Venkatpurwar V P, Rhodes S, Oien K A, Elliott M A, Tekwe C D, Jørgensen H G, Kumar M N V Ravi
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK.
Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK, G12 0ZD.
Toxicology. 2015 Apr 1;330:9-18. doi: 10.1016/j.tox.2015.01.017. Epub 2015 Jan 28.
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.
可生物降解的纳米颗粒作为药物载体越来越多地被用于解决药代动力学/药效学问题，然而纳米产品的安全性尚未得到系统的证实。在本研究中，对大鼠每日给药纳米或微粒包封的环孢素（CsA）28天，检测血液学、生化和组织学参数，以确定观察到的任何变化是药物依赖性还是载体依赖性。通过乳液技术制备了CsA包封的聚（丙交酯-共-乙交酯）[PLGA]纳米颗粒（nCsA）和微粒（mCsA）。将CsA（15、30、45mg/kg）通过灌胃给予Sprague Dawley（SD）大鼠，持续28天。在处死时进行组织组织学检查，同时跟踪血液学和生化指标。与未处理的对照组相比，无论是nCsA还是mCsA，45mg/kg剂量均导致体重显著减轻和食物摄入量降低。在所有剂量下，与对照组相比，nCsA和mCsA均使淋巴细胞数量显著减少，这与专利产品Neoral(®) 15相当。与mCsA相比，nCsA给药显示血清药物水平更高，可能是由于粒径较小便于吸收。除高剂量nCsA/mCsA组的铜蓝蛋白（CP）水平升高外，该治疗对炎症/氧化应激标志物或抗氧化酶水平没有明显影响。此外，在nCsA/mCsA处理的大鼠器官组织学中仅观察到细微的亚致死性变化。空白（无药物）颗粒未引起所研究参数的变化。因此，在评估整个产品的安全性时，考虑纳米产品中包封的药物极其重要，而不是仅仅依赖于粒径。本研究解决了一些关于微粒药物递送的问题，证明了CsA的安全递送同时实现了血清浓度的提高。
