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Attenuation of Carbon Tetrachloride-Induced Hepatic Injury with Curcumin-Loaded Solid Lipid Nanoparticles

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Abstract

Background and Objectives

Curcumin, an established pleiotropic agent, has potential for hepatoprotection owing to its powerful antioxidant, anti-inflammatory, and antifibrogenic properties. However, its poor bioavailability limits its use in therapeutics. In this study, we aimed to package curcumin into solid lipid nanoparticles (C-SLNs) to improve its bioavailability and compare the efficacy of C-SLNs with that of free curcumin and silymarin, a well-established hepatoprotectant in clinical use, against carbon tetrachloride (CCl4)-induced hepatic injury in rats, post-induction. A self-recovery group to which no treatment was given was also employed for quantifying self-healing of hepatic tissue, if any.

Material and Methods

C-SLNs (particle size 147.6 nm), prepared using a microemulsification technique, were administered to rats post-treatment with CCl4 (1 ml/kg body weight [BW] twice weekly for 2 weeks, followed by 1.5 ml/kg BW twice weekly for the subsequent 2 weeks). The extent of liver damage and repair in terms of histopathology and levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), oxidative stress markers (malondialdehyde, superoxide dismutase, and reduced glutathione) and a pro-inflammatory response marker, tumor necrosis factor (TNF)-α, were determined in both the CCl4 group and the treatment groups.

Results

C-SLNs (12.5 mg/kg) significantly (p < 0.001–0.005) attenuated histopathological changes and oxidative stress, and also decreased induction of ALT, AST, and TNF-α in comparison with free curcumin (100 mg/kg), silymarin (25 mg/kg), and self-recovery groups.

Conclusion

Curcumin could be used as a therapeutic agent for hepatic disorders, provided it is loaded into a suitable delivery system.

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References

  1. Jayaprakasha G, Rao L, Sakariah K. Antioxidant activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin. Food Chem. 2006;98(4):720–4.

    Article  CAS  Google Scholar 

  2. Tonnesen HH, Greenhil JVL. Studies on curcumin and curcuminoids XXII. Curcumin as a reducing agent and as a radical scavanger. Int J Pharm. 1992;87:79–87.

    Article  Google Scholar 

  3. Reyes-Gordillo K, Segovia J, Shibayama M, Vergara P, Moreno MG, Muriel P. Curcumin protects against acute liver damage in the rat by inhibiting NF-kappaB, proinflammatory cytokines production and oxidative stress. Biochim Biophys Acta. 2007;1770(6):989–96.

    Article  CAS  PubMed  Google Scholar 

  4. Arora RB, Kapoor V, Basu N, Jain AP. Anti-inflammatory studies on Curcuma longa (turmeric). Indian J Med Res. 1971;59(8):1289–95.

    CAS  PubMed  Google Scholar 

  5. Subramanian L, Selvam R, Mudaliar AL. Prevention of CCl4-induced hepatotoxicity by aqueous extract of tumeric. Nutr Res. 1999;19:429–41.

    Article  CAS  Google Scholar 

  6. Tonnesen HH, Masson M, Loftsson T. Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: solubility, chemical and photochemical stability. Int J Pharm. 2002;244(1–2):127–35.

    Article  CAS  PubMed  Google Scholar 

  7. Wang YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal. 1997;15(12):1867–76.

    Article  CAS  PubMed  Google Scholar 

  8. Ammon HPT, Wahl MA. Pharmacology of Curcuma longa. Planta Medica. 1991;57:1–7.

    Article  CAS  PubMed  Google Scholar 

  9. Sharma RA, McLelland HR, Hill KA, Ireson CR, Euden SA, Manson MM, et al. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin Cancer Res. 2001;7(7):1894–900.

    CAS  PubMed  Google Scholar 

  10. Maiti K, Mukherjee K, Gantait A, Saha BP, Mukherjee PK. Curcumin-phospholipid complex: preparation, therapeutic evaluation and pharmacokinetic study in rats. Int J Pharm. 2007;330(1–2):155–63.

    Article  CAS  PubMed  Google Scholar 

  11. Ravindranath V, Chandrasekhara N. Absorption and tissue distribution of curcumin in rats. Toxicology. 1980;16(3):259–65.

    Article  CAS  PubMed  Google Scholar 

  12. Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 1998;64(4):353–6.

