Amphiphilic Polyelectrolyte Graft Copolymers Enhance the Activity of Cyclic Dinucleotide STING Agonists.
Amphiphilic Polyelectrolyte Graft Copolymers Enhance the Activity of Cyclic Dinucleotide STING Agonists.
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两亲聚电解质移植物共聚物增强了环状二核苷酸刺痛激动剂的活性。
DOI：
10.1002/adhm.202001056
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发表时间：
2021-01
影响因子：
10
通讯作者：
Wilson JT
中科院分区：
文献类型：
--
作者：
Nguyen DC;Shae D;Pagendarm HM;Becker KW;Wehbe M;Kilchrist KV;Pastora LE;Palmer CR;Seber P;Christov PP;Duvall CL;Wilson JT
干扰素基因刺激因子（STING）的环二核苷酸（CDN）激动剂具有很大的治疗潜力，但其活性受到药物样性质的限制，限制了胞质生物利用度。在这里，我们通过合成和评价一系列新型的PEGMA-co-DEAEMA-co-BMA共聚物来解决这一挑战，这些共聚物具有pH响应性、膜去稳定活性以增强CDN、cGAMP的细胞内递送。我们合成了两种不同分子量（300和950 Da）的PEGMA共聚物，并在一定范围内的PEG质量分数和聚合物分子量，并阐明了共聚物结构，自组装，内体逃逸，和cGAMP活性之间的关系。我们鉴定了自组装成50-800 nm纳米颗粒的聚合物子集，并且可以通过简单的混合策略加载cGAMP，从而显著增强免疫刺激活性。我们发现增加的cGAMP活性与载体增强细胞内CDN摄取和促进内体去稳定化的能力高度相关，这一发现确立了有效的胞质递送作为CDN载体的标准。此外，我们证明了前导CDN载体制剂可以在肿瘤内免疫治疗模型中增强体内STING活化。总的来说，这些研究证明了PEGMA-共-DEAEMA-共-BMA共聚物作为CDN和潜在的其他细胞内作用药物货物的载体的效用。
Cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) hold great therapeutic potential, but their activity is hindered by poor drug-like properties that restrict cytosolic bioavailability. Here, we address this challenge through the synthesis and evaluation of a novel series of PEGMA-co-DEAEMA-co-BMA copolymers with pH-responsive, membrane-destabilizing activity to enhance intracellular delivery of the CDN, cGAMP. We synthesized copolymers with PEGMA of two different molecular weights (300 and 950 Da) and over a range of PEG mass fraction and polymer molecular weight, and elucidated relationships between copolymer structure, self-assembly, endosomal escape, and cGAMP activity. We identified a subset of polymers that self-assembled into 50-800 nm nanoparticles and could be loaded with cGAMP via a simple mixing strategy, resulting in significantly enhanced immunostimulatory activity. We found that increased cGAMP activity was highly correlated with the capacity of carriers to enhance intracellular CDN uptake and to promote endosomal destabilization, findings that establish efficient cytosolic delivery as a criterion for CDN carriers. Additionally, we demonstrated that a lead CDN carrier formulation could enhance STING activation in vivo in a model of intratumoral immunotherapy. Collectively, these investigations demonstrate the utility of PEGMA-co-DEAEMA-co-BMA copolymers as carriers for CDNs and potentially other cytosolically-acting drug cargo.
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影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1126/science.1244040
发表时间：
2013-09-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li XD;Wu J;Gao D;Wang H;Sun L;Chen ZJ
通讯作者：
Chen ZJ
影响因子：
4.9
作者：
Collier MA;Junkins RD;Gallovic MD;Johnson BM;Johnson MM;Macintyre AN;Sempowski GD;Bachelder EM;Ting JP;Ainslie KM
通讯作者：
Ainslie KM
影响因子：
15.9
作者：
Hanson, Melissa C.;Crespo, Monica R.;Irvine, Darrell J.
通讯作者：
Irvine, Darrell J.
影响因子：
3.9
作者：
Liu, Yu-Tao;Zhang, Kai;Shi, Yuan-Kai
通讯作者：
Shi, Yuan-Kai