Neutralizing tumor-promoting inflammation with polypeptide-dexamethasone conjugate for microenvironment modulation and colorectal cancer therapy
Neutralizing tumor-promoting inflammation with polypeptide-dexamethasone conjugate for microenvironment modulation and colorectal cancer therapy
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用多肽-地塞米松缀合物中和促肿瘤炎症，用于微环境调节和结直肠癌治疗
DOI：
10.1016/j.biomaterials.2019.119676
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发表时间：
2020-02-01
期刊：
影响因子：
14
通讯作者：
Chen, Xuesi
中科院分区：
文献类型：
--
作者：
Ma, Sheng;Song, Wantong;Chen, Xuesi
肿瘤被称为“无法愈合的伤口”。肿瘤促进性炎症在肿瘤发生、肿瘤进展、肿瘤转移以及化疗耐药性中起着至关重要的作用。因此，减少促肿瘤炎症可能是靶向肿瘤微环境进行癌症治疗的关键方面。地塞米松（DEX）是一种用于治疗多种不同炎症性疾病的商业药物，可以有效抑制引起炎症的物质的释放。然而，作为皮质类固醇药物，直接使用DEX会导致许多严重的副作用。在这项研究中，氧化还原和pH双重敏感的多肽-DEX缀合物（L-SS-DEX）被合成，并且与游离DEX相比，L-SS-DEX显著增加DEX在小鼠结肠直肠癌模型（CT 26）中的肿瘤蓄积。重要的是，在相同剂量（10 mg/kg）下，L-SS-DEX显示出优于游离DEX的上级抗肿瘤活性：与游离DEX治疗组的49%相比，L-SS-DEX治疗组的肿瘤抑制率为86%。肿瘤组织的进一步分析显示，与对照组相比，L-SS-DEX治疗后环氧合酶-2（考克斯-2）和α-平滑肌肌动蛋白（α-SMA）显著减少。此外，CT 26肿瘤的免疫抑制微环境在L-SS-DEX治疗后得到有效缓解，其特征在于增加的CD 8（+）T细胞浸润，M1/M2巨噬细胞的比例增加，以及调节性T细胞（TCFs）和髓源性抑制细胞（MDSC）的显著减少。上述结果表明，当适当递送时，抗炎药物在调节肿瘤微环境方面具有很大的潜力，并且还可以产生显著的肿瘤抑制作用。由于大量的抗炎药物已被用于临床，我们的研究结果可能会提供使用抗炎药物治疗癌症的改进的肿瘤治疗选择。
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 alpha-smooth muscle actin (alpha-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.