PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

Abstract

2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1−/−) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1−/− cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders.

The susceptibility of cochlear outer hair cells to cyclodextrin is not related to their electromotile activity

“…Although potentially promising, our study indicates that specifically targeting prestin did not provide protection of OHCs in response to HPβCD. Future efforts for the treatment of NPC1 disease should include effective drug delivery to avoid cochlear exposure, development of alternative small molecules that are more specific or non-toxic [ 4 , 47 ], and gene therapy [ 7 ].…”

Drug Delivery to the Brain across the Blood–Brain Barrier Using Nanomaterials

“…They can be made from cholesterol, fatty acids, or phospholipids. Because of their biocompatible and biodegradable properties, liposomes have the affinity to target BBB and increase circulation time . Due to their hydrophilic and hydrophobic components, liposomes can encapsulate water‐soluble and lipophilic drugs, thus increasing their bioavailability in the body.…”

Hydroxy-Propil-β-Cyclodextrin Inclusion Complexes of two Biphenylnicotinamide Derivatives: Formulation and Anti-Proliferative Activity Evaluation in Pancreatic Cancer Cell Models

“…These results evidenced a general improvement in the cytotoxic activity of these drugs following complexation, due to the increase in solubility in aqueous medium and to the enhancement of the plasmatic membrane permeability by HP-β-CD. As reported in the literature, this FDA approved excipient is characterized by a hydrophobic pocket capable of binding and solubilizing cholesterol, a critical component of the plasma membrane, thus having a role in the efflux and redistribution of cholesterol in mammalian cells [ 23 , 25 , 26 , 27 ]. Thus, the interaction of HP-β-CD with cholesterol in the plasma membrane can induce perturbation in the lipid bilayer, affecting the membrane properties such as fluidity and permeability.…”