A Microbial Siderophore-Inspired Self-Gelling Hydrogel for Noninvasive Anticancer Phototherapy

Microbial carboxyl and catechol siderophores have been shown to have natural iron-chelating abilities, suggesting that hyaluronic acid (HA) and the catechol compound, gallic acid (GA), may have iron-coordinating activities. Here, a photoresponsive self-gelling hydrogel that was both injectable and could be applied to the skin was developed on the basis of the abilities of HA and GA to form coordination bonds with ferric ions (Fe³⁺). The conjugate of HA and GA (HA-GA) instantly formed hydrogels in the presence of ferric ions and showed near-infrared (NIR)-responsive photothermal properties. Following their subcutaneous injection into mice, HA-GA and ferric ion formed a hydrogel, which remained at the injection site for at least 8 days. Intratumoral injection of HA-GA/Fe hydrogel into mice allowed repeated exposure of the tumor to NIR irradiation. This repeated NIR irradiation resulted in complete tumor ablation in KB carcinoma cell-xenografted mice and suppressed lung metastasis of 4T1-Luc orthotopic breast tumors. Application of HA-GA/Fe hydrogel to the skin of A375 melanoma-xenografted tumor sites, followed by NIR irradiation, also resulted in complete tumor ablation. These findings demonstrate that single applications of HA-GA/Fe hydrogel have photothermal anticancer effects against both solid tumors and skin cancers. SIGNIFICANCE: These findings provide new insights into noninvasive anticancer phototherapy using self-gelling hydrogels. Application of these hydrogels in preclinical models reduces the sizes of solid tumors and skin cancers without surgery, radiation, or chemotherapy.