Theranostic nanoplatform for cholesterol-impaired diseases

Cholesterol plays a crucial role in major cardiovascular and neurodegenerative diseases, including some rare genetic disorders showing altered cholesterol metabolism such as Niemann- Pick Type C. Cyclodextrins (CDs) a doughnut-shaped class of molecules - 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 hypothesise that the functionalisation of CDs onto SPIONs could represent an attractive theranostic platform to enhance the delivery of the cholesterol-mopping macrocycle. In this way, we could achieve tremendously improved therapy for neurodegenerative disorders. Such CD-based SPIONs are designed to target the lysosomal compartment where the cholesterol-mopping activity is most required. This delivery system has the advantages of selective uptake, the smart release of high concentrations of CD, and the possibility of tracking the uptake via the nanoparticle core. The combined targeting and release presents a novel way of greatly enhancing the effectiveness of current explorative CD-based therapies. Additionally, coupling the therapeutic agent to a superparamagnetic core combines the theranostic approach with magnetic resonance imaging in the clinic. This projects expected results may also contribute towards the treatment of neurodegenerative disorders with high social impact such as Alzheimers and Parkinsons. The research will be led by Dr. Antonino Puglisi at the Institute for Biologially Inspired Materials, BOKU.

Cholesterol plays a crucial role in major cardiovascular and neurodegenerative diseases, including some rare genetic disorders showing altered cholesterol metabolism. Cyclodextrins (CDs) - a doughnut-shaped class of molecules - have shown promising therapeutic efficacy based on their capacity to sequester and mobilise cholesterol. However, CD's administration suffers from several drawbacks due to their lack of specificity. Innovative pharmacological approaches are currently being investigated to counter cholesterol imbalance, particularly in the brain. We hypothesised that the modification of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) with CDs could represent an attractive platform to enhance CD's brain delivery and so achieving improved therapy for neurodegenerative disorders. The nanoparticles were designed in such a way tha the CDs were specifically released in the lysosomal compartment to then mobile cholesterol out to the cytosol and beyond through the formation of an inclusion complex. The system showed a significantly high rate of transport across the Blood-Brain Barrier indicating this nanoformulation may hold promise as a therapeutic approach for cholesterol-impaired diseases affecting the brain The combined targeting and release presents a novel way of greatly enhancing the effectiveness of current explorative CD-based therapies. This project's expected results may also contribute towards the treatment of neurodegenerative disorders with high social impact such as Alzheimer's and Parkinson's. The research will be led by Dr. Antonino Puglisi at the Institute for Biologially Inspired Materials, BOKU.