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Arachidonic Acid-Modified Lovastatin Discoidal Reconstituted High Density Lipoprotein Markedly Decreases the Drug Leakage during the Remodeling Behaviors Induced by Lecithin Cholesterol Acyltransferase

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ABSTRACT

Purpose

Our previous studies indicated that drug leaked from discoidal reconstituted high density lipoprotein (d-rHDL) during the remodeling behaviors induced by lecithin cholesterol acyl transferase (LCAT) abundant in circulation, thus decreasing the drug amount delivered into the target. In this study, arachidonic acid (AA)-modified d-rHDL loaded with lovastatin (LT) were engineered as AA-LT-d-rHDL to explore whether AA modification could reduce the drug leakage during the remodeling behaviors induced by LCAT and further deliver more drug into target cells to improve efficacy.

Methods

After successful preparation of AA-LT-d-rHDL with different AA modification amount, a series of in vitro remodeling behaviors were investigated. Furthermore, inhibition on macrophage-derived foam cell formation was chosen to evaluate drug efficacy of AA-LT-d-rHDL.

Results

In vitro physicochemical characterizations studies showed that all LT-d-rHDL and AA-LT-d-rHDL preparations had nano-size, negative surface charge, high entrapment efficiency (EE) and comparable drug loading efficiency (DL). With increment of AA modification amount, AA-LT-d-rHDL manifested lower reactivity with LCAT, thus significantly reducing the undesired drug leakage during the remodeling behaviors induced by LCAT, eventually exerting stronger efficacy on inhibition of macrophage-derived foam cell formation.

Conclusion

AA-LT-d-rHDL could decrease the drug leakage during the remodeling behaviors induced by LCAT and fulfill efficient drug delivery.

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Abbreviations

AA:

arachidonic acid

AA-LT-d-rHDL:

AA-modified rHDL loaded with lovastatin

apoAI:

apolipoprotein AI

CE:

cholesterol esters

d-HDL:

discoidal HDL

d-rHDL:

discoidal reconstituted HDL

DL:

drug loading efficiency

EE:

entrapment efficiency

FC:

free cholesterol

HDL:

high density lipoprotein

LCAT:

lecithin cholesterol acyltransferase

LT:

lovastatin

LT-d-rHDL:

rHDL loaded with lovastatin

LT-L:

lovastatin liposome

LT-S:

lovastatin solution

MDF:

maximum denaturation fluorescence

MTT:

3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide

RC:

reduced cholesterol

RCT:

reverse cholesterol transport

rHDL:

reconstituted HDL

s-HDL:

spherical HDL

s-rHDL:

spherical reconstituted HDL

TC:

total cholesterol

TEM:

transmission electron microscopy

REFERENCES

  1. Damiano MG, Mutharasan RK, Tripathy S, McMahon KM, Thaxton CS. Templated high density lipoprotein nanoparticles as potential therapies and for molecular delivery. Adv Drug Deliv Rev. 2012. doi:10.1016/j.addr.2012.07.013.

    PubMed  Google Scholar 

  2. Ding Y, Wang W, Feng M, Wang Y, Zhou J, Ding X, et al. A biomimetic nanovector-mediated targeted cholesterol-conjugated siRNA delivery for tumor gene therapy. Biomaterials. 2012;33(34):8893–905.

    Article  CAS  PubMed  Google Scholar 

  3. McMahon KM, Mutharasan RK, Tripathy S, Veliceasa D, Bobeica M, Shumaker DK, et al. Biomimetic high density lipoprotein nanoparticles for nucleic acid delivery. Nano letters. 2011;11(3):1208–14.

