Multimodality imaging in vivo for preclinical assessment of tumor-targeted doxorubicin nanoparticles.

This study presents a new multimodal imaging approach that includes high-frequency ultrasound, fluorescence intensity, confocal, and spectral imaging to improve the preclinical evaluation of new therapeutics in vivo. Here we use this approach to assess in vivo the therapeutic efficacy of the novel chemotherapy construct, HerDox during and after treatment. HerDox is comprised of doxorubicin non-covalently assembled in a viral-like particle targeted to HER2+ tumor cells, causing tumor cell death at over 10-fold lower dose compared to the untargeted drug, while sparing the heart. Whereas our initial proof-of-principle studies on HerDox used tumor growth/shrinkage rates as a measure of therapeutic efficacy, here we show that multimodal imaging deployed during and after treatment can supplement traditional modes of tumor monitoring to further characterize the particle in tissues of treated mice. Specifically, we show here that tumor cell apoptosis elicited by HerDox can be monitored in vivo during treatment using high frequency ultrasound imaging, while in situ confocal imaging of excised tumors shows that HerDox indeed penetrated tumor tissue and can be detected at the subcellular level, including in the nucleus, via Dox fluorescence. In addition, ratiometric spectral imaging of the same tumor tissue enables quantitative discrimination of HerDox fluorescence from autofluorescence in situ. In contrast to standard approaches of preclinical assessment, this new method provides multiple/complementary information that may shorten the time required for initial evaluation of in vivo efficacy, thus potentially reducing the time and cost for translating new drug molecules into the clinic

Generalized Warped Disk Equations

The manner in which warps in accretion disks evolve depends on the magnitude of the viscosity. ... See full text for complete abstract

Investigating photoexcitation-induced mitochondrial damage by chemotherapeutic corroles using multimode optical imaging

We recently reported that a targeted, brightly fluorescent gallium corrole (HerGa) is highly effective for breast tumor detection and treatment. Unlike structurally similar porphryins, HerGa exhibits tumor-targeted toxicity without the need for photoexcitation. We have now examined whether photoexcitation further modulates HerGa toxicity, using multimode optical imaging of live cells, including two-photon excited fluorescence, differential interference contrast (DIC), spectral, and lifetime imaging. Using two-photon excited fluorescence imaging, we observed that light at specific wavelengths augments the HerGa-mediated mitochondrial membrane potential disruption of breast cancer cells in situ. In addition, DIC, spectral, and fluorescence lifetime imaging enabled us to both validate cell damage by HerGa photoexcitation and investigate HerGa internalization, thus allowing optimization of light dose and timing. Our demonstration of HerGa phototoxicity opens the way for development of new methods of cancer intervention using tumor-targeted corroles

Disk Imaging Survey of Chemistry with SMA: II. Southern Sky Protoplanetary Disk Data and Full Sample Statistics

This is the second in a series of papers based on data from DISCS, a Submillimeter Array observing program aimed at spatially and spectrally resolving the chemical composition of 12 protoplanetary disks. We present data on six Southern sky sources - IM Lup, SAO 206462 (HD 135344b), HD 142527, AS 209, AS 205 and V4046 Sgr - which complement the six sources in the Taurus star forming region reported previously. CO 2-1 and HCO+ 3-2 emission are detected and resolved in all disks and show velocity patterns consistent with Keplerian rotation. Where detected, the emission from DCO+ 3-2, N2H+ 3-2, H2CO 3-2 and 4-3,HCN 3-2 and CN 2-1 are also generally spatially resolved. The detection rates are highest toward the M and K stars, while the F star SAO 206462 has only weak CN and HCN emission, and H2CO alone is detected toward HD 142527. These findings together with the statistics from the previous Taurus disks, support the hypothesis that high detection rates of many small molecules depend on the presence of a cold and protected disk midplane, which is less common around F and A stars compared to M and K stars. Disk-averaged variations in the proposed radiation tracer CN/HCN are found to be small, despite two orders of magnitude range of spectral types and accretion rates. In contrast, the resolved images suggest that the CN/HCN emission ratio varies with disk radius in at least two of the systems. There are no clear observational differences in the disk chemistry between the classical/full T Tauri disks and transitional disks. Furthermore, the observed line emission does not depend on measured accretion luminosities or the number of infrared lines detected, which suggests that the chemistry outside of 100 AU is not coupled to the physical processes that drive the chemistry in the innermost few AU.Comment: accepted for publication in ApJ, 41 pages including 7 figure

Atmospheric circulation of hot Jupiters: Coupled radiative-dynamical general circulation model simulations of HD 189733b and HD 209458b

