Zhu Zhengxi
Department of Chemical Engineering and Materials Science, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Mol Pharm. 2014 Mar 3;11(3):776-86. doi: 10.1021/mp500025e. Epub 2014 Feb 12.
Flash nanoprecipitation (FNP) can generate hydrophobic drug nanoparticles in ∼ 100 nm with a much higher drug loading (e.g., > 40 wt %) than traditional nanocarriers (e.g., < 20 wt %). This paper studies the effects of drug molecules on nanoparticle stability made via FNP and demonstrates that chemically bonding a drug compound (e.g., paclitaxel) with a cleavable hydrophobic moiety of organosilicate (e.g., triethoxysilicate) is able to enhance the particle size stability. A nonionic amphiphilic diblock copolymer, poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG), is used as a model surfactant to provide steric stabilization. The experiments here show that the lower the drug solubility in the aqueous medium, the more stable the particles in terms of Ostwald ripening, which are consistent with the prediction by the LSW theory. The initial particle size distribution is sufficiently narrow and of insignificance to Ostwald ripening. To correlate the particle stability with hydrophobicity, this study introduces the n-octanol/water partition coefficient (LogP), a hydrophobicity indication, into the FNP technique. A comparison of various drugs and their analogues shows that LogP of a drug is a better hydrophobicity indication than the solubility parameter (δ) and correlates well with the particle stability. Empirically, with ACDLogP > ∼ 12, nanoparticles have good stability; with ∼ 2 < ACDLogP < ∼ 9, nanoparticles show fast Ostwald ripening and interparticle recrystallization; with ACDLogP < ∼ 2, the drug is very likely difficult to form nanoparticles. This rule creates a quick way to predict particle stability for a randomly selected drug structure and helps to enable a fast preclinical drug screen.
快速纳米沉淀法（FNP）能够生成粒径约为100 nm的疏水性药物纳米颗粒，其载药量（如>40 wt%）远高于传统纳米载体（如<20 wt%）。本文研究了药物分子对通过FNP制备的纳米颗粒稳定性的影响，并证明将药物化合物（如紫杉醇）与有机硅（如三乙氧基硅烷）的可裂解疏水部分进行化学键合能够提高颗粒尺寸稳定性。使用非离子两亲性二嵌段共聚物聚（乳酸-共-乙醇酸）-嵌段-聚（乙二醇）（PLGA-b-PEG）作为模型表面活性剂来提供空间稳定作用。此处的实验表明，药物在水性介质中的溶解度越低，颗粒在奥斯特瓦尔德熟化方面就越稳定，这与LSW理论的预测一致。初始粒度分布足够窄，对奥斯特瓦尔德熟化影响不大。为了将颗粒稳定性与疏水性相关联，本研究将正辛醇/水分配系数（LogP，一种疏水性指标）引入FNP技术。对各种药物及其类似物的比较表明，药物的LogP比溶解度参数（δ）是更好的疏水性指标，并且与颗粒稳定性具有良好的相关性。根据经验，当ACDLogP > ∼ 12时，纳米颗粒具有良好的稳定性；当 ∼ 2 < ACDLogP < ∼ 9时，纳米颗粒表现出快速的奥斯特瓦尔德熟化和颗粒间重结晶；当ACDLogP < ∼ 2时，药物很可能难以形成纳米颗粒。该规则为预测随机选择的药物结构的颗粒稳定性创造了一种快速方法，并有助于实现快速的临床前药物筛选。
