Abstract
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 mobilise cholesterol. However, the administration of monomeric CDs suffers from several drawbacks due to their lack of specificity and poor pharmacokinetics. We present core-shell superparamagnetic iron oxide nanoparticles (SPIONs) functionalised with CDs appended to poly (2-methyl-2-oxazoline) polymers grafted in a dense brush to the iron oxide core. The CD-decorated nanoparticles (CySPIONs) are designed so that the macrocycle is specifically cleaved off the nanoparticle’s shell at a slightly acidic pH. In the intended use, free monomeric CDs will then mobilise cholesterol out of the lysosome to the cytosol and beyond through the formation of an inclusion complex. Hence, its suitability as a therapeutic platform to remove cholesterol in the lysosomal compartment. Synthesis and full characterization of the polymer as well as of the core-shell SPION are presented. Cholesterol-binding activity is shown through an enzymatic assay.
Highlights
Cholesterol is a major component of cell membranes, and it plays an essential role in ordinary neuronal physiology (Simons and Gerl, 2010)
Cyclodextrins (Davis and Brewster, 2004) (CDs) and their derivatives are emerging as promising therapeutic tools in the treatment of cholesterol-associated vascular and neurodegenerative diseases (Camilleri et al, 1994; Yao et al, 2012; Coisne et al, 2016) as well in the treatment of Niemann-Pick disease Type C (NPC) (Liu, 2012; Calias, 2017; Hastings et al, 2019; NeßlauerAnna-Maria et al, 2019)
We propose a novel class of Cyclodextrin-decorated superparamagnetic iron oxide nanoparticles (SPIONs) (CySPIONs) tailored to treat cholesterol-impaired diseases
Summary
Cholesterol is a major component of cell membranes, and it plays an essential role in ordinary neuronal physiology (Simons and Gerl, 2010). Innovative pharmacological approaches aiming at counteracting cholesterol imbalance, in the brain, are investigated. In such a context, cyclodextrins (Davis and Brewster, 2004) (CDs) and their derivatives are emerging as promising therapeutic tools in the treatment of cholesterol-associated vascular and neurodegenerative diseases (Camilleri et al, 1994; Yao et al, 2012; Coisne et al, 2016) as well in the treatment of Niemann-Pick disease Type C (NPC) (Liu, 2012; Calias, 2017; Hastings et al, 2019; NeßlauerAnna-Maria et al, 2019). Based on its cholesterol-extracting action, a chemical modification of the seven membered-ring of the series (βCD), the 2-hydroxypropylβ-cyclodextrin (HPβCD) is currently in phase I/II [NCT03893071] and phase II/III [NCT03893071] clinical trials for NPC treatment. CD treatments have significant shortcomings, mainly due to poor pharmacokinetics and bioavailability (Loftsson et al, 2016), in the Cholesterol Mopping SPIONs
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