86/90Y-Labeled Ultrasmall Mesoporous Silica Nanoparticles for Cancer Theranostics

468 Objectives: Theranostic nanoparticles are expected to revolutionize future disease management. Despite promising preclinical theranostic outcomes, engineered nanomaterials still face major challenges for future clinical translation due to limitations such as high (>30 %ID/g) and long-term (>months) accumulation in the reticuloendothelial system (RES), lack of highly specific disease (such as tumor) targeting capability and lack of agents that can enable accurate tracking and therapy. Herein, we report novel ultrasmall mesoporous silica nanoparticles (USMSN) with enhanced in vivo accumulation in the tumor, as well as rapid clearance from the RES organs via the hepatobiliary route. USMSN were conjugated with the theranostic isotope pair 90/86Y for simultaneous PET imaging and radiotherapy in murine breast cancer models. Methods: USMSNs were synthesized using a facile one pot synthesis method, by carefully tuning the ratio of silica precursor and capping agent (polyethylene glycol-silane), followed by thorough characterization. USMSNs were further conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radiolabeling with two isotopes of yttrium: 86Y (t1/2: 14.7 h) used for PET imaging and 90Y (t1/2: 64 h) for therapeutic purposes. 86Y-DOTA-USMSN were injected intravenously into 4T1 tumor bearing mice, followed by serial PET imaging and ex vivo biodistribution study to investigate their in vivo pharmacokinetics. For therapeutic studies, 4T1 tumor bearing mice (n=5 per group) were divided into 4 groups: 90Y-DOTA-USMSN (140 µCi), 90Y-DOTA (140 µCi), USMSN only and PBS only. Tumor growth and mouse body weight were monitored every other day. Cerenkov luminescence imaging (CLI) was also performed every other day on the mice injected with 90Y-DOTA-USMSN and 90Y-DOTA to monitor tumor uptake of the 90Y-labeled agents. Blood and histological analyses were performed at 0, 7, and 15 days post-injection, to evaluate treatment efficacy and safety. Results: Highly uniform, cubical mesoporous USMSN of ~ 9.89 ± 1.27 nm , with a high specific surface area of ~ 156.2 m2/g were successfully synthesized. 86Y-DOTA-USMSN showed prolonged blood circulation with significant signal from the blood pool at up to 24 h post-injection (p.i.) (from 29.4 ± 4.2 at 0.5h p.i to 10.2 ± 0.9 %ID/g at 24h p.i.). A rapid and prominent accumulation in the 4T1 tumor was observed which peaked at 24h p.i. (4.6 ± 0.8, 5.1 ± 0.4, 7.4 ± 1.1, 9.2 ± 1.6, 12.7 ± 0.9 and 10.4 ± 0.6 %ID/g at 0.5, 2, 6, 12, 24 and 48h p.i. respectively). 90Y-DOTA-USMSN treatment demonstrated significant reduction in tumor volume (relative tumor volumes of 0.78 ± 0.19, 0.74 ± 0.21, 0.77 ± 0.18, 0.85 ± 1.41, 0.85 ± 0.50 and 0.91 ± 0.24 at days 1, 3, 5, 7, 9 and 11 p.i) compared to 90Y-DOTA (relative tumor volumes from 1.19 ± 0.21 at day 1 p.i to 2.74 ± 0.42 at day 11 p.i). These results were further confirmed by CLI which demonstrated persistent but temporally shrinking uptake of 90Y-DOTA-USMSN in the 4T1 tumors. Conclusions: We have successfully demonstrated the first example of cancer theranostics in a preclinical model with 86/90Y-DOTA-USMSN. In vivo PET imaging demonstrated prolonged blood circulation and excellent tumor contrast with 86Y-DOTA-USMSN. CLI confirmed persistent retention of 90Y-DOTA-USMSN in the tumor and a significant inhibition of tumor growth, altogether indicating promising potential of USMSNs in future clinical cancer theranostics.