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1、The preliminary evaluation on cholesterol-modified pullulan as a drug nanocarrier 胆固醇改性普鲁兰多糖作为药物纳米粒载体的初步评价 Abstract To further develop cholesterol-modified pullulan self-aggregated nanoparticles (CHSPNs) as a drug nanocarrier, CHSP was synthesized and characterized. Its cholesterol degree determined
2、 by 1H NMR was 5.2 cholesterol groups per hundred glucose units. CHSPNs were prepared in aqueous media and characterized by dynamic laser light-scattering (DLS), zeta potential and transmission electron microscopy (TEM). These nanoparticles were almost spherical in shape, and the zeta potentials of
3、CHSPNs were near zero in aqueous media. CHSPNs can be stable at least 2 months with no significant size and zeta potential changes. 为了进一步开发胆固醇改性的普鲁兰多糖自聚集纳米粒 子（CHSPNs）作为药物纳米载体，合成和表征CHSP。通过 核磁共振H谱测定的其胆固醇度为每100个葡萄糖单位5.2个胆 固醇基团。 CHSPNs在水性介质中制备，并通过动态激光散射 （DLS），电位和透射电镜（TEM）表征。这些纳米粒子几 本都是球形的，并且CHSPN的电位在水介质
4、中接近零。 CHSPNs可以稳定至少2个月，没有明显的大小和电位变化。 CHSP：胆固醇琥珀酰基普鲁兰 synthesize：合成 characterized：表征 aqueous media：水性介质 DLS：动态激光散射 TEM：透射电镜 Single dose toxicity test in mice was investigated for the safety evaluation of CHSPNs as a drug nanocarrier, and the result showed CHSPNs were well tolerated at the dose of 200m
5、g/kg in mice. Epirubicin (EPI)-loaded CHSPNs (EPI-CHSPNs) were prepared and the in vivo pharmacokinetics and biodistribution were studied. Compared with the EPI solution, EPI-CHSPNs have exhibited higher plasma drug concentration, longer half-life time (t1/2) and the larger area under-the-curve (AUC
6、). Moreover, the drug level of EPI- CHSPNs increased in liver and decreased in heart. The results indicated that CHSPNs were stable, safe and may be a promising drug delivery carrier. 对小鼠的单剂量毒性试验进行了关于胆固醇改性的普鲁兰多 糖自聚集纳米粒子作为药物纳米载体的安全性评价的研究，结果 显示CHSPNs在小鼠中以200mg / kg的剂量耐受性良好。加载表柔 比星（EPI）制备CHSPNs（EPI-CHS
7、PNs），并且进行体内药代 动力学和生物分布研究。与EPI溶液相比，EPI-CHSPNs显示更高 的血浆药物浓度，更长的半衰期(t1/2)和更大的曲线下面积（ AUC）。此外，EPI-CHSPNs的药物水平在肝脏中增加并在心脏 中减少。结果表明，CHSPNs是稳定，安全的，可能是一个有希 望的药物传递载体。 toxicity：毒性的 EPI：表柔比星 pharmacokinetics：药代动力学 biodistribution：生物分布 plasma：血浆 ACU：曲线下面积 Keywords Cholesterol-modified pullulan epirubicin nanoparti
8、cles pharmacokinetics stability toxicity 胆固醇改性的普鲁兰多糖 表柔比星 纳米颗粒 药代动力学 稳定性 毒性 Introduction Nanomaterials are structures with at least one dimension of 100nm or less. These materials have specific physic-chemical properties different to bulk materials of the same composition, and are increasingly being
9、 used for commercial purposes such as fillers, catalysts, semiconductors, cosmetics, microelectronics and drug carriers (Landsiedel et al., 2010). Using the nanoparticles (NPs) to deliver drugs, the absorption of poorly water-soluble pharmaceuticals may be improved and led to prolong pharmacological
10、 effect, enhance drug bioavailability and increase the patients compliance (Goncalves et al., 2010). 纳米材料是具有100nm或更小尺寸的结构。这些材料具有 特定物理化学性质,不同于相同组成的散装材料，并且越来越多 地用于商业目的，例如填料，催化剂，半导体，化妆品，微电 子学和药物载体。使用纳米颗粒（NPs）来递送药物，可以改 善对水溶性差的药物的吸收，并导致延长药理作用，增强药物 生物利用度和增加患者的依从性。 dimension：尺寸 filler:填料 catalysts：催化剂 semi
11、conductors：半导体 microelectronics：微电子学 bioavailability：生物利用度 The unusual physic-chemical properties of NPs are attributable to their small size, chemical composition, surface structure, solubility, shape and aggregation. The biological impacts and the biokinetics of NPs are dependent on their physicoc
12、hemical parameters, which can modify cellular uptake, protein binding, clearance, metabolism, translocation from portal of entry to the target site. However, the properties may also cause new side effects and differential toxicity profiles. The pharmacokinetic profiles of the parent drug and the dru
13、g encapsulated in the NPs are often different. In vivo systems are extremely complicated and the data of nanotoxicity from the cell culture systems are imperfect. Therefore, it is very important to understand the relationship between the NPs physic- chemical properties and its behavior in vivo . 纳米粒
14、子的不寻常的物理化学性质归因于它们的小尺寸， 化学组成，表面结构，溶解性，形状和聚集。 NPs的生物学影响 和生物动力学取决于其物理化学参数，其可以改变细胞摄取，蛋 白质结合，清除，代谢，从入口到目标位点的转运。然而，性质 也可能引起新的副作用和不同的毒性特征。母体药物和包封在 NPs中的药物的药代动力学概况通常是不同的。体内系统是非常 复杂的，并且来自细胞培养系统的纳米毒性的数据是不完美的。 因此，理解NPs的物理化学性质和其在体内的行为之间的关系是 非常重要的。 surface structure：表面结构 biokinetics：生物动力学 parameters：参数 metabolis
15、m：代谢 parent drug：母体药物 encapsulate：包封 Pullulan, a very important neutral and linear natural polysaccharide, has many advantages as a macromolecular drug carrier, e.g. highly water-soluble, non-toxic, nonmutagenic, edible, lacks immunogenicity, and usefulness as a plasma expander, multiple hydroxyl gr
16、oups that can readily be modified chemically. Many investigations have reported that some amphiphilic pullulan derivatives can form self-aggregated NPs to be used as the carrier for drug delivery . Cholesterol-modified pullulan (CHP), as one of amphiphilic pullulan derivatives, can be synthesized using 1,6-hexyldiisocyanate linkages by the reaction between cholesterol and pullulan , and its selfaggregated CHP NPs can be used as drug delivery
