Presentation Information
[P04-475]Development of Metal Ion-Loaded Boronated Polysaccharide Nanogels for Enhancing BNCT-Induced Abscopal Effect
○Kansuke Ota1, Riku Kawasaki1, Yu Sanada2, Natsuko Kondo2, Minoru Suzuki2, Yoshihiro Sasaki3, Kazunari Akiyoshi3, Takeshi Nagasaki4, Keita Yamana1, Atsushi Ikeda1 (1. Grad. Sch. of Adv. Sci. and Eng., Hiroshima Univ. (Japan), 2. KURNS (Japan), 3. Grad. Sch. of Eng., Kyoto Univ. (Japan), 4. Grad. Sch. of Eng., Osaka Metropolitan Univ. (Japan))
Keywords:
BNCT,Nanogel,Metal ion
Background:
To enhance the systemic antitumor efficacy of BNCT, we aimed to co-induce ferroptosis via iron co-delivery and activate the cancer-immunity cycle through tumor-responsive delivery of immune checkpoint inhibitors (ICIs) using a boron-based nanogel system. BNCT is based on the nuclear reaction between 10B and thermal neutrons. Because the effective range of high linear energy transfer particles is confined within a single cell, BNCT is a highly selective and minimally invasive therapy. Cancer cell destruction during BNCT releases tumor antigens and damage-associated molecular patterns (DAMPs), which may induce systemic immunity. Thus, regression of distant lesions (abscopal effect) is expected, although rarely observed, requiring enhancement strategies. We focused on iron-dependent cell death, ferroptosis, which exhibits immunogenic features including antigens and DAMPs release [1]. By co-delivering iron ions with a boron agent, we aimed to achieve cooperative tumor cell killing while promoting antigen presentation. To overcome tumor immune evasion, ICIs were encapsulated into a nanoassembly-based boron agent with tumor-specific release. Boronated polysaccharide nanogels were developed and evaluated for metastatic cancer treatment.
Methods:
Fluorescent dextran was conjugated with 4-borono-L-phenylalanine (L-BPA) and deferoxamine (DFO) to synthesize BPA-DFO-Dex. The conjugate self-assembled in ultrapure water, followed by the addition of ferric chloride to form iron-loaded nanogels (Fe-NGs). ICIs were subsequently encapsulated to obtain ICI-Fe-NGs. BNCT efficacy was evaluated in vitro and in vivo using murine melanoma cells (B16F10) and a metastatic melanoma mouse model via cytotoxicity assays, confocal imaging, and tumor growth analysis.
Results:
Dynamic light scattering showed particle sizes of ~120 nm. Fe-NGs showed higher cytotoxicity than the clinically used sorbitol-BPA complex and iron-free nanogels, suggesting synergy between BNCT and ferroptosis. Confocal imaging showed increased intracellular Fe2+, lipid peroxidation (LPO), and reactive oxygen species (ROS) in both monolayer cultures and spheroids, indicating ferroptosis. In vivo, BNCT with ICI-Fe-NGs significantly suppressed tumor growth at both primary and distant non-irradiated sites.
Discussion:
Fe-NGs suggest ferroptosis enhances BNCT efficacy. ICI-Fe-NGs indicate that EPR-mediated accumulation, LAT1-dependent uptake, and ICI-mediated maintenance of a pro-inflammatory tumor microenvironment improve therapeutic outcomes. Suppression of distant tumors implies systemic immune activation.
Conclusion:
These findings suggest that immunogenic cell death induced by BNCT and ferroptosis activates the systemic cancer-immunity cycle, leading to the abscopal effect and regression of distant tumors. Furthermore, LAT1-dependent uptake and ICI-mediated immune activation may further enhance antitumor responses.
Reference:
[1] L. Galluzzi et al., Cancer Cell, 2026, 44(2), 281-305.
To enhance the systemic antitumor efficacy of BNCT, we aimed to co-induce ferroptosis via iron co-delivery and activate the cancer-immunity cycle through tumor-responsive delivery of immune checkpoint inhibitors (ICIs) using a boron-based nanogel system. BNCT is based on the nuclear reaction between 10B and thermal neutrons. Because the effective range of high linear energy transfer particles is confined within a single cell, BNCT is a highly selective and minimally invasive therapy. Cancer cell destruction during BNCT releases tumor antigens and damage-associated molecular patterns (DAMPs), which may induce systemic immunity. Thus, regression of distant lesions (abscopal effect) is expected, although rarely observed, requiring enhancement strategies. We focused on iron-dependent cell death, ferroptosis, which exhibits immunogenic features including antigens and DAMPs release [1]. By co-delivering iron ions with a boron agent, we aimed to achieve cooperative tumor cell killing while promoting antigen presentation. To overcome tumor immune evasion, ICIs were encapsulated into a nanoassembly-based boron agent with tumor-specific release. Boronated polysaccharide nanogels were developed and evaluated for metastatic cancer treatment.
Methods:
Fluorescent dextran was conjugated with 4-borono-L-phenylalanine (L-BPA) and deferoxamine (DFO) to synthesize BPA-DFO-Dex. The conjugate self-assembled in ultrapure water, followed by the addition of ferric chloride to form iron-loaded nanogels (Fe-NGs). ICIs were subsequently encapsulated to obtain ICI-Fe-NGs. BNCT efficacy was evaluated in vitro and in vivo using murine melanoma cells (B16F10) and a metastatic melanoma mouse model via cytotoxicity assays, confocal imaging, and tumor growth analysis.
Results:
Dynamic light scattering showed particle sizes of ~120 nm. Fe-NGs showed higher cytotoxicity than the clinically used sorbitol-BPA complex and iron-free nanogels, suggesting synergy between BNCT and ferroptosis. Confocal imaging showed increased intracellular Fe2+, lipid peroxidation (LPO), and reactive oxygen species (ROS) in both monolayer cultures and spheroids, indicating ferroptosis. In vivo, BNCT with ICI-Fe-NGs significantly suppressed tumor growth at both primary and distant non-irradiated sites.
Discussion:
Fe-NGs suggest ferroptosis enhances BNCT efficacy. ICI-Fe-NGs indicate that EPR-mediated accumulation, LAT1-dependent uptake, and ICI-mediated maintenance of a pro-inflammatory tumor microenvironment improve therapeutic outcomes. Suppression of distant tumors implies systemic immune activation.
Conclusion:
These findings suggest that immunogenic cell death induced by BNCT and ferroptosis activates the systemic cancer-immunity cycle, leading to the abscopal effect and regression of distant tumors. Furthermore, LAT1-dependent uptake and ICI-mediated immune activation may further enhance antitumor responses.
Reference:
[1] L. Galluzzi et al., Cancer Cell, 2026, 44(2), 281-305.
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