Branched-chain and dendritic lipids for nanoparticles

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% a...