隐形丹参酮IIA固体脂质纳米粒:poloxamer 188 包衣对体外吞噬以及大鼠体内药动学的影响
Stealth tanshinone IIA-loaded solid lipid nanoparticles: effects of poloxamer 188 coating on in vitro phagocytosis and in vivo pharmacokinetics in rats
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摘要:
以普罗沙姆188为修饰剂制备了隐形丹参酮IIA固体脂质纳米粒 (TA-SSLNs), 并对其体外吞噬特性和体内药动学进行了评价。采用溶剂乳化蒸发法制备了纳米粒; 对纳米粒的理化性质包括粒径, zeta电位, 微观结构和稳定性等进行了表征; 通过将TA-SSLNs和普通的丹参酮IIA固体脂质纳米粒 (TA-NSLNs) 与小鼠腹腔巨噬细胞共孵育来考察两种纳米粒的体外细胞吞噬特性; 以丹参酮IIA溶液剂 (TA-SOL) 为对照, 考察了TA-NSLNs和TA-SSLNs在大鼠体内的药动学行为。所制备的纳米粒平均粒径为 (91.3 ± 3.4) nm, zeta电位为 (−19.7 ± 1.6) mV, 载药量为 (4.7 ± 0.5) %, 包封率为 (92.5 ± 2.1) %; 吞噬试验结果表明, poloxamer 188的修饰可以显著降低TA-SSLNs的吞噬量; 体内试验表明, TA-SSLNs, TA-NSLNs和TA-SOL的血药浓度数据均符合二室模型, 与TA-SOL相比, TA-SSLNs和TA-NSLNs的AUC分别增加了3.70和1.28倍, 它们的MRT分别是5.286, 3.051和0.820 h。使用poloxamer 188可以降低微粒被血浆蛋白调理的作用, 从而减少巨噬细胞的吞噬, 并改变纳米粒的体内药动学行为, 增加AUC, 延长其在血液中的循环时间。
Abstract:Stealth tanshinone IIA-loaded solid lipid nanoparticles (TA-SSLNs) have been prepared and the influence of poloxamer 188 coating on in vitro phagocytosis and in vivo pharmacokinetics in rats were evaluated. TA-SSLNs have been prepared by a nanoprecipitation/solvent diffusion method. Poloxamer 188 was used as a stealth agent. The physicochemical parameters of TA-SSLNs were characterized in terms of particle size, zeta potential, transmission electron microscopy and stability. In vitro, phagocytosis was investigated by incubating TA-SSLNs and non-stealth tanshinone IIA-loaded solid lipid nanoparticles (TA-NSLNs) with murine macrophages. In vivo, pharmacokinetics of TA-SSLNs and TA-NSLNs after a single dose intravenous injection to rat has been studied. The control was tanshinone IIA solution (TA-SOL). The results showed that TA-SSLNs had an average diameter of (91.3 ± 3.4) nm, zeta potential of (−19.7 ± 1.6) mV, drug loading of (4.7 ± 0.5) % and entrapment efficiency of (92.5 ± 2.1) %. Phagocytosis studies showed significant differences between TA- SSLNs and TA-NSLNs and demonstrated that the poloxamer 188 coating could decrease the macrophage uptake. In vivo experiments showed that the plasma concentration data of TA-SSLNs, TA-NSLNs and TA-SOL were all fitted to a two-compartment model. Areas under curve (AUCs) of TA-NSLNs and TA-SSLNs were 1.28 and 3.70 times than that of TA-SOL, respectively. TA-SSLNs had generated a long circulating time in blood with a mean residence time (MRT) of 5.286 h, compared to 3.051 h of TA-NSLNs and 0.820 h of TA-SOL. Poloxamer 188 modification on solid lipid nanoparticles (SLNs) reduced opsonization by serum proteins and the macrophage uptake. AUC of tanshinone IIA increased as a function of SLNs. In addition, TA-SSLNs exhibited much longer circulation lifetimes for tanshinone IIA than TA-NSLNs. The pharmacokinetic behavior of the incorporated drug can be modified by changing the surface characteristics of SLNs with the use of poloxamer 188.
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