Maaz Aida, Blagbrough Ian S, De Bank Paul A
Mol Pharm. 2024 Mar 4;21(3):1108-1124. doi: 10.1021/acs.molpharmaceut.3c00639. Epub 2024 Feb 9.
The olfactory region of the nasal cavity directly links the brain to the external environment, presenting a potential direct route to the central nervous system (CNS). However, targeting drugs to the olfactory region is challenging and relies on a combination of drug formulation, delivery device, and administration technique to navigate human nasal anatomy. In addition, in vitro and in vivo models utilized to evaluate the performance of nasal formulations do not accurately reflect deposition and uptake in the human nasal cavity. The current study describes the development of a respirable poly(lactic--glycolic acid) nanoparticle (PLGA NP) formulation, delivered via a pressurized metered dose inhaler (pMDI), and a cell-containing three-dimensional (3D) human nasal cast model for deposition assessment of nasal formulations in the olfactory region. Fluorescent PLGA NPs (193 ± 3 nm by dynamic light scattering) were successfully formulated in an HFA134a-based pMDI and were collected intact following aerosolization. RPMI 2650 cells, widely employed as a nasal epithelial model, were grown at the air-liquid interface (ALI) for 14 days to develop a suitable barrier function prior to exposure to the aerosolized PLGA NPs in a glass deposition apparatus. Direct aerosol exposure was shown to have little effect on cell viability. Compared to an aqueous NP suspension, the transport rate of the aerosolized NPs across the RPMI 2650 barrier was higher at all time points indicating the potential advantages of delivery via aerosolization and the importance of employing ALI cellular models for testing respirable formulations. The PLGA NPs were then aerosolized into a 3D-printed human nasal cavity model with an insert of ALI RPMI 2650 cells positioned in the olfactory region. Cells remained highly viable, and there was significant deposition of the fluorescent NPs on the ALI cultures. This study is a proof of concept that pMDI delivery of NPs is a viable means of targeting the olfactory region for nose-to-brain drug delivery (NTBDD). The cell-based model allows not only maintenance under ALI culture conditions but also sampling from the basal chamber compartment; hence, this model could be adapted to assess drug deposition, uptake, and transport kinetics in parallel under real-life settings.
鼻腔的嗅觉区域直接将大脑与外部环境相连，为中枢神经系统（CNS）提供了一条潜在的直接通路。然而，将药物靶向输送至嗅觉区域具有挑战性，这依赖于药物制剂、给药装置和给药技术的组合，以适应人类鼻腔的解剖结构。此外，用于评估鼻腔制剂性能的体外和体内模型并不能准确反映药物在人类鼻腔中的沉积和摄取情况。本研究描述了一种可吸入的聚乳酸-乙醇酸纳米颗粒（PLGA NP）制剂的研发过程，该制剂通过压力定量吸入器（pMDI）给药，并建立了一种含细胞的三维（3D）人体鼻腔铸型模型，用于评估鼻腔制剂在嗅觉区域的沉积情况。通过动态光散射法制备的荧光PLGA NPs（粒径为193±3 nm）成功地被载入基于HFA134a的pMDI中，并在雾化后完整回收。广泛用作鼻上皮模型的RPMI 2650细胞在气液界面（ALI）培养14天，以形成合适的屏障功能，然后在玻璃沉积装置中暴露于雾化的PLGA NPs。直接气溶胶暴露对细胞活力影响很小。与水性NP悬浮液相比，雾化NP在所有时间点穿过RPMI 2650屏障的转运速率更高，这表明通过雾化给药的潜在优势以及采用ALI细胞模型测试可吸入制剂的重要性。然后将PLGA NPs雾化到一个3D打印的人体鼻腔模型中，该模型在嗅觉区域插入了ALI RPMI 2650细胞。细胞保持高度活力，荧光NP在ALI培养物上有显著沉积。本研究证明了通过pMDI输送NP是一种可行的方法，可将药物靶向输送至嗅觉区域，用于鼻-脑给药（NTBDD）。基于细胞的模型不仅允许在ALI培养条件下进行维持培养，还允许从基底腔室取样；因此，该模型可用于在实际环境中并行评估药物沉积、摄取和转运动力学。
