China Science

Targeting the minor groove of DNA through binding to a small molecule has long been considered an important molecular-recognition strategy in biology. A wide range of synthetic heterocyclic molecules bind noncovalently in the minor groove of the double helix and are also effective against a number of human and animal diseases. A classic structural concept, the isohelicity principle, has guided much of this work: such heterocyclic molecules require a shape that complements the convex surface of the minor groove. Researchers have used this principle to design molecules that can read DNA sequences. This principle also predicts that molecules that lack the complementary shape requirement would only bind weakly to DNA. Recently, however, researchers have unexpectedly found that some essentially linear compounds, which do not have this feature, can have high DNA affinity. In this Account, we discuss an alternative recognition concept based on these new findings. We demonstrate that highly structured water molecules can play a key role in mediating between the ligand and DNA minor groove without loss of binding affinity. Combined structural and thermodynamic approaches to understanding the behavior of these molecules have shown that there are different categories of bound water in their DNA complexes. For example, application of this water-bridging concept to the phenylamidine platform has resulted in the discovery of molecules with high levels of biological activity and low nonspecific toxicity. Some of these molecules are now in advanced clinical trials.

Binh Nguyen#8224?Stephen Neidle#8225?W. David Wilson#8224?

MUC1 gene encodes a transmembrane mucin glycoprotein that is overexpressed in human breast cancer; colon cancer. The objective of this study was to develop an in situ gel delivery system containing paclitaxel (PTX); mucoadhesives for sustained; targeted delivery of anticancer drugs. The delivery system consisted of chitosan; glyceryl monooleate (GMO) in 0.33M citric acid containing PTX. The in vitro release of PTX from the gel was performed in presence; absence of Tween 80 at drug loads of 0.18%, 0.30%,; 0.54% (wt/wt), in Sorensen’s phosphate buffer (pH 7.4) at 37°C. Different mucin-producing cell lines (Calu-3

Saurabh Jauhari1?Alekha K. Dash1Email:adash@creighton.edu
[1] School of Pharmacy & Health Professions, Creighton University Medical Center, 2500 California Plaza, Omaha, NE

The purpose of this research was to analyze the pharmacological properties of a homologous series of nitrogen mustard (N-mustard) agents formed after inserting 1 to 9 methylene groups (-CH2-) between 2-N(CH2CH2Cl)2 groups. These compounds were shown to have significant correlations; associations in their properties after analysis by pattern recognition methods including hierarchical classification, cluster analysis, nonmetric multi-dimensional scaling (MDS), detrended correspondence analysis, K-means cluster analysis, discriminant analysis,; self-organizing tree algorithm (SOTA) analysis. Detrended correspondence analysis showed a linear-like association of the 9 homologs,; hierarchical classification showed that each homolog had great similarity to at least one other member of the series—as did cluster analysis using paired-group distance measure. Nonmetric multi-dimensional scaling was able to discriminate homologs 2; 3 (by number of methylene groups) from homologs 4, 5,; 6 as a group,; from homologs 7, 8,; 9 as a group. Discriminant analysis, K-means cluster analysis,; hierarchical classification distinguished the high molecular weight homologs from low molecular weight homologs. As the number of methylene groups increased the aqueous solubility decreased, dermal permeation coefficient increased, Log P increased, molar volume increased, parachor increased,; index of refraction decreased. Application of pattern recognition methods discerned useful interrelationships within the homologous series that will determine specific; beneficial clinical applications for each homolog; methods of administration.

Ronald Bartzatt1Email:bartzatt@mail.unomaha.edu?Laura Donigan1
[1] Department of Chemistry, Laboratory of Pharmaceutical Studies, University of Nebraska, Durham Science Center, 6001 Dodge St, 68182 Omaha, NE

The objective of this study was to develop an efficient tumor vasculature targeted liposome delivery system for combretastatin A4, a novel antivascular agent. Liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, distearoyl phosphoethanolamine-polyethylene-glycol-2000 conjugate (DSPE-PEG),; DSPE-PEG-maleimide were prepared by the lipid film hydration; extrusion process. Cyclic RGD (Arg-Gly-Asp) peptides with affinity for ?v?3-integrins expressed on tumor vascular endothelial cells were coupled to the distal end of PEG on the liposomes sterically stabilized with PEG (long circulating liposomes, LCL). The liposome delivery system was characterized in terms of size, lamellarity, ligand density, drug loading,; leakage properties. Targeting nature of the delivery system was evaluated in vitro using cultured human umbilical vein endothelial cells (HUVEC). Electron microscopic observations of the formulations revealed presence of small unilamellar liposomes of ?120 nm in diameter. High performance liquid chromatography determination of ligand coupling to the liposome surface indicated that more than 99% of the RGD peptides were reacted with maleimide groups on the liposome surface. Up to 3 mg/mL of stable liposomal combretastatin A4 loading was achieved with ?80% of this being entrapped within the liposomes. In the in vitro cell culture studies, targeted liposomes showed significantly higher binding to their target cells than non-targeted liposomes, presumably through specific interaction of the RGD with its receptors on the cell surface. It was concluded that the targeting properties of the prepared delivery system would potentially improve the therapeutic benefits of combretastatin A4 compared with nontargeted liposomes or solution dosage forms.

