Carrier-Free Small-Molecule Drug Nanoassembly Elicits Chemoimmunotherapy via Co-inhibition of PD-L1/mTOR,ACS Applied Bio Materials

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Carrier-Free Small-Molecule Drug Nanoassembly Elicits Chemoimmunotherapy via Co-inhibition of PD-L1/mTOR
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2020-06-07 , DOI: 10.1021/acsabm.0c00470
Qian Yang ₁ , Yao Xiao ₁ , Qingya Liu ₁ , Xuewen Xu ₁ , Jinrong Peng ₁

Affiliation

The growth and progression of tumor are promoted by multiple cytokines, which are overactivated in the tumor microenvironment. Co-inhibiting the activities of these cytokines is expected to realize the enhanced therapeutic outcome of cancer. However, reasonable combinational strategies are still limited. Herein, a nanoassembly structure that was totally formed by the assembly of small-molecule inhibitors is constructed for the co-inhibition of mTOR and PD-L1. Together with the NIR dye IR783, Rapa and (+)-JQ1 assemble to form a stable nanoassembly structure with controllable particle size. The JQ1/Rapa-IR783 nanoassembly efficiently downregulates the PD-L1 level as well as the level of PKM2. The combination of Rapa and (+)-JQ1 enhances the apoptosis of cancer cells compared with that following treatment with Rapa or (+)-JQ1 alone. In vivo assays conducted to evaluate tumor growth inhibition mediated by the nanoassemblies revealed that the simultaneous delivery of Rapa and (+)-JQ1 not only inhibited the growth of primary tumors but also alleviated pulmonary metastasis by reinvigorating the immune system as the result of the downregulation of both mTOR and PD-L1. It demonstrates that the nanoassembly structure is a promising candidate for the codelivery of immunomodulator for enhanced cancer immunotherapy.

中文翻译：

无载体小分子药物纳米组装通过共抑制 PD-L1/mTOR 引发化学免疫疗法

多种细胞因子促进肿瘤的生长和进展，这些细胞因子在肿瘤微环境中被过度激活。共同抑制这些细胞因子的活性有望实现增强的癌症治疗效果。然而，合理的组合策略仍然有限。在此，构建了一个完全由小分子抑制剂组装形成的纳米组装结构，用于mTOR和PD-L1的共抑制。Rapa 和 (+)-JQ1 与 NIR 染料 IR783 一起组装形成粒径可控的稳定纳米组装结构。JQ1/Rapa-IR783 纳米组装有效地下调 PD-L1 水平以及 PKM2 水平。与单独使用 Rapa 或 (+)-JQ1 治疗相比，Rapa 和 (+)-JQ1 的组合增强了癌细胞的凋亡。为评估纳米组件介导的肿瘤生长抑制而进行的体内试验表明，同时递送 Rapa 和 (+)-JQ1 不仅抑制了原发性肿瘤的生长，而且由于下调的结果，通过重振免疫系统来减轻肺转移mTOR 和 PD-L1。这表明纳米组装结构是用于增强癌症免疫治疗的免疫调节剂的协同传递的有希望的候选者。

更新日期：2020-07-20

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