In vitro and in vivo delivery of atorvastatin: A comparative study of anti-inflammatory activity of atorvastatin loaded copolymeric micelles

Abstract

Statins have been shown to exert ‘pleiotropic effects’ independent of their cholesterol lowering actions that include anti-inflammatory properties. In this study we synthesized mono methoxy poly (ethylene glycol)–poly (ε-caprolactone) (mPEG-PCL) di block copolymers. The structure of the copolymers was characterized by H nuclear magnetic resonance, Fourier-transform infrared spectroscopy, differential scanning calorimetry and gel permeation chromatography techniques. In this method, atorvastatin was encapsulated within micelles through a single-step nano-precipitation method, leading to the formation of atorvastatin-loaded mPEG-PCL (atorvastatin/mPEG-PCL) micelles. The resulting micelles were characterized further by various techniques such as dynamic light scattering and atomic force microscopy. In this study the anti-inflammatory activity of atorvastatin and atorvastatin/mPEG-PCL micelles on acute models of inflammation are analyzed, to compare the effect of indometacin in rats. Carrageenan induces rat paw edema; six animals of each group (10 groups) received indometacin, atorvastatin, and atorvastatin/mPEG-PCL micelles orally 1, 6, 12 and 24 h before carrageenan injection in paw. The paw edema thickness measured at 1, 2, 3 and 4 h after injection and percentage inhibition of edema in various groups were calculated. The results showed that the zeta potential of micelles was about −16.6 mV and the average size was 81.7 nm. Atorvastatin was encapsulated into mPEG-PCL micelles with loading capacity of 14.60 ± 0.96% and encapsulation efficiency of 62.50 ± 0.84%. Atorvastatin and atorvastatin/mPEG-PCL micelles showed significant anti-inflammatory activity in the present study. The anti-inflammatory activity of atorvastatin and atorvastatin/mPEG-PCL micelles was significant in comparison with indometacin. Atorvastatin/mPEG-PCL micelles showed more anti-inflammatory activity than atorvastatin. This study revealed the anti-inflammatory activity of atorvastatin and atorvastatin/mPEG-PCL micelles and suggested the statins have a potential inflammatory activity along with its lipid lowering properties. Contrary to anti-inflammatory effects, the pro-inflammatory responses are independent of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition and can be mediated directly by atorvastatin.

Keywords

Copolymer sustained release micelles atorvastatin anti-inflammatory

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References

Kwak

Mulhaupt

and March

Atherosclerosis: anti-inflammatory and immunomodulatory activities of statins. Autoimmun Rev 2003; 2: 332–338.

Chen

Ikeda

Shimpo

et al . Direct effects of statins on cell primarily involved in atherosclerosis. Hypertens Res 2000; 23: 187–192.

Weitz

SG.

Statins as anti-inflammatory agents. Sciences 2002; 23: 482–487.

Youssef

Stu¨ Ve

Patarroyo

et al . The HMG-CoA reductase inhibitors, atorvastatin, promotes a Th2 bias and reverse paralysis in central nervous system autoimmune disease. Nature 2002; 420: 78–84.

Zelvyte

Dominaitiene

Crisby

et al . Modulation of inflammatory mediators and ppara and nfnb expression by pravastatin in response to lipoprotein in human monocyte in vitro. Pharmacol Res 2002; 45: 147–154.

Downs

Clarfield

Weis

et al . Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998; 279: 1615–1622.

Ridker

Rifai

Pfeffer

et al . Inflammation, pravastatin and risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998; 98: 839–844.

Arnaud

Braunersreuther

and Mach

Toward immunomodulatory and anti-inflammatory properties of statins. Trends Cardiovasc Med 2005; 15: 202–206.

Steinberg

Hypercholestrolemia and inflammation in atherogenesis: two sides of the same coin. Mol Nutr Food Res 2005; 49: 995–998.

10.

Stoll

and Bendszus

Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 2006; 37: 1923–1932.

11.

Danafar

Rostamizadeh

Davaran

et al . Co-delivery of hydrophilic and hydrophobic drugs by micelles: a new approach using drug conjugated PEG-PCL nanoparticles. Drug Dev Ind Pharm 2017; 43: 1908–1918.

12.

