Flash Fabrication of Orally Targeted Nanocomplexes for Improved Transport of Salmon Calcitonin across the Intestine
Flash Fabrication of Orally Targeted Nanocomplexes for Improved Transport of Salmon Calcitonin across the Intestine
复制标题
快速制备口服靶向纳米复合物以改善鲑鱼降钙素在肠道中的运输
DOI：
10.1021/acs.molpharmaceut.9b00827
复制
发表时间：
2020
影响因子：
4.9
通讯作者：
Chen Yongming
中科院分区：
文献类型：
--
作者：
Sun Lilong;Le Zhicheng;He Shuran;Liu Jingyan;Liu Lixin;Leong Kam W.;Mao Hai-Quan;Liu Zhijia;Chen Yongming
鲑鱼降钙素（salmoncalcitonin，sCT）是一种有效的钙调节肽类激素，在临床上广泛应用于多种骨疾病的治疗。然而，由于sCT的血浆半衰期短和治疗需要高剂量，因此需要频繁注射，这阻碍了sCT的治疗有用性。口服给药是一种流行的给药方式，因为它方便患者自我管理和高患者的依从性，而口服给药的sCT目前仍然是一个巨大的挑战，由于在胃肠道（GI）的存在，多种障碍。在这里，我们引入了一种口服靶向递送系统，以通过细胞旁渗透途径和胆汁酸途径增加sCT在肠道中的转运。在该系统中，基于sCT的乙二醇壳聚糖-牛磺胆酸缀合物（GC-T）/硫酸葡聚糖（DS）三元纳米复合物（NC-T）通过快速纳米复合（FNC）过程以动力学控制模式制备。优化的NC-T具有良好的控制性能，具有均匀的和低于60 nm的流体动力学直径，高批次间重现性，良好的物理或化学稳定性，以及药物缓释行为。研究表明，NC-T由于其表面功能化牛磺胆酸配体，可以有效地提高肠道吸收和通透性。在大鼠模型中，口服NC-T显示出明显的低钙血症作用，相对口服生物利用度为10.9%。体内试验也表明，NC-T诱导长期口服给药后没有可观察到的副作用。因此，口服靶向纳米复合物可能是改善治疗肽口服转运的有前途的候选者。
Salmon calcitonin (sCT) is a potent calcium-regulating peptide hormone and widely applied for the treatment of some bone diseases clinically. However, the therapeutic usefulness of sCT is hindered by the frequent injection required, owing to its short plasma half-life and therapeutic need for a high dose. Oral delivery is a popular modality of administration for patients because of its convenience to self-administration and high patient compliance, while orally administered sCT remains a great challenge currently due to the existence of multiple barriers in the gastrointestinal (GI) tract. Here, we introduced an orally targeted delivery system to increase the transport of sCT across the intestine through both the paracellular permeation route and the bile acid pathway. In this system, sCT-based glycol chitosan-taurocholic acid conjugate (GC-T)/dextran sulfate (DS) ternary nanocomplexes (NC-T) were produced by a flash nanocomplexation (FNC) process in a kinetically controlled mode. The optimized NC-T exhibited well-controlled properties with a uniform and sub-60 nm hydrodynamic diameter, high batch-to-batch reproducibility, good physical or chemical stability, as well as sustained drug release behaviors. The studies revealed that NC-T could effectively improve the intestinal uptake and permeability, owing to its surface functionalization with the taurocholic acid ligand. In the rat model, orally administered NC-T showed an obvious hypocalcemia effect and a relative oral bioavailability of 10.9%. An in vivo assay also demonstrated that NC-T induced no observable side effect after long-term oral administration. As a result, the orally targeted nanocomplex might be a promising candidate for improving the oral transport of therapeutic peptides.