State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China.
Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
Biomater Sci. 2023 Oct 10;11(20):6823-6833. doi: 10.1039/d3bm00585b.
Although immunotherapy has achieved great success in the treatment of a variety of tumors, its efficacy for glioblastoma (GBM) is still limited. Both the immunosuppressive tumor microenvironment (TME) and poor penetration of immunotherapeutic agents into tumors contributed to the poor anti-glioma immunity. Herein, we develop an injectable prodrug-loaded hydrogel delivery system with sono-activatable properties for sonodynamic therapy (SDT)-triggered immunomodulation for GBM treatment. The prodrug alginate hydrogels (APN), which contain semiconducting polymer nanoparticles (SPNs) and the NLG919 prodrug linked by singlet oxygen (O)-cleavable linkers, are formed coordination of alginate solution with Ca in the TME. SPNs serve as sonosensitizers to produce O upon ultrasound (US) irradiation for SDT. The generated O not only induce immunogenic cell death, but also break O-cleavable linkers to precisely activate the NLG919 prodrug. Antitumor immunity is significantly amplified due to the reversal of immunosuppression mediated by indolamine 2,3-dioxygenase-dependent tryptophan metabolism. This smart prodrug hydrogel platform potently inhibits tumor growth in orthotopic glioma-bearing mice. Collectively, this work provides a sono-activatable hydrogel platform for precise sono-immunotherapy against GBM.
尽管免疫疗法在治疗多种肿瘤方面取得了巨大成功，但它对胶质母细胞瘤（GBM）的疗效仍然有限。免疫抑制性肿瘤微环境（TME）和免疫治疗剂在肿瘤内的渗透不良都导致了抗胶质瘤免疫能力差。在此，我们开发了一种具有声激活特性的可注射前药负载水凝胶递送系统，用于声动力学疗法（SDT）触发的免疫调节治疗 GBM。前药海藻酸钠水凝胶（APN）由半导体聚合物纳米粒子（SPN）和通过单线态氧（O）可裂解键连接的 NLG919 前药组成，在 TME 中形成海藻酸钠溶液与 Ca 的配位。SPN 作为声敏剂，在超声（US）照射下产生 O 用于 SDT。生成的 O 不仅诱导免疫原性细胞死亡，还可以精确地激活 O-可裂解键来激活 NLG919 前药。由于吲哚胺 2,3-双加氧酶依赖性色氨酸代谢介导的免疫抑制作用的逆转，抗肿瘤免疫得到了显著增强。这种智能前药水凝胶平台在荷原位胶质母细胞瘤小鼠中强烈抑制肿瘤生长。总之，这项工作提供了一种针对 GBM 的精确声免疫治疗的声激活水凝胶平台。
