Glycopolymer Self-Assemblies with Gold(I) Complexed to the Core as a Delivery System for Auranofin

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• 作者：Samuel Pearson ; Hongxu Lu ; Martina H. Stenzel
• 刊名：Macromolecules
• 出版年：2015
• 出版时间：February 24, 2015
• 年：2015
• 卷：48
• 期：4
• 页码：1065-1076
• 全文大小：581K
• ISSN：1520-5835

文摘

A new glycomonomer 1 containing a thioacetate group in the anomeric position and mimicking the thiosugar ligand of the gold-based drug auranofin was designed and synthesized in four steps from d-glucose. Both CPADB-mediated homopolymerization and chain extension of a hydrophilic poly(OEGMEMA) macroRAFT agent were well-controlled with dispersities (膼) below 1.2, highlighting the suitability of thioacetate as a thiol protecting group in RAFT polymerization. Using the homopolymer as a test system, the thioacetate protective groups were selectively removed using hydrazine acetate, and AuPEt₃Cl was subsequently complexed to the exposed thiols to generate a polymeric auranofin analogue with 52% complexation efficiency. Extension of this successful procedure to three block copolymers with differing hydrophobic block lengths, poly(OEGMEMA)₃₄-b-poly(1)₄₇, poly(F-OEGMEMA)₃₂-b-poly(1)₂₇, and poly(F-OEGMEMA)₃₂-b-poly(1)₇ (where 鈥淔鈥?in the last two indicates the incorporation of 2 wt % fluorescein methacrylate into the hydrophilic block), produced well-defined complexed block copolymers with complexation efficiencies comparable to that of the homopolymer. Self-assembly of the longest complexed polymer poly(OEGMEMA)₃₄-b-poly(1-AuPEt₃)₄₇ generated spherical micelles with a hydrodynamic diameter D_h of 28 nm when prepared by slow water addition to a dilute DMF solution. The IC₅₀ value against OVCAR-3 cells in a serum-free media was 44 渭M on a gold concentration basis, compared to 0.3 渭M for auranofin itself. The two shorter fluorescent complexed block copolymers formed spherical micelles with D_h 23 and 9 nm, respectively, and proved more cytotoxic than their longer counterpart, both displaying IC₅₀ values of 13.5 渭M. The addition of serum to the cell growth medium reduced the cytotoxicity of auranofin by a factor of 3.6 but had a less marked effect on the fluorescent micellar systems, reducing their toxicities by between 2.4 and 2.8 times. These micellar systems therefore show less susceptibility to deactivation by serum proteins (which is the primary limitation to auranofin鈥檚 in vivo effectiveness) than the free auranofin, suggesting some protective benefit offered by the hydrophilic shell. Fluorescence microscopy of the two fluorescent systems revealed an accumulation in the lysosomes of the OVCAR-3 cells. The cytotoxicity mechanism may therefore differ from that of auranofin, which is known to interact with mitochondrial proteins.