Neutralizing tumor-promoting inflammation with polypeptide-dexamethasone conjugate for microenvironment modulation and colorectal cancer therapy.

Tumor is known as "a wound that does not heal". Tumor-promoting inflammation plays a crucial role in carcinogenesis, tumor progression, tumor metastasis, as well as chemotherapy resistance. Therefore, reducing tumor-promoting inflammation may be a key aspect in targeting the tumor microenvironment for cancer therapy. Dexamethasone (DEX), a commercial drug in the treatment of many different inflammatory diseases, can effectively inhibit the release of substances causing inflammation. However, as a corticosteroid medication, direct use of DEX results in many severe side effects. In this study, a redox and pH dual sensitive polypeptide-DEX conjugate (L-SS-DEX) was synthesized, and the L-SS-DEX dramatically increased the tumoral accumulation of DEX in murine colorectal cancer model (CT26) compared to free DEX. Importantly, at equal dose (10 mg/kg), L-SS-DEX showed superior antitumor activity over free DEX: 86% tumor suppression rate of L-SS-DEX treatment group compared to 49% of free DEX treatment group. Further analysis of the tumor tissues showed that cyclooxygenase-2 (COX-2) and α-smooth muscle actin (α-SMA) were significantly reduced after the L-SS-DEX treatment compared with control groups. In addition, the immunosuppressive microenvironment of the CT26 tumor was effectively relieved after L-SS-DEX treatment, characterized by increased CD8 T cell infiltration, increased ratio of M1 over M2 macrophages, as well as markedly decrease in regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). The above results suggest that anti-inflammatory drugs hold great potential in modulating the tumor microenvironment when delivered properly, and can also result in significant tumor inhibition effects. Since dramatic amounts of anti-inflammatory drugs have been used in clinic, our results may provide improved tumor therapy options of using anti-inflammatory drugs for cancer therapy.