Fully Degradable Hydrophilic Polyals for Protein Modification

Abstract

Modification of proteins with hydrophilic polymers is an effective strategy for regulation of protein pharmacokinetics. However, conjugates of slowly or nonbiodegradable materials, such as poly(ethylene glycol), are known to cause long-lasting cell vacuolization, in particular in renal epithelium. Conjugates of more degradable polymers, e.g., polysaccharides, have a significant risk of immunotoxicity. Polymers that combine complete degradability, long circulation in vivo, and low immuno and chemical toxicity would be most beneficial as protein conjugate components. This study explores new fully biodegradable hydrophilic polymers, hydrophilic polyals. They are nontoxic, stable at physiological conditions, and undergo proton-catalyzed hydrolysis at lysosomal pH. The model enzyme-polyal conjugates were prepared with 61-98% yield using conventional and novel conjugation techniques and retained 90-95% of specific activity. The model conjugates showed a significant prolongation of protein circulation in rodents, with a 5-fold reduction in the renal accumulation. The data suggests that hydrophilic polyals may be useful in designing protein conjugates with improved properties.

PEG Analogs Synthesized by Ring-Opening Metathesis Polymerization for Reversible Bioconjugation

“…The unsaturated rPEGs were previously reported to undergo depolymerization via a lithium-templated backbiting metathesis to reform the unsaturated 12-crown-4 monomer in high yield in dichloromethane/tetrahydrofuran . Reversible protein–polymer conjugates can be prepared using main-chain degradable polymers to facilitate efficient renal clearance of the polymer after hydrolytic, reductive, or enzymatic degradation, or by using cleavable conjugation linkers. − However, there is far less investigation into the development of polymers for protein conjugation that are cleavable by nonbioavailable chemoselective triggers, such as organometallic reagents. While not feasible for therapeutics in the human body, this strategy may have applications in biotechnology such as biosensing and point-of-care diagnostics.…”

Degradable PEGylated protein conjugates utilizing RAFT polymerization

“…Several backbone degradable non-PEG polymer-protein conjugates have been developed. Most of these conjugates consist of sugar-based or sugar-derived polymers such as hydroxyethyl starch 21 , polysialic acid 22 , dextran derivitives 23 or dextrin 24 . In addition, recently, ring opening polymerization has been used to synthesize a poly(ε-caprolactone) which was covalently bound to bovine serum albumin 25 .…”

Rod-Shaped Micelles Based on PHF-g-(PCL-PEG) with pH-Triggered Doxorubicin Release and Enhanced Cellular Uptake

“…As expected (according to the peculiarity of acetals), the hydrolysis of PHF was pH-dependent. 33 Incubation under simulative plasmatic pH (pH 7.4) for 13 days did not affect the GPC elution curve. However, incubation at pH 5.0 brought palpable significant fragmentation (Figure 2).…”