Preparation and characterization of multimodal hybrid organic and inorganic nanocrystals of camptothecin and gold.

We demonstrate a novel inorganic-organic crystalline nanoconstruct, where gold atoms were imbedded in the crystal lattices as defects of camptothecin nanocrystals, suggesting its potential use as simultaneous agents for cancer therapy and bioimaging. The incorporation of gold, a potential computed tomography (CT) contrast agent, in the nanocrystals of camptothecin was detected by transmission electron microscope (TEM) and further quantified by energy dispersive X-ray spectrometry (EDS) and inductively coupled plasma-optical emission spectrometers (ICP-OES). Due to gold's high attenuation coefficient, only a relatively small amount needs to be present in order to create a good noise-to-contrast ratio in CT imaging. The imbedded gold atoms and clusters are expected to share the same biological fate as the camptothecin nanocrystals, reaching and accumulating in tumor site due to the enhanced permeation and retention (EPR) effect.

Preparation and characterization of multimodal hybrid organic and inorganic nanocrystals of camptothecin and gold

We demonstrate a novel inorganic-organic crystalline nanoconstruct, where gold atoms were imbedded in the crystal lattices as defects of camptothecin nanocrystals, suggesting its potential use as simultaneous agents for cancer therapy and bioimaging. The incorporation of gold, a potential computed tomography (CT) contrast agent, in the nanocrystals of camptothecin was detected by transmission electron microscope (TEM) and further quantified by energy dispersive X-ray spectrometry (EDS) and inductively coupled plasma-optical emission spectrometers (ICP-OES). Due to gold's high attenuation coefficient, only a relatively small amount needs to be present in order to create a good noise-to-contrast ratio in CT imaging. The imbedded gold atoms and clusters are expected to share the same biological fate as the camptothecin nanocrystals, reaching and accumulating in tumor site due to the enhanced permeation and retention (EPR) effect.

In vivo investigation of hybrid Paclitaxel nanocrystals with dual fluorescent probes for cancer theranostics.

PURPOSE: To develop novel hybrid paclitaxel (PTX) nanocrystals, in which bioactivatable (MMPSense® 750 FAST) and near infrared (Flamma Fluor® FPR-648) fluorophores are physically incorporated, and to evaluate their anticancer efficacy and diagnostic properties in breast cancer xenograft murine model. METHODS: The pure and hybrid paclitaxel nanocrystals were prepared by an anti-solvent method, and their physical properties were characterized. The tumor volume change and body weight change were evaluated to assess the treatment efficacy and toxicity. Bioimaging of treated mice was obtained non-invasively in vivo. RESULTS: The released MMPSense molecules from the hybrid nanocrystals were activated by matrix metalloproteinases (MMPs) in vivo, similarly to the free MMPSense, demonstrating its ability to monitor cancer progression. Concurrently, the entrapped FPR-648 was imaged at a different wavelength. Furthermore, when administered at 20 mg/kg, the nanocrystal formulations exerted comparable efficacy as Taxol®, but with decreased toxicity. CONCLUSIONS: Hybrid nanocrystals that physically integrated two fluorophores were successfully prepared from solution. Hybrid nanocrystals were shown not only exerting antitumor activity, but also demonstrating the potential of multi-modular bioimaging for diagnostics.

Biodistribution and bioimaging studies of hybrid paclitaxel nanocrystals: lessons learned of the EPR effect and image-guided drug delivery.

Paclitaxel (PTX) nanocrystals (200 nm) were produced by crystallization from a solution. Antitumor efficacy and toxicity were examined through a survival study in a human HT-29 colon cancer xenograft murine model. The antitumor activity of the nanocrystal treatments was comparable with that by the conventional solubilization formulation (Taxol®), but yielded less toxicity as indicated by the result of a survival study. Tritium-labeled PTX nanocrystals were further produced with a near infrared (NIR) fluorescent dye physically integrated in the crystal lattice. Biodistribution and tumor accumulation of the tritium-labeled PTX nanocrystals were determined immediately after intravenous administration and up to 48 h by scintillation counting. Whole-body optical imaging of animals was concurrently carried out; fluorescent intensities were also measured from excised tumors and major organs of euthanized animals. It was found that drug accumulation in the tumor was less than 1% of 20mg/kg intravenous dose. Qualitatively correlation was identified between the biodistribution determined by using tritium-labeled particles and that using optical imaging, but quantitative divergence existed. The divergent results suggest possible ways to improve the design of hybrid nanocrystals for cancer therapy and diagnosis. The study also raises questions of the general role of the enhanced permeability and retention (EPR) effect in tumor targeting and the effectiveness of bioimaging, specifically for theranostics, in tracking drug distribution and pharmacokinetics.

Liver transplant center risk tolerance.

Recent changes in Center for Medicare & Medicaid Services (CMS) condition for participation, using benchmark volume/outcomes requirements for certification, have been implemented. Consequently, the ability of a transplant center to assess its risk tolerance is important in successful management. An analysis of SRTR data was performed to determine donor/recipient risk factors for graft loss or patient death in the first year. Each transplant performed was then assigned a prospective relative risk (RR) of failure. Using a Monte-Carlo simulation, transplants were selected at random that met the centers' acceptable risk tolerance. Transplant center volume was fixed and its risk tolerance was adjusted to determine the impact on outcomes. The model was run 1000 times on centers with varying volume. The modeling demonstrates that centers with smaller annual volumes must use a more risk taking strategy than larger volume centers to avoid being flagged for CMS volume requirements. The modeling also demonstrates optimal risk taking strategies for centers based upon volume to minimize the probability of being flagged for not meeting volume or outcomes benchmarks. Small volume centers must perform higher risk transplants to meet current CMS requirements and are at risk for adverse action secondary to chance alone.

