Intracellular aggregation of peptide-reprogrammed small molecule nanoassemblies enhances cancer chemotherapy and combinatorial immunotherapy.
Intracellular aggregation of peptide-reprogrammed small molecule nanoassemblies enhances cancer chemotherapy and combinatorial immunotherapy.
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肽重编程小分子纳米组件的细胞内聚集增强癌症化疗和组合免疫治疗
DOI：
10.1016/j.apsb.2020.06.013
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Qian Z
中科院分区：
文献类型：
--
作者：
Peng J;Xiao Y;Yang Q;Liu Q;Chen Y;Shi K;Hao Y;Han R;Qian Z
纳米治疗剂的细胞内保留对于其治疗活性是必不可少的。将纳米治疗剂固定在靶细胞类型内可以调节各种细胞行为。然而，用于纳米颗粒的细胞内固定的策略是有限的。在本文中，合成顺铂前药并用作谷胱甘肽（GSH）活化的接头以诱导顺铂前药/IR 820/多西他赛纳米组装体的聚集。纳米组装体已经用含肽部分重新编程，用于肿瘤靶向和PD-1/PD-L1阻断。纳米组装体的聚集依赖于GSH浓度。体外和体内评估显示，GSH诱导的纳米组装体的细胞内聚集通过增强肿瘤部位中化疗剂的积累和延长其保留并诱导活性氧（ROS）产生和免疫原性细胞死亡来增强原发性肿瘤中的治疗活性。此外，纳米组装体使免疫细胞，特别是全身免疫细胞恢复活力，从而减轻肺转移，即使原发性肿瘤部位中的免疫细胞群体由于化疗剂的增强积累而受到抑制。这种策略为纳米颗粒的细胞内固定在体外和体内提供了一个有前途的选择。顺铂前体药物的合成和使用作为谷胱甘肽响应连接体诱导细胞内絮凝的纳米组装体，完全由小分子治疗剂形成。它实现了治疗药物的细胞内固定化，并调节细胞行为，以增强癌症化疗和联合免疫治疗。
The intracellular retention of nanotherapeutics is essential for their therapeutic activity. The immobilization of nanotherapeutics inside target cell types can regulate various cell behaviors. However, strategies for the intracellular immobilization of nanoparticles are limited. Herein, a cisplatin prodrug was synthesized and utilized as a glutathione (GSH)-activated linker to induce aggregation of the cisplatin prodrug/IR820/docetaxel nanoassembly. The nanoassembly has been reprogrammed with peptide-containing moieties for tumor-targeting and PD-1/PD-L1 blockade. The aggregation of the nanoassemblies is dependent on GSH concentration. Evaluations in vitro and in vivo revealed that GSH-induced intracellular aggregation of the nanoassemblies enhances therapeutic activity in primary tumors by enhancing the accumulation and prolonging the retention of the chemotherapeutics in the tumor site and inducing reactive oxygen species (ROS) generation and immunogenic cell death. Moreover, the nanoassemblies reinvigorate the immunocytes, especially the systemic immunocytes, and thereby alleviate pulmonary metastasis, even though the population of immunocytes in the primary tumor site is suppressed due to the enhanced accumulation of chemotherapeutics. This strategy provides a promising option for the intracellular immobilization of nanoparticles in vitro and in vivo. Cisplatin prodrug is synthesized and utilized as the glutathione response linker to induce the intracellular flocculation of the nanoassemblies which totally formed by small molecular therapeutics. It realizes intracellular immobilization of therapeutics and regulate the cell behavior to enhance cancer chemotherapy and combinational immunotherapy.
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