Development of Biodegradable Nanoparticles for Oral Delivery of Ellagic Acid and Evaluation of Their Antioxidant Efficacy Against Cyclosporine A-Induced Nephrotoxicity in Rats
Ellagic acid (EA), a dietary antioxidant associated with poor biopharmaceutical properties, was encapsulated into poly(lactide-co-glycolide) (PLGA) and polycaprolactone (PCL) nanoparticles to improve oral bioavailability.
Materials and Methods
EA-loaded nanoparticles were prepared following emulsion–diffusion–evaporation method employing didodecyldimethyl ammonium bromide (DMAB) and polyvinyl alcohol (PVA) as stabilizers. In vitro release was investigated in phosphate buffer (pH 7.4). The in situ permeation studies were performed in rats. The antioxidant potential of the DMAB-stabilized nanoparticulate formulations was evaluated against cyclosporine A (CyA)-induced nephrotoxicity in rats.
EA-loaded PLGA and PCL nanoparticles have been succesfully prepared employing PEG 400 as co-solvent to solubilize EA. The stabilizers influenced the particle size and encapsulation efficiency. DMAB when used as stabilizer to particles of ~120 nm and ~50% encapsulation, whereas PVA led to ~290 nm and ~60% encapsulation at 5% initial loading (w/w of polymer). The in vitro release of EA from the nanoparticles followed Higuchi's square root pattern and was faster with PVA-stabilized particles in comparison to those stabilized with DMAB. From the in situ permeation studies in rats, it was evident that intestinal uptake of EA as DMAB-stabilized nanoparticles was significantly higher as compared to the sodium carboxymethyl cellulose suspension and the PVA-stabilized particles. EA and EA nanoparticles were able to prevent the CyA-induced nephrotoxicity in rats as evident by biochemical parameters as well as kidney histopathology.
The present study demonstrates the potential of EA nanoparticulate formulations in the prevention of CyA-induced nephrotoxicity at three times lower dose suggesting improved oral bioavailability of EA.
- H. Sies. Oxidative stress: oxidants and antioxidants. Exp. Physiol. 82:291–295 (1997).
- B. Halliwell and J. M. Gutteridge. Lipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy. Lancet 13:96–1397 (1984).
- M. Hashida. Inhibition of metastatic tumor growth by targeted delivery of antioxidant enzymes. J. Control. Release 109:101–107 (2005). CrossRef
- Y. Gilgun-sherki, E. Melamed, and D. Offen. Oxidative stress induced neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40:959–975 (2001). CrossRef
- S. Beatty, H. Koh, M. Phil, D. Henson, and M. Boulton. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv. Ophthalmol. 45:115–134 (2000). CrossRef
- R. A. Floyd. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc. Soc. Exp. Biol. Med. 222:236 (1999). CrossRef
- R. Rezzani. Exploring cyclosporine A-side effects and the protective role-played by antioxidants: the morphological and immunohistochemical studies. Histol. Histopathol. 21:301–316 (2006).
- A. Atessahin, S. Yilmaz, I. Karahan, A. Ceribasi, and A. Karaoglu. Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology 212:116–123 (2005). CrossRef
- M. Khan, J. C. Shobha, I. K. Mohan, M. U. R. Naidu, C. Sundaram, S. Singh, P. Kuppusamy, and V. K. Kutala. Protective effect of Spirulina against doxorubicin-induced cardiotoxicity. Phytother. Res. 19:1030–1037 (2005). CrossRef
- R. K. Y. Zee-Cheng and C. C. Cheng. Ellagic acid. Drugs Future 11:1029–1033 (1986).
- D. Venkat Ratnam, D. D. Ankola, V. Bhardwaj, D. K. Sahana, and M. N. V. R. Kumar. Role of antioxidants in prophylaxis and therapy: a pharmaceutical perspective. J. Control. Release 113:189–207 (2006). CrossRef
- G. L. Amidon, H. Lennernas, V. P. Shah, and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12:413–420 (1995). CrossRef
- I. Bala, V. Bhardwaj, S. Hariharan, and M. N. V. R. Kumar. Analytical methods for assay of ellagic acid and its solubility studies. J. Pharm. Biomed. Anal. 40:206–210 (2006). CrossRef
- I. Bala, V. Bhardwaj, S. Hariharan, S. V. Kharade, N. Roy, and M. N. V. R. Kumar. Sustained release nanoparticulate formulation containing antioxidant ellagic acid as potential prophylaxis system for oral administration. J. Drug Target. 14:27–34 (2006). CrossRef
- B. Doyle and L. A. Griffiths. The metabolism of ellagic acid in the rat. Xenobiotica 10:247–256 (1980). CrossRef
- R. W. Teel. Distribution and metabolism of ellagic acid in the mouse following intraperitoneal administration. Cancer Lett. 34:165–171 (1987). CrossRef
- V. Bhardwaj, S. Hariharan, I. Bala, A. Lamprecht, N. Kumar, R. Panchagnula, and M. N. V. R. Kumar. Pharmaceutical aspects of polymeric nanoparticles for oral delivery. J. Biomed. Nanotech. 1:235–258 (2005). CrossRef
