Detecting the functional complexities between high-density lipoprotein mimetics.

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.

• Authors: Yoshitaka J Sei, Jungho Ahn, Taeyoung Kim, Eunjung Shin, Angel J Santiago-Lopez, Seung Soon Jang, Noo Li Jeon, Young C Jang, YongTae Kim
• Journal: Biomaterials (Biomaterials) Vol. 170 Pg. 58-69 (07 2018) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 29653287 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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