Cholesterol plays a crucial role in major cardiovascular and neurodegenerative diseases, including Alzheimer’s disease and rare genetic disorders showing altered cholesterol metabolism. Cyclodextrins (CDs) have shown promising therapeutic efficacy based on their capacity to sequester and mobilize cholesterol. However, the administration of monomeric CDs suffers from several drawbacks due to their lack of specificity and poor pharmacokinetics.<br/>We present core-shell superparamagnetic iron oxide nanoparticles functionalized with CDs appended to poly(2-methyl-2-oxazoline) polymers grafted in a dense brush to the iron oxide core. The CD-decorated nanoparticle design cleaves off the macrocycle at a slightly acidic pH. Hence, it is suitable as a therapeutic platform to remove cholesterol in the lysosomal compartment. The core-shell nanoparticles and the novel polymers that are key to their activity are thoroughly characterized. We demonstrate the cholesterol-mopping activity of the pH-responsive nanoparticles with an enzymatic assay and on in vitro cell cultures.

Lysosome-triggered, cholesterol-mopping nanoparticles for treatment of neurodegenerative diseases

ACS Spring 2022

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