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Suppression of Remodeling Behaviors with Arachidonic Acid Modification for Enhanced in vivo Antiatherogenic Efficacies of Lovastatin-loaded Discoidal Recombinant High Density Lipoprotein

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ABSTRACT

Purpose

A series of in vitro evaluation in our previous studies had proved that arachidonic acid (AA) modification could suppress the remodeling behaviors of lovastatin-loaded discoidal reconstituted high density lipoprotein (LT-d-rHDL) by restraining the reactivity with lecithin cholesterol acyltransferase (LCAT) for reducing undesired drug leakage. This study focuses on the investigation of AA-modified LT-d-rHDL (AA-LT-d-rHDL) in atherosclerotic New Zealand White (NZW) rabbit models to explore whether AA modification could enhance drug targeting delivery and improve antiatherogenic efficacies in vivo.

Methods

After pharmacokinetics of AA-LT-d-rHDL modified with different AA amount were investigated in atherosclerotic NZW rabbits, atherosclerotic lesions targeting property was assessed by ex vivo imaging of aortic tree and drug distribution. Furthermore, their antiatherogenic efficacies were elaborately evaluated and compared by typical biochemical indices.

Results

With AA modification amount augmenting, circulation time of AA-LT-d-rHDL was prolonged, and drug accumulation in the target locus was increased, eventually the significant appreciation in antiatherogenic efficacies were further supported by lower level of bad cholesterol, decreased atherosclerotic lesions areas and mean intima-media thickness (MIT), markedly attenuated matrix metalloproteinase-9 (MMP-9) protein expression and macrophage infiltration.

Conclusion

This proof-of-concept study demonstrated that AA-LT-d-rHDL could enhance drug accumulation in atherosclerotic lesion and impede atherosclerosis progression more effectively.

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Abbreviations

AA:

Arachidonic acid

AA-LT-d-rHDL:

AA-modified rHDL loaded with lovastatin

apoA-I:

Apolipoproteina-I

DL:

Drug loading efficiency

d-rHDL:

Discoidal recombinant HDL

EE:

Entrapment efficiency

HDL:

High density lipoprotein

HDL-C:

High density lipoprotein cholesterol

LCAT:

Lecithin cholesterol acyltransferase

LDL-C:

Low density lipoprotein cholesterol

LT-d-rHDL:

Lovastatin-loaded rHD

MIT:

Intima-media thickness

MMP-9:

Matrix metalloproteinase-9

RCT:

Reverse cholesterol transport

rHDL:

Recombinant HDL

s-rHDL:

Spherical recombinant HDL

TC:

Total cholesterol

TG:

Triglyceride

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was financially supported by National Natural Science Foundation of China (No. 81273466), Specialized Research Fund for the Doctoral Program of Higher Education (20120096120005) and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. We also acknowledged kind help in animal study from Institute of Veterinary Medicine (Jiangsu Academy of Agricultural Sciences, Nanjing, Jiangsu) and kind support in evaluation of antiatherogenic efficacies from KeyGEN BioTECH (Changhong Road No. 439, Nanjing, Jiangsu).

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    Authors and Affiliations

    1. Department of Pharmaceutics, China Pharmaceutical University, No.24, Tongjia Lane, Nanjing, 210009, People’s Republic of China

      Hongliang He, Mengyuan Zhang, Lisha Liu, Shuangshuang Zhang, Jianping Liu & Wenli Zhang

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    1. Hongliang He
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    2. Mengyuan Zhang
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    Correspondence to Jianping Liu or Wenli Zhang.

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    Hongliang He and Mengyuan Zhang contributed equally to this work.

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    He, H., Zhang, M., Liu, L. et al. Suppression of Remodeling Behaviors with Arachidonic Acid Modification for Enhanced in vivo Antiatherogenic Efficacies of Lovastatin-loaded Discoidal Recombinant High Density Lipoprotein. Pharm Res 32, 3415–3431 (2015). https://doi.org/10.1007/s11095-015-1719-x

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