Photosynthetic pathway and ecological adaptation explain stomatal trait diversity amongst grasses.

• The evolution of C(4) photosynthesis in plants has allowed the maintenance of high CO(2) assimilation rates despite lower stomatal conductances. This underpins the greater water-use efficiency in C(4) species and their tendency to occupy drier, more seasonal environments than their C(3) relatives. • The basis of interspecific variation in maximum stomatal conductance to water (g(max) ), as defined by stomatal density and size, was investigated in a common-environment screening experiment. Stomatal traits were measured in 28 species from seven grass lineages, and comparative methods were used to test for predicted effects of C(3) and C(4) photosynthesis, annual precipitation and habitat wetness on g(max) . • Novel results were as follows: significant phylogenetic patterns exist in g(max) and its determinants, stomatal size and stomatal density; C(4) species consistently have lower g(max) than their C(3) relatives, associated with a shift towards smaller stomata at a given density. A direct relationship between g(max) and precipitation was not supported. However, we confirmed associations between C(4) photosynthesis and lower precipitation, and showed steeper stomatal size-density relationships and higher g(max) in wetter habitats. • The observed relationships between stomatal patterning, photosynthetic pathway and habitat provide a clear example of the interplay between anatomical traits, physiological innovation and ecological adaptation in plants.

Hybrid nanocrystals: achieving concurrent therapeutic and bioimaging functionalities toward solid tumors.

Bioimaging and therapeutic agents accumulated in ectopic tumors following intravenous administration of hybrid nanocrystals to tumor-bearing mice. Solid, nanosized paclitaxel crystals physically incorporated fluorescent molecules throughout the crystal lattice and retained fluorescent properties in the solid state. Hybrid nanocrystals were significantly localized in solid tumors and remained in the tumor for several days. An anticancer effect is expected of these hybrid nanocrystals.

Preparation and antitumor study of camptothecin nanocrystals.

Camptothecin (CPT) is a potent, broad spectrum antitumor agent that inhibits the activity of DNA topoisomerase I. Due to its poor solubility and stability and consequent delivery challenges, its clinical use is nevertheless limited. We aim to use nanocrystal formulation as a way to circumvent the difficult solubilization practice. Specifically, camptothecin nanocrystals were prepared with a sonication-precipitation method without additional stabilizing surfactants. Particle characteristics, cellular cytotoxicity, and animal antitumor effect were examined. CPT nanocrystals were tested to be more potent to MCF-7 cells than CPT solution in vitro. When tested in MCF-7 xenografted BALB/c mice, the CPT nanocrystals exhibited significant suppression of tumor growth. The drug concentration in the tumor was five times more at 24h by using the nanocrystal treatment than by using the drug salt solution. Storage stability study indicated that the nanocrystals were stable for at least six months. Overall, CPT nanocrystals were considered to be potentially feasible to overcome formulation challenges for drug delivery and to be used in clinic.

Ab initio investigation of dissolution mechanisms in aluminosilicate minerals.

The reactions of aluminosilicate clusters with water are investigated using ab initio calculations. There are several reaction sites on a mineral surface, and, in the case of aluminosilicates, the dissolution chemistry is dictated by chemically distinct surface termination sites: Al and Si. Environmental factors such as pH determine the protonation state and configuration around these terminal sites. The dissolution mechanisms for Al- and Si-terminated sites in protonated, neutral, and deprotonated states are determined using density functional theory calculations. In all protonation states, Si are tetra-coordinated; however, the ability of Al to exist in tetra-, penta-, and hexa-coordination states makes the dissolution mechanisms for the two types of terminal sites fundamentally different. The calculated barrier heights for Al-terminated sites are predicted to be lower than those for Si-terminated sites, a trend that has been observed in experimental studies. The sensitivity of the calculations on the choice of density functionals and basis sets is tested using three functionals: B3LYP, PBE1PBE, and M05-2X, in combination with the 6-311+G(d,p) and MG3S basis sets. For all these calculations, the geometries of the stationary points along the reaction path and the barrier heights are presented.

Spatial genetic structure in the Laperrine's olive (Olea europaea subsp. laperrinei), a long-living tree from the central Saharan mountains.

The Laperrine's olive (Olea europaea subsp. laperrinei) is an emblematic species of the Sahelo-Saharan Mountains. Populations of this tree are locally threatened by extinction due to climatic vicissitudes and human activities, particularly in Niger and Algeria. In order to study the spatial genetic structure and the dynamics of O. e. laperrinei populations, we sampled trees in four isolated mountain ranges (Tassili n'Ajjer and Hoggar (Algeria), Tamgak and Bagzane (Niger)). A total of 237 genets were identified using nuclear microsatellites. Phylogenetic reconstruction based on plastid DNA data supported a maternal origin of O. e. laperrinei populations in South Algeria, where a higher allelic richness was observed. Based on nuclear microsatellite data, two levels of structure were revealed: first, individuals from Niger and Algeria were separated in two distinct groups; second, four less differentiated clusters corresponded to the four studied mountain ranges. These results give support to the fact that desert barriers have greatly limited long distance gene flow. Within populations, pairwise kinship coefficients were significantly correlated to geographical distance for Niger populations but not for Algerian mountains. Historical factors and habitat heterogeneity may explain the differences observed. We conclude that the Hoggar acts as an important genetic reservoir that has to be taken into account in future conservation programmes. Moreover, very isolated endangered populations (for example, Bagzane) displaying evident genetic particularities have to be urgently considered for their endemism.