rigid silica ultrathin nanoshells were synthesized as a chemically stable US tumor marking contrast agent with continuous in vivo US imaging lifetime. Iron (III) was included into the silica shell network to promote biodegradability from serum transferrin proteins. It was shown previously that the removal of iron from the silica shell network via transferrin fragments the nanoshells for effective biodegradation. Folate was conjugated to the surface of the silica nanoshells via the 3-aminopropyltriethoxysilane (APTES) linker. Folate has been shown in the literature to bind to prostate specific membrane antigen (PSMA) with a high binding affinity due to folate hydrolase activity. Conjugating the silica nanoshell surface with folate targets the ultrathin silica nanoshells towards the LnCAP tumor where PSMA is significantly up-regulated. The surface modified ultrathin silica nanoshells were filled with liquid perfluorocarbon (PFC) which underwent acoustic droplet vaporization (ADV) during US insonation. The phase transition of PFC from liquid to vapor generated a large amount of PFC microbubbles that created contrast during US imaging. In vitro experiments with US have demonstrated that the ultrathin silica nanoshells can be imaged for at least 3 hours under color Doppler imaging, exhibiting a continuous US imaging lifetime. In vivo experiments have shown that folate conjugated silica nanoshells were able to accumulate and persist within the tumor region for up to 12 days post-injection, observable with US imaging. Surface conjugation with polyethylene glycol (PEG) increased the ultrasound signal at the tumor by increasing the particles accumulating at the tumor site. When exposed to high intensity focused ultrasound (HIFU), the particles were able to enhance the HIFU power and liquefy tumor tissue. With particles present, the HIFU duty cycle can be lowered to 2 %, minimizing tissue thermal deposition. By synthesizing ultrathin silica nanoshells with a folate-conjugated surface, it is has been demonstrated that folate-conjugated ultrathin rigid silica nanoshells can accumulate in the LnCAP tumor persistently for 12 days. PEGylation of the particles further increase the particle accumulation concentration in the tumor, acting as a HIFU sensitizing agent for ultrasound histotripsy. Through intelligent surface modification, liquid PFC filled silica particles can act as a multi-functional theranostic agent for ultrasound diagnosis.