Caspofungin Functionalized Polymethacrylates with Antifungal Properties

We describe the synthesis of hydrophilic poly(poly(ethylene glycol) methyl ether methacrylate) (PmPEGMA) and hydrophobic poly(methyl methacrylate) (PMMA) caspofungin conjugates by a post-polymerization modification of copolymers containing 10 mol % pentafluorophenyl methacrylate (PFPMA), which were obtained via reversible addition-fragmentation chain transfer copolymerization. The coupling of the clinically used antifungal caspofungin was confirmed and quantified in detail by a combination of ¹H-, ¹⁹F- and diffusion-ordered NMR spectroscopy, UV-vis spectroscopy, and size exclusion chromatography. The trifunctional amine-containing antifungal was attached via several amide bonds to the hydrophobic PMMA, but sterical hindrance induced by the mPEGMA side chains prohibited intramolecular double functionalization. Both polymer-drug conjugates revealed activity against important human-pathogenic fungi, that is, two strains of <i>Aspergillus fumigatus</i> and one strain of <i>Candida albicans</i> (2.5 mg L^-1 < MEC < 8 mg L^-1, MIC₅₀ = 4 mg L^-1), whereas RAW 264.7 macrophages as well as HeLa cells remained unaffected at these concentrations.