A pH-sensitive Macromolecular Prodrug as TLR7/8 Targeting Immune Response Modifier.
A pH-sensitive Macromolecular Prodrug as TLR7/8 Targeting Immune Response Modifier.
复制标题
DOI：
10.1002/chem.201702942
复制
发表时间：
2017-12-14
期刊：
影响因子：
--
通讯作者：
Schöfberger W
中科院分区：
文献类型：
--
作者：
Aichhorn S;Linhardt A;Halfmann A;Nadlinger M;Kirchberger S;Stadler M;Dillinger B;Distel M;Dohnal A;Teasdale I;Schöfberger W
报道了用于合成Toll样受体(TLR)7/8特异性前体药物的新型官能化咪唑并喹啉衍生物(ImQ)的化学合成和生物活性。在斑马鱼幼体中，证实了ImQs诱导炎症的活性。在共价连接到可完全生物降解的聚磷腈聚合物(ImQ聚合物)后，这些大分子前药被设计成在细胞内经历对pH敏感的ImQs释放，通过与内体TLR7/8(危险信号)结合来诱导炎症。我们发现，在pH 为5时，ImQ从前药中解离，指向内涵体前药的降解性。IMQ-聚合物强烈激活小鼠脾细胞中卵清蛋白特异的T 细胞，表现为CD8+T 细胞上IL-2受体(CD2 5)的增殖和表达增加，同时伴有强烈的干扰素-γ释放。本文提出的ImQ前药被建议形成新型纳米疫苗的基础，例如，用于静脉或肿瘤内肿瘤免疫治疗的应用，以触发生理性抗肿瘤免疫反应。
The chemical synthesis and biological activity of novel functionalized imidazoquinoline derivatives (ImQ) to generate Toll‐like receptor (TLR) 7/8 specific prodrugs are presented. In vivo activity of ImQs to induce inflammation was confirmed in zebrafish larvae. After covalent ligation to fully biodegradable polyphosphazenes (ImQ‐polymer), the macromolecular prodrugs were designed to undergo intracellular pH‐sensitive release of ImQs to induce inflammation through binding to endosomal TLR7/8 (danger signal). We showed ImQ dissociation from prodrugs at a pH 5 pointing towards endosomal prodrug degradability. ImQ‐polymers strongly activated ovalbumin‐specific T cells in murine splenocytes as shown by increased proliferation and expression of the IL‐2 receptor (CD25) on CD8+ T cells accompanied by strong IFN‐γ release. ImQ prodrugs presented here are suggested to form the basis of novel nanovaccines, for example, for intravenous or intratumoral cancer immunotherapeutic applications to trigger physiological antitumor immune responses.
登录
查看更多内容
影响因子：
16.6
作者：
Han, Xinping;Wu, Jimmy
通讯作者：
Wu, Jimmy
DOI：
10.1073/pnas.1600816113
发表时间：
2016-07-19
影响因子：
11.1
作者：
Nuhn, Lutz;Vanparijs, Nane;De Geest, Bruno G.
通讯作者：
De Geest, Bruno G.
影响因子：
5
作者：
Linhardt, Anne;Koenig, Michael;Teasdale, Ian
通讯作者：
Teasdale, Ian
影响因子：
46.9
作者：
Lynn GM;Laga R;Darrah PA;Ishizuka AS;Balaci AJ;Dulcey AE;Pechar M;Pola R;Gerner MY;Yamamoto A;Buechler CR;Quinn KM;Smelkinson MG;Vanek O;Cawood R;Hills T;Vasalatiy O;Kastenmüller K;Francica JR;Stutts L;Tom JK;Ryu KA;Esser-Kahn AP;Etrych T;Fisher KD;Seymour LW;Seder RA
通讯作者：
Seder RA
影响因子：
4.5
作者：
Dohnal, A. M.;Witt, V.;Felzmann, T.
通讯作者：
Felzmann, T.