Pharmacokinetics of curcumin-loaded PLGA and PLGA-PEG blend nanoparticles after oral administration in rats.

The aim of this study was to assess the potential of nanoparticles to improve the pharmacokinetics of curcumin, with a primary goal of enhancing its bioavailability. Polylactic-co-glycolic acid (PLGA) and PLGA-polyethylene glycol (PEG) (PLGA-PEG) blend nanoparticles containing curcumin were obtained by a single-emulsion solvent-evaporation technique, resulting in particles size smaller than 200 nm. The encapsulation efficiency was over 70% for both formulations. The in vitro release study showed that curcumin was released more slowly from the PLGA nanoparticles than from the PLGA-PEG nanoparticles. A LC-MS/MS method was developed and validated to quantify curcumin in rat plasma. The nanoparticles were orally administered at a single dose in rats, and the pharmacokinetic parameters were evaluated and compared with the curcumin aqueous suspension. It was observed that both nanoparticles formulations were able to sustain the curcumin delivery over time, but greater efficiency was obtained with the PLGA-PEG nanoparticles, which showed better results in all of the pharmacokinetic parameters analyzed. The PLGA and PLGA-PEG nanoparticles increased the curcumin mean half-life in approximately 4 and 6h, respectively, and the C(max) of curcumin increased 2.9- and 7.4-fold, respectively. The distribution and metabolism of curcumin decreased when it was carried by nanoparticles, particularly PLGA-PEG nanoparticles. The bioavailability of curcumin-loaded PLGA-PEG nanoparticles was 3.5-fold greater than the curcumin from PLGA nanoparticles. Compared to the curcumin aqueous suspension, the PLGA and PLGA-PEG nanoparticles increased the curcumin bioavailability by 15.6- and 55.4-fold, respectively. These results suggest that PLGA and, in particular, PLGA-PEG blend nanoparticles are potential carriers for the oral delivery of curcumin.

[1]  Lisbeth Illum,et al.  Long circulating microparticulate drug carriers , 1995 .

[2]  Soriano,et al.  The role of PEG on the stability in digestive fluids and in vivo fate of PEG-PLA nanoparticles following oral administration. , 2000, Colloids and surfaces. B, Biointerfaces.

[3]  M. Gremião,et al.  Intranasal delivery of zidovudine by PLA and PLA-PEG blend nanoparticles. , 2010, International journal of pharmaceutics.

[4]  Robert Langer,et al.  PEG-coated nanospheres from amphiphilic diblock and multiblock copolymers: Investigation of their drug encapsulation and release characteristics1 , 1997 .

[5]  H. Lou,et al.  Validated LC/MS/MS assay for curcumin and tetrahydrocurcumin in rat plasma and application to pharmacokinetic study of phospholipid complex of curcumin. , 2006, Journal of pharmaceutical and biomedical analysis.

[6]  C. Mohanty,et al.  The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation. , 2010, Biomaterials.

[7]  R. Das,et al.  Encapsulation of curcumin in alginate-chitosan-pluronic composite nanoparticles for delivery to cancer cells. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[8]  N. Khalil,et al.  Colloidal polymeric nanoparticles and brain drug delivery. , 2009, Current drug delivery.

[9]  E. Carraro,et al.  Potential of polymeric nanoparticles in AIDS treatment and prevention , 2011, Expert opinion on drug delivery.

[10]  S. Dulchavsky,et al.  Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro. , 2004, Biochemical pharmacology.

[11]  A. Lamprecht,et al.  Oral bioavailability of a low molecular weight heparin using a polymeric delivery system. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[12]  B. Aggarwal,et al.  Curcumin as "Curecumin": from kitchen to clinic. , 2008, Biochemical pharmacology.

[13]  Lie-Chwen Lin,et al.  Curcumin and its nano-formulation: the kinetics of tissue distribution and blood-brain barrier penetration. , 2011, International journal of pharmaceutics.

[14]  B. Aggarwal,et al.  Cyclodextrin-complexed curcumin exhibits anti-inflammatory and antiproliferative activities superior to those of curcumin through higher cellular uptake. , 2010, Biochemical pharmacology.