    Article  CAS  PubMed  Google Scholar 

  13. Li L, Braiteh FS, Kurzrock R. Liposome-encapsulated curcumin: in vitro and in vivo effects on proliferation, apoptosis, signaling, and angiogenesis. Cancer. 2005;104(6):1322–31.

    Article  CAS  PubMed  Google Scholar 

  14. Ma Z, Shayeganpour A, Brocks DR, Lavasanifar A, Samuel J. High-performance liquid chromatography analysis of curcumin in rat plasma: application to pharmacokinetics of polymeric micellar formulation of curcumin. Biomed Chromatogr. 2007;21(5):546–52.

    Article  CAS  PubMed  Google Scholar 

  15. Liu A, Lou H, Zhao L, Fan P. Validated LC/MS/MS assay for curcumin and tetrahydrocurcumin in rat plasma and application to pharmacokinetic study of phospholipid complex of curcumin. J Pharm Biomed Anal. 2006;40(3):720–7.

    Article  CAS  PubMed  Google Scholar 

  16. Anand P, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007;4(6):807–18.

    Article  CAS  PubMed  Google Scholar 

  17. Mathew A, Fukuda T, Nagaoka Y, Hasumura T, Morimoto H, Yoshida Y, Maekawa T, Venugopal K, Kumar DS. Curcumin loaded-PLGA nanoparticles conjugated with Tet-1 peptide for potential use in Alzheimer’s disease. PLoS ONE. 2012;7(3):e32616. doi:10.1371/journal.pone.0032616.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Yadav A, Lomash V, Samim M, Flora SJ. Curcumin encapsulated in chitosan nanoparticles: a novel strategy for the treatment of arsenic toxicity. Chem Biol Interact. 2012;199(1):49–61.

    Article  CAS  PubMed  Google Scholar 

  19. Grama CN, Suryanarayana P, Patil MA, Raghu G, Balakrishna N, et al. Efficacy of biodegradable curcumin nanoparticles in delaying cataract in diabetic rat model. PLoS ONE. 2013;8(10):e78217. doi:10.1371/journal.pone.0078217.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Yallapu MM, Othman SF, Curtis ET, Bauer NA, Chauhan N, Kumar D, Jaggi M, Chauhan SC. Curcumin-loaded magnetic nanoparticles for breast cancer therapeutics and imaging applications. Int J Nanomed. 2012;7:1761–79.

    CAS  Google Scholar 

  21. Yallapu MM, Ebeling MC, Khan S, Sundram V, Chauhan N, Gupta BK, Puumala SE, Jaggi M, Chauhan SC. Novel curcumin-loaded magnetic nanoparticles for pancreatic cancer treatment. Mol Cancer Ther. 2013;12(8):1471–80. doi:10.1158/1535-7163.

    Article  CAS  PubMed  Google Scholar 

  22. Sandhir R, Yadav A, Mehrotra A, Sunkaria A, Singh A, Sharma S. Curcumin nanoparticles attenuate neurochemical and neurobehavioral deficits in experimental model of Huntington’s disease. Neuro Mol Med. 2013. doi:10.1007/s12017-013-8261-y.

  23. Bisht S, Khan MA, Bekhit M, Bai H, Cornish T, Mizuma M, Rudek MA, Zhao M, Maitra A, Ray B, Lahiri D, Maitra A, Anders RA. A polymeric nanoparticle formulation of curcumin (NanoCurc™) ameliorates CCl4-induced hepatic injury and fibrosis through reduction of pro-inflammatory cytokines and stellate cell activation. Lab Invest. 2011;91(9):1383–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Sankar P, Gopal Telang A, Kalaivanan R, Karunakaran V, Manikam K, Sarkar SN. Effects of nanoparticle-encapsulated curcumin on arsenic-induced liver toxicity in rats. Environ Toxicol. 2013. doi:10.1002/tox.21940.

  25. Kaur IP, Bhandari R, Bhandari S, Kakkar V. Potential of solid lipid nanoparticles for brain targeting. J Control Release. 2008;127:97–109.

    Article  CAS  PubMed  Google Scholar 

  26. Kakkar V, Singh S, Singla D, Kaur IP. Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. Mol Nutr Food Res. 2011;55(3):495–503.

    Article  CAS  PubMed  Google Scholar 

  27. Muller RH, Keck CM. Challenges and solutions for the delivery of biotech drugs—a review of drug nanocrystal technology and lipid nanoparticles. J Biotechnol. 2004;113(1–3):151–70.

