Abstract
Polymer-peptide conjugates are a promising class of compounds, where polymers can be used to overcome some of the limitations associated with peptides intended for therapeutic and/or diagnostic applications. Linear polymers such as poly(ethylene glycol) can be conjugated through terminal moieties and have therefore limited loading capacities. In this research, functionalised linear poly(ethylene glycol)s are utilised for peptide conjugation, to increase their potential loading capacities. These poly(ethylene glycol) derivatives are conjugated to peptide sequences containing representative side-chain functionalised amino acids, using different conjugation chemistries, including copper-catalysed azide-alkyne cycloaddition, amide coupling and thiol-ene reactions. Conjugation of a sequence containing the RGD motif to poly(allyl glycidyl ether) by the thiol-ene reaction, provided a conjugate which could be used in platelet adhesion studies.
Highlights
Peptides have the potential to be excellent therapeutic and targeting moieties, their clinical use is limited by their lack of bioavailability, short plasma half-life due to rapid clearance through kidneys, poor stability as a result of enzymatic degradation and potential immunogenicity [1,2].Effective solutions to improve the delivery and/or pharmacokinetic and pharmacodynamic properties of therapeutic peptides have been sought
Dendrimers and multi-arm Polyethylene glycol (PEG) such as star-PEGs. Another option is to polymerise an epoxide monomer yielding a linear polyether backbone reminiscent of PEG, but containing a functional group allowing the conjugation of the cargo along this backbone, or to co-polymerise this monomer with an unfunctionalised ethylene oxide monomer [14]. These homo- and co-polymers should maintain the capacity of the PEG chain to associate with two to three water molecules at each monomeric unit, a property which significantly contributes to the benefits imparted by PEG to biopharmaceutical agents, and allow the conjugation of multiple copies of this agent through the repeating functional group
They were purified by Size-Exclusion Chromatography (SEC) using Sephadex LH20 to remove byproducts and analysed by 1H-NMR, MALDI-TOF MS and analytical RP-HPLC where possible
Summary
Peptides have the potential to be excellent therapeutic and targeting moieties, their clinical use is limited by their lack of bioavailability, short plasma half-life due to rapid clearance through kidneys, poor stability as a result of enzymatic degradation and potential immunogenicity [1,2]. First and second generation PEGs, based on a linear backbone, are inherently characterised by a low loading capacity The latter can be increased by the generation of more complex structures, for example, PEG dendrimers and multi-arm PEGs such as star-PEGs. The latter can be increased by the generation of more complex structures, for example, PEG dendrimers and multi-arm PEGs such as star-PEGs Another option is to polymerise an epoxide monomer yielding a linear polyether backbone reminiscent of PEG, but containing a functional group allowing the conjugation of the cargo along this backbone, or to co-polymerise this monomer with an unfunctionalised ethylene oxide monomer [14]. The synthesis of PAGE homo-polymers, their functionalisation with a synthetic peptide and their comparison to other PEG-based structures with potential high peptide loading capacities are reported
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