iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes

Polymersomes are versatile nanoscale vesicles that can be used for cytoplasmic delivery of payloads. Recently, we demonstrated that pH-sensitive polymersomes exhibit an intrinsic selectivity towards intraperitoneal tumor lesions. A tumor homing peptide, iRGD, harbors a cryptic C-end Rule (CendR) motif that is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. iRGD functionalization increases tumor selectivity and therapeutic efficacy of systemic drug-loaded nanoparticles in many tumor models. Here we studied whether intraperitoneally administered paclitaxel-loaded iRGD-polymersomes show improved efficacy in the treatment of peritoneal carcinomatosis. First, we demonstrated that the pH-sensitive polymersomes functionalized with RPARPAR (a prototypic CendR peptide) or iRGD internalize in the cells that express NRP-1, and that internalized polymersomes release their cargo inside the cytosol. CendR-targeted polymersomes loaded with paclitaxel were more cytotoxic on NRP-1-positive cells than on NRP-1-negative cells. In mice bearing peritoneal tumors of gastric (MKN-45P) or colon (CT26) origin, intraperitoneally administered RPARPAR and iRGD-polymersomes showed higher tumor-selective accumulation and penetration than untargeted polymersomes. Finally, iRGD-polymersomes loaded with paclitaxel showed improved efficacy in peritoneal tumor growth inhibition and in suppression of local dissemination compared to the pristine paclitaxel-polymersomes or Abraxane. Our study demonstrates that iRGD-functionalization improves efficacy of paclitaxel-polymersomes for intraperitoneal treatment of peritoneal carcinomatosis

Adaptive Density Estimation on the Circle by Nearly-Tight Frames

This work is concerned with the study of asymptotic properties of nonparametric density estimates in the framework of circular data. The estimation procedure here applied is based on wavelet thresholding methods: the wavelets used are the so-called Mexican needlets, which describe a nearly-tight frame on the circle. We study the asymptotic behaviour of the $L^{2}$-risk function for these estimates, in particular its adaptivity, proving that its rate of convergence is nearly optimal.Comment: 30 pages, 3 figure

Constraining the WMAP9 bispectrum and trispectrum with needlets

We develop a needlet approach to estimate the amplitude of general (including non-separable) bispectra and trispectra in the cosmic microwave background, and apply this to the WMAP 9-year data. We obtain estimates for the `orthogonal' bispectrum mode, yielding results which are consistent with the WMAP 7-year data. We do not observe the frequency-dependence suggested by the WMAP team's analysis of the 9-year data. We present 1-$\sigma$ constraints on the `local' trispectrum shape \gnl/10^5= -4.1\pm 2.3, the `$c1$' equilateral model \gnl^{c_1}/10^6= -0.8\pm 2.9, and the constant model \gnl^{\rm{const}}/10^6= -0.2\pm 1.8, together with a $95\%$ confidence-level upper bound on the multifield local parameter \taunl<22000. We estimate the bias on these parameters produced by point sources. The techniques developed in this paper should prove useful for other datasets such as Planck.Comment: 21 pages - matches published versio

A multi-level solver for Gaussian constrained CMB realizations

Updated to match published version (no major changes)Updated to match published version (no major changes)Updated to match published version (no major changes)We present a multi-level solver for drawing constrained Gaussian realizations or finding the maximum likelihood estimate of the CMB sky, given noisy sky maps with partial sky coverage. The method converges substantially faster than existing Conjugate Gradient (CG) methods for the same problem. For instance, for the 143 GHz Planck frequency channel, only 3 multi-level W-cycles result in an absolute error smaller than 1 microKelvin in any pixel. Using 16 CPU cores, this translates to a computational expense of 6 minutes wall time per realization, plus 8 minutes wall time for a power spectrum-dependent precomputation. Each additional W-cycle reduces the error by more than an order of magnitude, at an additional computational cost of 2 minutes. For comparison, we have never been able to achieve similar absolute convergence with conventional CG methods for this high signal-to-noise data set, even after thousands of CG iterations and employing expensive preconditioners. The solver is part of the Commander 2 code, which is available with an open source license at http://commander.bitbucket.org/

Revisiting direct electron transfer in nanostructured carbon laccase oxygen cathodes

The biocatalytic electroreduction of oxygen has been studied on large surface area graphite and Vulcan® carbon electrodes with adsorbed Trametes trogii laccase. The electrokinetics of the O2 reduction reaction (ORR) was studied at different electrode potentials, O2 partial pressures and concentrations of hydrogen peroxide.Even though the overpotential at 0.25 mA·cm-2 for the ORR at T1Cu of the adsorbed laccase on carbon is 0.8 V lower than for Pt of similar geometric area, the rate of the reaction and thus the operative current density is limited by the enzyme reaction rate at the T2/T3 cluster site for the adsorbed enzyme. The transition potential for the rate determining step from the direct electron transfer (DET) to the enzyme reaction shifts to higher potentials at higher oxygen partial pressure.Hydrogen peroxide produced by the ORR on bare carbon support participates in an inhibition mechanism, with uncompetitive predominance at high H2O2 concentration, non-competitive contribution can be detected at low inhibitor concentration