The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment.
The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment.
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DOI：
10.1039/d1na00308a
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发表时间：
2021-08-25
影响因子：
4.7
通讯作者：
Karathanasis E
中科院分区：
文献类型：
--
作者：
Becicka WM;Bielecki PA;Lorkowski ME;Moon TJ;Zhang Y;Atukorale PU;Covarrubias G;Karathanasis E
免疫疗法的功效通常受到免疫抑制性肿瘤微环境的限制，该微环境中充满了功能失调的先天免疫细胞。为了重新编程肿瘤驻留的先天免疫细胞，我们开发了免疫刺激性二氧化硅介孔纳米粒子（immuno-MSN）。免疫-MSN 的货物是干扰素基因刺激剂 (STING) 激动剂，可激活先天免疫细胞，从而产生干扰素 (IFN) β。通过熟练地将其货物运输到免疫细胞中，与游离激动剂相比，免疫 MSN 诱导的 IFN-β 分泌量增加了 9 倍。虽然外部 PEG 屏蔽历来用于保护纳米颗粒免受免疫识别，但聚乙二醇化免疫刺激纳米颗粒需要在免疫逃避之间取得平衡，以避免肿瘤中靶免疫细胞的异位积累和摄取。使用转移性乳腺癌的 4T1 小鼠模型和流式细胞术，确定聚乙二醇化程度显着影响肿瘤固有免疫细胞对“空”MSN 的摄取。负载激动剂的免疫 MSN 变体的情况并非如此。应该指出的是，“空”MSN 的表面电荷为正电荷，而不是负载激动剂的免疫 MSN 的中性电荷。然而，尽管注射后 24 小时三种免疫 MSN 变体的细胞摄取相似，但我们观察到使用轻度聚乙二醇化的免疫 MSN 变体对 APC 的激活和扩增有显着的有益作用，尤其是在肺转移中。免疫疗法的功效通常受到免疫抑制性肿瘤微环境的限制，该微环境中充满了功能失调的先天免疫细胞。
The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. To reprogram the tumor-resident innate immune cells, we developed immunostimulatory silica mesoporous nanoparticles (immuno-MSN). The cargo of immuno-MSN is a Stimulator of Interferon Gene (STING) agonist, which activates innate immune cells leading to production of interferon (IFN) β. By proficiently trafficking its cargo into immune cells, the immuno-MSN induced a 9-fold increase of IFN-β secretion compared to free agonist. While an external PEG shield has historically been used to protect nanoparticles from immune recognition, a PEGylated immunostimulatory nanoparticle needs to strike a balance between immune evasion to avoid off-site accumulation and uptake by target immune cells in tumors. Using the 4T1 mouse model of metastatic breast cancer and flow cytometry, it was determined that the degree of PEGylation significantly influenced the uptake of ‘empty’ MSNs by tumor-resident innate immune cells. This was not the case for the agonist-loaded immuno-MSN variants. It should be noted the surface charge of the ‘empty’ MSNs was positive rather than neutral for the agonist-loaded immuno-MSNs. However, even though the cellular uptake was similar at 24 h after injection for the three immuno-MSN variants, we observed a significant beneficial effect on the activation and expansion of APCs especially in lung metastasis using the lightly PEGylated immuno-MSN variant. The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells.
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DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1016/j.jconrel.2020.11.014
发表时间：
2021-02-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Lorkowski ME;Atukorale PU;Bielecki PA;Tong KH;Covarrubias G;Zhang Y;Loutrianakis G;Moon TJ;Santulli AR;Becicka WM;Karathanasis E
通讯作者：
Karathanasis E
影响因子：
168.9
作者：
Pages, Franck;Mlecnik, Bernhard;Galon, Jerome
通讯作者：
Galon, Jerome
肿瘤来源的CGAMP触发非肿瘤细胞中的刺激介导的干扰素反应激活NK细胞反应。
影响因子：
32.4
作者：
Marcus A;Mao AJ;Lensink-Vasan M;Wang L;Vance RE;Raulet DH
通讯作者：
Raulet DH
影响因子：
5.8
作者：
Gref, R;Lück, M;Müller, RH
通讯作者：
Müller, RH