Comparison of Tumor Binding Across Tumor Types and Cell Lines to Support Free Drug Considerations for Oncology Drug Discovery.

Tumor binding is an important parameter to derive unbound tumor concentration to explore pharmacokinetics (PK) and pharmacodynamics (PD) relationships for oncology disease targets. Tumor binding was evaluated using eleven matrices, including various commonly used ex vivo human and mouse xenograft and syngeneic tumors, tumor cell lines and liver as a surrogate tissue. The results showed that tumor binding is highly correlated among the different tumors and tumor cell lines except for the mouse melanoma (B16F10) tumor type. Liver fraction unbound (fu) has a good correlation with B16F10 tumor binding. Liver also demonstrates a two-fold equivalency, on average, with binding of other tumor types when a scaling factor is applied. Predictive models were developed for tumor binding, with correlations established with LogD (acids), predicted muscle fu (neutrals) and measured plasma protein binding (bases) to estimate tumor fu when experimental data are not available. Many approaches can be applied to obtain and estimate tumor binding values. One strategy proposed is to use a surrogate tumor tissue, such as mouse xenograft ovarian cancer (OVCAR3) tumor, as a surrogate for tumor binding (except for B16F10) to provide an early assessment of unbound tumor concentrations for development of PK/PD relationships.

Enhanced Si Passivation and PERC Solar Cell Efficiency by Atomic Layer Deposited Aluminum Oxide with Two-step Post Annealing.

In this study, aluminum oxide (Al2O3) films were prepared by a spatial atomic layer deposition using deionized water and trimethylaluminum, followed by oxygen (O2), forming gas (FG), or two-step annealing. Minority carrier lifetime of the samples was measured by Sinton WCT-120. Field-effect passivation and chemical passivation were evaluated by fixed oxide charge (Qf) and interface defect density (Dit), respectively, using capacitance-voltage measurement. The results show that O2 annealing gives a high Qf of - 3.9 × 1012 cm-2, whereas FG annealing leads to excellent Si interface hydrogenation with a low Dit of 3.7 × 1011 eV-1 cm-2. Based on the consideration of the best field-effect passivation brought by oxygen annealing and the best chemical passivation brought by forming gas, the two-step annealing process was optimized. It is verified that the Al2O3 film annealed sequentially in oxygen and then in forming gas exhibits a high Qf (2.4 × 1012 cm-2) and a low Dit (3.1 × 1011 eV-1 cm-2), yielding the best minority carrier lifetime of 1097 µs. The SiNx/Al2O3 passivation stack with two-step annealing has a lifetime of 2072 µs, close to the intrinsic lifetime limit. Finally, the passivated emitter and rear cell conversion efficiency was improved from 21.61% by using an industry annealing process to 21.97% by using the two-step annealing process.

Accelerated bone growth in vitro by the conjugation of BMP2 peptide with hydroxyapatite on titanium alloy.

Titanium alloys have been widely used in orthopedic practice due to their inherent bioactivity, however it is still insufficient to truly and reliably incorporate into living bone. In this work, polydopamine film was employed to induce the growth of hydroxyapatite (HA) on titanium alloy to enhance its osteoconductivity. Bone morphogenetic protein-2 (BMP2) peptide was absorbed into the HA particles for osteoinductivity. The precipitation of HA and the existence of BMP2 peptide were examined by X-ray diffraction, X-ray photoelectron spectroscopy and fluorescence microscopy. The dissolution of HA and the release of BMP2 peptide were monitored by measuring the concentrations of calcium ions and BMP2 peptide in phosphate buffered saline solution, respectively. The effect of BMP2 peptide incorporated into HA coating on bone growth was evaluated in vitro by cell culture tests, including cell attachment, alkaline phosphatase (ALP) activity, and gene expression. The results show that the HA particles grown on the substrate are mediated by the polydopamine film. The BMP2 peptide is distributed uniformly on HA-coated substrate and released in a sustained manner. Moreover, the conjunction of HA and BMP2 peptide increases cell adhesion, ALP activity and gene expression of osteogenic markers, which are potentially useful in the development of enhanced orthopedic medical devices.

Initial attachment of osteoblastic cells onto sol-gel derived fluoridated hydroxyapatite coatings.

Initial cell attachment and spreading of anchorage-dependent cells onto the material surface are crucial concerns for the development of more effective implants. In this study, MG63 cells were employed to investigate the initial cell response to sol-gel derived fluoridated hydroxyapatite (FHA) coatings. Along with that, surface roughness, wettability, and protein adsorption were also characterized for those FHA coatings, respectively. It was observed that both the surface roughness and contact angle have a slight increase in response to the incorporation of more fluorine ions. All FHA coatings showed similar amount of adsorbed proteins (approximately 1.6 microg/cm(2)) upon testing in culture medium. Cell counting showed that no significant difference was observed for the amount of initially attached cells between HA and fluoridated HA coatings during the first 4 h culture. On the other hand, the well-spread cell on all prepared coating surface indicates that the incorporated fluorine ions have no adverse effect on cell spreading process. Therefore, it was suggested from this study that the prepared fluoridated hydroxyapatite coatings have comparable bioactivity to that of pure hydroxyapatite coating, and these results are meaningful for further investigation for application of FHA coatings.

Osteoblastic cell response on fluoridated hydroxyapatite coatings.

Fluoridated hydroxyapatite (FHA) coatings were deposited onto Ti6Al4V substrates by sol-gel dip-coating method. X-ray photoelectron spectroscopy results showed that fluoride ions were successfully incorporated into the hydroxyapatite (HA) lattice structure. The dissolution behavior in Tris-buffered physiological saline indicated that all fluoridated HA coatings had lower solubility than that of the pure HA coating. The lowest solubility was obtained at fluoride ion concentrations of 0.8-1.1M. In vitro cell responses were evaluated with human osteosarcoma MG63 cells in terms of cell morphology, proliferation and differentiation (alkaline phosphatase activity and osteocalcin level). For all coatings tested, similar cell morphologies and good cell viability were observed. Coatings fluoridated to 0.8-1.1 had a stronger stimulating effect on cell proliferation and differentiation activities. The influences on cell phenotypes were attributed mainly to a combined ion effect of Ca, P and F released from the coating during dissolution. For the best dissolution resistance and cell activities, it is recommended that the molar level of fluoride ion be from 0.8 to 1.1, such that the coating takes the form of Ca(10)(PO(4))(6)(OH)(1.2-0.9)F(0.8-1.1).