    Article  CAS  PubMed  Google Scholar 

  4. Shin J-Y, Yang Y, Heo P, Lee J-C, Kong B, Cho JY, et al. pH-responsive high-density lipoprotein-like nanoparticles to release paclitaxel at acidic pH in cancer chemotherapy. Int J Nanomedicine. 2012;7:2805–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Jia J, Xiao Y, Liu J, Zhang W, He H, Chen L, et al. Preparation, characterizations, and in vitro metabolic processes of paclitaxel‐loaded discoidal recombinant high‐density lipoproteins. Journal of pharmaceutical sciences. 2012;101(8):2900–8.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang W, He H, Liu J, Wang J, Zhang S, Zhang S, et al. Pharmacokinetics and atherosclerotic lesions targeting effects of tanshinone IIA discoidal and spherical biomimetic high density lipoproteins. Biomaterials. 2012;34(1):306–19.

    Article  PubMed  Google Scholar 

  7. Gu X, Zhang W, Liu J, Shaw JP, Shen Y, Xu Y, et al. Preparation and characterization of a lovastatin-loaded protein-free nanostructured lipid carrier resembling high-density lipoprotein and evaluation of its targeting to foam cells. AAPS PharmSciTech. 2011;12(4):1200–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Brewer Jr HB. High-Density Lipoprotein Metabolism. Atlas of Atherosclerosis and Metabolic Syndrome: Springer; 2011. p. 93–111.

  9. Sviridov D. High‐density lipoproteins: structure, metabolism, function and TherapeuticsBy anatol kontush and M. John Chapman. Chem Med Chem. 2013;8(4):669–70.

    Article  CAS  Google Scholar 

  10. Wang J, Jia J, Liu J, He H, Zhang W, Li Z. Tumor targeting effects of a novel modified paclitaxel-loaded discoidal mimic high density lipoproteins. Drug Delivery. 2013;0:1–8.

    Article  Google Scholar 

  11. Zhang M, Jia J, Liu J, He H, Liu L. A novel modified paclitaxel-loaded discoidal recombinant high-density lipoproteins: preparation, characterizations and in vivo evaluation. Asian Journal of Pharmaceutical Sciences. 2013.

  12. Huggins KW, Curtiss LK, Gebre AK, Parks JS. Effect of long chain polyunsaturated fatty acids in the sn-2 position of phosphatidylcholine on the interaction with recombinant high density lipoprotein apolipoprotein AI. Journal of lipid research. 1998;39(12):2423–31.

    CAS  PubMed  Google Scholar 

  13. Sparks DL, Chatterjee C, Young E, Renwick J, Pandey NR. Lipoprotein charge and vascular lipid metabolism. Chemistry and physics of lipids. 2008;154(1):1–6.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang W-L, Xiao Y, Liu J-P, Wu Z-M, Gu X, Xu Y-M, et al. Structure and remodeling behavior of drug-loaded high density lipoproteins and their atherosclerotic plaque targeting mechanism in foam cell model. International journal of pharmaceutics. 2011;419(1):314–21.

    Article  CAS  PubMed  Google Scholar 

  15. Rye K-A, Hime NJ, Barter PJ. The influence of sphingomyelin on the structure and function of reconstituted high density lipoproteins. J Biol Chem. 1996;271(8):4243–50.

    Article  CAS  PubMed  Google Scholar 

  16. Kontogiannopoulos KN, Assimopoulou AN, Dimas K, Papageorgiou VP. Shikonin‐loaded liposomes as a new drug delivery system: physicochemical characterization and in vitro cytotoxicity. Eur J Lipid Sci Technol. 2011;113(9):1113–23.

    Article  CAS  Google Scholar 

  17. Su Z, Niu J, Xiao Y, Ping Q, Sun M, Huang A, et al. Effect of octreotide–polyethylene glycol (100) monostearate modification on the pharmacokinetics and cellular uptake of nanostructured lipid carrier loaded with hydroxycamptothecine. Molecular pharmaceutics. 2011;8(5):1641–51.

    Article  CAS  PubMed  Google Scholar 

  18. Yang L, Ling W, Ma J, Tang Z, Wu C. Effect of lysophosphatidylcholine on cholesterol efflux from macrophage foam cells. Chinese Journal of Pathophysiology. 2002;18(1):28–31.

