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Characterization of apolipoprotein A-I peptide phospholipid interaction and its effect on HDL nanodisc assembly

Authors Patel H, Ding B, Ernst K, Shen L, Yuan W, Tang J, Drake LR, Kang J, Li Y, Chen Z, Schwendeman A

Received 12 July 2018

Accepted for publication 6 March 2019

Published 30 April 2019 Volume 2019:14 Pages 3069—3086


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. Thomas J. Webster

Hiren Patel,1 Bei Ding,2 Kelsey Ernst,3 Lei Shen,2 Wenmin Yuan,3 Jie Tang,3 Lindsey R Drake,1 Jukyung Kang,3 Yaoxin Li,2 Zhan Chen,2 Anna Schwendeman1,3,4

1Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; 2Department of Chemistry, University of Michigan, Ann Arbor, MI, USA; 3Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA; 4Biointerfaces Institute, University of Michigan, Ann Arbor, MI, USA

Background: Synthetic HDLs (sHDLs), small nanodiscs of apolipoprotein mimetic peptides surrounding lipid bilayers, were developed clinically for atheroma regression in cardiovascular patients. Formation of HDL involves interaction of apolipoprotein A-I (ApoA-I) with phospholipid bilayers and assembly into lipid-protein nanodiscs.
Purpose: The objective of this study is to improve understanding of physico-chemical aspects of HDL biogenesis such as the thermodynamics of ApoA-I-peptide membrane insertion, lipid binding, and HDL self-assembly to improve our ability to form homogeneous sHDL nanodiscs that are suitable for clinical administration.
Methods: The ApoA-I-mimetic peptide, 22A, was combined with either egg sphingomyelin (eSM) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) phospholipid vesicles to form sHDL. The sHDL assembly process was investigated through lipid vehicle solubilization assays and characterization of purity, size, and morphology of resulting nanoparticles via gel permeation chromatography (GPC), dynamic light scattering (DLS), and transmission electron microscopy (TEM). Peptide-lipid interactions involved were further probed by sum frequency generation (SFG) vibrational spectroscopy and attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). The pharmacokinetics of eSM-sHDL and POPC-sHDL nanodiscs were investigated in Sprague Dawley rats.
Results: sHDL formation was temperature-dependent, with spontaneous formation of sHDL nanoparticles occurring only at temperatures exceeding lipid transition temperatures as evidenced by DLS, GPC, and TEM characterization. SFG and ATR-FTIR spectroscopy findings support a change in peptide-lipid bilayer interactions at temperatures above the lipid transition temperature. Lipid-22A interactions were stronger with eSM than with POPC, which resulted in the formation of more homogeneous sHDL nanoparticles with longer in vivo circulation time as evidenced the PK study.
Conclusion: Physico-chemical characteristics of sHDL are in part determined by phospholipid composition. Optimization of phospholipid composition may be utilized to improve the stability and homogeneity of sHDL.

Keywords: apoA-1 mimetic peptide, high-density lipoprotein (HDL), large unilamellar vesicle (LUV), sum frequency generation (SFG), dynamic light scattering (DLS), transmission electron microscopy (TEM)

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