The progressive accumulation of amyloid-beta
(Aβ) in specific
areas of the brain is a common prelude to late-onset of Alzheimer’s
disease (AD). Although activation of liver X receptors (LXR) with
agonists decreases Aβ levels and ameliorates contextual memory
deficit, concomitant hypercholesterolemia/hypertriglyceridemia limits
their clinical application. DMHCA (
N
,
N
-dimethyl-3β-hydroxycholenamide) is an LXR partial agonist
that, despite inducing the expression of apolipoprotein E (main responsible
of Aβ drainage from the brain) without increasing cholesterol/triglyceride
levels, shows nil activity
in vivo
because of a low
solubility and inability to cross the blood brain barrier. Herein,
we describe a polymer therapeutic for the delivery of DMHCA. The covalent
incorporation of DMHCA into a PEG-dendritic scaffold via carboxylate
esters produces an amphiphilic copolymer that efficiently self-assembles
into nanometric micelles that exert a biological effect in primary
cultures of the central nervous system (CNS) and experimental animals
using the intranasal route. After CNS biodistribution and effective
doses of DMHCA micelles were determined in nontransgenic mice, a transgenic
AD-like mouse model of cerebral amyloidosis was treated with the micelles
for 21 days. The benefits of the treatment included prevention of
memory deterioration and a significant reduction of hippocampal Aβ
oligomers without affecting plasma lipid levels. These results represent
a proof of principle for further clinical developments of DMHCA delivery
systems.
Dendritic-polysaccharide PIC micelles represent promising delivery systems where dendritic rigidity and polysaccharide stiffness synchronize to determine the stability of the micelles, their kinetics of intracellular drug release, and cytotoxicity.
Herein, we describe the synthesis of an aptadendrimer by covalent bioconjugation of a gallic acid–triethylene glycol (GATG) dendrimer with the G-quadruplex (G4) AT11 aptamer (a modified version of AS1411) at the surface. We evaluated the loading and interaction of an acridine orange ligand, termed C8, that acts as an anticancer drug and binder/stabilizer of the G4 structure of AT11. Dynamic light scattering experiments demonstrated that the aptadendrimer was approximately 3.1 nm in diameter. Both steady-state and time-resolved fluorescence anisotropy evidenced the interaction between the aptadendrimer and C8. Additionally, we demonstrated that the iodine atom of the C8 ligand acts as an effective intramolecular quencher in solution, while upon complexation with the aptadendrimer, it adopts a more extended conformation. Docking studies support this conclusion. Release experiments show a delivery of C8 after 4 h. The aptadendrimers tend to localize in the cytoplasm of various cell lines studied as demonstrated by confocal microscopy. The internalization of the aptadendrimers is not nucleolin-mediated or by passive diffusion, but via endocytosis. MTT studies with prostate cancer cells and non-malignant cells evidenced high cytotoxicity mainly due to the C8 ligand. The rapid internalization of the aptadendrimers and the fluorescence properties make them attractive for the development of potential nanocarriers.
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