title: Drug- not carrier-dependent haematological and biochemical changes in a repeated dose study of cyclosporine encapsulated polyester nano- and micro-particles: size does not matter.
abstract: Biodegradable nanoparticles are being considered more often as drug carriers to address pharmacokinetic/pharmacodynamic issues, yet nano-product safety has not been systematically proven. In this study, haematological, biochemical and histological parameters were examined on 28 day daily dosing of rats with nano- or micro-particle encapsulated cyclosporine (CsA) to confirm if any changes observed were drug or carrier dependent. CsA encapsulated poly(lactide-co-glycolide) [PLGA] nano- (nCsA) and micro-particles (mCsA) were prepared by emulsion techniques. CsA (15, 30, 45 mg/kg) were administered by oral gavage to Sprague Dawley (SD) rats over 28 days. Haematological and biochemical metrics were followed with tissue histology performed on sacrifice. Whether presented as nCsA or mCsA, 45 mg/kg dose caused significant loss of body weight and lowered food consumption compared to untreated control. Across the doses, both nCsA and mCsA produce significant decreases in lymphocyte numbers compared to controls, commensurate with the proprietary product, Neoral(®) 15. Dosing with nCsA showed higher serum drug levels than mCsA presumably owing to the smaller particle size facilitating absorption. The treatment had no noticeable effects on inflammatory/oxidative stress markers or antioxidant enzyme levels, except an increase in ceruloplasmin (CP) levels for high dose nCsA/mCsA group. Further, only subtle, sub-lethal changes were observed in histology of nCsA/mCsA treated rat organs. Blank (drug-free) particles did not induce changes in the parameters studied. Therefore, it is extremely important that the encapsulated drug in the nano-products is considered when safety of the overall product is assessed rather than relying on just the particle size. This study has addressed some concerns surrounding particulate drug delivery, demonstrating safe delivery of CsA whilst achieving augmented serum concentrations.
authors: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK.
authors: V P
authors: VP
authors: Venkatpurwar
authors: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK, G12 0ZD.
authors: S
authors: S
authors: Rhodes
authors: Molecular Pathology, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK, G61 1BD.
authors: K A
authors: KA
authors: Oien
authors: Cancer Research UK Formulation Unit, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK.
authors: M A
authors: MA
authors: Elliott
authors: Department of Epidemiology and Biostatistics, School of Public Health, 1266 Texas A&M University, College Station, Texas 77843-1266, USA.
authors: C D
authors: CD
authors: Tekwe
authors: Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK, G12 0ZD.
authors: H G
authors: HG
authors: Jørgensen
authors: Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Centre, Texas A&M University, College Station, TX 77843-1114, USA. Electronic address: mnvrkumar@tamhsc.edu.
authors: M N V Ravi
authors: MN
authors: Kumar
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000097:blood* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000633:toxicity*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008863:Microspheres; D053758:Nanoparticles / Q000633:toxicity*; D010316:Particle Size; D011091:Polyesters / Q000633:toxicity*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004337:Drug Carriers; D011091:Polyesters; D016572:Cyclosporine
keywords: Biodegradable; Cyclosporine; Microparticles; Nanoparticles; Nanotoxicology; Oral; Polyester; Toxicity