NAT MATER ：新型纳米给药策略加强肿瘤免疫治疗

7月15日，Nature Materials杂志在线报道了一种新型纳米技术通过持续高效低给药，克服肿瘤微环境对免疫治疗的干扰，可大大提高肿瘤免疫治疗的疗效。

肿瘤微环境通过多种免疫机制，如分泌转化生长因子-β（TGF-β），抑制局部肿瘤免疫反应，从而阻挠常规免疫治疗。因此，高剂量的白细胞介素-2（IL-2），一种转移性黑色素瘤的常规治疗细胞因子，只能诱导有限的免疫反应。

为克服肿瘤微环境的免疫抑制性质，研究者开发了纳米脂质体聚合凝胶(nanolipogels; nLGs)药物络合环糊精和由细胞因子包被的可生物降解的聚合物。这些物质，可以持续的方式向肿瘤微环境传输疏水小分子抑制剂和水溶性蛋白因子。

nLGs释放TGF-β抑制剂和IL-2显著延迟肿瘤的生长，提高荷瘤小鼠的生存率，并增加自然杀伤细胞的活性和肿瘤内激活的CD8 + T细胞浸润。

研究表明，nLGs在肿瘤免疫治疗中的疗效，是激活先天免疫和适应性免疫反应的结果。

doi:10.1016/j.cell.2011.10.017
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Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy

Jason Park,Stephen H. Wrzesinski,Eric Stern,Michael Look,Jason Criscione,Ragy Ragheb,Steven M. Jay,Stacey L. Demento,Atu Agawu,Paula Licona Limon,Anthony F. Ferrandino,David Gonzalez,Ann Habermann,Richard A. Flavell& Tarek M. Fahmy

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.