Ali Raisuddin, Qamar Wajhul, Kalam Mohd Abul, Binkhathlan Ziyad
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
ACS Omega. 2024 Sep 19;9(40):41830-41840. doi: 10.1021/acsomega.4c06264. eCollection 2024 Oct 8.
Lung cancer is a major public health concern, with a high incidence and fatality rate. Its treatment is very difficult, as it is mostly diagnosed in advanced stages. Non-small cell lung carcinoma (NSCLC) is the major form of lung carcinoma that persists. Brigatinib (BGT), a powerful small-molecule tyrosine kinase inhibitor, has demonstrated significant therapeutic potential in the treatment of NSCLC with anaplastic lymphoma kinase (ALK) mutations. However, the therapeutic applicability of BGT is hampered by its low solubility and bioavailability. In this study, we developed a mixed micelle system comprising Soluplus and TPGS loaded with BGT. BGT was encapsulated into the mixed micelles using various combinations of Soluplus and TPGS, with encapsulation efficiency (EE%) ranging from 52.43 ± 1.07 to 97.88 ± 2.25%. The dynamic light scattering data showed that the mixed micelles ranged in size from 75.7 ± 0.46 to 204.3 ± 5.40 nm. The selected mixed micelles (F6) showed approximately 38% BGT release in the first 2 h, and subsequently, within 72 h, the release was 94.50 ± 5.90%. The NMR experiment confirmed the formation of micelles. Additionally, the mixed micelles showed significantly higher cellular uptake ( < 0.05) and increased cytotoxicity ( < 0.05) as compared to the free BGT. Specifically, the obtained IC values for BGT-loaded Soluplus-TPGS mixed micelles and free BGT were 22.59 ± 6.07 and 61.45 ± 6.35 μg/mL, respectively. The results of the in vitro stability experiment showed that the selected mixed micelle (F6) was stable at both room temperature and 4 °C, with only minor changes in size and PDI. Our results indicate great potential for the developed Soluplus-TPGS mixed micelles as a delivery system for BGT.
肺癌是一个重大的公共卫生问题，发病率和死亡率都很高。由于其大多在晚期才被诊断出来，所以治疗非常困难。非小细胞肺癌（NSCLC）是持续存在的主要肺癌形式。布加替尼（BGT）是一种强效小分子酪氨酸激酶抑制剂，在治疗具有间变性淋巴瘤激酶（ALK）突变的NSCLC方面已显示出显著的治疗潜力。然而，BGT的治疗适用性因其低溶解度和生物利用度而受到阻碍。在本研究中，我们开发了一种包含负载BGT的Solupuls和TPGS的混合胶束系统。使用Solupuls和TPGS的各种组合将BGT封装到混合胶束中，包封率（EE%）范围为52.43±1.07至97.88±2.25%。动态光散射数据表明，混合胶束的尺寸范围为75.7±0.46至204.3±5.40nm。所选的混合胶束（F6）在前2小时内显示约38%的BGT释放，随后在72小时内，释放率为94.50±5.90%。核磁共振实验证实了胶束的形成。此外，与游离BGT相比，混合胶束显示出显著更高的细胞摄取率（<０.０５）和增加的细胞毒性（<０.０５）。具体而言，负载BGT的Solupuls - TPGS混合胶束和游离BGT的获得的IC值分别为22.59±6.07和61.45±6.35μg/mL。体外稳定性实验结果表明，所选的混合胶束（F6）在室温和4℃下均稳定，尺寸和PDI仅有微小变化。我们的结果表明，所开发的Solupuls - TPGS混合胶束作为BGT的递送系统具有巨大潜力。
