The rational design of a synthetic polymer nanoparticle that neutralizes a toxic peptide in vivo
The rational design of a synthetic polymer nanoparticle that neutralizes a toxic peptide in vivo
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DOI：
10.1073/pnas.1112828109
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发表时间：
2012-01-03
影响因子：
11.1
通讯作者：
Shea, Kenneth J.
中科院分区：
文献类型：
--
作者：
Hoshino, Yu;Koide, Hiroyuki;Shea, Kenneth J.
合成聚合物纳米颗粒（NPs）结合有毒分子并在体内中和它们的功能，是“塑料解毒剂”的重要兴趣。近年来，合成具有靶肽亲和力的聚合物NPs的方法已被报道。然而，合成材料在体内的性能是一个更大的挑战。颗粒大小、表面电荷和疏水性不仅会影响NPs与目标毒素的结合亲和力和能力，还会影响NPs的毒性以及NPs周围蛋白质“冕”的产生，这些“冕”可以改变或抑制预期的性能。在这里，我们报告了体内应用的塑料解毒剂的设计原理。优化NP中功能单体的选择和比例，最大限度地提高了与目标肽的结合亲和力和能力。体外和体内NPs的生物相容性测试揭示了调整表面电荷和疏水性的重要性，以减少NP毒性并防止与血浆蛋白的非特异性相互作用诱导的聚集。NPs在体内的毒素中和能力与体外的结合亲和力和能力有很强的相关性。此外，体内成像实验证实NPs加速了毒性肽的清除，并最终积聚在肝脏的巨噬细胞中。这些结果为设计塑料解毒剂提供了一个平台，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。
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.