Design of an innovative nanovehicle to enhance brain permeability of a novel 5-HT6 receptor antagonist

IF 5.2 2区 医学 Q1 PHARMACOLOGY & PHARMACY International Journal of Pharmaceutics: X Pub Date : 2024-10-21 DOI:10.1016/j.ijpx.2024.100296
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Abstract

An innovative nanovehicle based on lipid nanocapsules (LNC) was designed to facilitate the passage of a new 5-HT6 receptor antagonist, namely PUC-10, through the blood-brain barrier. PUC-10 is a new synthetic N-arylsulfonylindole that has demonstrated potent 5-HT6 receptor antagonist activity, but it exhibits poor solubility in water, which indicates limited absorption. The lipid nanocapsules designed had a nanometric size (53 nm), a monomodal distribution (PI<0.2), a negative Z potential (−17 ± 7 mV) and allowed efficient PUC-10 encapsulation (74 %). Furthermore, the LNC demonstrated to be stable for at least 4 weeks at 4 °C (storage conditions), for at least 4 h in DMEM at pH 7.4, and for 18 h in water with 5 % DMSO, with both latter conditions maintained at 37 °C. They also demonstrated that cell viability was not affected at the different concentrations studied. Finally, in vitro studies that simulate the blood brain barrier (PAMPA-BBB) demonstrated that the nanoencapsulation of PUC-10 promoted their penetration through the blood-brain barrier, with a calculated permeability of 1.3 × 10−8 cm/s, compared to the null permeability exhibited by non-nanoencapsulated PUC-10.

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设计创新型纳米载体,提高新型 5-HT6 受体拮抗剂的脑渗透性
我们设计了一种基于脂质纳米囊(LNC)的创新纳米载体,以促进新型 5-HT6 受体拮抗剂 PUC-10 通过血脑屏障。PUC-10 是一种新合成的 N-芳基磺酰基吲哚类药物,具有强效的 5-HT6 受体拮抗剂活性,但在水中的溶解度较低,这表明其吸收能力有限。所设计的脂质纳米胶囊具有纳米级尺寸(53 纳米)、单模分布(PI<0.2)、负 Z 电位(-17 ± 7 mV),可有效封装 PUC-10(74%)。此外,LNC 在 4 °C(储存条件)下至少稳定 4 周,在 pH 值为 7.4 的 DMEM 中至少稳定 4 小时,在含有 5 % DMSO 的水中稳定 18 小时,后两种条件均保持在 37 °C。他们还证明,在研究的不同浓度下,细胞活力均未受到影响。最后,模拟血脑屏障(PAMPA-BBB)的体外研究表明,PUC-10 的纳米包囊促进了其在血脑屏障中的渗透,计算出的渗透率为 1.3 × 10-8 厘米/秒,而非纳米包囊的 PUC-10 的渗透率为零。
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来源期刊
International Journal of Pharmaceutics: X
International Journal of Pharmaceutics: X Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
6.60
自引率
0.00%
发文量
32
审稿时长
24 days
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