Hydrophilic Polycarbonates: Promising Degradable Alternatives to Poly(ethylene glycol)-Based Stealth Materials

Abstract

Poly(ethylene glycol) (PEG) represents the gold standard for stealth polymers in polymer-based therapeutic delivery. Unfortunately, PEG has some limitations which warrant the examination of alternative polymers. High molecular weight PEG (>40 kDa) can accumulate in tissue, and in some patients, PEG can provoke an immunological response and/or an accelerated blood clearance upon repeated exposure. As an alternative to PEG, watersoluble, nonfouling polycarbonates have been developed. These hydrophilic polycarbonates, prepared by acid-catalyzed ring-opening polymerization, contain hydroxyl groups attached to the polymer side chain via an amide linkage. These materials offer an enzymatically and hydrolytically degradable alternative to PEG. The results of cell viability studies and LD 50 studies indicate that these materials have minimal toxicity. Nonfouling behavior and the ability to resist/reduce aggregation with proteins were demonstrated. Diblock copolymers were also synthesized to demonstrate that these polymers can be utilized for micellar drug delivery systems.

Synthetic Polymers from Sugar-Based Monomers

“…105 ROP of cyclic carbonate monomers yielded hydrophilic polycarbonates, which are a promising alternative to PEG-based stealth materials. 106 Among successful applications of sugarbased polycarbonates, 92 the following are of special interest: self-assembled glycopolymer micelles with a high density of Dgalactose in the shell displayed strong interaction with a specific Chem. Rev.…”

Protein–polymer conjugation — moving beyond PEGylation

“…Side-chain functionalization can be done either pre- or post-polymerization, with the latter option offering more tolerance to different substituents [61]. The versatility of this highly modular approach was demonstrated by synthesis of a range of functional polycarbonates, which are of particular relevance to peptide/protein-polymer conjugates, such as polycarbonates with PEG [59], hydroxylcontaining [62●] and zwitterionic side-chains [63], all of which demonstrated promising protein-resistant properties and toxicity profiles.…”

“…Selective chemical modification of the heterocycles can then be carried out using desired alkylating agents to generate polycarbonates with a diverse range of side-chain chemistries. Reprinted with permission from Hedrick and coworkers [62●]. Copyright 2014 American Chemical Society.…”

Self-assembly of bioactive peptides, peptide conjugates, and peptide mimetic materials

“…[82][83][84][85] Immunogenic response to PEG has been reported. 84,86 Furthermore, synthetic PEG may contain impurities or unreacted monomer which is highly toxic. PEG-peptide and PEG-protein hydrogels and alternatives based on other synthetic polymers are the subject of recent reviews.…”