(T0930-03-19) Mesoporous Silica Nanoparticles-Based Radionuclide Therapy Demonstrates Immunomodulatory Effects and Enhanced Treatment Outcome in Peritoneal Cancer Model

Purpose: Peritoneal metastasis is common in patients with ovarian, gastric, pancreatic and colon cancers, yet face delivery challenges due to limited tumor blood supply. We have demonstrated the therapeutic efficacy of intraperitoneally delivered radionuclide-loaded Mesoporous Silica Nanoparticles (¹⁶⁶Ho-MSNs) in peritoneal metastases.¹ While the direct cytotoxic effects of ionizing radiation are well-established, emerging evidence suggests radiation can elicit immunomodulatory responses through multiple mechanisms, including enhanced tumor-associated antigen release, upregulation of proinflammatory cytokines, increased T cell priming and activation. Thus, we aim to investigate the immunomodulatory properties of ¹⁶⁶Ho-MSNs, and the subsequent treatment outcomes.

Methods: The therapeutic efficacy of radionuclide ¹⁶⁶Ho-MSNs was evaluated in immunocompetent peritoneal cancer model. Luciferase over expressed CT26 murine colon cancer cells were intraperitoneally injected into female Balb/c mice. Seven days post-tumor implantation, mice received i.p. administration of either ¹⁶⁶Ho-MSNs (100 µCi), non-radioactive ¹⁶⁵Ho-MSNs, or saline. After 7 days of initial treatment, mice were rechallenged subcutaneously with CT26 cells. Disease progression was monitored through bioluminescence using IVIS Spectrum CT. The immunomodulatory effects were further investigated using CT26 3D cancer spheroids incubated with Raw264.7 murine macrophages, examining macrophage infiltration patterns, phenotypic changes and cytokine profiling.

Results: ¹⁶⁶Ho-MSNs treated mice displayed superior survival with low burden of ascites compared to the saline and ¹⁶⁵Ho-MSN without radioactivity groups. Notably, mice treated with ¹⁶⁶Ho-MSNs exhibited marked inhibition of subcutaneously reimplanted tumors in 9 out of 10 mice, suggesting activation of systemic anti-tumor immunity. In the 3D cancer spheroid model, exposing to ¹⁶⁶Ho-MSNs (50µCi at 4mm distance) increased the cell kill to approximately 20% after 24-hours. Furthermore, the irradiated spheroids demonstrated significantly enhanced macrophage infiltration and maturation compared to the non-irradiated controls. Moreover, the pro-inflammatory cytokines (TNF-α and IL-6) were enhanced in ¹⁶⁶Ho-MSNs treated spheroids suggesting the potential immune response.

Conclusion: This study demonstrates that the intraperitoneal delivery of ¹⁶⁶Ho-MSNs resulted in effective local radiotherapy while simultaneously activating systemic anti-tumor immune responses, as evidenced by increased lifespan of mice, decreased ascites production, and inhibition of reimplanted subcutaneous tumors, compared to the controls. These results establish ¹⁶⁶Ho-MSNs as a promising internal radiotherapy modality combining the benefits of targeted radiation delivery with immunomodulation for improved cancer treatment outcomes.

References: 1. Hargrove D, Ranjbar S, Darji M, Nam S, Dawson RJ, Katugampola S, Lin X, Brown A, Carrasco-Rojas N, Goodwin C, Howell RW, Bolch WE, Jay M, Salner A, Lu X*. Tumor specific delivery and radiation-enhanced tumor penetration of mesoporous silica nanoparticles for effective radionuclide therapy of ovarian peritoneal metastasis. International Journal of Pharmaceutics, Volume 669, 25 January 2025, 125071.

Acknowledgements: We appreciate the financial support from the National Cancer Institute of the National Institutes of Health R41CA239989, R44CA239989, and the Research Scholar Grant RSG-15-011-01-CDD from the American Cancer Society.

In-vivo setup for the experiment.