Combinatorial synthesis of redox-responsive cationic polypeptoids for intracellular protein delivery application
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mbinatorial synthesis of redox-responsive cationic polypeptoids for intracellular protein delivery application *
Zhicheng Le, Tong Xiao, Zhijia Liu , Xingliang Liu, Hong Liu, Lixin Liu & Yongming Chen
*
School of Materials Science and Engineering, Key Laboratory of Polymeric Composite and Functional Materials of Ministry of Education, GD Research Center for Functional Biomaterials Engineering and Technology, Sun Yat-sen University, Guangzhou 510275, China Received May 10, 2020; accepted June 23, 2020; published online August 13, 2020
Biologics play an essential role in treating various indications from cancers to the metabolic diseases, while the current development of new classes of intracellular-acting protein drugs is still hindered because of high molecular mass and overall hydrophilicity of proteins creating extremely poor permeability across cell membrane. Hence, there remains an unmet need to develop safe, potent approaches to augment intracellular protein delivery efficiency. Here, we described a facile multicomponent reaction system for generating a small library of redox-responsive cationic polypeptoids with high biocompatibility. The co-assembly of optimized polymer with protein leads to the formation of compacted nanocomplexes with smaller size and high encapsulation efficiency, thus improving cellular internalization via the macropinocytosis and/or caveolae-mediated endocytosis mainly. After endo-lysosomal escape, the nanocomplexes can be disassociated to efficiently release cargo proteins into the cytosol, owing to the intracellular glutathione (GSH)-triggered rapid cleavage of disulfide bonds in polymers backbone. As a result, we screened a promising platform reagent for efficient cytosolic protein delivery application. multicomponent reaction, cationic polypeptoid, redox-responsive, intracellular delivery, protein Citation:
Le Z, Xiao T, Liu Z, Liu X, Liu H, Liu L, Chen Y. Combinatorial synthesis of redox-responsive cationic polypeptoids for intracellular protein delivery application. Sci China Chem, 2020, 63, https://doi.org/10.1007/s11426-020-9802-0
Biopharmaceutical drugs including therapeutic proteins, cytokines, enzymes and monoclonal antibodies have emerged as a popular therapeutic modality for the effective treatment of various indications from cancers to the metabolic diseases, owing to their high specificity and potency coupled with lower adverse effects [1–3]. For example, statistically, protein drugs accounted for 70% of the top ten drugs by sales globally in 2019 [4]. However, current protein therapeutics are primarily exploited to exert at the extracellular targets due to the high molecular mass and hydrophilicity of biomacromolecules leading to extremely poor permeability across cell membrane [2,5]. Additionally, a large number of studies demonstrated that protein drugs have *Corresponding authors (email: [email protected]; [email protected])
huge potentials for more specifically modulating the intracellular targets in comparison with conventional small molecule dru
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