Abstract
Polyethylene glycol (PEG) at the moment is considered the leading polymer for protein conjugation in view of its unique properties, as well as to its low toxicity in humans, qualities which have been confirmed by its extensive use in clinical practice. Other polymers that are safe, biodegradable and custom-designed have, nevertheless, also been investigated as potential candidates for protein conjugation. This review will focus on natural polymers and synthetic linear polymers that have been used for protein delivery and the results associated with their use. Genetic fusion approaches for the preparation of protein-polypeptide conjugates will be also reviewed and compared with the best known chemical conjugation ones.
Highlights
Polyethylene glycol (PEG) at the moment is considered the leading polymer for protein conjugation in view of its unique properties, as well as to its low toxicity in humans, qualities which have been confirmed by its extensive use in clinical practice
These studies paved the way for the conjugation of polymers to proteins, a technique that has improved the effectiveness of biologics by overcoming important shortcomings, such as instability, short half-lives and immunogenicity, which have often limited their use in clinical practice
Its effectiveness in prolonging the in vivo terminal half-life and in reducing the immunogenicity of conjugated proteins has been proven by several studies and further corroborated by the profile of conjugates, until now, solely of PEG, currently in clinical use [5]
Summary
Dextrans (initially approved as plasma expanders) were probably the first and most studied in this class of polymers [43,44]. The polymer was oxidized by periodate yielding aldehyde groups, which, in turn, were reacted with protein amino groups (Figure 1) This method is still currently applied to couple proteins to dextran and polysaccharides in general, it is affected by the multiplicity of binding groups in the polymer backbone that might yield undesired cross-linked bonds if coupling conditions are not well controlled. PSA was activated by controlled periodate oxidation, making it possible to achieve a single aldehyde group at the non-reducing end of the polymer, where three vicinal hydroxyl groups are present. This approach yields an end chain functionalized PSA with a single aldehyde per polymer chain, thereby avoiding potential cross-linking problems in the subsequent conjugation with proteins [62]. Issue for a comprehensive review of HA’s potential as a carrier of drugs and proteins [76]
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