Brain-targeting delivery of MMB4 DMS using carrier-free nanomedicine CRT-MMB4@MDZ

Drug Deliv. 2021 Dec;28(1):1822-1835. doi: 10.1080/10717544.2021.1968977.

Abstract

Brain-targeting delivery of 1,1'-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] dimethanesulfonate (MMB4 DMS) is limited by its hydrophilic property and chemical instability. In order to solve this problem, herein, we develop a facile protocol through combining antisolvent precipitation and emulsion-solvent evaporation method to synthesize midazolam (MDZ) coated MMB4 DMS (MMB4@MDZ) nanoparticles. The as-prepared MMB4@MDZ had a MMB4 DMS nanocrystal (MMB4-NC) core and a MDZ shell. The MDZ shell prevented the MMB4-NC core from contacting the aqueous environment, and thus, guaranteed the chemical stability of MMB4 DMS. Most charmingly, the iron mimic cyclic peptide CRTIGPSVC (CRT) was modified on MMB4@MDZ surfaces to produce CRT-MMB4@MDZ which was endowed with ability to absorb transferrin (Tf)-abundant corona. Taking advantages of the Tf-abundant corona, CRT-MMB4@MDZ achieved transferrin receptor (TfR)-mediated brain-targeting delivery. With the fascinating chemical stability and brain-targeting delivery effect, CRT-MMB4@MDZ showed great clinical transform prospect as a brand-new nanomedicine. Of particular importance, this work promised not only a core-shell carrier-free nanomedicine platform for effective delivery of unstable water-soluble drug, but also a protein corona-manipulating strategy for targeting delivery.

Keywords: MMB4 DMS; core–shell nanoparticle; molecular simulation; nanocrystal; protein corona.

MeSH terms

  • Animals
  • Antidotes / administration & dosage
  • Antidotes / pharmacokinetics*
  • Brain / metabolism*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Liberation
  • Drug Stability
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Midazolam / administration & dosage
  • Midazolam / pharmacokinetics*
  • Nanoparticles / chemistry*
  • Oximes / chemistry*
  • Particle Size
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Transferrin / metabolism
  • Surface Properties

Substances

  • Antidotes
  • Oximes
  • Receptors, Transferrin
  • N,N'-monomethylenebis(pyridiniumaldoxime)
  • Midazolam

Grants and funding

This study was supported by China Postdoctoral Science Foundation (No. 2019M664014).