Reversible Bioconjugation: Biodegradable Poly(phosphate)‐Protein Conjugates

Abstract

Protein-polymer conjugates are widely used to improve the pharmacokinetic properties of therapeutic proteins. Commercially available conjugates employ poly(ethylene glycol) (PEG) as the protective polymer; however, PEG has a number of shortcomings, including non-biodegradability and immunogenicity, that call for the development of alternatives. Here, the synthesis of biodegradable poly(phosphate), that is, poly(ethyl ethylene phosphate) (PEEP), by organo-catalyzed anionic ring-opening polymerization exhibiting dispersity values Ð < 1.3 is reported. Polymers with molecular weights between 2000 and 33 200 g mol are then ω-functionalized with a succinimidyl carbonate group and subsequently conjugated to model proteins. These are the first conjugates based on polyphosphates which degraded upon exposure to phosphodiesterase. As is the case for PEGylated therapeutics, residual in vitro activity of the PPEylated conjugates depends on the extent of protein modification. These results suggest that PEEP exhibits the desired properties of a biopolymer for use in next generation, fully degradable drug delivery systems.

Nanosized Delivery Systems for Therapeutic Proteins: Clinically Validated Technologies and Advanced Development Strategies

“…Protein conjugation with biodegradable poly(ethyl ethylene phosphate) (PEEP) was also reported (Steinbach et al, 2017). PPEylated BSA and catalase showed comparable activity to their PEG-equivalent.…”

In Vitro and In Vivo Studies of Biodegradability and Biocompatibility of Poly(εCL)-b-Poly(EtOEP)-Based Films

“…Ethylene phosphates, phosphonates and phosphoramidates with short alkyl substituents ( Scheme 1 a) represent promising cyclic substrates for the synthesis of copolymers with hydrophilic biodegradable blocks using catalytic ring-opening polymerization (ROP, Scheme 1 b) [ 5 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. 2-Ethoxy-1,3,2-dioxaphospholane 2-oxide (ethyl ethylene phosphate, EtOEP) is one of the most reliable monomers for the preparation of hydrophilic polyphosphoesters (PPEs) due to high reactivity and low tendency to form branched polymers [ 15 , 16 , 17 ]. Block copolymers poly(εCL)- b -poly(EtOEP) were synthesized previously using tin (II) octanoate as a catalyst [ 15 ].…”

Surface-attached poly(phosphoester)-hydrogels with benzophenone groups

“…For example, PPEylated nano-particles or proteins that were obtained by grafting PPE chains exhibited reduced protein adsorption and low interaction with human immune cells and were thus very similar to PEGylated nanocarriers. 9,16,17 To study the bioactivity of PPEs on macroscopic planar surfaces, we designed PPE-copolymers and terpolymers that can form surface-attached polymer networks by simultaneous photo-induced inter-chain crosslinking and surface attachment (Scheme 1). The advantage of this method of surface functionalization is that it is straightforward, efficient and that the thickness of the coating can be tuned over a wider range than when using other methods (e.g.…”