Ramakrishna Nallamothu1Email:rnallamo@utmem.edu?George C. Wood1?Christopher B. Pattillo2?Robert C. Scott2?Mohammad F. Kiani2?Bob M. Moore4?Laura A. Thoma1
[1] Parenteral Medications Laboratories, Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, TN, 26 S Dunlap St, Room 214, 38163 Memphis, TN ;[2] Department of Mechanical Engineering, Temple University, Philadelphia, PA ;[3] Department of Radiation Oncology, Temple University, Philadelphia, PA ;[4] Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, TN

Surface intermixing behavior during thin-film deposition in the Co–Al system was investigated on the atomic scale by three-dimensional classical molecular dynamics simulation. Asymmetry of the surface intermixing was observed: Al deposition on a Co substrate resulted in an Al thin-film with an atomically sharp interface, while a Co thin-film deposited on an Al substrate had an interfacial intermixing layer of B2 structure. This phenomenon is discussed in terms of the kinetics of atomic intermixing on the surface. A kinetic criterion for the atomic intermixing is whether the increased kinetic energy of the deposited atom near the surface is larger than the energy barrier to atomic intermixing on the surface. Local acceleration of the deposited atoms near the surface provides an explanation of the puzzling phenomenon of the significant intermixing under low-energy deposition conditions such as thermal evaporation or molecular beam epitaxy.

Sang-Pil Kima?Seung-Cheol Leea?Kwang-Ryeol LeeaEmail:krlee@kist.re.kr?Yong-Chae Chungb
[a]Computational Science Center, Future Fusion Research Laboratory, Korea Institute of Science and Technology, Seoul 136–791, Republic of Korea;[b]Division of Materials Science Engineering, Hanyang University, Seoul 133–791, Republic of Korea

Simulations of a monatomic model amorphous matrix embedded with approximately 37% of a body-centered cubic phase demonstrate mechanisms by which nanocrystallites can alter the mechanical response of metallic glass. Three effects affect the resulting ductility: (i) the presence of weak amorphous–crystalline interfaces, (ii) the fraction of nanocrystallites oriented to prevent twinning relative to the loading stress, and (iii) the shear-induced growth and dissolution of the nanocrystallites when they are impinged by shear bands. While the first effect dominates in these simulations due to system size limitations, the third effect appears to be crucial for understanding the ductility of experimental samples. These simulations indicate that shear-induced growth of existing nanocrystallites, rather than nucleation of new crystalline regions, may account for the observed enhancement in ductility.

Yunfeng Shia?Michael L. FalkaEmail:mfalk@umich.edu
[a]Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109-2136, USA

An empirically determined measure of the solute drag force called the drag factor is derived and defined. The drag factor is the derivative of mobility with respect to grain size, and describes well the drag effect of solute in the six different aluminas measured. A normalized drag factor allows direct comparison of different dopants, and validation of theoretically predicted trends. This construction is used to verify that the role of magnesia and rare-earth dopants in reducing the grain-growth rate is due to solute drag from the intrinsic mobility. These dopants segregate to the core of the grain-boundary, which differs from classical solute drag models that derive the drag effect from solute in the near-boundary lattice. The solute drag factor is also used to understand the role of drag in grain-boundaries that have mobilities that are enhanced relative to the pure material. This new approach for analyzing grain-growth advances the understanding of microstructural evolution and its relationship to properties.

Shen J. DillonaEmail:sjd6@lehigh.edu?Shantanu K. Beheraa?Martin P. Harmera
[a]Center for Advanced Materials; Nanotechnology, Lehigh University, Bethlehem, PA 18015, USA

This is the second of a two-part paper intended to develop a framework for collecting data, quantifying characteristics and subsequently representing microstructural information from polycrystalline materials. The framework is motivated by the need for incorporating accurate three-dimensional grain-level morphology and crystallography in computational analysis models that are currently gaining momentum. Following the quantification of microstructural features in the first part, this paper focuses on the development of models and codes for generating statistically equivalent synthetic microstructures. With input in the form of statistical characterization data obtained from serial-sectioning of the microstructures, this module is intended to provide computational modeling efforts with a microstructure representation that is statistically similar to the actual polycrystalline material.

Michael GroeberaEmail:groeber.9@osu.edu?Somnath GhoshbEmail:ghosh.5@osu.edu?Michael D. UchiccEmail:Michael.Uchic@wpafb.af.mil?Dennis M. DimidukcEmail:Dennis.Dimiduk@wpafb.af.mil
[a]Graduate Research Associate, Materials Science; Engineering, The Ohio State University, Columbus, OH 43210, USA;[b]Nordholt Professor, Mechanical Engineering; Materials Science; Engineering, The Ohio State University, Columbus, OH 43210, USA;[c]Air Force Research Laboratory, Materials; Manufacturing Directorate, AFRL/MLLMD, Wright-Patterson AFB, OH 45433, USA