BACKGROUND & AIMS:
:Some Pluronics, particularly F127, are known to stabilize nanospheres and prolong their circulation time in vivo. However, these copolymers of poly(ethylene glycol) (PEG) and poly(propylene glycol) are not biodegradable, and despite the long history, there is no approved commercial product using F127 for parenteral administration until now. Meanwhile, hydroxyethyl starch (HES) is a biodegradable polymer that is currently investigated as a substitute for PEG. In order to produce a fully biodegradable amphiphilic polymer, we esterified different molar masses of HES with lauric acid to get different molar substitutions. These polymers, as well as Pluronic F68 and F127, were used to stabilize poly(lactic-co-glycolic acid) (PLGA) nanospheres prepared by nanoprecipitation. For physicochemical characterization, the particle size, zeta potential, and the thickness of the adsorbed polymer layer were measured. The ability of the polymer coating to prevent the adsorption of human serum albumin (HSA) and fibrinogen (FBG) was evaluated. Finally, the phagocytosis of the stabilized nanospheres by a monocyte macrophage cell line (J774.2) was assessed. Results show that the PLGA nanospheres had an average particle size of 110-140 nm. The thickness of the adsorbed polymer layer increases with the increase in molar mass, and is generally higher for HES laurates than the studied Pluronics. Pluronic F68, F127 as well as the HES laurates with low molar substitution prevented the adsorption of HSA. HES laurates with low molar substitution and F127, but not F68, prevented the adsorption of FBG. The phagocytosis experiments showed that the HES laurates, particularly the one with the highest molar mass, could reduce the uptake of the nanospheres better than F68 and comparable to F127. Finally, these results warrant in vivo experiments to evaluate how the HES laurates can affect the pharmacokinetics and fate of the nanospheres.
背景与目标:
: 已知某些Pluronics,尤其是F127,可以稳定纳米球并延长其在体内的循环时间。但是,这些聚 (乙二醇) (PEG) 和聚 (丙二醇) 的共聚物是不可生物降解的,尽管历史悠久,但到目前为止,尚无批准的使用F127进行肠胃外给药的商业产品。同时,羟乙基淀粉 (HES) 是一种可生物降解的聚合物,目前正在研究作为PEG的替代品。为了生产完全可生物降解的两亲聚合物,我们用月桂酸酯化了不同摩尔质量的HES,以获得不同的摩尔取代。这些聚合物以及Pluronic F68和F127用于稳定通过纳米沉淀制备的聚 (乳酸-乙醇酸) (PLGA) 纳米球。为了进行物理化学表征,测量了吸附聚合物层的粒径,zeta电位和厚度。评估了聚合物涂层防止人血清白蛋白 (HSA) 和纤维蛋白原 (FBG) 吸附的能力。最后,评估了单核巨噬细胞细胞系 (J774.2) 对稳定纳米球的吞噬作用。结果表明,PLGA纳米球的平均粒径为110-140 nm。吸附的聚合物层的厚度随着摩尔质量的增加而增加,对于HES月桂酸酯,其厚度通常高于所研究的Pluronics。Pluronic F68,F127以及具有低摩尔取代度的HES月桂酸酯阻止了HSA的吸附。具有低摩尔取代度的HES月桂酸酯和F127 (而不是F68) 阻止了FBG的吸附。吞噬实验表明,HES月桂酸酯,尤其是摩尔质量最高的月桂酸酯,可以比F68更好地降低纳米球的吸收,与f127相当。最后,这些结果值得进行体内实验,以评估HES月桂酸酯如何影响纳米球的药代动力学和命运。