Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists.
Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists.
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DOI：
10.1021/acs.molpharmaceut.8b00579
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发表时间：
2018-11-05
影响因子：
4.9
通讯作者：
Ainslie KM
中科院分区：
文献类型：
--
作者：
Collier MA;Junkins RD;Gallovic MD;Johnson BM;Johnson MM;Macintyre AN;Sempowski GD;Bachelder EM;Ting JP;Ainslie KM
疫苗是预防传染病最有效的工具;然而，亚单位疫苗被认为是最安全的类型，免疫原性差，需要佐剂来产生强烈和持续的免疫应答。作为佐剂，病原体相关分子模式（PAMP）通过其同源模式识别受体（PRR）提供有效的免疫刺激特性和明确的作用机制。它们的活性可以通过组合两种或更多种PAMP，特别是那些激活多种免疫信号传导途径的PAMP来进一步增强。然而，许多PRR的胞质定位需要PAMP的细胞内递送以获得最佳生物活性，这对于干扰素基因刺激物（STING）PRR尤其如此。我们使用包封STING激动剂3′3′-环GMP-AMP（cGAMP）的缩醛化葡聚糖（Ace-DEX）微粒（MP）与可溶性PAMPS组合，用原代小鼠骨髓来源的树突状细胞（BMDCs）筛选共递送佐剂的效果。我们鉴定了cGAMP MP和可溶性Toll样受体7/8（TLR 7/8）激动剂瑞喹莫特（R848）的共递送引起最广泛的细胞因子应答。然后通过电喷雾将cGAMP和R848共包封在Ace-DEX MP内。使用模型抗原卵清蛋白，我们观察到共包封cGAMP和R848的Ace-DEX MP（cGAMP/R848 Ace-DEX MP）诱导抗原特异性细胞免疫，以及平衡的Th 1/Th 2体液应答，其大于单独的cGAMP Ace-DEX MP和在单独的MP中递送的PAMP。这些数据表明负载有STING和TLR 7/8激动剂的聚合物Ace-DEX MP代表有效的细胞和体液疫苗佐剂。
Vaccines are the most effective tool for preventing infectious diseases; however, subunit vaccines, considered the safest type, suffer from poor immunogenicity and require adjuvants to create a strong and sustained immune response. As adjuvants, pathogen-associated molecular patterns (PAMPs) offer potent immunostimulatory properties and defined mechanisms of action through their cognate pattern recognition receptors (PRRs). Their activity can be further enhanced through combining two or more PAMPs, particularly those that activate multiple immune signaling pathways. However, the cytosolic localization of many PRRs requires intracellular delivery of PAMPs for optimal biological activity, which is particularly true of the stimulator of interferon genes (STING) PRR. Using acetalated dextran (Ace-DEX) microparticles (MPs) encapsulating STING agonist 3′3′-cyclic GMP-AMP (cGAMP) combined with soluble PAMPS, we screened the effect of codelivery of adjuvants using primary mouse bone marrow derived dendritic cells (BMDCs). We identified that codelivery of cGAMP MPs and soluble Toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) elicited the broadest cytokine response. cGAMP and R848 were then coencapsulated within Ace-DEX MPs via electrospray. Using the model antigen ovalbumin, we observed that Ace-DEX MPs coencapsulating cGAMP and R848 (cGAMP/R848 Ace-DEX MPs) induced antigen-specific cellular immunity, and a balanced Th1/Th2 humoral response that was greater than cGAMP Ace-DEX MPs alone and PAMPs delivered in separate MPs. These data indicate that polymeric Ace-DEX MPs loaded with STING and TLR7/8 agonists represent a potent cellular and humoral vaccine adjuvant.
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影响因子：
7.3
作者：
Awate S;Babiuk LA;Mutwiri G
通讯作者：
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影响因子：
14
作者：
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DOI：
10.1073/pnas.0901592106
发表时间：
2009-04-07
影响因子：
11.1
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15.3
作者：
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通讯作者：
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