Hydrolytically Degradable PEGylated Polyelectrolyte Nanocomplexes for Protein Delivery
Hydrolytically Degradable PEGylated Polyelectrolyte Nanocomplexes for Protein Delivery
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DOI：
10.1021/acs.biomac.8b00785
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发表时间：
2018-08-01
影响因子：
6.2
通讯作者：
Fuerst, Thomas R.
中科院分区：
文献类型：
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作者：
Andrianov, Alexander K.;Marin, Alexander;Fuerst, Thomas R.
合成了一种新型的带相反电荷的聚磷腈聚电解质，该聚电解质含有接枝的聚乙二醇（PEG）链，可作为可生物降解的PEG化蛋白质载体组装的模块组件。这些大分子对应物，其中包含羧酸或叔氨基，然后在接近生理条件下配制成纳米级的超分子组装体，低于100 nm。通过zeta电位测量评估的具有电中性表面电荷的纳米复合物在水溶液中是稳定的，这表明其紧凑的亲水性PEG复合物“核”亲水性PEG“壳”结构。聚乙二醇化聚磷腈纳米复合物作为治疗性蛋白L-天冬酰胺酶（L-ASP）的非共价聚乙二醇化试剂的研究在体外证明了它们显著降低蛋白抗原性的能力，如使用酶联免疫吸附测定（ELISA）通过抗体结合所测量的。纳米复合物的包封不影响L-ASP的酶活性，但提高了其热稳定性和抗蛋白水解性。凝胶渗透色谱（GPC）的实验表明，所有合成的聚磷腈表现出组成控制的水解降解性在中性pH值的水溶液中，并在较低的温度下表现出更大的稳定性。总的来说，能够在水溶液中自发自组装成PEG化纳米颗粒的新型可水解降解的聚磷腈聚电解质可以潜在地实现修饰治疗性蛋白质而不需要其共价修饰的简单且有效的方法。
Novel oppositely charged polyphosphazene polyelectrolytes containing grafted poly(ethylene glycol) (PEG) chains were synthesized as modular components for the assembly of biodegradable PEGylated protein delivery vehicles. These macromolecular counterparts, which contained either carboxylic acid or tertiary amino groups, were then formulated at near physiological conditions into supramolecular assemblies of nanoscale level, below 100 nm. Nanocomplexes with electroneutral surface charge, as assessed by zeta potential measurements, were stable in aqueous solutions, which suggests their compact polyelectrolyte complex "core" hydrophilic PEG "shell" structure. Investigation of PEGylated polyphosphazene nanocomplexes as agents for noncovalent PEGylation of the therapeutic protein L-asparaginase (L-ASP) in vitro demonstrated their ability to dramatically reduce protein antigenicity, as measured by antibody binding using enzyme linked immunosorbent assay (ELISA). Encapsulation in nanocomplexes did not affect enzymatic activity of L-ASP, but improved its thermal stability and proteolytic resistance. Gel permeation chromatography (GPC) experiments revealed that all synthesized polyphosphazenes exhibited composition controlled hydrolytic degradability in aqueous solutions at neutral pH and showed greater stability at lower temperatures. Overall, novel hydrolytically degradable polyphosphazene polyelectrolytes capable of spontaneous self-assembly into PEGylated nanoparticulates in aqueous solutions can potentially enable a simple and effective approach to modifying therapeutic proteins without the need for their covalent modification.