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

A new glycomonomer <b>1</b> 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 (<i><i><i>Đ</i></i></i>) 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-<i>b</i>-poly­(<b>1</b>)₄₇, poly­(F-OEGMEMA)₃₂-<i>b</i>-poly­(<b>1</b>)₂₇, and poly­(F-OEGMEMA)₃₂-<i>b</i>-poly­(<b>1</b>)₇ (where “F” 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-<i>b</i>-poly­(<b>1</b>-AuPEt₃)₄₇ generated spherical micelles with a hydrodynamic diameter <i>D</i>_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 μM on a gold concentration basis, compared to 0.3 μM for auranofin itself. The two shorter fluorescent complexed block copolymers formed spherical micelles with <i>D</i>_h 23 and 9 nm, respectively, and proved more cytotoxic than their longer counterpart, both displaying IC₅₀ values of 13.5 μM. 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’s <i>in vivo</i> 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

Structural and Mechanical Properties of Supramolecular Polyethylenes

Thymine (Thy) or 2,6-diamino-1,3,5-triazine (DAT) end-groups were efficiently installed on well-defined polyethylenes (PEs) synthesized by catalyzed chain growth (CCG) polymerization. Mono- and bifunctional low-molar mass PEs (1200–1500 g·mol^–1) formed lamellar morphologies with long-range order upon cooling from the melt due to microphase segregation of polar supramolecular units and apolar PE chains. Crystallization of Thy functions into rigid planes at 180 °C induced very long-range lamellar order in Thy-functionalized PEs and dramatically suppressed PE crystallization (from 67% to 19%). DAT-functionalized PEs, whose end-groups do not crystallize, showed slightly reduced PE crystallinity (62%) and less long-range order, since assembly was instead driven by PE crystallization. Mechanical analysis of the bifunctional PEs demonstrated high moduli roughly proportional to PE crystallinity but low strains at break due to the absence of chain entanglements and/or tie chains between crystalline lamellae. This work offers important insights for designing supramolecular systems with tunable thermal and mechanical properties

Nanodiamonds with Surface Grafted Polymer Chains as Vehicles for Cell Imaging and Cisplatin Delivery: Enhancement of Cell Toxicity by POEGMEMA Coating

Nanodiamonds (NDs) are highly promising drug carriers due to their biocompatibility, manipulable surface chemistry, and nonbleaching flourescence. In this communication, we compare the cytotoxicity of three ND-cisplatin systems in which cisplatin was incorporated via direct attachment to the ND surface, physical adsorption within a poly­(oligo­(ethylene glycol) methyl ether methacrylate) POEGMEMA surface coating, or complexation to 1,1-di-<i>tert</i>-butyl 3-(2-methacryloyloxy)­ethyl)­butane-1,1,3-tricarboxylate (MAETC) groups of a POEGMEMA-<i>st</i>-PMAETC surface layer. The polymer layers were introduced by grafting from RAFT-functionalized ND particles. All three ND systems displayed lower IC₅₀ values than free cisplatin in A2870 and A2870cis ovarian cancer cells. The two polymer-containing systems outperformed their “naked” counterpart, with the POEGMEMA-coated particles the most cytotoxic, displaying an IC₅₀ of 1.5 μM, more than an order of magnitude lower than that of cisplatin. The enhanced cytotoxicity is attributed to promotion of cellular uptake by the hydrophilic surface polymer