Steroids
are the standard therapy for autoimmune hepatitis (AIH)
but the long-lasting administration is hampered by severe side effects.
Methods to improve the tropism of the drug toward the liver are therefore
required. Among them, conjugation to nanoparticles represents one
possible strategy. In this study, we exploited the natural liver tropism
of Avidin-Nucleic-Acid-Nano-Assemblies (ANANAS) to carry dexamethasone
selectively to the liver in an AIH animal model. An acid-labile biotin-hydrazone
linker was developed for reversible dexamethasone loading onto ANANAS.
The biodistribution, pharmacokinetics and efficacy of free and ANANAS-linked
dexamethasone (ANANAS–Hz–Dex) in healthy and AIH mice
were investigated upon intraperitoneal administration. In ANANAS-treated
animals, the free drug was detected only in the liver. Super-resolution
microscopy showed that nanoparticles segregate inside lysosomes of
liver immunocompetent cells, mainly involved in AIH progression. In
agreement with these observational results, chronic low-dose treatment
with ANANAS–Hz–Dex reduced the expression of liver inflammation
markers and, in contrast to the free drug, also the levels of circulating
AIH-specific autoantibodies. These data suggest that the ANANAS carrier
attenuates AIH-related liver damage without drug accumulation in off-site
tissues. The safety and biodegradability of the ANANAS carrier make
this formulation a promising tool for the treatment of autoimmune
liver disorders.
A new paradigm for the aetiopathology of phenylketonuria suggests the presence of amyloid-like assemblies in the brains of transgenic mouse models and patients with phenylketonuria, possibly shedding light on the selective cognitive deficit associated with this disease. Paralleling the amyloidogenic route that identifies different stages of peptide aggregation, corresponding to different levels of toxicity, we experimentally address for the first time, the physico-chemical properties of phenylalanine aggregates via Small Angle, Wide Angle X-ray Scattering and Atomic Force Microscopy. Results are consistent with the presence of well-structured, aligned fibres generated by milliMolar concentrations of phenylalanine. Moreover, the amyloid-modulating doxycycline agent affects the local structure of phenylalanine aggregates, preventing the formation of well-ordered crystalline structures. Phenylalanine assemblies prove toxic in vitro to immortalized cell lines and primary neuronal cells. Furthermore, these assemblies also cause dendritic sprouting alterations and synaptic protein impairment in neurons. Doxycycline counteracts these toxic effects, suggesting an approach for the development of future innovative non-dietary preventive therapies.
Tetralactam macrocycles can be functionalized by a variety of cross-coupling reactions. A modular "toolbox" strategy is presented that allows 1) several tetralactam macrocycles to be covalently connected with each other or with a central spacer, 2) the macrocycles to be substituted with or connected to different chromophores, and 3) metal-coordination sites to be attached to the macrocycles. With this approach a series of different oligo-macrocyclic hosts was obtained with great structural diversity and enormous potential for further functionalization. Rotaxanes made on the basis of these macrocycles have been synthesized to demonstrate their utility in building more complex supramolecular architectures.
Over
the last years, advancements in the use of nanoparticles for
biomedical applications have clearly showcased their potential for
the preparation of improved imaging and drug-delivery systems. However,
compared to the vast number of currently studied nanoparticles for
such applications, only a few successfully translate into clinical
practice. A common “barrier” that prevents nanoparticles
from efficiently delivering their payload to the target site after
administration is related to liver filtering, mainly due to nanoparticle
uptake by macrophages. This work reports the physicochemical and biological
investigation of disulfide-bridged organosilica nanoparticles with
cage-like morphology, OSCs, assessing in detail their bioaccumulation in vivo. The fate of intravenously injected 20 nm OSCs was
investigated in both healthy and tumor-bearing mice. Interestingly,
OSCs exclusively colocalize with hepatic sinusoidal endothelial cells
(LSECs) while avoiding Kupffer-cell uptake (less than 6%) under both
physiological and pathological conditions. Our findings suggest that
organosilica nanocages hold the potential to be used as nanotools
for LSECs modulation, potentially impacting key biological processes
such as tumor cell extravasation and hepatic immunity to invading
metastatic cells or a tolerogenic state in intrahepatic immune cells
in autoimmune diseases.
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