Bioconjugate Chemistry
Bioconjugate Chemistry
5 years ago

Hydrolyzable Poly[Poly(Ethylene Glycol) Methyl Ether Acrylate]–Colistin Prodrugs through Copper-Mediated Photoinduced Living Radical Polymerization

Hydrolyzable Poly[Poly(Ethylene Glycol) Methyl Ether Acrylate]–Colistin Prodrugs through Copper-Mediated Photoinduced Living Radical Polymerization
Paul Wilson, Thomas P. Davis, Kristian Kempe, Michael R. Whittaker, Chongyu Zhu, Vasiliki Nikolaou, Elena K. Schneider, Jian Li, Tobias Klein, Tony Velkov, David M. Haddleton
Through the recently developed copper-mediated photoinduced living radical polymerization (CP-LRP), a novel and well-defined polymeric prodrug of the antimicrobial lipopeptide colistin has been developed. A colistin initiator (Boc5–col–Br2) was synthesized through the modification of colistin on both of its threonine residues using a cleavable initiator linker, 2-(2-bromo-2-methylpropanoyloxy) acetic acid (BMPAA), and used for the polymerization of acrylates via CP-LRP. Polymerization proceeds from both sites of the colistin initiator, and through the polymerization of poly(ethylene glycol) methyl ether acrylate (PEGA480), three water-soluble polymer–colistin conjugates (col–PPEGA, having degrees of polymerization of 5, 10, and 20) were achieved with high yield (conversion of ≥93%) and narrow dispersities (Đ < 1.3) in 2–4 h. Little or no effect on the structure and activity of the colistin was observed during the synthesis, and most of the active colistin can be recovered from the conjugates in vitro within 2 days. Furthermore, in vitro biological analyses including disk diffusion, broth microdilution, and time-kill studies suggested that all of the conjugates have the ability to inhibit the growth of multidrug-resistant (MDR) Gram-negative bacteria, of which col–PPEGA DP5 and DP10 showed similar or better antibacterial performance compared to the clinically relevant colistin prodrug CMS, indicating their potential as an alternative antimicrobial therapy. Moreover, considering the control over the polymerization, the CP-LRP technique has the potential to provide an alternative platform for the development of polymer bioconjugates.

Publisher URL: http://dx.doi.org/10.1021/acs.bioconjchem.7b00242

DOI: 10.1021/acs.bioconjchem.7b00242

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