Conatumumab (AMG 655) coated nanoparticles for targeted pro-apoptotic drug delivery

Colloidal nanoparticle drug delivery systems have attracted much interest for their ability to enable effective formulation and delivery of therapeutic agents. The selective delivery of these nanoparticles to the disease site can be enhanced by coating the surface of the nanoparticles with targeting moieties, such as antibodies. In this current work, we demonstrate that antibodies on the surface of the particles can also elicit key biological effects. Specifically, we demonstrate the induction of apoptosis in colorectal HCT116 cancer cells using PLGA nanoparticles coated with Conatumumab (AMG 655) death receptor 5-specific antibodies (DR5-NP). We show that DR5-NP preferentially target DR5-expressing cells and present a sufficient density of antibody paratopes to induce apoptosis via DR5, unlike free AMG 655 or non-targeted control nanoparticles. We also demonstrate that DR5-targeted nanoparticles encapsulating the cytotoxic drug camptothecin are effectively targeted to the tumour cells, thereby producing enhanced cytotoxic effects through simultaneous drug delivery and apoptosis induction. These results demonstrate that antibodies on nanoparticulate surfaces can be exploited for dual modes of action to enhance the therapeutic utility of the modality. (C) 2011 Elsevier Ltd. All rights reserved.

Themed Issue: ‘Crossing Borders’

Edited special issue

Thermodynamic Properties of Mixtures Containing Ionic Liquids. 4. LLE of Binary Mixtures of [C2MIM][NTf2] with Propan-1-ol, Butan-1-ol, and Pentan-1-ol and [C4MIM][NTf2] with Cyclohexanol and 1,2-Hexanediol Including Studies of the Influence of Small Amounts of Water

Experimental data are presented for liquid-liquid equilibria of mixtures of the room-temperature ionic liquid 1-ethyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl)imide ([C2MIM][NTf2]) with the three alcohols propan-1-ol, butan-1-ol, and pentan-1-ol and for the 1-butyl-3-methyl-imidazolium bis(trifluoromethylsulfonyl) imide ([C4MIM][NTf2]) with cyclohexanol and 1,2-hexanediol in the temperature range of 275 K to 345 K at ambient pressure. The synthetic method has been used. Cloud points at a given composition were observed by varying the temperature and using light scattering to detect the phase splitting. In addition, the influence of small amounts of water on the demixing temperatures of binary mixtures of [C2MIM][NTf2] and propan-1-ol, butan-1-ol, and pentan-1-ol was investigated.

On the progenitor of the type IIP SN 2013ej in M74

We use natural seeing imaging of SN 2013ej in M74 to identify a progenitor candidate in archival Hubble Space Telescope (HST) + Advanced Camera for Survey images. We find a source coincident with the supernova (SN) in the F814W filter within the total 75 mas (~3 pc astrometric uncertainty; however, the position of the progenitor candidate in contemporaneous F435W and F555W filters is significantly offset. We conclude that the 'progenitor candidate' is in fact two physically unrelated sources; a blue source which is likely unrelated to the SN, and a red source which we suggest exploded as SN 2013ej. Deep images with the same instrument on board HST taken when the SN has faded (in approximately two year's time) will allow us to accurately characterize the unrelated neighbouring source and hence determine the intrinsic flux of the progenitor in three filters.We suggest that the F814W flux is dominated by the progenitor of SN 2013ej, and assuming a bolometric correction appropriate to an M-type supergiant, we estimate that the mass of the progenitor of SN 2013ej was between 8 and 15.5M⊙. 

Partisanship and Public Reason

In the large body of literature concerning John Rawls’s Political Liberalism (1993) and his conception of public reason, little attention has been paid to the implications that the constraints of public reason have for partisans, i.e. citizens who participate in politics through political parties. This paper argues that even on the basis of a ‘mild’ understanding of Rawls’s conception of the constraints of public reason, which takes into account the various stipulations Rawls provided throughout his later work, when applied to partisans the constraints of public reason lose none or little of their hindering force. This seriously undermines the contribution that parties and partisans can provide to the change and the varieties of public reason that Rawls himself advocates as a response to social change and, therefore, to political justification and legitimacy. Parties articulate, coordinate and enhance societal demands which, without their support, may remain unheard and fail to change the acceptable terms of public reason and political justification. If the political speech of partisans is restrained, this potential for change (and, therefore, its contribution to political legitimacy) is seriously undermined.

Distribution of Uranium and Thorium in Dolomitic Gravel Fill and Shale Saprolite

The objectives of this study were to examine (1) the distribution of U and Th in dolomitic gravel fill and shale saprolite, and (2) the removal of uranium from acidic groundwater by dolomitic gravel through precipitation with amorphous basaluminite at the U.S. DOE Oak Ridge Integrated Field Research Challenge (ORIFRC) field site west of the Oak Ridge Y-12 National Security Complex in East Tennessee. Media reactivity and sustainability are a technical concern with the deployment of any subsurface reactive media. Because the gravel was placed in the subsurface and exposed to contaminated groundwater for over 20 years, it provided a unique opportunity to study the solid and water phase geochemical conditions within the media after this length of exposure. This study illustrates that dolomite gravel can remove U from acidic contaminated groundwater with high levels of Al3+, Ca2+, NO3−, and SO42− over the long term. As the groundwater flows through high pH carbonate gravel, U containing amorphous basaluminite precipitates as the pH increases. This is due to an increase in groundwater pH from 3.2 to ∼6.5 as it comes in contact with the gravel. Therefore, carbonate gravel could be considered as a possible treatment medium for removal and sequestration of U and other pH sensitive metals from acidic contaminated groundwater. Thorium concentrations are also high in the carbonate gravel. Thorium generally shows an inverse relationship with U from the surface down into the deeper saprolite. Barite precipitated in the shallow saprolite directly below the dolomitic gravel from barium present in the acidic contaminated groundwater.