Coward

Marei

Yang

et al . Statin-induced proinflammatory response in mitogen-activated peripheral blood mononuclear cells through the activation of caspase-1 and IL-18 secretion in monocytes. J Immunol 2006; 1; 176: 5284–5292.

13.

Manjili

Malvandi

Mousavi

et al . In vitro and in vivo delivery of artemisinin loaded PCL–PEG–PCL micelles and its pharmacokinetic study. Artif Cells Nanomed Biotechnol 2017; 1–11. DOI: 10.1080/21691401.2017.1347880.

14.

Lin

and Kawashima

The influence of three poly (oxyethylene)poly(oxypropylene) surface-active block copolymers on the solubility behavior of indomethacin. Pharm Acta Helv 1985; 60: n339–n344.

15.

Danafar

Applications of copolymeric nanoparticles in drug delivery systems. Drug Res 2016; 66: 506–519.

16.

Yokoyama

Okano

and Kataoka

Improved synthesis of adriamycin-conjugated poly(ethylene oxide)–poly(aspartic acid) block copolymer and formation of unimodal micellar structure with controlled amount of physically entrapped adriamycin. J Control Release 1994; 32: 269–277.

17.

Danafar

Study of the composition of polycaprolactone/poly (ethylene glycol)/polycaprolactone copolymer and drug-to-polymer ratio on drug loading efficiency of curcumin to nanoparticles. Jundishapur J Nat Pharm Prod 2017; 12: e34179.

18.

Batrakova

Dorodnych

Klinskii

et al . Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: in vivo evaluation of anti-cancer activity. Br J Cancer 1996; 74: 1545–1552.

19.

Nosrati

Salehiabar

Davaran

et al . New advances strategies for surface functionalization of iron oxide magnetic nano particles (IONPs). Res Chem Intermed 2017; 43: 7423–7442.

20.

Nosrati

Salehiabar

Manjili

et al . Preparation of magnetic albumin nanoparticles via a simple and one-pot desolvation and co-precipitation method for medical and pharmaceutical applications. Int J Biol Macromol. Epub ahead of print 2017. DOI: 10.1016/j.ijbiomac.2017.10.180.

21.

Salehiabar M, Nosrati H, Davaran S, et al. Facile synthesis and characterization of l-aspartic acid coated iron oxide magnetic nanoparticles (IONPs) for biomedical applications. Drug Res 2017. DOI: 10.1055/s-0043-120197.

22.

Gharebaghi

Dalali

Ahmadi

et al . Preparation of wormlike polymeric nanoparticles coated with silica for delivery of methotrexate and evaluation of anticancer activity against MCF7 cells. J Biomater Appl 2017; 31: 1305–1316.

23.

Danafar

Jaberizadeh

and Andalib

In vitro and in vivo delivery of gliclazide loaded mPEG-PCL micelles and its kinetic release and solubility study. Artif Cells NanomedBiotechnol 2017; 1–12. DOI: 10.1080/21691401.2017.1386191.

24.

Kheiri Manjili

Sharafi

Attari

et al . vivo delivery of sulforaphane by PCL–PEG–PCL copolymeric-based micelles. Artif Cells Nanomed Biotechnol 2017; 45: 1725–1739.

25.

Danafar

Manjili

and Najafi

Study of copolymer composition on drug loading efficiency of enalapril in polymersomes and cytotoxicity of drug loaded nanoparticles. Drug Res 2016; 66: 495–504.

26.

Nomani

Nosrati

Manjili

et al . Preparation and characterization of copolymeric polymersomes for protein delivery. Drug Res 2017; 67: 458–465.

27.

Danafar

and Hamidi

A rapid and sensitive LC–MS method for determination of ezetimibe concentration in human plasma: application to a bioequivalence study. Chromatographia 2013; 23: 1667–1675.

28.

Danafar

and Hamaidi

Pharmacokinetics and bioequivalence study of amlodipine and atorvastatin in healthy male volunteers by LC-MS. Pharm Sci 2015; 21: 167–174.

29.

Watson

DA.

Simple method for the determination of serum cholesterol. Clin Chem Acta 1960; 5: 589.

30.

Fossati

and Principe

Serum triglycerides determined colorimetrically with an enzyme that produce hydrogen peroxide. Clin Chem 1982; 28: 2077–2080.