[15]  M. R. Kumar,et al.  Nanoparticle encapsulation improves oral bioavailability of curcumin by at least 9-fold when compared to curcumin administered with piperine as absorption enhancer. , 2009, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[16]  K. Avgoustakis,et al.  Pegylated poly(lactide) and poly(lactide-co-glycolide) nanoparticles: preparation, properties and possible applications in drug delivery. , 2004, Current drug delivery.

[17]  Nicholas A Peppas,et al.  Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. , 2006, International journal of pharmaceutics.

[18]  Fengyi Zhang,et al.  PLGA nanoparticles improve the oral bioavailability of curcumin in rats: characterizations and mechanisms. , 2011, Journal of agricultural and food chemistry.

[19]  Kenji Suzuki,et al.  Curcumin attenuates hyperglycaemia-mediated AMPK activation and oxidative stress in cerebrum of streptozotocin-induced diabetic rat , 2011, Free radical research.

[20]  B. Aggarwal,et al.  Curcumin and cancer: an "old-age" disease with an "age-old" solution. , 2008, Cancer letters.

[21]  J. Weinstein,et al.  Inhibition of human immunodeficiency virus type-1 integrase by curcumin. , 1995, Biochemical pharmacology.

[22]  Olivier Rouaud,et al.  Microencapsulation by solvent evaporation: state of the art for process engineering approaches. , 2008, International journal of pharmaceutics.

[23]  B. Aggarwal,et al.  Anticancer potential of curcumin: preclinical and clinical studies. , 2003, Anticancer research.

[24]  R. Pandey,et al.  Transport of liposomal and albumin loaded curcumin to living cells: an absorption and fluorescence spectroscopic study. , 2006, Biochimica et biophysica acta.

[25]  B. Aggarwal,et al.  Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. , 2009, The international journal of biochemistry & cell biology.

[26]  H. Ohshima,et al.  Curcumin, an anti-tumour promoter and anti-inflammatory agent, inhibits induction of nitric oxide synthase in activated macrophages. , 1995, Biochemical and biophysical research communications.

[27]  I. Kaur,et al.  Pharmacokinetic applicability of a validated liquid chromatography tandem mass spectroscopy method for orally administered curcumin loaded solid lipid nanoparticles to rats. , 2010, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[28]  Ricky A. Sharma,et al.  Pharmacokinetics and pharmacodynamics of curcumin. , 2007, Advances in experimental medicine and biology.

[29]  Robert A Newman,et al.  Bioavailability of curcumin: problems and promises. , 2007, Molecular pharmaceutics.

[30]  W. Tiyaboonchai,et al.  Formulation and characterization of curcuminoids loaded solid lipid nanoparticles. , 2007, International journal of pharmaceutics.

[31]  O. Oliveira,et al.  Curcumin antifungal and antioxidant activities are increased in the presence of ascorbic acid , 2012 .

[32]  R. Bodmeier,et al.  Oral evaluation in rabbits of cyclosporin-loaded Eudragit RS or RL nanoparticles. , 2005, International journal of pharmaceutics.

[33]  T. Tsai,et al.  Oral bioavailability of curcumin in rat and the herbal analysis from Curcuma longa by LC-MS/MS. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[34]  Zhen-zhou Shen,et al.  Curcumin exerts multiple suppressive effects on human breast carcinoma cells , 2002, International journal of cancer.

[35]  M. Gremião,et al.  Zidovudine-loaded PLA and PLA-PEG blend nanoparticles: influence of polymer type on phagocytic uptake by polymorphonuclear cells. , 2009, Journal of pharmaceutical sciences.

[36]  R. Gurny,et al.  Biodegradable nanoparticles — From sustained release formulations to improved site specific drug delivery , 1996 .

[37]  B. Aggarwal,et al.  Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake, and increased bioactivity in vitro and superior bioavailability in vivo. , 2010, Biochemical pharmacology.

[38]  Sudesh Kumar Yadav,et al.  Biodegradable polymeric nanoparticles based drug delivery systems. , 2010, Colloids and surfaces. B, Biointerfaces.

[39]  V. Torchilin,et al.  Which polymers can make nanoparticulate drug carriers long-circulating? , 1995 .

[40]  T. Masuda,et al.  Chemical studies on antioxidant mechanism of curcuminoid: analysis of radical reaction products from curcumin. , 1999, Journal of agricultural and food chemistry.

[41]  Eric Pridgen,et al.  Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles , 2008, Molecular pharmaceutics.