We present global, three-dimensional numerical simulations of HD 189733b and HD 209458b that couple the atmospheric dynamics to a realistic representation of non-gray cloud-free radiative transfer. The model, which we call the Substellar and Planetary Atmospheric Radiation and Circulation (SPARC) model, adopts the MITgcm for the dynamics and uses the radiative model of McKay, Marley, Fortney, and collaborators for the radiation. Like earlier work with simplified forcing, our simulations develop a broad eastward equatorial jet, mean westward flow at higher latitudes, and substantial flow over the poles at low pressure. For HD 189733b, our simulations without TiO and VO opacity can explain the broad features of the observed 8 and 24-micron light curves, including the modest day-night flux variation and the fact that the planet/star flux ratio peaks before the secondary eclipse. Our simulations also provide reasonable matches to the Spitzer secondary-eclipse depths at 4.5, 5.8, 8, 16, and 24 microns and the groundbased upper limit at 2.2 microns. However, we substantially underpredict the 3.6-micron secondary-eclipse depth, suggesting that our simulations are too cold in the 0.1-1 bar region. Predicted temporal variability in secondary-eclipse depths is ~1% at Spitzer bandpasses, consistent with recent observational upper limits at 8 microns. We also show that nonsynchronous rotation can significantly alter the jet structure. For HD 209458b, we include TiO and VO opacity; these simulations develop a hot (>2000 K) dayside stratosphere. Despite this stratosphere, we do not reproduce current Spitzer photometry of this planet. Light curves in Spitzer bandpasses show modest phase variation and satisfy the observational upper limit on day-night phase variation at 8 microns. (abridged)Comment: 20 pages (emulate-apj format), 21 figures, final version now published in ApJ. Includes expanded discussion of radiative-transfer methods and two new figure

A Spatially Resolved Inner Hole in the Disk around GM Aurigae

We present 0.3 arcsec resolution observations of the disk around GM Aurigae with the Submillimeter Array (SMA) at a wavelength of 860 um and with the Plateau de Bure Interferometer at a wavelength of 1.3 mm. These observations probe the distribution of disk material on spatial scales commensurate with the size of the inner hole predicted by models of the spectral energy distribution. The data clearly indicate a sharp decrease in millimeter optical depth at the disk center, consistent with a deficit of material at distances less than ~20 AU from the star. We refine the accretion disk model of Calvet et al. (2005) based on the unresolved spectral energy distribution (SED) and demonstrate that it reproduces well the spatially resolved millimeter continuum data at both available wavelengths. We also present complementary SMA observations of CO J=3-2 and J=2-1 emission from the disk at 2" resolution. The observed CO morphology is consistent with the continuum model prediction, with two significant deviations: (1) the emission displays a larger CO J=3-2/J=2-1 line ratio than predicted, which may indicate additional heating of gas in the upper disk layers; and (2) the position angle of the kinematic rotation pattern differs by 11 +/- 2 degrees from that measured at smaller scales from the dust continuum, which may indicate the presence of a warp. We note that photoevaporation, grain growth, and binarity are unlikely mechanisms for inducing the observed sharp decrease in opacity or surface density at the disk center. The inner hole plausibly results from the dynamical influence of a planet on the disk material. Warping induced by a planet could also potentially explain the difference in position angle between the continuum and CO data sets.Comment: 12 pages, 6 figures, accepted for publication in Ap

Photoexcitation of tumor-targeted corroles induces singlet oxygen-mediated augmentation of cytotoxicity

The tumor-targeted corrole particle, HerGa, displays preferential toxicity to tumors in vivo and can be tracked via fluorescence for simultaneous detection, imaging, and treatment. We have recently uncovered an additional feature of HerGa in that its cytotoxicity is enhanced by light irradiation. In the present study, we have elucidated the cellular mechanisms for HerGa photoexcitation-mediated cell damage using fluorescence optical imaging. In particular, we found that light irradiation of HerGa produces singlet oxygen, causing mitochondrial damage and cytochrome c release, thus promoting apoptotic cell death. An understanding of the mechanisms of cell death induced by HerGa, particularly under conditions of light-mediated excitation, may direct future efforts in further customizing this nanoparticle for additional therapeutic applications and enhanced potency

Resolved Images of Large Cavities in Protoplanetary Transition Disks

Circumstellar disks are thought to experience a rapid "transition" phase in their evolution that can have a considerable impact on the formation and early development of planetary systems. We present new and archival high angular resolution (0.3" = 40-75 AU) Submillimeter Array (SMA) observations of the 880 micron dust continuum emission from 12 such transition disks in nearby star-forming regions. In each case, we directly resolve a dust-depleted disk cavity around the central star. Using radiative transfer calculations, we interpret these dust disk structures in a homogeneous, parametric model framework by reproducing their SMA visibilities and SEDs. The cavities in these disks are large (R_cav = 15-73 AU) and substantially depleted of small (~um-sized) dust grains, although their mass contents are still uncertain. The structures of the remnant material at larger radii are comparable to normal disks. We demonstrate that these large cavities are common among the millimeter-bright disk population, comprising at least 20% of the disks in the bright half of the millimeter luminosity (disk mass) distribution. Utilizing these results, we assess some of the physical mechanisms proposed to account for transition disk structures. As has been shown before, photoevaporation models do not produce the large cavity sizes, accretion rates, and disk masses representative of this sample. It would be difficult to achieve a sufficient decrease of the dust optical depths in these cavities by particle growth alone: substantial growth (to meter sizes or beyond) must occur in large (tens of AU) regions of low turbulence without also producing an abundance of small particles. Given those challenges, we suggest instead that the observations are most commensurate with dynamical clearing due to tidal interactions with low-mass companions --young brown dwarfs or giant planets on long-period orbits.Comment: ApJ, in pres