Probing Amyloid ß Interactions with Synthetic Heparan Sulfate Oligosaccharides.

Heparan sulfate (HS) can play important roles in the biology and pathology of amyloid ß (Aß), a hallmark of Alzheimer's disease. To better understand the structure-activity relationship of HS/Aß interactions, synthetic HS oligosaccharides ranging from tetrasaccharides to decasaccharides have been utilized to study Aß interactions. Surface plasmon resonance experiments showed that the highly sulfated HS tetrasaccharides bearing full 2-O, 6-O, and N-sulfations exhibited the strongest binding with Aß among the tetrasaccharides investigated. Elongating the glycan length to hexa- and deca-saccharides significantly enhanced Aß affinity compared to the corresponding HS tetrasaccharide. Solid state NMR studies of the complexes of Aß with HS hexa- and deca-saccharides showed most significant chemical shift perturbation in the C-terminus residues of Aß. The strong binding HS oligosaccharides could reduce the cellular toxicities induced by Aß. This study provides new insights into HS/Aß interactions, highlighting how synthetic structurally well-defined HS oligosaccharides can assist in biological understanding of Aß.

Effective atherosclerotic plaque inflammation inhibition with targeted drug delivery by hyaluronan conjugated atorvastatin nanoparticles.

Atherosclerosis is associated with inflammation in the arteries, which is a major cause of heart attacks and strokes. Reducing the extent of local inflammation at atherosclerotic plaques can be an attractive strategy to combat atherosclerosis. While statins can exhibit direct anti-inflammatory activities, the high dose required for such a therapy renders it unrealistic due to their low systemic bioavailabilities and potential side effects. To overcome this, a new hyaluronan (HA)-atorvastatin (ATV) conjugate was designed with the hydrophobic statin ATV forming the core of the nanoparticle (HA-ATV-NP). The HA on the NPs can selectively bind with CD44, a cell surface receptor overexpressed on cells residing in atherosclerotic plaques and known to play important roles in plaque development. HA-ATV-NPs exhibited significantly higher anti-inflammatory effects on macrophages compared to ATV alone in vitro. Furthermore, when administered in an apolipoprotein E (ApoE)-knockout mouse model of atherosclerosis following a 1-week treatment regimen, HA-ATV-NPs markedly decreased inflammation in advanced atherosclerotic plaques, which were monitored through contrast agent aided magnetic resonance imaging. These results suggest CD44 targeting with HA-ATV-NPs is an attractive strategy to reduce harmful inflammation in atherosclerotic plaques.