(M1130-11-75) Radiation-Induced Tumor Penetration of Mesoporous Silica Nanoparticles for Enhanced Treatment of Ovarian Cancer Peritoneal Metastasis

Purpose: Nanomedicines have been approved by the FDA for clinical applications, the limited penetration of therapeutic agents in tumor tissues remains a significant barrier to their effectiveness. To overcome this issue, we developed a radiotherapeutic nanoparticle-based system using mesoporous silica nanoparticles (MSNs) to deliver Holmium-166 (¹⁶⁶Ho) for the treatment of solid tumors. The goals of the research were to investigate radiation-enhanced penetration, estimate absorbed doses, determine a dosing regimen for tumor suppression of MSNs, and their ability to increase mouse life span.

Methods: ¹⁶⁵Ho was loaded into MSNs by mixing the suspension for 24 hours at room temperature (RT). Nanoparticle Tracking Analysis (NTA) and Transmission Electron Microscopy (TEM) were used to investigate particle size and morphology. Energy Dispersive X-ray Spectroscopy (EDX) was performed to confirm holmium loading and to understand the elemental mapping of ¹⁶⁵Ho on the nanoparticle. ¹⁶⁵Ho-MSNs were neutron activated to their radioactive form ¹⁶⁶Ho-MSNs. Peritoneal metastatic ovarian cancer model induced in female nude mice was used for in vivo studies. Two groups of mice injected with mixture of ¹⁶⁵Ho-MSN/MSN- Cy5.5 and ¹⁶⁶Ho-MSN/MSN-Cy5.5, respectively were euthanized, and their tumor tissues were taken out after 1 week of administration. The cryosectioned tumor tissues were then evaluated by confocal microscopy for comparison of nanoparticle tumor penetration. Absorbed doses for each tissue was calculated and compared using MIRDcalc. Dose response and tolerability studies were performed to determine the desired dosing regimen. Optimized dose was used to conduct in vivo efficacy and toxicity of ¹⁶⁶Ho-MSN and intraperitoneally administered cisplatin.

Results: Our results showed that the IP delivery of radioactive ¹⁶⁶Ho-MSN can effectively promote the penetration of the radioactive nanoparticles deep into the peritoneal tumors (Figure 1). It was observed that 24h post administration of radioactive ¹⁶⁶Ho-MSN, around 63% of ¹⁶⁵Ho-MSNs were found within the first 200 µm from the tumor edge and a small population of 28% was found as deep as 400 µm, while non-radioactive ¹⁶⁵Ho-MSN could only migrate 30-50 µm. These numbers changed, as after 7 days of treatment of ¹⁶⁶Ho-MSN, the particle population within the first 200 µm shrunk to 56% with another 28% of the total population moving to 600 µm deep. This shift from 200 µm highlights enhanced penetration of MSNs. Highest radiation doses were absorbed by the tumors standing as a proof that our nanoparticle system displays high tumor tissue specificity. The enhanced penetration leads to uniform radiation distribution within the tumors, coupled with selective tumor accumulation and limited off-target radiation exposure. The potential radiation dosing regimen consisting of two 100 µCi ¹⁶⁶Ho-MSN doses separated by 6 days decreased tumor activity and increased the overall lifespan of IP tumor-bearing mice. We also determined the potential synergistic effects of combining ¹⁶⁶Ho-MSNs with intraperitoneal cisplatin-based chemotherapy to reduce high rates of recurrence. Compared to IP cisplatin alone, ¹⁶⁶Ho-MSNs were able to significantly improve the median survival of the mice by 27 days and the combination of both treatments improved median survival by 31 days.

Conclusion: The development of this novel internal radiation therapy system has the potential to improve treatment efficacy while reducing toxicities for patients with late-stage ovarian cancer that has metastasized to the peritoneal cavity.

Acknowledgements: Research reported in this abstract was supported by the National Cancer Institute of the National Institutes of Health under Award Number R44CA239989. Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Figure 1. Confocal images of tumor slices from mice treated with radioactive 166Ho-MSN and non-radioactive 165Ho-MSN.