PDF(Sci-hub)
Abstract：
Nowadays many drugs with improved therapeutic efficacy are discovered but cannot be utilized due to their low solubility and insufficient bioavailability. An example of such a drug molecule is a protein kinase C inhibitor that influences an enzyme which plays an important role in several signal transduction cascades. The aim of this study was to formulate a stable nanoparticle dispersion of the PKC inhibitor encapsulated into PLGA nanoparticles (NPs). Encapsulation of the PKC inhibitor into PLGA NPs of 100-200 nm diameter should provide a targeted delivery to the inflammation sites. The NPs were prepared via nanoprecipitation and different surfactants were investigated: Fully and partially hydrolyzed poly(vinyl alcohol) (PVA, Mowiol X-88 and X-98), poloxamers (Pluronic F68 and F127) and polysorbates (Tween 20 and 80). From all surfactants tested, only NPs prepared with partially hydrolyzed PVA (Mowiol X-88) provided the desired stability throughout the downstream processes. These NPs were subsequently analyzed regarding their particle size, polydispersity, encapsulation efficiency and loading capacity. Dynamic light scattering results revealed that monodisperse NPs of 150-220 nm were formed, a size range that favors targeted delivery. The drug encapsulation efficiency varied from 31 to 75% with a drug loading of 1.3-2%. Moreover, the long-term stability was studied and the residual amount of PVA of the NP solutions was quantified via nuclear magnetic resonance (NMR) measurements. The shell-less hen\'s egg model was used to test toxic effects (hemorrhage, vascular lysis, thrombosis, hemolysis and lethality) of the NPs in a more complex biological system under dynamic flow conditions.
摘要：
现在发现了许多具有改善的治疗功效的药物,但由于它们的低溶解度和不足的生物利用度而不能使用。这种药物分子的实例是蛋白激酶C抑制剂,其影响在几个信号转导级联中起重要作用的酶。本研究的目的是配制包封到PLGA纳米颗粒(NP)中的PKC抑制剂的稳定纳米颗粒分散体。将PKC抑制剂包封到直径为100-200nm的PLGANP中应当提供靶向递送至炎症部位。纳米粒子是通过纳米沉淀制备的，并研究了不同的表面活性剂：完全和部分水解的聚乙烯醇（PVA，MowiolX-88和X-98），泊洛沙姆（PluronicF68和F127）和聚山梨醇酯（吐温20和80）。从所有测试的表面活性剂中，只有用部分水解的PVA(MowiolX-88)制备的NP在整个下游过程中提供所需的稳定性。随后分析了这些NP的粒径，多分散性，封装效率和装载能力。动态光散射结果表明，形成了150-220nm的单分散NP，有利于定向交付的尺寸范围。药物包封效率在31%至75%之间变化,载药量为1.3-2%。此外，研究了长期稳定性，并通过核磁共振（NMR）测量定量了NP溶液中PVA的残留量。无壳鸡蛋模型用于测试毒性作用(出血，血管溶解,血栓形成,在动态流动条件下，NPs在更复杂的生物系统中的溶血和致死性）。
