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.

Catalytic properties of beta zeolite exchanged with Pd and Fe for toluene total oxidation

Dealuminated beta zeolites exchanged with Pd and Fe were prepared to investigate the influence of iron and dealumination on the activity and selectivity of Pd/BEA zeolite for toluene total oxidation. The specific areas determined by BET method and EPR studies allowed to know that the palladium would be more easily agglomerated on the BEA than on the DBEA. Moreover, a quantification of the palladium saturation on the BEA zeolite was deduced by EPR. Effects of dynamic and static oxidation and weak and strong reduction treatments were studied by EPR. Several isolated and interacted Pd+ species and hole centers were detected. The Pd was much reduced after the catalytic test in dealuminated and Fe doped samples. This result could be directly correlated to the catalytic deactivation. The deactivation could be also explain by the type of coke deposed on the catalyst and by the hydroscopic behavior of the samples. Addition of Fe or dealumination could prevent the deactivation and then lead to better catalysts for VOCs oxidation.

Novel anti-inflammatory compound SEN1176 alleviates behavioural deficits induced following bilateral intrahippocampal injection of aggregated amyloid-beta(1-42).

Behavioral effects of a novel anti-inflammatory SEN1176 were investigated. This pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine suppresses amyloid-ß (Aß)1-42-induced macrophage production of nitric oxide, TNF-a, IL-1ß, and IL-6 in a dose-dependent fashion, an activity profile consistent with SEN1176 being a neuroinflammation inhibitor. Using male Sprague-Dawley rats, SEN1176 was examined relative to detrimental behavioral effects induced following bilateral intrahippocampal (IH) injections of aggregated Aß1-42. The rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement, enabling measurement of parameters of operant performance that reflect aspects of learning and memory. Under the ALCR schedule, orally administered SEN1176 at 5, 20, or 30 mg/kg was effective in reducing the behavioral deficit caused by bilateral IH aggregated Aß1-42 injections in a dose-related manner over a 90-day treatment period. SEN1176 at 20 and 30 mg/kg significantly reduced lever switching errors and, at doses of 5, 10, and 30 mg/kg, significantly reduced incorrect lever perseverations, indicating a reduction of the behavioral deficit induced as a result of inflammation following IH Aß1-42 injections. When treatment with SEN1176 was instigated 30 days after IH Aß1-42 injections, it resulted in progressive protection, and withdrawal of SEN1176 treatment 60 days after IH Aß1-42 injections revealed partial retention of the protective effect. SEN1176 also significantly reduced numbers of activated astrocytes adjacent to the aggregated Aß1-42 injection sites. These results indicate the potential of SEN1176 for alleviating chronic neuroinflammatory processes related to brain Aß deposition that affect learning and memory in Alzheimer's disease.

Gingival fibroblast response to cyclosporin A and transforming growth factor beta(1)

This study investigates a potential role for TGF beta(1), in the pathogenesis of cyclosporin A-induced gingival overgrowth (CsA-OG). TGF beta(1) was localized immunohistochemically in the connective tissue of both normal gingiva and CsA-OG. Intense staining for TGF beta(1) was detected at the tips of the dermal papillae of the overgrown gingiva. In addition, fibroblasts derived from healthy gingiva and fibroblasts derived from CsA-OG were cultured both as monolayers or embedded in a 3D-collagen gel. Fibroblast activity was monitored in terms of protein and collagen production in the presence of (i) 1 ng/ml TGF beta(1), (ii) 500 ng/ml CsA, or (iii) 500 ng/ml CsA and 1 ng/ml TGF beta(1). In monolayer culture TGF beta(1) significantly increased protein and collagen production in all cell strains (p

Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related increase in IL-1 beta levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1 beta production levels (P

High-performance liquid chromatographic determination of 17 beta-estradiol and 17 beta-estradiol-3-acetate solubilities and diffusion coefficients in silicone elastomeric intravaginal rings

