Arborescent Polypeptides for Sustained Drug Delivery
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Arborescent Polypeptides for Sustained Drug Delivery Mosa Alsehli and Mario Gauthier* Department of Chemistry, Institute for Polymer Research, University of Waterloo, Waterloo, ON N2L 3G1, Canada
ABSTRACT Polypeptides are receiving increasing attention as building blocks to create nanostructures for biomedical applications. The first goal of this investigation was to explore the influence of the reaction conditions in the synthesis of well-defined dendritic graft (arborescent) polypeptides from amine-terminated poly(γ-benzyl L-glutamate) (PBG) chains. The optimization was carried out in terms of the reaction temperature, solvent, reaction time, and mole ratio of reactants and coupling agents. Size exclusion chromatography served to evaluate the grafting reaction in terms of grafting yield (fraction of side chains coupled with the substrate) and coupling efficiency (fraction of coupling sites consumed on the substrate). The maximum grafting yield and coupling efficiency achieved were 67% and 74%, respectively. These arborescent PBG substrates were subsequently grafted with poly(ethylene oxide) segments forming a hydrophilic shell, to obtain water-dispersible unimolecular micelles useful as delivery vehicles for doxorubicin. INTRODUCTION Dendrigraft polymers (referring collectively to arborescent and dendrimer-like star polymer structures) are a subset of dendritic polymers [1, 2]. Whereas monomers are invariably employed in the synthesis of dendrimers, reactive polymers serve as building blocks in successive grafting reactions for the synthesis of dendrigraft polymers. Since a large number of coupling sites are randomly distributed on the grafting substrates, a rapid increase in molar mass is observed per arborescent polymer generation while narrow molar mass distributions (dispersity Ð = Mw/Mn < 1.10) are maintained. Unimolecular micelles, namely single-molecule micelles with a covalently bonded structure, are obtained by grafting hydrophilic segments onto a hydrophobic arborescent polymer substrate. These micellar structures are stable regardless of their concentration, which would make them very attractive as nanocarriers for drugs, genes, and diagnostic agents [3-9]. Polypeptides are receiving increasing attention as building blocks to construct nanostructures for biomedical applications such as micelles [10]. The development of synthetic polypeptides with tunable dendritic topologies and well-defined structures is therefore of great interest. Peptides are commonly synthesized by successive coupling reactions of the carboxylic and amino acid groups of -amino acids [11], using carbodiimide reagents combined with 1hydroxybenzotriazole (HOBt) to avoid isomerization and increase the coupling yield [13]. Alternate methods and strategies have been developed for that purpose however, including the ring-opening polymerization of N-carboxyanhydride derivatives of amino acids [12]. We used this latter approach for the synthesis of well-defined (Ð < 1.10) arborescent polypeptides using poly(γ-benzyl L-glutamate) (PBG) bui
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