An albumin-bound drug conjugate of paclitaxel and indoleamine-2,3-dioxygenase inhibitor for enhanced cancer chemo-immunotherapy

Abstract

Despite the promising target of immunosuppressive enzyme indoleamine-2,3-dioxygenase (IDO) for cancer immunotherapy, IDO blockade monotherapy does not show significant benefit to cancer patients in the clinic. Recent research has focused on the combinatorial therapy of the IDO inhibitor and the immune checkpoint blockade or chemotherapy. Here, we synthesize a drug conjugate methyltryptophan-paclitaxel (MP) by linking the IDO inhibitor, D-1-methyltryptophan (D-1MT), to the chemotherapeutic agent, paclitaxel (PTX), through an ester bond. MP exhibits a similar tubulin-stabilizing effect to PTX. Like PTX, MP binds to human serum albumin to form albumin-bound MP nanoparticles (MP NPs) with a particle size of ∼115 nm in diameter. MP NPs significantly improve the tumor concentration of D-1MT due to the hydrolysis of MP in tumors. The codelivery of PTX and D-1MT offered by MP NPs in tumors significantly enhances the anti-tumor effect compared with the albumin-bound PTX NPs. Immune cell phenotyping reveals that MP NPs ameliorate the immune environment through increasing the number of the effector CD8⁺ T cells, and decreasing the population of regulatory T cells and granulocyte-like myeloid-derived suppressor cells. These results prove that the design of the twin drug from the IDO inhibitor and PTX synergizes the anti-tumor effect and shows promise in clinical translation.