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Influence of Fatty Acid Modification on Uptake of Lovastatin-Loaded Reconstituted High Density Lipoprotein by Foam Cells

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Abstract

Purpose

Spherical reconstituted high density lipoprotein (rHDL) can target atherosclerotic lesions by the very low density lipoprotein (VLDL) receptor, which is seldom expressed in liver. By promoting this pathway, the targeting efficiency was hyphothesized to be improved due to avoiding undesired uptake in liver mediated by the scavenger receptor class B type I (SR-BI). In this study, how fatty acid modification in spherical rHDL influenced the VLDL receptor-mediated endocytosis pathway was investigated.

Methods

Stearic acid (SA) and arachidonic acid (AA) with different saturation levels were utilized to modify the lovastatin-loaded rHDL (LS-rHDL). Phagocytosis test on foam cells with or without cholesteryl ester transfer protein (CETP) expression was conducted to observe the cellular uptake of the SA or AA modified rHDL and the non-modified one. Raman spectroscopy, guanidine hydrochloride (Gdn-HCl) denaturation experiment and in vitro evaluation of drug release were used to analyze the related mechanism.

Results

In comparison with the non-modified rHDL, AA modification could reduce the packing order of the rHDL phospholipid acyl chains, leading to the decreased apoA-I binding extent with lipid and the increased drug release, while the opposite was true for SA modification. The AA-modified rHDL exhibited a higher uptake of foam cells expressing CETP than the non-modified one, while the SA-modified one showed the lowest cellular uptake among the three rHDLs.

Conclusions

Increased unsaturation level can facilitate lipid-interchange process where the cargo in rHDL core may transfer to VLDL more easily, and then promote the endocytosis mediated by the VLDL receptor.

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Abbreviations

AA:

Arachidonic acid

apoA-I:

Apolipoprotein A-I

CE:

Cholesterol ester

CETP:

Cholesteryl ester transfer protein

DL:

Drug loading capacity

DLS:

Dynamic light scattering

EE:

Entrapment efficiency

Gdn-HCl:

Guanidine hydrochloride

HDL:

High density lipoprotein

LS:

Lovastatin

LS-AA-NLC:

AA modified LS-NLC

LS-AA-rHDL:

AA modified LS-rHDL

LS-SA-NLC:

SA modified LS-NLC

LS-SA-rHDL:

SA modified LS-rHDL

LS-NLC:

LS-loaded nanostructured lipid carrier

LS-rHDL:

LS-loaded reconstituted high density lipoprotein

R-rHDL:

Rhodamine-loaded rHDL

rHDL:

Reconstituted high density lipoprotein

SA:

Stearic acid

SR-BI:

Scavenger receptor class B type I

TA:

Tanshinone IIA

TEM:

Transmission electron microscopy

TG:

Triglyceride

VLDL:

Very low density lipoprotein

WMF:

Wavelength of maximum fluorescence

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Author notes

  1. Yun Yang and Ji Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China

    Yun Yang, Ji Wang, Hongliang He, Wenli Zhang, Yuansheng Zhang & Jianping Liu

  2. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Pharmacy School of Stomatology, The Fourth Military Medical University, 145 West Road, Xi’an, 710032, Changle, People’s Republic of China

    Ji Wang

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  1. Yun Yang
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  2. Ji Wang
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  4. Wenli Zhang
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Correspondence to Wenli Zhang or Jianping Liu.

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Yang, Y., Wang, J., He, H. et al. Influence of Fatty Acid Modification on Uptake of Lovastatin-Loaded Reconstituted High Density Lipoprotein by Foam Cells. Pharm Res 35, 134 (2018). https://doi.org/10.1007/s11095-018-2419-0

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  • DOI: https://doi.org/10.1007/s11095-018-2419-0

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