Nanophotosensitizers Based on Celecoxib-Conjugated Chitosan Using a Thioketal Linkage for the Reactive Oxygen Species-Mediated Delivery of Chlorin E6 and Treatment of Oral Cancer Cells

A celecoxib (CELE)-grafted chitosan copolymer was synthesized using a thioketal linkage for oxidative stress-mediated delivery of chlorin e6 (Ce6) and enhanced photodynamic therapy (PDT) against oral squamous carcinoma. CELE was conjugated to the amine groups of chitosan using thioketal dicarboxylic acid as a linker, resulting in the synthesis of a CELE-grafted chitosan (ChitoCELE) copolymer. The ChitoCELE copolymer was reconstituted in water, and Ce6 was subsequently incorporated to produce Ce6-incorporated ChitoCELE nanophotosensitizers. These nanophotosensitizers exhibited a spherical morphology with a diameter of less than 200 nm. Disintegration of the nanophotosensitizers was observed upon exposure to hydrogen peroxide, leading to an increased drug release rate. These results indicated that the nanophotosensitizers are sensitive to oxidative stress <i>in vitro</i>. The intracellular uptake of Ce6, production of reactive oxygen species (ROS), and PDT-induced cytotoxicity were all higher following treatment with the nanophotosensitizers compared to treatment with free Ce6. Interestingly, CELE enhanced ROS production when combined with Ce6, indicating that CELE and ChitoCELE conjugates can amplify the PDT efficacy of Ce6-incorporated nanophotosensitizers. In an <i>in vivo</i> tumor xenograft model using KB oral squamous carcinoma cells, the nanophotosensitizers were preferentially delivered to solid tumors and efficiently suppressed tumor growth.