Antibody co-administration robustly improves proton therapy with radiosensitizing nanoparticles: a mathematical modeling study
- 1University of Castilla-La Mancha
Abstract
Radiosensitizing nanoparticles represent a promising approach for enhancing the efficacy of proton radiotherapy; however, their performance is constrained by restricted penetration into tumor tissue, resulting in preferential perivascular accumulation. Here, we develop a spatially distributed mathematical model of a growing tumor undergoing proton therapy with intravenously administered radiosensitizing nanoparticles to investigate treatment optimization strategies. Using physiologically plausible parameter ranges informed by our own experimental measurements and published data, we demonstrate that co-administration of targeted nanoparticles with antibodies binding to the same tumor receptors can overcome transport-induced localization and promote a more uniform intratumoral redistribution of nanoparticles before irradiation. Population-level simulations across heterogeneous parameter sets suggest that moderate antibody doses consistently prolong tumor regrowth time, whereas higher antibody doses produce a pronounced and robust increase in tumor cure probability under a single high-dose irradiation regimen representative of preclinical settings. A key conceptual result of our analysis is the asymmetric risk associated with antibody co-administration. In contrast to antibody--drug conjugates, for which excessive dosing of unconjugated antibodies may severely compromise therapeutic efficacy, co-administration of antibodies with nanoparticle-based radiosensitizers constitutes a "safe-by-design" strategy with respect to tumor cell kill in the modeled single high-dose irradiation setting: although excessive antibody doses may yield suboptimal outcomes, they cannot reduce tumor cell kill below that achieved with targeted nanoparticles administered without antibodies. These findings identify antibody-mediated spatial redistribution of radiosensitizing nanoparticles as a favorable strategy that is expected to provide robust therapeutic benefit despite substantial variability in tumor characteristics.
Related
- Radiosensitizing Effect of Gold Nanoparticles Stabilized with Sodium Citrate and Thioglycolic Acid on MDA-MB-231 and MCF7 Breast Cancer Cells.
- Comparison of subcutaneous and intravenous administration of the monoclonal antibody CSX-1004 on fentanyl-induced respiratory depression in squirrel monkeys
- Targeted photodynamic therapy for colorectal cancer using antibody-conjugated green-synthesised nanoparticles.
- Targeting androgen receptor as a novel radiosensitizing therapy to improve long-term survival and anti-tumor immunity in glioblastoma via TGF-β/Smad3 Axis reprogramming.
- Persistent Injection-Site Nodules After the Administration of Long-Acting Cabotegravir/Rilpivirine
BibTeX
@misc{kuznetsov2026antibody,
title = {{Antibody co-administration robustly improves proton therapy with radiosensitizing nanoparticles: a mathematical modeling study}},
author = {M. Kuznetsov and A. Kolobov},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.30.748121},
url = {https://www.biorxiv.org/content/10.64898/2026.08.30.748121v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Antibody co-administration robustly improves proton therapy with radiosensitizing nanoparticles: a mathematical modeling study
AU - M. Kuznetsov
AU - A. Kolobov
PY - 2026
DA - 2026/08/30
PB - bioRxiv
DO - 10.64898/2026.08.30.748121
UR - https://www.biorxiv.org/content/10.64898/2026.08.30.748121v1
AB - Radiosensitizing nanoparticles represent a promising approach for enhancing the efficacy of proton radiotherapy; however, their performance is constrained by restricted penetration into tumor tissue, resulting in preferential perivascular accumulation. Here, we develop a spatially distributed mathematical model of a growing tumor undergoing proton therapy with intravenously administered radiosensitizing nanoparticles to investigate treatment optimization strategies. Using physiologically plausible parameter ranges informed by our own experimental measurements and published data, we demonstrate that co-administration of targeted nanoparticles with antibodies binding to the same tumor receptors can overcome transport-induced localization and promote a more uniform intratumoral redistribution of nanoparticles before irradiation. Population-level simulations across heterogeneous parameter sets suggest that moderate antibody doses consistently prolong tumor regrowth time, whereas higher antibody doses produce a pronounced and robust increase in tumor cure probability under a single high-dose irradiation regimen representative of preclinical settings. A key conceptual result of our analysis is the asymmetric risk associated with antibody co-administration. In contrast to antibody--drug conjugates, for which excessive dosing of unconjugated antibodies may severely compromise therapeutic efficacy, co-administration of antibodies with nanoparticle-based radiosensitizers constitutes a "safe-by-design" strategy with respect to tumor cell kill in the modeled single high-dose irradiation setting: although excessive antibody doses may yield suboptimal outcomes, they cannot reduce tumor cell kill below that achieved with targeted nanoparticles administered without antibodies. These findings identify antibody-mediated spatial redistribution of radiosensitizing nanoparticles as a favorable strategy that is expected to provide robust therapeutic benefit despite substantial variability in tumor characteristics.
ER -