Abstract Itraconazole (ITZ) is an FDA-approved antifungal agent that has recently been explored for novel biological properties. In particular, ITZ was identified as a potent inhibitor of the hedgehog (Hh) pathway, a cell signalling pathway that has been linked to a variety of cancers and accounts for ∼25% of paediatric medulloblastoma (MB) cases. To date, there is not a targeted therapeutic option for paediatric MB, resulting in long-term side effects such as hormone deficiency, organ damage and secondary cancers. A primary obstacle for developing targeted therapy for brain ailments is the presence of the blood–brain barrier (BBB), which protects the brain from potentially harmful substances. Due to its size and hydrophobicity, ITZ does not penetrate the BBB. Alternatively, liposomes are being increasingly used within the clinic to increase drug bioavailability, target specificity and BBB permeability. With this in mind, we have successfully developed ITZ-containing liposomes with an optimal size for BBB penetration (<100 nm) and encapsulation efficiency (∼95%) by utilizing a continuous manufacturing approach—turbulent coaxial jet in co-flow. Our preliminary in vitro data demonstrate that these liposomes inhibit the Hh pathway, albeit at a reduced level in comparison to free ITZ. (196/250 words)

中文翻译：

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抑制刺猬通路的伊曲康唑脂质体的制备及评价

摘要 伊曲康唑 (ITZ) 是 FDA 批准的抗真菌剂，最近已对其新的生物学特性进行了探索。特别是，ITZ 被确定为刺猬 (Hh) 通路的强效抑制剂，该通路与多种癌症有关，约占儿童髓母细胞瘤 (MB) 病例的 25%。迄今为止，还没有针对儿科 MB 的靶向治疗方案，导致长期副作用，如激素缺乏、器官损伤和继发性癌症。开发针对脑部疾病的靶向治疗的一个主要障碍是血脑屏障 (BBB) 的存在，它可以保护大脑免受潜在有害物质的侵害。由于其尺寸和疏水性，ITZ 不会渗透 BBB。或者，脂质体越来越多地用于临床，以提高药物生物利用度、靶点特异性和 BBB 渗透性。考虑到这一点，我们通过利用连续制造方法——共流湍流同轴射流，成功开发了具有最佳尺寸的 BBB 渗透（<100 nm）和封装效率（~95%）的含 ITZ 脂质体。我们的初步体外数据表明，这些脂质体抑制 Hh 通路，尽管与游离 ITZ 相比水平降低。（196/250 字）我们的初步体外数据表明，这些脂质体抑制 Hh 通路，尽管与游离 ITZ 相比水平降低。（196/250 字）我们的初步体外数据表明，这些脂质体抑制 Hh 通路，尽管与游离 ITZ 相比水平降低。（196/250 字）