Smart Delivery of Actives by Polyrotaxanes Providing New Options for the Treatment of Niemann-Pick Typ C Disease

3/13/2019 14:45 - 15:20

The systemic treatment of a disease with small molecule drugs is often limited by rapid renal clearance. High and frequent doses are necessary for drug activity, however that in turn augments the cellular toxicity and the side effects of the drug in an organism.

Polymeric delivery vehicles have been employed to improve both the solubility and the bioavailability of drugs to improve their efficacy and/or diminish their toxicity. These vehicles can also improve the retention of the drug in the human body due to reduced renal clearance because of their higher molar mass. Targeting is also possible through incorporation of ligands that promote active transport into specific cells via receptor-mediated endocytosis.

Besides various polymeric carriers, polyrotaxanes are interesting alternative carrier entities that can act as supramolecular prodrugs. Polyrotaxanes are molecules where many macrocyclic rings are strung onto a polymer chain. They are kinetically less stable than polymeric prodrugs because there are no covalent bonds that have to be cleaved to release the active, but by far more stable than physical mixtures due to the topological bond between the threaded rings and the polymeric backbone.[3] The dissociation rate of a polyrotaxane can be controlled by the type of stopper groups attached along the polymer or at the chain ends to allow slow release of the threaded rings. An example for such a macromolecular prodrug is our new Hydroxypropyl-β-Cyclodextrin (HP-β-CD) polyrotaxane. It was designed to act as a slow release formulation of HP-b-CD in the treatment of the Niemann Pick type C disease. The polyrotaxane is based on a polyalkylene phosphate core to improve the pharmacokinetics of this HP-β-CD construct. Our findings show that HP-β-CD was slowly released from the polyrotaxane over a 30 day period. The polyrotaxane showed no toxicity in MTS assays and persistently diminished cholesterol levels in NPC1 cells by 20% relative to untreated cells. These results demonstrate the therapeutic potential of these novel polyrotaxane constructs as supramolecular drug delivery system.