Detecting the functional complexities between high-density lipoprotein mimetics

Yoshitaka J Sei; Jungho Ahn; Taeyoung Kim; Eunjung Shin; Angel J Santiago-Lopez; Seung Soon Jang; Noo Li Jeon; Young C Jang; YongTae Kim

doi:10.1016/j.biomaterials.2018.04.011

Detecting the functional complexities between high-density lipoprotein mimetics

Biomaterials. 2018 Jul:170:58-69. doi: 10.1016/j.biomaterials.2018.04.011. Epub 2018 Apr 6.

Authors

Yoshitaka J Sei¹, Jungho Ahn², Taeyoung Kim³, Eunjung Shin⁴, Angel J Santiago-Lopez⁵, Seung Soon Jang⁶, Noo Li Jeon⁷, Young C Jang⁸, YongTae Kim⁹

Affiliations

¹ George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
² George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, 151-744, South Korea.
³ George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁴ School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁵ Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁶ Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁷ School of Mechanical and Aerospace Engineering, Seoul National University, Seoul, 151-744, South Korea.
⁸ Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA.
⁹ George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA; Institute for Electronics and Nanotechnology, Georgia Institute of Technology, Atlanta, GA 30332, USA. Electronic address: ytkim@gatech.edu.

Abstract

High-density lipoprotein (HDL) is a key regulator of lipid homeostasis through its native roles like reverse cholesterol transport. The reconstitution of this natural nanoparticle (NP) has become a nexus between nanomedicine and multi-disease therapies, for which a major portion of HDL functionality is attributed to its primary scaffolding protein, apolipoprotein A1 (apoA1). ApoA1-mimetic peptides were formulated as cost-effective alternatives to apoA1-based therapies; reverse-4F (r4F) is one such peptide used as part of a nanoparticle platform. While similarities between r4F- and apoA1-based HDL-mimetic nanoparticles have been identified, key functional differences native to HDL have remained undetected. In the present study, we executed a multidisciplinary approach to uncover these differences by exploring the form, function, and medical applicability of engineered HDL-mimetic NPs (eHNPs) made from r4F (eHNP-r4F) and from apoA1 (eHNP-A1). Comparative analyses of the eHNPs through computational molecular dynamics (MD), advanced microfluidic NP synthesis and screening technologies, and in vivo animal model studies extracted distinguishable eHNP characteristics: the eHNPs share identical structural and compositional characteristics with distinct differences in NP stability and organization; eHNP-A1 could more significantly stimulate anti-inflammatory responses characteristic of the scavenger receptor class B type 1 (SR-B1) mediated pathways; and eHNP-A1 could outperform eHNP-r4F in the delivery of a model hydrophobic drug to an in vivo tumor. The biomimetic microfluidic technologies and MD simulations uniquely enabled our comparative analysis through which we determined that while eHNP-r4F is a capable NP with properties mimicking natural eHNP-A1, challenges remain in reconstituting the full functionality of NPs naturally derived from humans.

Keywords: ApoA1-mimetic; Apolipoprotein A1; Drug delivery; Microfluidics; Nanoparticles.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Anti-Inflammatory Agents / pharmacology
Apolipoprotein A-I / metabolism
Biomimetic Materials / metabolism*
Doxorubicin / pharmacology
Drug Delivery Systems
Endothelial Cells / drug effects
Endothelial Cells / metabolism
Female
HL-60 Cells
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Lipoproteins, HDL / metabolism*
Macrophages / drug effects
Macrophages / metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
Nanoparticles / chemistry
Nanoparticles / ultrastructure
Peptides / metabolism
Time Factors
Tissue Engineering
Xenograft Model Antitumor Assays

Substances

Anti-Inflammatory Agents
Apolipoprotein A-I
Lipoproteins, HDL
Peptides
Doxorubicin

Abstract

Publication types

MeSH terms

Substances

Grants and funding