(517f) CO-Delivery of Paclitaxel and Imatinib By PEG Derivatized NLG Carrier As Enhanced Immunochemotherapy

Indoleamine 2,3-dioxygenase (IDO), which catalyzes the initial and rate-limiting step in the tryptophan catabolism along the kynurenine pathway, is an immunosuppressive enzyme that can lead to T cell anergy, apoptosis and potential induction of regulatory T cells (T_reg cells). The consideration of IDO has driven the development of several IDO inhibitors including NLG919, an immunotherapy drug that targets IDO with high efficacy, into the clinical trial for treating solid tumor. Immunochemotherapy that combines the chemotherapeutic agents with the immune checkpoint inhibitors represents one of attractive strategies for cancer treatment. Previously, our group has developed a PEG_2K-Fmoc-NLG micellar system that can effectively deliver anticancer drug Paclitaxel (PTX) and showed enhanced effect with chemotherapy to inhibit tumor growth. NLG is known as an enzymatic inhibitor of IDO, but due to the feedback mechanism, the decrease of enzymatic metabolites would lead to the up-regulation of IDO expression. For long-term treatment, increased dose of this formulation would be necessary to maintain the same effect for treating cancer. Meanwhile, we also found PTX itself could up-regulate IDO mRNA expression. Hence we screened out another anti-cancer drug Imatinib (Gleevec®) which shows a down-regulation effect on IDO expression and developed a PEG_5K-(Fmoc-NLG)₂ prodrug carrier for effective co-delivery of Paclitaxel and Imatinib.

In this study, we have developed a simple and dual-functional nanomicellar system that consists of NLG-based hydrophobic domain, a PEG hydrophilic segment and a drug-interactive Fmoc motif. In addition to significantly enhancement of drug loading capacity and formulation stability, our improved PEG_5K-(Fmoc-NLG)₂ system also ensured the effective co-delivery of the prodrug PEG-NLG and two anti-cancer agents PTX and IMA to the targeted tumor site. The rapid release of PTX could mediate the killing of tumor cells and/or cause direct effect on immune cells, which resulted in enhanced antigen presentation that lead to immune response. Meanwhile, the slow release of NLG919 from the prodrug facilitated the immune response by preventing or slowing down the development of IDO-induced immune escape. More importantly, the release of IMA blocked IDO at the level of gene expression, which further sustained or enhanced the magnitude of immune response. No synergism has been found in the combination of PTX and IMA in inhibiting tumor cell proliferation in vitro. However, we observed an enhanced anti-tumor activity of PTX+IMA loaded PEG_5k-(Fmoc-NLG)₂ micellar system in an immunocompetent mouse model, which suggests that the efficacy of IMA might come from its immune-stimulatory effect. Indeed, it seems to be bright for combining IDO inhibitors and targeted drugs, which can interfere with immune escape pathways as enhanced immunochemotherapy.