Poly(ethylene glycol) (PEG) is the polymer of choice in drug delivery systems due to its biocompatibility and hydrophilicity. For over 20 years, this polymer has been widely used in the drug delivery of small drugs, proteins, oligonucleotides, and liposomes, improving the stability and pharmacokinetics of many drugs. However, despite the extensive clinical experience with PEG, concerns have emerged related to its use. These include hypersensitivity, purity, and nonbiodegradability. Moreover, conventional PEG is a mixture of polymers that can complicate drug synthesis and purification leading to unwanted immunogenic reactions. Studies have shown that uniform PEGylated drugs may be more effective than conventional PEGylated drugs as they can overcome issues related to molecular heterogeneity and immunogenicity. This has led to significant research efforts to develop synthetic procedures to produce uniform PEGs (monodisperse PEGs). As a result, iterative step-by-step controlled synthesis methods have been created over time and have shown promising results. Nonetheless, these procedures have presented numerous challenges due to their iterative nature and the requirement for multiple purification steps, resulting in increased costs and time consumption. Despite these challenges, the synthetic procedures went through several improvements. This review summarizes and discusses recent advances in the synthesis of uniform PEGs and its derivatives with a focus on overall yields, scalability, and purity of the polymers. Additionally, the available characterization methods for assessing polymer monodispersity are discussed as well as uniform PEG applications, side effects, and possible alternative polymers that can overcome the drawbacks.

中文翻译：

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争取均匀：实现聚乙二醇均匀的进展和挑战回顾

聚乙二醇 (PEG) 由于其生物相容性和亲水性而成为药物输送系统的首选聚合物。 20多年来，这种聚合物已广泛应用于小药物、蛋白质、寡核苷酸和脂质体的药物递送，提高了许多药物的稳定性和药代动力学。然而，尽管 PEG 具有丰富的临床经验，但对其使用的担忧还是出现了。这些包括超敏性、纯度和不可生物降解性。此外，传统的 PEG 是聚合物的混合物，会使药物合成和纯化变得复杂，从而导致不必要的免疫原性反应。研究表明，统一的聚乙二醇化药物可能比传统的聚乙二醇化药物更有效，因为它们可以克服与分子异质性和免疫原性相关的问题。这导致人们进行了大量的研究工作来开发合成程序来生产均匀的 PEG（单分散 PEG）。因此，随着时间的推移，逐步创建了迭代的受控合成方法，并显示出了有希望的结果。尽管如此，这些程序由于其迭代性质和需要多个纯化步骤而带来了许多挑战，导致成本和时间消耗增加。尽管存在这些挑战，合成程序还是经历了一些改进。本综述总结并讨论了均匀 PEG 及其衍生物合成的最新进展，重点关注聚合物的总体产率、可扩展性和纯度。此外，还讨论了用于评估聚合物单分散性的可用表征方法以及统一的 PEG 应用、副作用以及可以克服这些缺点的可能的替代聚合物。