Pharmacokinetics,biocompatibility and bioavailability of a controlled release monoclonal antibody formulation

The sustained and localized delivery of monoclonal antibodies has become highly relevant, because of the increasing number of investigated local delivery applications in recent years. As the local delivery of antibodies is associated with high technological hurdles, very few successful approaches have been reported in the literature so far. Alginate-based delivery systems were previously described as promising sustained release formulations for monoclonal antibodies (mAbs). In order to further investigate their applicability, a single-dose animal study was conducted to compare the biocompatibility, the pharmacokinetics and the bioavailability of a human monoclonal antibody liquid formulation with two alginate-based sustained delivery systems after subcutaneous administration in rats. 28 days after injection, the depot systems were still found in the subcutis of the animals. A calcium cross-linked alginate formulation, which was injected as a hydrogel, was present as multiple compartments separated by subcutaneous tissue. An in situ forming alginate formulation was recovered as a single compact and cohesive structure. It can be assumed that the multiple compartments of the hydrogel formulation led to almost identical pharmacokinetic profiles for all tested animals, whereas the compact nature of the in situ forming system resulted in large interindividual variations in pharmacokinetics. As compared to the liquid formulation the hydrogel formulations led to lower mAb serum levels, and the in situ forming system to a shift in the time to reach the maximum mAb serum concentration (T_max) from 2 to 4 days. Importantly, it was shown that after 28 days only marginal amounts of residual mAb were present in the alginate matrix and in the tissue at the injection site indicating nearly complete release. In line with this finding, systemic drug bioavailability was not affected by using the controlled release systems. This study successfully demonstrates the suitability and underlines the potential of polyanionic systems for local and controlled mAb delivery.     

Pituitary-adrenal axis regulation in CRH-deficient mice

Corticotropin-releasing hormone (CRH)-deficient (knockout (KO)) mice demonstrate severely impaired adrenal responses to restraint, ether, and fasting, and lack the normal diurnal glucocorticoid (GC) rhythm. Here, we summarize recent studies determining the role of CRH in augmenting plasma adrenocorticotrophic hormone (ACTH) concentration after glucocorticoid withdrawal and pituitary-adrenal axis stimulation in the context of inflammation. Even though GC insufficient, basal pituitary proopiomelanocortin (POMC) mRNA, ACTH peptide content within the pituitary, and plasma ACTH concentrations are not elevated in CRH KO mice. POMC mRNA content in CRH KO mice increases following adrenalectomy, and this increase is reversed by GC, but not aldosterone, replacement. In marked contrast to the increase in POMC mRNA, plasma ACTH does not increase in the CRH KO mice following adrenalectomy. Administration of CRH to adrenalectomized CRH KO mice results in acute, robust ACTH secretion. Thus, loss of GC feedback can increase POMC gene expression in the pituitary, but CRH action is essential for increased secretion of ACTH into the circulation. While GC secretion is impaired in CRH KO mice after most stimuli, we have found near-normal GC responses to inflammation and systemic immune challenge. Studies in mice with CRH and IL-6 deficiency reveal that IL-6 is essential for activation of the pituitary-adrenal axis during inflammatory and other stressors in the absence of CRH.     

Interventional catheter occlusion of the atrial septal defect of the secundum type--experiences with "CardioSeal" and "Angel Wings"

Between July 1996 and July 1998, 34 patients (female n = 16, male n = 18) were scheduled for catheter--interventional occlusion (ASDO) of an atrium septum defect of secundum type (ASD II). Median age was 7.9 years (2.5-54.6), weight 23.1 kg (9-97). 9 defects were closed with "Angel Wings" (AW) and 25 ASD occlusions were attempted with "CardioSeal" (CS). 30 patients had simple ASD II, 3 persisting foramen ovale with suspected paradoxal cerebral embolization and 1 significant residual shunt at atrial level after corrective heart surgery for interrupted aortic arch type B. ASDO was successful in 31/34 cases (91%). One CS was removed surgically due to significant left to right shunt after release and two CS devices were withdrawn back into the sheath. Median ASD diameter was 11.9 mm (6-16), balloon occlusive diameter was 15 mm (6-20) and median left to right shunt was 40% (6-64%). On follow up minimal left to right shunt was seen in 5/31 patients (16%). In selected patients catheter--interventional ASDO may be a good alternative to surgical ASD closure.     

Reaction control of metal-assisted chemical etching for silicon-based zone plate nanostructures

Metal-assisted chemical etching (MACE) reaction parameters were investigated for the fabrication of specially designed silicon-based X-ray zone plate nanostructures using a gold catalyst pattern and etching solutions composed of HF and H₂O₂. Etching depth, zone verticality and zone roughness were studied as a function of etching solution composition, temperature and processing time. Homogeneous, vertical etching with increasing depth is observed at increasing H₂O₂ concentrations and elevated processing temperatures, implying a balance in the hole injection and silica dissolution kinetics at the gold–silicon interface. The etching depth decreases and zone roughness increases at the highest investigated H₂O₂ concentration and temperature. Possible reasons for these observations are discussed based on reaction chemistry and zone plate design. Optimum MACE conditions are found at HF : H₂O₂ concentrations of 4.7 M : 0.68 M and room temperature with an etching rate of ≈0.7 μm min⁻¹, which is about an order of magnitude higher than previous reports. Moreover, our results show that a grid catalyst design is important for successful fabrication of vertical high aspect ratio silicon nanostructures.

Specially designed X-ray zone plates with high aspect-ratios have been fabricated via metal-assisted chemical etching, by controlling the reaction kinetics.     

Hydrophobicity of Lipid-Conjugated siRNAs Predicts Productive Loading to Small Extracellular Vesicles

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Optimized Cholesterol-siRNA Chemistry Improves Productive Loading onto Extracellular Vesicles

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