    CAS  Google Scholar 

  19. Murakami T, Wijagkanalan W, Hashida M, Tsuchida K. Intracellular drug delivery by genetically engineered high-density lipoprotein nanoparticles. Nanomedicine. 2010;5(6):867–79.

    Article  CAS  PubMed  Google Scholar 

  20. Hofnagel O, Luechtenborg B, Weissen-Plenz G, Robenek H. Statins and foam cell formation: impact on LDL oxidation and uptake of oxidized lipoproteins via scavenger receptors. Biochimica et biophysica acta (BBA)-molecular and cell biology of. Lipids. 2007;1771(9):1117–24.

    CAS  Google Scholar 

  21. Lin J, Li M, Wang Z, He S, Ma X, Li D. The role of CD4+ CD25+ regulatory T cells in macrophage-derived foam-cell formation. Journal of lipid research. 2010;51(5):1208–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Xu G, Watanabe T, Iso Y, Koba S, Sakai T, Nagashima M, et al. Preventive effects of heregulin-β1 on macrophage foam cell formation and atherosclerosis. Circulation research. 2009;105(5):500–10.

    Article  CAS  PubMed  Google Scholar 

  23. Zhao Z-Z, Wang Z, Li G-H, Wang R, Tan J-M, Cao X, et al. Hydrogen sulfide inhibits macrophage-derived foam cell formation. Experimental Biology and Medicine. 2011;236(2):169–76.

    Article  CAS  PubMed  Google Scholar 

  24. Liu G, Ma S, Li S, Cheng R, Meng F, Liu H, et al. The highly efficient delivery of exogenous proteins into cells mediated by biodegradable chimaeric polymersomes. Biomaterials. 2010;31(29):7575–85.

    Article  CAS  PubMed  Google Scholar 

  25. Xu S, Liu Z, Huang Y, Le K, Tang F, Huang H, et al. Tanshinone II-a inhibits oxidized LDL-induced LOX-1 expression in macrophages by reducing intracellular superoxide radical generation and NF-κB activation. Transl Res. 2012;160(2):114–24.

    Article  CAS  PubMed  Google Scholar 

  26. Sung HJ, Kim J, Kim Y, Jang S-W, Ko J. N-acetyl cysteine suppresses the foam cell formation that is induced by oxidized low density lipoprotein via regulation of gene expression. Molecular biology reports. 2012;39(3):3001–7.

    Article  CAS  PubMed  Google Scholar 

  27. Hata H, Sakaguchi N, Yoshitomi H, Iwakura Y, Sekikawa K, Azuma Y, et al. Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T cell–mediated spontaneous autoimmune arthritis in mice. J Clin Investig. 2004;114(4):582–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Ishii T, Itoh K, Ruiz E, Leake DS, Unoki H, Yamamoto M, et al. Role of nrf2 in the regulation of cd36 and stress protein expression in murine macrophages activation by oxidatively modified LDL and 4-hydroxynonenal. Circulation research. 2004;94(5):609–16.

    Article  CAS  PubMed  Google Scholar 

  29. Xie C, Kang J, Chen J-R, Lazarenko OP, Ferguson ME, Badger TM, et al. Lowbush blueberries inhibit scavenger receptors CD36 and SR-a expression and attenuate foam cell formation in ApoE-deficient mice. Food & Function. 2011;2(10):588–94.

    Article  CAS  Google Scholar 

  30. Hrboticky N, Draude G, Hapfelmeier G, Lorenz R, Weber P. Lovastatin decreases the receptor-mediated degradation of acetylated and oxidized LDLs in human blood monocytes during the early stage of differentiation into macrophages. Arteriosclerosis, thrombosis, and vascular biology. 1999;19(5):1267–75.

