Block polyelectrolyte micelles formed by poly(styrene-5-sodium acrylate) in aqueous solutions were characterized by static light scattering (SLS). Initially, the solutions contained gel-like particles; the kinetics of disentanglement of these particles were measured from the intensity of the scattered light at different angles as a function of heating time at 100 °C. It was found that after ca. 50 h of heating no further changes occurred in the scattered intensity. The effect of different sodium chloride concentrations on the aggregation numbers (N), radii of gyration (Rg), and second virial coefficients (A2) of the resulting micellar solutions was determined for two block copolymers, PS(6)-5-PANa(180) and PS( 23)-6-PANa-(300). It was found that N increased as a function of salt concentration at low salt contents, but the values remained constant above ca. 0.10 M NaCl. A range of samples with PS block lengths ranging from 6 to 71 units and PANa block lengths ranging from 44 to 780 units was measured in 2.5 M NaCl. As expected, the length of the insoluble block had a much greater effect on the aggregation numbers than that of the soluble block. The data were examined according to the scaling predictions of the star model and several mean-field models. Comparison with several of the models showed good agreement with experimental values of N, calculated core radius CRc), and Rg as a function of block lengths. The core radii values of the micelles agreed very well with those determined independently for similar samples measured in the solid state by small-angle X-ray scattering (SAXS). From this result, it was concluded that the micelles in 2.5 M NaCl exist singly, i.e., that no supermicellar aggregates are present and that the core is solvent free.

Critical micelle concentrations (cmcs) of block polyelectrolyte micelles formed from poly-(styrene-6-sodium acrylate) in aqueous and NaCl salt solutions were investigated by fluorescence measurements of solubilized pyrene. The measurements were made for a range of PS block lengths (6 to 110 units) and of PANa block lengths (15-2400 units). For the series consisting of 11 and 23 units of PS, which had been prepared with a wide range of PANa lengths, the cmc was found to pass through a maximum as a function of the soluble (PANa) block length. It was observed that as the length of the PS block increased, the dependence of the log cmc versus the PANa block length decreased. For all samples except the PS(6) series at low salt concentrations, the log cmc values were found to decrease linearly as a function of the square root of the NaCl concentration (VCa) which was varied from 0.10-2.5 M. The shape of the gradient d(log cmc)/d(VCa) versus the log of the number of PANa units was found to follow a curve of the same shape for the block polyelectrolyte micelles consisting of 6, 11, and 23 units of PS. The behavior of the curve was explained on the basis of polyelectrolyte conformations.

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The lysosomal cysteine protease cathepsin K is a target for osteoporosis therapy. The aryl-piperazine-containing cathepsin K inhibitor CRA-013783/L-006235 (1) displays greater than 4000-fold selectivity against the lysosomal/endosomal antitargets cathepsin B, L, and S. However, 1 and other aryl-piperazine-containing analogues, including balicatib (10), are approximately 10-100-fold more potent in cell-based enzyme occupancy assays than against each purified enzyme. This phenomenon arises from their basic, lipophilic nature, which results in lysosomal trapping. Consistent with its lysosomotropic nature, 1 accumulates in cells and in rat tissues of high lysosome content. In contrast, nonbasic aryl-morpholino-containing analogues do not exhibit lysosomotropic properties. Increased off-target activities of basic cathepsin K inhibitors were observed in a cell-based cathepsin S antigen presentation assay. No potency increases of basic inhibitors in a functional cathepsin K bone resorption whole cell assay were detected. Therefore, basic cathepsin K inhibitors, such as 1, suffer from reduced functional selectivities compared to those predicted using purified enzyme assays.

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