Characterization of hydroxypropyl-beta-cyclodextrins used in the treatment of Niemann-Pick Disease type C1

PLoS One. 2017 Apr 17;12(4):e0175478. doi: 10.1371/journal.pone.0175478. eCollection 2017.

Abstract

2-Hydroxypropyl-beta-cyclodextrin (HPβCD) has gained recent attention as a potential therapeutic intervention in the treatment of the rare autosomal-recessive, neurodegenerative lysosomal storage disorder Niemann-Pick Disease Type C1 (NPC1). Notably, HPβCD formulations are not comprised of a single molecular species, but instead are complex mixtures of species with differing degrees of hydroxypropylation of the cyclodextrin ring. The degree of substitution is a critical aspect of the complex mixture as it influences binding to other molecules and thus could potentially modulate biological effects. VTS-270 (Kleptose HPB) and Trappsol® Cyclo™ are HPβCD products under investigation as novel treatments for NPC1. The purpose of the present work is to compare these two different products; analyses were based on ion distribution and abundance profiles using mass spectrometry methodology as a means for assessing key molecular distinctions between products. The method incorporated electrospray ionization and analysis with a linear low-field ion mobility quadrupole time-of-flight instrument. We observed that the number of hydroxypropyl groups (the degrees of substitution) are substantially different between the two products and greater in Trappsol Cyclo than in VTS-270. The principal ions of both samples are ammonium adducts. Isotope clusters for each of the major ions show doubly charged homodimers of the ammonium adducts. In addition, both products show doubly charged homodimers from adduction of both a proton and ammonium. Doubly charged heterodimers are also present, but are more intense in Trappsol Cyclo than in VTS-270. Based on the analytical differences observed between VTS-270 and Trappsol Cyclo with respect to the degree of substitution, the composition and fingerprint of the complex mixture, and the impurity profiles, these products cannot be considered to be the same; the potential biological and clinical implications of these differences are not presently known.

MeSH terms

  • 2-Hydroxypropyl-beta-cyclodextrin
  • Ammonium Compounds / chemistry
  • Drug Contamination
  • Humans
  • Ions / chemistry
  • Niemann-Pick Disease, Type C / drug therapy*
  • Spectrometry, Mass, Electrospray Ionization / methods
  • beta-Cyclodextrins / chemistry*
  • beta-Cyclodextrins / therapeutic use*

Substances

  • Ammonium Compounds
  • Ions
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin

Grants and funding

This work was supported by the Intramural Program of The Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH). Editorial assistance was provided by Peloton Advantage, LLC, Parsippany, NJ, USA, and funded by Vtesse, Inc., Gaithersburg, MD. Vtesse Inc. provided support in the form of salary for author AD, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.