A rapid, sensitive reversed-phase high-performance liquid chromatographic method has been developed for the determination of in vitro release of 17 beta-estradiol and its ester prodrug, 17 beta-estradiol-3-acetate, from silicone intravaginal rings. Partial hydrolysis of the acetate under the aqueous conditions provided by the 1% benzalkonium chloride release medium necessitates its conversion to 17 beta-estradiol prior to HPLC analysis. Both steroid peaks have been fully resolved from the benzalkonium chloride peaks by the reported chromatographic method,which employs a C-18 bonded reversed-phase column, an acetonitrile-water (50:50, v/v) mobile phase and a UV detection wavelength of 281 nm. The peak area versus 17 beta-estradiol concentration was found to be linear over the range of 0.0137-1347 mu g ml(-1) The HPLC method has also been used to determine the silicone solubilities and diffusion coefficients of the two related steroids. The almost 100-fold increase in 17 beta-estradiol-3-acetate release from the silicone core-type intravaginal rings compared to 17 beta-estradiol is shown to be due to a 60-fold increase in silicone solubility and a one and a half-fold increase in diffusitivity. The results demonstrate that an effective estrogen replacement therapy dose of 17 beta-estradiol may be administered from a silicone intravaginal reservoir device containing the labile 17 beta-estradiol-3-acetate prodrug. (C) 2000 Elsevier Science B.V. All rights reserved.

Hydrothermal synthesis of a continuous zeolite Beta layer by optimization of time, temperature and heating rate of the precursor mixture

Highly crystalline zeolite Beta coatings in a range of Si/Al ratios of 12-23 were synthesized on a surface-modified molybdenum substrate by hydrothermal synthesis. The average thickness of the coatings was ca. 2 mu m corresponding to a coverage of 2.5 gm(-2). The coatings were obtained from a viscous Na, K, and TEAOH containing aluminosilicate precursor mixture with silica sol as reactive silicon source. A mechanism for the in situ growth of zeolite Beta coatings is proposed. According to this mechanism, the deposition of an amorphous gel layer on the substrate surface in the initial stage of the synthesis is an important step for the crystallization of continuous zeolite Beta coatings. The heating rate of the precursor mixture and the synthesis temperature were optimized to control the level of supersaturation and to stimulate the initial formation of a gel layer. At a Si/Al ratio of 23, fast heating and a temperature of 150 degrees C are required to obtain high coverage, while at a Si/Al ratio of 15, hydrothermal synthesis has to be performed with a slow initial heating rate at 140 degrees C. (c) 2007 Elsevier Inc. All rights reserved.

Method for the in situ preparation of a single layer of zeolite Beta crystals on a molybdenum substrate for microreactor applications

A method for the hydrothermal synthesis of a single layer of zeolite Beta crystals on a molybdenum substrate for microreactor applications has been developed. Before the hydrothermal synthesis, the surface of the substrate was modified by an etching procedure that increases the roughness at the nanoscale level without completely eliminating the surface lay structure. Then, thin films of Al2O3 (170 nm) and TiO2 (50 nm) were successively deposited by atomic layer deposition (ALD) on the substrate. The internal Al2O3 film protects the Mo substrate from oxidation up to 550 degrees C in an oxidative environment. The high wettability of the external TiO2 film after UV irradiation increases zeolite nucleation on its surface. The role of the metal precursor (TiCl4 vs TiI4), deposition temperature (300 vs 500 degrees C), and film thickness (50 vs 100 nm) was investigated to obtain titania films with the slowest decay in the superhydrophilic behavior after UV irradiation. Zeolite Beta coatings with a Si/Al ratio of 23 were grown at 140 degrees C for 48 It. After ion exchange with a 10(-4) M cobalt acetate solution, the activity of the coatings was determined in the ammoxidation of ethylene to acetonitrile in a microstructured reactor. A maximum reaction rate of 220 mu mol C2H3N g(-1) s(-1) was obtained at 500 degrees C, with 42% carbon selectivity to acetonitrile. (C) 2007 Elsevier Inc. All rights reserved.