    Article  CAS  PubMed  Google Scholar 

  28. Jores K, Mehnert W, Drechsler M, Bunjes H, Johann C, Mader K. Investigations on the structure of solid lipid nanoparticles (SLN) and oil-loaded solid lipid nanoparticles by photon correlation spectroscopy, field-flow fractionation and transmission electron microscopy. J Control Release. 2004;95(2):217–27.

    Article  CAS  PubMed  Google Scholar 

  29. Hu L, Tang X, Cui F. Solid lipid nanoparticles (SLNs) to improve oral bioavailability of poorly soluble drugs. J Pharm Pharmacol. 2004;56(12):1527–35.

    Article  CAS  PubMed  Google Scholar 

  30. Hu L, Xing Q, Meng J, Shang C. Preparation and enhanced oral bioavailability of cryptotanshinone-loaded solid lipid nanoparticles. AAPS PharmSciTech. 2010;11(2):582–7.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Freitas C, Muller RH. Effect of light and temperature on zeta potential and physical stability in solid lipid nanoparticle (SLN (TM)) dispersions. Int J Pharm. 1998;168:221–9.

    Article  CAS  Google Scholar 

  32. Rivera-Espinoza Y, Muriel P. Pharmacological actions of curcumin in liver diseases or damage. Liver Int. 2009;29(10):1457–66.

    Article  CAS  PubMed  Google Scholar 

  33. Muriel P, Rivera-Espinoza Y. Beneficial drugs for liver diseases. J Appl Toxicol. 2008;28(2):93–103.

    Article  CAS  PubMed  Google Scholar 

  34. Rechnagel RO, Glende EA Jr. Carbon tetrachloride hepatotoxicity: an example of lethal cleavage. CRC Crit Rev Toxicol. 1973;2(3):263–97.

    Article  CAS  PubMed  Google Scholar 

  35. Perez Tamayo R. Is cirrhosis of the liver experimentally produced by CCl4 and adequate model of human cirrhosis? Hepatology. 1983;3(1):112–20.

    Article  CAS  PubMed  Google Scholar 

  36. Du WD, Zhang YE, Zhai WR, Zhou XM. Dynamic changes of type I, III and IV collagen synthesis and distribution of collagen-producing cells in carbon tetrachloride-induced rat liver fibrosis. World J Gastroenterol. 1999;5(5):397–403.

    CAS  PubMed  Google Scholar 

  37. Pradhan SC, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian J Med Res. 2006;124(5):491–504.

    CAS  PubMed  Google Scholar 

  38. Kakkar V, Kaur IP. Evaluating potential of curcumin loaded solid lipid nanoparticles in aluminium induced behavioural, biochemical and histopathological alterations in mice brain. Food Chem Toxicol. 2011;49(11):2906–13.

    Article  CAS  PubMed  Google Scholar 

  39. Yang KY, Lin LC, Tseng TY, Wang SC, Tsai TH. Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC–MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;853(1–2):183–9.

    Article  CAS  PubMed  Google Scholar 

  40. Wahlstrom B, Blennow G. A study on the fate of curcumin in the rat. Acta Pharmacol Toxicol (Copenh). 1978;43(2):86–92.

    Article  CAS  Google Scholar 

  41. Manjunath K, Reddy JS, Venkateswarlu V. Solid lipid nanoparticles as drug delivery systems. Methods Find Exp Clin Pharmacol. 2005;27(2):127–44.

    Article  CAS  PubMed  Google Scholar 

  42. Gopal N, Sengottuvelu S. Hepatoprotective activity of Clerodendrum inerme against CCl4 induced hepatic injury in rats. Fitoterapia. 2008;79(1):24–6.

    Article  CAS  PubMed  Google Scholar 

  43. Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol. 1957;28(1):56–63.

    CAS  PubMed  Google Scholar 

  44. Wills ED. Mechanisms of lipid peroxide formation in animal tissues. Biochem J. 1966;99(3):667–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Kono Y. Generation of superoxide radical during autoxidation of hydroxylamine and an assay for superoxide dismutase. Arch Biochem Biophys. 1978;186(1):189–95.

    Article  CAS  PubMed  Google Scholar 

  46. Jollow DJ, Mitchell JR, Zampaglione N, Gillette JR. Bromobenzene-induced liver necrosis. Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabolite. Pharmacology. 1974;11(3):151–69.

    Article  CAS  PubMed  Google Scholar 

  47. Morisco F, Vitaglione P, Amoruso D, Russo B, Fogliano V, Caporaso N. Foods and liver health. Mol Aspects Med. 2008;29(1–2):144–50.

