Supramolecular Nanofibers of Curcumin for Highly Amplified Radiosensitization of Colorectal Cancers to Ionizing Radiation

抄録

Background: Enormous efforts have been made to increase the radiosensitivity of cancer cells to ionizing radiation by developing various kinds of radiosensitizers. However, concurrent chemo-radiation therapy often leads to severe side effects in the clinic. Herbal medicines with potential anticancer effects have attracted intensive interests. Our lab has previously investigated the radiosensitizing role of curcumin in the treatment of colorectal cancer. Nevertheless, the poor solubility of curcumin greatly hampered its potential application in previous studies. Here we developed a new curcumin-based supramolecular nanofiber (Cur-SNF) by virtue of a self-assembling peptide, which gives a superb performance in boosting the radiosensitivity of colorectal cancers to ionizing radiation.

Methods: Cur-SNFs were synthesized and characterized for morphology, release kinetics and uptake efficiency. Cytotoxicity and radiosensitizing test were evaluated by XTT and clonogenic assay. Possible mechanisms under the radiosensitizing effect of Cur-SNFs were examined by western blotting and EMSA. In vivo radiosensitizing effect was investigated in a xenograft model of colorectal HCT116 cells with further detection of protein and cytokine expressions.

Results: Cur-SNFs is able to self-assemble into small-molecule hydrogel and nanofibers, with a fixed drug loading content of 38.2%. In vitro and in vivo radiosensitizing studies reveal that as compared to free curcumin, Cur-SNFs can serve as a far better radiosensitizer to sensitize colorectal cancer cells toward ionizing radiation thanks to the supramolecular nanostructure. Due to the super high radiosensitization efficacy, Cur-SNFs in combination with radiation realize significant reduction in tumor volume in colorectal tumor-bearing mouse model. The molecular mechanisms of such radiosensitization effect are clearly investigated, which demonstrate that the more potent in vitro and in vivo radiosensitization by Cur-SNFs than free curcumin is mediated through the efficient inhibition of radiation-induced NF-kB activation and downstream NF-kB regulated gene products and cytokines.

Conclusion: This is the first example of curcumin-based supramolecular nanomaterials used as a radiosensitizer. The supramolecular nanofibers achieve the highest radiosensitizing activity among currently reported curcumin-based radiosensitizers. This work not only manifests that supramolecular nanomaterials can serve as an advanced nanoplatform on which to develop superior radiosensitizers, but also narrows the gap between supramolecular nanomaterials and clinical radiation therapy.