Protein–polymer conjugation — moving beyond PEGylation

Abstract

In this review, we summarize —from a materials science perspective— the current state of the field of polymer conjugates of peptide and protein drugs, with a focus on polymers that have been developed as alternatives to the current gold standard, poly(ethylene glycol) (PEG). PEGylation, or the covalent conjugation of PEG to biological therapeutics to improve their therapeutic efficacy by increasing their circulation half-lives and stability, has been the gold standard in the pharmaceutical industry for several decades. After years of research and development, the limitations of PEG, specifically its non-degradability and immunogenicity have become increasingly apparent. While PEG is still currently the best polymer available with the longest clinical track record, extensive research is underway to develop alternative materials in an effort to address these limitations of PEG. Many of these alternative materials have shown promise, though most of them are still in an early stage of development and their in vivo distribution, mechanism of degradation, route of elimination and immunogenicity have not been investigated to a similar extent as for PEG. Thus, further in-depth in vivo testing is essential to validate whether any of the alternative materials discussed in this review qualify as a replacement for PEG.

Recent progress in development of siRNA delivery vehicles for cancer therapy

“…An effective approach to limit protein absorption is surface-coating with non-ionic, hydrophilic, and flexible polymer brushes, e.g., PEG, poly(N-vinyl pyrrolidone) (PVP), poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA), and poly(oxazoline), which all generate steric repulsive forces on the nanoparticle surface [62]. The impact of these polymer brushes on circulation kinetics and biodistribution of delivery vehicles was well explained in other reviews [63][64][65]. Among these polymer brushes, PEG has been most widely used over many years, and approved as an injectable material by Food and Drug Administration (FDA) in United States [66,67].…”

Synthesis and characterization of heparosan-granulocyte-colony stimulating factor conjugates: a natural sugar-based drug delivery system to treat neutropenia

“…However, PEG employed in drug conjugates has potential liabilities including lack of a safe degradation pathway, accumulation in some tissues, emerging immunogenicity, and potential triggering of the complement system (Verhoef et al 2014;Zhang et al 2014) . Therefore, PEGylation alternatives have been explored although all have their caveats (Qi and Chilkoti 2015).…”

“…Unlike most other polysaccharides found in Nature and/or used currently being explored in drug delivery (e.g., polysialic acid, hydroxyethylstarch) (Qi and Chilkoti 2015), the heparosan chain can be produced in a very defined, targeted fashion via chemoenzymatic synthesis.…”

An Overview of Various Carriers for siRNA Delivery

“…However, as research has advanced concerning PEGylation, limitations such as non-degradability have been demonstrated in PEGs, causing concerns over their usage. [70] Additionally, there have been reports of the PEGs themselves causing immunogenicity, especially with repeated usage in the same individual. [71] Thus, research has begun for finding alternatives to PEG such as with polysaccharides.…”

“…[71] Thus, research has begun for finding alternatives to PEG such as with polysaccharides. [70,71] Naked siRNA can also undergo chemical modifications to improve their effectiveness. Without modifications, naked siRNA face obstacles that will later be discussed in greater detail such as potential nuclease degradation, off-target effects, etc.…”