    Article  CAS  PubMed  Google Scholar 

  48. Slater TF. Free-radical mechanisms in tissue injury. Biochem J. 1984;222(1):1–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Liu SL, Degli Esposti S, Yao T, Diehl AM, Zern MA. Vitamin E therapy of acute CCl4-induced hepatic injury in mice is associated with inhibition of nuclear factor kappa B binding. Hepatology. 1995;22(5):1474–81.

    CAS  PubMed  Google Scholar 

  50. Hernandez-Munoz R, Diaz-Munoz M, Chagoya de Sanchez V. Possible role of cell redox state on collagen metabolism in carbon tetrachloride-induced cirrhosis as evidenced by adenosine administration to rats. Biochim Biophys Acta. 1994;1200(2):93–9.

    Article  CAS  PubMed  Google Scholar 

  51. Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003;33(2):105–36.

    Article  CAS  PubMed  Google Scholar 

  52. Czaja MJ, Xu J, Alt E. Prevention of carbon tetrachloride-induced rat liver injury by soluble tumor necrosis factor receptor. Gastroenterology. 1995;108(6):1849–54.

    Article  CAS  PubMed  Google Scholar 

  53. Fu Y, Zheng S, Lin J, Ryerse J, Chen A. Curcumin protects the rat liver from CCl4-caused injury and fibrogenesis by attenuating oxidative stress and suppressing inflammation. Mol Pharmacol. 2008;73(2):399–409.

    Article  CAS  PubMed  Google Scholar 

  54. He SM, Chan E, Zhou SF. ADME properties of herbal medicines in humans: evidence, challenges and strategies. Curr Pharm Des. 2011;17(4):357–407.

    Article  CAS  PubMed  Google Scholar 

  55. Bhandari R, Kaur IP. Pharmacokinetics, tissue distribution and relative bioavailability of isoniazid-solid lipid nanoparticles. Int J Pharm. 2013;441:202–12.

    Article  CAS  PubMed  Google Scholar 

  56. Bhandari R, Kaur IP. A method to prepare solid lipid nanoparticles with improved entrapment efficiency of hydrophilic drugs. Curr Nanosci. 2013;9:211–20.

    Article  Google Scholar 

  57. Hu Y, Xie J, Tong YW, Wang CH. Effect of PEG conformation and particle size on the cellular uptake efficiency of nanoparticles with the HepG2 cells. J Control Release. 2007;118(1):7–17.

    Article  CAS  PubMed  Google Scholar 

  58. Liang HF, Yang TF, Huang CT, Chen MC, Sung HW. Preparation of nanoparticles composed of poly(gamma-glutamic acid)-poly(lactide) block copolymers and evaluation of their uptake by HepG2 cells. J Control Release. 2005;105(3):213–25.

    Article  CAS  PubMed  Google Scholar 

  59. Hashida M, Takemura S, Nishikawa M, Takakura Y. Targeted delivery of plasmid DNA complexed with galactosylated poly(l-lysine). J Control Release. 1998;53(1–3):301–10.

    Article  CAS  PubMed  Google Scholar 

  60. Li L, Wang H, Ong ZY, Xu K, Ee PLR, Zheng S, Hedrick JL, Yang YY. Polymer- and lipid-based nanoparticle therapeutics for the treatment of liver diseases. Nano Today. 2010;5:296–312.

    Article  CAS  Google Scholar 

  61. He J, Hou S, Lu W, Zhu L, Feng J. Preparation, pharmacokinetics and body distribution of silymarin-loaded solid lipid nanoparticles after oral administration. J Biomed Nanotechnol. 2007;3(4):195–202.

    Article  CAS  Google Scholar 

  62. Kakkar V, Kaur IP. Antidepressant activity of curcumin loaded solid lipid nanoparticles (C-SLNs) in mice. Am J Pharm Tech Res. 2012;2(3):34–46.

    Google Scholar 

  63. Kakkar V, Muppu SK, Chopra K, Kaur IP. Curcumin loaded solid lipid nanoparticles: an efficient formulation approach for cerebral ischemic reperfusion injury in rats. Eur J Pharm Biopharm. 2013;6411(13):00059.

    Google Scholar 

  64. Kakkar V, Mishra AK, Chuttani K, Kaur IP. Proof of concept studies to confirm the delivery of curcumin loaded solid lipid nanoparticles (C-SLNs) to brain. Int J Pharm. 2013;448(2):354–9.

