Department of Materials Science and Engineering, Technion - Israel Institute of Technology, Haifa 3200003, Israel.
Department of Biotechnology and Food Engineering, Technion - Israel Institute of Technology, Haifa 3200003, Israel.
Acta Biomater. 2023 Mar 1;158:449-462. doi: 10.1016/j.actbio.2022.12.060. Epub 2022 Dec 31.
Nanonization of poorly water-soluble drugs has shown great potential in improving their oral bioavailability by increasing drug dissolution rate and adhesion to the gastrointestinal mucus. However, the fundamental features that govern the particle-mucus interactions have not been investigated in a systematic way before. In this work, we synthesize mucin hydrogels that mimic those of freshly excised porcine mucin. By using fluorescent pure curcumin particles, we characterize the effect of particle size (200 nm, and 1.2 and 1.3 μm), concentration (18, 35, and 71 μg mL), and hydrogel crosslinking density on the diffusion-driven particle penetration in vitro. Next, we derive a phenomenological model that describes the physics behind the diffusion-derived penetration and considers the contributions of the key parameters assessed in vitro. Finally, we challenge our model by assessing the oral pharmacokinetics of an anti-cancer model drug, namely dasatinib, in pristine and nanonized forms and two clinically relevant doses in rats. For a dose of 10 mg kg, drug nanonization leads to a significant ∼8- and ∼21-fold increase of the drug oral bioavailability and half-life, respectively, with respect to the unprocessed drug. When the dose of the nanoparticles was increased to 15 mg kg, the oral bioavailability increased though not significantly, suggesting the saturation of the mucus penetration sites, as demonstrated by the in vitro model. Our overall results reveal the potential of this approach to pave the way for the development of tools that enable a more rational design of nano-drug delivery systems for mucosal administration. STATEMENT OF SIGNIFICANCE: The development of experimental-theoretical tools to understand and predict the diffusion-driven penetration of particles into mucus is crucial not only to rationalize the design of nanomedicines for mucosal administration but also to anticipate the risks of the exposure of the body to nano-pollutants. However, a systematic study of such tools is still lacking. Here we introduce an experimental-theoretical approach to predict the diffusion-driven penetration of particles into mucus and investigate the effect of three key parameters on this interaction. Then, we challenge the model in a preliminary oral pharmacokinetics study in rats which shows a very good correlation with in vitro results. Overall, this work represents a robust platform for the modelling of the interaction of particles with mucosae under dynamic conditions.
将疏水性药物纳米化已被证明可以通过提高药物溶解速率和与胃肠道黏液的黏附性来显著提高其口服生物利用度。然而，以前并没有系统地研究控制颗粒-黏液相互作用的基本特征。在这项工作中，我们合成了模拟新鲜猪黏液的黏蛋白水凝胶。通过使用荧光纯姜黄素颗粒，我们表征了粒径（200nm 和 1.2μm、1.3μm）、浓度（18μg/mL、35μg/mL、71μg/mL）和水凝胶交联密度对体外扩散驱动颗粒渗透的影响。接下来，我们推导出一个描述扩散驱动渗透背后物理机制的唯象模型，并考虑了体外评估的关键参数的贡献。最后，我们通过评估原型和纳米化形式的抗癌模型药物达沙替尼以及两种临床相关剂量在大鼠体内的药代动力学，来挑战我们的模型。对于 10mg/kg 的剂量，药物纳米化使药物口服生物利用度和半衰期分别显著提高了约 8 倍和 21 倍，与未处理药物相比。当纳米颗粒的剂量增加到 15mg/kg 时，尽管口服生物利用度没有显著增加，但由于体外模型表明黏液渗透位点的饱和，这表明药物纳米化可能会增加药物的口服生物利用度。我们的整体结果揭示了这种方法的潜力，为开发更合理的黏膜给药纳米药物传递系统设计工具铺平了道路。 意义声明：开发用于理解和预测颗粒扩散驱动进入黏液的实验理论工具不仅对于合理化黏膜给药的纳米药物设计至关重要，而且对于预测人体暴露于纳米污染物的风险也至关重要。然而，这种工具的系统研究仍然缺乏。在这里，我们引入了一种实验理论方法来预测颗粒扩散驱动进入黏液的穿透，并研究了三个关键参数对这种相互作用的影响。然后，我们在大鼠的初步口服药代动力学研究中挑战了该模型，该研究与体外结果具有很好的相关性。总体而言，这项工作代表了一个在动态条件下对颗粒与黏液相互作用进行建模的强大平台。
