Branched-Chain and Dendritic Lipids for Nanoparticles


Authors: M.W. Meanwell, C. O’Sullivan, P. Howard and T.M. Fyles

Journal: Canadian Journal of Chemistry

DOI: 10.1139/cjc-2016-0462

Publication - Abstract

November 01, 2016

Abstract:

Lipid nanoparticles (LNPs) for drug-delivery applications are largely derived from natural lipids. Synthetic lipids, particularly those incorporating branched hydrocarbons and hyper-branched hydrocarbon architectures, may afford enhanced lipophilicity with enhanced fluidity and thereby lead to LNP stabilization. Hydrocarbon anchors based on serinol diesters were prepared from linear Cn (n = 14, 16, 18) and branched (n = 16) acids with Boc-protected serinol. These diesters were further dimerized on an iminodiacetamide backbone to provide eight branched-chain and dendritic lipid anchors. Derivatization of these core structures provided eight PEG-lipids and seven thiopurine linked lipid–drug conjugates. LNPs were prepared by microfluidic mixing from mixed lipids in ethanol diluted into aqueous media. The lipid–drug conjugates incorporated 5 mol% of a phosphocholine and 5 mol% of a commercial PEG-lipid to form LNPs with a thiopurine drug loading of 15 wt%. The PEG–lipids prepared were formulated at 1.5 mol% as a surface stabilizer to LNPs containing dsDNA lipoplexes. The stability of the LNPs was assessed under different storage conditions through monitoring of particle size. For both LNPs from lipid–thiopurine conjugates and the PEG-lipid systems, there is strong preliminary evidence that hydrocarbon branching results in LNP stabilization. Four of the lipid–drug conjugate formulations were stable to cell culture conditions (10% serum, 37 °C) and the toxicity of these LNPs was assessed in two cell lines relative to the free thiopurines in the medium. The observed toxicity is consistent with cellular uptake of the LNPs and reductive release of the cargo thiopurine within the cell.

Advanced Search

close
  • Publications
  • Application Notes
  • Posters
  • Workshops
  • Videos & Webinars
  • Articles
Search

Browse by Category

  • Application
    • Diagnostic and Imaging
    • Genetic Medicine
    • Hematology
    • Metabolic Disorders
    • Neuroscience
    • Oncology
    • Skeletal Disorders
    • Targeted Drug Delivery
    • Vaccines
    • Other Applications
    • Cell therapy
  • Formulation
    • Liposomes
    • Nucleic Acid Lipid Nanoparticles
    • Polymeric Nanoparticles
    • Other Formulations
  • Payload
    • DNA
    • microRNA
    • mRNA
    • siRNA
    • Small Molecule Drugs
    • Other Payloads


related content

Publication - Abstract

Nanopharmaceuticals aim at translating the unique features of nano-scale materials into therapeutic products and consequently their development relies critically on the progression in manufacturing technology to allow scalable processes complying w...

Read More


Publication - Abstract

A Combinatorial Library of Lipid Nanoparticles for RNA Delivery to Leukocytes

S. Ramishetti, I. Hazan-Halevy, R. Palakuri, S. Chatterjee, S.N. Gonna, N. Dammes, I. Freilich, L.K. Shmuel, D. Danino and D. Peer

Lipid nanoparticles (LNPs) are the most advanced nonviral platforms for small interfering RNA (siRNA) delivery that are clinically approved. These LNPs, based on ionizable lipids, are found in the liver and are now gaining much attention in the field of RNA therapeutics. The prev...
Read More


Sign Up and Stay Informed
Sign up today to automatically receive new Cytiva, formerly Precision NanoSystems application notes, conference posters, relevant science publications, and webinar invites.