    Article  CAS  PubMed  Google Scholar 

  65. Dong MX, Jia Y, Zhang YB, Li CC, Geng YT, Zhou L, et al. Emodin protects rat liver from CCl(4)-induced fibrogenesis via inhibition of hepatic stellate cells activation. World J Gastroenterol. 2009;15(38):4753–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Sallie R, Tredger JM, Williams R. Drugs and the liver. Part 1: Testing liver function. Biopharm Drug Dispos. 1991;12(4):251–9.

    Article  CAS  PubMed  Google Scholar 

  67. Javed S, Kohli K, Ali M. Reassessing bioavailability of silymarin. Altern Med Rev. 2011;16(3):239–49.

    PubMed  Google Scholar 

  68. Mansour MA. Protective effects of thymoquinone and desferrioxamine against hepatotoxicity of carbon tetrachloride in mice. Life Sci. 2000;66(26):2583–91.

    Article  CAS  PubMed  Google Scholar 

  69. Barry J, Fritz M, Brender JR, Smith PE, Lee DK, Ramamoorthy A. Determining the effects of lipophilic drugs on membrane structure by solid-state NMR spectroscopy: the case of the antioxidant curcumin. J Am Chem Soc. 2009;131(12):4490–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Curtis SJ, Moritz M, Snodgrass PJ. Serum enzymes derived from liver cell fractions. I. The response to carbon tetrachloride intoxication in rats. Gastroenterology. 1972;62(1):84–92.

    CAS  PubMed  Google Scholar 

  71. Feher J, Lengyel G. Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Curr Pharm Biotechnol. 2012;13(1):210–7.

    Article  CAS  PubMed  Google Scholar 

  72. Wu G, Fang YZ, Yang S, Lupton JR, Turner ND. Glutathione metabolism and its implications for health. J Nutr. 2004;134(3):489–92.

    CAS  PubMed  Google Scholar 

  73. Blair IA. Endogenous glutathione adducts. Curr Drug Metab. 2006;7(8):853–72.

    Article  CAS  PubMed  Google Scholar 

  74. Shukitt-Hale B, Erat SA, Joseph JA. Spatial learning and memory deficits induced by dopamine administration with decreased glutathione. Free Radic Biol Med. 1998;24(7–8):1149–58.

    Article  CAS  PubMed  Google Scholar 

  75. Roy S, Sannigrahi S, Majumdar S, Ghosh B, Sarkar B. Resveratrol regulates antioxidant status, inhibits cytokine expression and restricts apoptosis in carbon tetrachloride induced rat hepatic injury. Oxid Med Cell Longev. 2011;2011(703676):15.

    Google Scholar 

  76. Hernandez-Munoz I, de la Torre P, Sanchez-Alcazar JA, Garcia I, Santiago E, Munoz-Yague MT, et al. Tumor necrosis factor alpha inhibits collagen alpha 1(I) gene expression in rat hepatic stellate cells through a G protein. Gastroenterology. 1997;113(2):625–40.

    Article  CAS  PubMed  Google Scholar 

  77. Berghe TV, Denecker G, Brouckaert G, Vadimovisch Krysko D, D’Herde K, Vandenabeele P. More than one way to die: methods to determine TNF-induced apoptosis and necrosis. Methods Mol Med. 2004;98:101–26.

    Google Scholar 

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Acknowledgments

The Senior Research Fellowship and contingent grant provided to Neha Singh by the Indian Council of Medical Research (ICMR), New Delhi, India, is gratefully acknowledged. The authors are thankful to Mr. Dinesh Sharma and the Sophisticated Analytical Instrumentation Facility (SAIF), Panjab University, Chandigarh, India, for transmission electron microscopic analysis. The authors declare that they have no conflicts of interest that are directly relevant to the content of this article.

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Authors and Affiliations

  1. Department of Biotechnology, Panjab University, Chandigarh, India

    Neha Singh & Neeraj Khullar

  2. Department of Pharmaceutics, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India

    Vandita Kakkar & Indu Pal Kaur

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  1. Neha Singh
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  2. Neeraj Khullar
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Correspondence to Indu Pal Kaur.

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Singh, N., Khullar, N., Kakkar, V. et al. Attenuation of Carbon Tetrachloride-Induced Hepatic Injury with Curcumin-Loaded Solid Lipid Nanoparticles. BioDrugs 28, 297–312 (2014). https://doi.org/10.1007/s40259-014-0086-1

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