    Article  CAS  PubMed  Google Scholar 

  31. Pietsch A, Erl W, Lorenz RL. Lovastatin reduces expression of the combined adhesion and scavenger receptor CD36 in human monocytic cells. Biochemical pharmacology. 1996;52(3):433–9.

    Article  CAS  PubMed  Google Scholar 

  32. Lin R, Liu J, Peng N, Yang G, Gan W, Wang W. Lovastatin reduces nuclear factor κB activation induced by C-reactive protein in human vascular endothelial cells. Biol Pharm Bull. 2005;28(9):1630–4.

    Article  CAS  PubMed  Google Scholar 

  33. Miyata R, Hiraiwa K, Cheng JC, Bai N, Vincent R, Francis GA, et al. Statins attenuate the development of atherosclerosis and endothelial dysfunction induced by exposure to urban particulate matter (PM10). Pharmacology: Toxicology and Applied; 2013.

    Google Scholar 

  34. Obi C, Wysokinski W, Karnicki K, Owen WG, McBane RD. Inhibition of platelet-rich arterial thrombus in vivo acute antithrombotic effect of intravenous HMG-CoA Reductase therapy. Arteriosclerosis, thrombosis, and vascular biology. 2009;29(9):1271–6.

    Article  CAS  PubMed  Google Scholar 

  35. Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovascular research. 2000;47(4):648–57.

    Article  CAS  PubMed  Google Scholar 

  36. Parks JS, Huggins KW, Gebre AK, Burleson ER. Phosphatidylcholine fluidity and structure affect lecithin: cholesterol acyltransferase activity. Journal of lipid research. 2000;41(4):546–53.

    CAS  PubMed  Google Scholar 

  37. Rye K-A, Duong M, Psaltis MK, Curtiss LK, Bonnet DJ, Stocker R, et al. Evidence that phospholipids play a key role in pre-β apoA-I formation and high-density lipoprotein remodeling. Biochemistry. 2002;41(41):12538–45.

    Article  CAS  PubMed  Google Scholar 

  38. Stamler CJ, Breznan D, Neville TA, Viau FJ, Camlioglu E, Sparks DL. Phosphatidylinositol promotes cholesterol transport in vivo. Journal of lipid research. 2000;41(8):1214–21.

    CAS  PubMed  Google Scholar 

  39. Tian L, Luo N, Zhu X, Chung B-H, Garvey WT, Fu Y. Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses. Atherosclerosis. 2012;221(1):66–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Libby P, Okamoto Y, Rocha VZ, Folco E. Inflammation in atherosclerosis. Circ J. 2010;74:213–20.

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was financially supported by National Natural Science Foundation of China (No. 81273466), Jiangsu Province Ordinary College and University Innovative Research Programs (No. CXZZ12-0317) and the Special Found Project of Universities’ Basic Scientific Research of Central Authorities (No. ZJ11253). We also acknowledged inspiring suggestions from Professor Qi Chen (Department of Pathophysiology, Nan Jing Medical University).

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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, Lisha Liu, Ji Wang, Wenli Zhang, Mengyuan Zhang & Jianping Liu

  2. Atherosclerosis Research Centre Laboratory of Molecular Intervention with Cardiovascular Diseases, Nanjing Medical University, No.118 Hanzhong Road, Nanjing, 210029, People’s Republic of China

    Hui Bai & Yan Zhang

  3. School of Pharmacy, University of Auckland, Private Bag 92019, Auckland, New Zealand

    Zimei Wu

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  1. Hongliang He
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  2. Lisha Liu
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Correspondence to Jianping Liu.

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He, H., Liu, L., Bai, H. et al. Arachidonic Acid-Modified Lovastatin Discoidal Reconstituted High Density Lipoprotein Markedly Decreases the Drug Leakage during the Remodeling Behaviors Induced by Lecithin Cholesterol Acyltransferase. Pharm Res 31, 1689–1709 (2014). https://doi.org/10.1007/s11095-013-1273-3

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