- S. Hariharan, V. Bharadwaj, I. Bala, J. Sitterberg, U. Bakowsky, and M. N. V. R. Kumar. Design of estradiol loaded PLGA nanoparticulate formulations: a potential oral delivery system for hormone therapy. Pharm. Res. 23:184–195 (2005). CrossRef
- L. Araujo, M. Sheppard, R. Lobenberg, and J. Kreuter. Uptake of PMMA nanoparticles from the gastrointestinal tract after oral administration to rats: modification of the body distribution after suspension in surfactant solutions and in oil vehicles. Int. J. Pharm. 176:209–224 (1999). CrossRef
- P. Arbos, M. A. Campanero, M. A. Arangoa, and J. M. Irache. Nanoparticles with specific bioadhesive properties to circumvent the pre-systemic degradation of fluorinated pyrimidines. J. Control. Release 96:55–65 (2004). CrossRef
- I. Bala, S. Hariharan, and M. N. V. R. Kumar. PLGA Nanoparticles in drug delivery: the state of the art. Crit. Rev. Ther. Drug Carr. Syst. 21:387–422 (2004). CrossRef
- I. Bala, V. Bhardwaj, S. Hariharan, J. Sitterberg, U. Bakowsky, and M. N. V. R. Kumar. Design of biodegradable nanoparticles: a novel approach to encapsulating poorly soluble phytochemical ellagic acid. Nanotechnology 16:2819–2822 (2005). CrossRef
- H. Ohkawa, N. Ohishi, and K. Yagi. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal. Biochem. 95:351–358 (1979). CrossRef
- C. Hsu, Z. Cui, R. J. Mumper, and M. Jay. Preparation and characterization of novel coenzyme Q10 nanoparticles engineered from microemulsion precursors. AAPS PharmSciTech 4:1–12 (2003). CrossRef
- M. H. El-Shabouri. Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A. Int. J. Pharm. 249:101–108 (2002). CrossRef
- S. K. Sahoo, J. Panyam, S. Prabha, and V. Labhasetwar. Residual polyvinyl alcohol associatedwith poly (d,l-lactide-co-glycolide). nanoparticles affects their physical properties and cellular uptake. J. Control. Release 82:105–114 (2002). CrossRef
- I. Durak, H. I. Karabacak, S. Buyukkocak, M. Y. Cimen, M. Kacmaz, E. Omeroglu, and H. S. Ozturk. Impaired antioxidant defense system in the kidney tissues from rabbits treated with cyclosporine. Protective effects of vitamins E and C. Nephron 78:207–211 (1998). CrossRef
- K. C. Mun. Effect of epigallocatechin gallate on renal function in cyclosporine-induced nephrotoxicity. Transplant. Proc. 36:2133–2134 (2004). CrossRef
- V. Chander, N. Tirkey, and K. Chopra. Resveratrol, a polyphenolic phytoalexin protects against cyclosporine-induced nephrotoxicity through nitric oxide dependent mechanism. Toxicology 210:55–64 (2005). CrossRef
- M. Tariq, C. Morais, S. Sobki, M. Al Sulaiman, and A. Al Khader. N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats. Nephrol. Dial. Transplant. 14:923–929 (1999). CrossRef
- K. V. Kumar, M. U. Naidu, A. A. Shifow, A. Prayag, and K. S. Ratnakar. Melatonin: an antioxidant protects against cyclosporine-induced nephrotoxicity. Transplantation 67:1065–1068 (1999). CrossRef
- G. Inselmann, J. Hannemann, and K. Baumann. Cyclosporine A induced lipid peroxidation and influence on glucose-6-phosphatase in rat hepatic and renal microsomes. Res. Commun. Chem. Pathol. Pharmacol. 68:189–203 (1990).
- J. L. Italia, V. Bhardwaj, and M. N. V. R. Kumar. Disease, destination, dose and delivery aspects of ciclosporin: the state of the art. Drug Discov. Today 11:846–854 (2006). CrossRef
- T. F. Andoh, M. P. Gardner, and W. M. Bennett. Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity. Transplantation 64:1236–1240 (1997). CrossRef
- W. M. Bennett, A. DeMattes, and M. M. Meyer. Chronic cyclosporine nephropathy: the Achilles’ heel of immunosuppressive therapy. Kidney Int. 50:1089–1100 (1996).
- N. Origlia, M. Migliori, V. Panichi, C. Filippi, A. Bertelli, A. Carpi, and L. Giovannini. Protective effect of L-propionylcarnitine in chronic cyclosporine-a induced nephrotoxicity. Biomed. Pharmacother. 60:77–81 (2006). CrossRef
- Development of Biodegradable Nanoparticles for Oral Delivery of Ellagic Acid and Evaluation of Their Antioxidant Efficacy Against Cyclosporine A-Induced Nephrotoxicity in Rats
Volume 24, Issue 5 , pp 899-908
- Cover Date
- Print ISSN
- Online ISSN
- Kluwer Academic Publishers-Plenum Publishers
- Additional Links
- cyclosporine A
- ellagic acid
- free radicals
- oral delivery
- Industry Sectors
- Author Affiliations
- 1. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab, 160062, India
- 2. Centre for Pharmaceutical Nanotechnology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab, 160062, India
- 3. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab, 160062, India