IDO-triggered swellable polymeric micelles for IDO inhibition and targeted cancer immunotherapy

Abstract

Indoleamine 2,3-dioxygenase (IDO) has been studied as a promising target for cancer immunotherapy. IDO catalyzes the oxidation of tryptophan into kynurenine, which subsequently activates regulatory T cells, thereby promoting an immunosuppressive microenvironment in the tumor tissue. Due to its overexpression in tumor cells, IDO itself could be a tumor-specific stimulus for targeted cancer therapy. Toward this objective, we developed IDO-triggered swellable micelles for targeted cancer immunotherapy. The micelles are prepared by the self-assembly of amphiphilic polymers containing polymerized tryptophan as a hydrophobic block. The micelles exhibited IDO-responsive behavior via solubility conversion of the hydrophobic core triggered by the oxidation of tryptophan residues into kynurenine. The micelles were internalized into tumor cells and disassembled by overexpressed IDO. Loaded with IDO inhibitor, the micelle presented enhanced therapeutic antitumor effect, and effector T-cells were recruited into the tumor tissue. We demonstrated that overexpressed IDO in cancer cells could be utilized as a tumor-specific stimulus, and utilizing an IDO-responsive drug delivery system holds great promise for targeted cancer therapy and immunomodulation.