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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The rational design of a synthetic polymer nanoparticle that neutralizes a toxic peptide in vivo
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The rational design of a synthetic polymer nanoparticle that neutralizes a toxic peptide in vivo

机译：体内中和毒性肽的合成聚合物纳米粒子的合理设计

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摘要

Synthetic polymer nanoparticles (NPs) that bind venomous molecules and neutralize their function in vivo are of significant interest as "plastic antidotes." Recently, procedures to synthesize polymer NPs with affinity for target peptides have been reported. However, the performance of synthetic materials in vivo is a far greater challenge. Particle size, surface charge, and hydrophobicity affect not only the binding affinity and capacity to the target toxin but also the toxicity of NPs and the creation of a "corona" of proteins around NPs that can alter and or suppress the intended performance. Here, we report the design rationale of a plastic antidote for in vivo applications. Optimizing the choice and ratio of functional monomers incorporated in the NP maximized the binding affinity and capacity toward a target peptide. Biocompatibility tests of the NPs in vitro and in vivo revealed the importance of tuning surface charge and hydrophobicity to minimize NP toxicity and prevent aggregation induced by nonspecific interactions with plasma proteins. The toxin neutralization capacity of NPs in vivo showed a strong correlation with binding affinity and capacity in vitro. Furthermore, in vivo imaging experiments established the NPs accelerate clearance of the toxic peptide and eventually accumulate in macrophages in the liver. These results provide a platform to design plastic antidotes and reveal the potential and possible limitations of using synthetic polymer nanoparticles as plastic antidotes.
机译：结合有毒分子并在体内中和其功能的合成聚合物纳米粒子（NPs）作为“塑料解毒剂”引起了人们的极大兴趣。最近，已经报道了合成对目标肽具有亲和力的聚合物NP的方法。然而，合成材料在体内的性能是更大的挑战。粒径，表面电荷和疏水性不仅影响与靶毒素的结合亲和力和能力，而且影响NP的毒性以及NP周围蛋白质的“电晕”的产生，这些蛋白质可以改变和/或抑制预期的性能。在这里，我们报告了一种在体内应用的塑料解毒剂的设计原理。优化掺入NP中的功能性单体的选择和比例可使结合亲和力和对目标肽的能力最大化。在体外和体内对NP进行的生物相容性测试表明，调整表面电荷和疏水性以最大程度地降低NP毒性并防止与血浆蛋白的非特异性相互作用引起的聚集的重要性。体内NPs的毒素中和能力与体外结合亲和力和能力具有很强的相关性。此外，体内成像实验确定了NP可加速毒性肽的清除，并最终在肝脏的巨噬细胞中积累。这些结果提供了设计塑料解毒剂的平台，并揭示了使用合成聚合物纳米颗粒作为塑料解毒剂的潜力和可能的局限性。

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    Yu Hoshino; Hiroyuki Koide; Keiichi Furuya; Walter W. Haberaecker III; Shih-Hui Lee; Takashi Kodama; Hiroaki Kanazawa; Naoto Oku; Kenneth J. Shea;

  • 作者单位

    Department of Chemical Engineering, Kyushu University, 744 Motooka, Fukuoka 819-0395, Japan;

    Department of Chemistry, University of California Irvine, Irvine, CA 92697;

    Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan;

    Department of Chemistry, University of California Irvine, Irvine, CA 92697;

    Department of Chemistry, University of California Irvine, Irvine, CA 92697;

    Department of Mechanical Engineering, Stanford University, Stanford, CA 94305;

    Department of Functional Anatomy, School of Nursing, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan;

    Department of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan;

    Department of Chemistry, University of California Irvine, Irvine, CA 92697;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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