Tumor disaggregation sensitizes radio-therapy for low rectal tumor

Hypoxia within solid tumors has been identified as one of the main obstacles in radiotherapy due to the severely reduced radiosensitivity. Current strategies to alleviate tumor hypoxia mainly rely on oxygen supplementation using oxygen carriers (e.g., hemoglobin- or perfluorocarbon-based systems), hypoxia-activated prodrugs, or tumor oxygen consumption modulators, leading to limited efficacies due to poor tumor-specific targeting, insufficient oxygen delivery in the complex tumor microenvironment, and potential systemic toxicity. Here we propose an alternative but novel strategy for radiosensitization in colorectal cancer radiotherapy by uncompacting the tumor tissue via tumor disaggregation, thus alleviating tumor hypoxia and enhancing radiosensitivity. This strategy has been realized by developing a nanomedicine composed of ethylene diamine tetraacetic acid-loaded layered double hydroxide (LDH/EDTA) featuring intratumoral acidity-responsive EDTA release. The released EDTA deprives Ca²⁺ ions from the intercellular cadherins that connect tumor cells through EDTA- Ca²⁺ chelation, thus disrupting the inter-cellular junctions in tumor tissue by cadherin damages. As a result, compactness and rigidity of tumor tissues are greatly reduced, and the ambient oxygen is allowed to diffuse deep into the tumor interior, thereby alleviating the hypoxia of solid tumors and effectively enhancing their sensitivity to radiotherapy. This work proposes a novel yet facile strategy to enhance radiosensitivity simply by overcoming the physical barriers of tumors and alleviating hypoxia.