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Inhalable bedaquiline-loaded cubosomes for the treatment of non-small cell lung cancer (NSCLC)
International Journal of Pharmaceutics ( IF 5.8 ) Pub Date : 2021-08-24 , DOI: 10.1016/j.ijpharm.2021.121046
Suyash M Patil 1 , Shruti S Sawant 1 , Nitesh K Kunda 1
Affiliation  

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths globally. Treatment-related adverse effects and development of drug resistance limit the available treatment options for most patients. Therefore, newer drug candidates and drug delivery systems that have limited adverse effects with significant anti-cancer efficacy are needed. For NSCLC treatment, delivering drugs via inhalation is highly beneficial as it requires lower doses and limits systemic toxicity. Bedaquiline (BQ), an FDA-approved anti-tuberculosis drug has previously shown excellent anti-cancer efficacy. However, poor aqueous solubility limits its delivery via the lungs. In this project, we developed inhalable BQ-loaded cubosome (BQLC) nanocarriers against NSCLC. The BQLC were prepared using a solvent evaporation technique with the cubosomal nanocarriers exhibiting a particle size of 150.2 ± 5.1 nm, zeta potential of (+) 35.4 ± 2.3 mV, and encapsulation efficiency of 51.85 ± 4.83%. The solid-state characterization (DSC and XRD) confirmed drug encapsulation and in an amorphous form within the cubosomes. The BQLC nanocarriers showed excellent aerodynamic properties after nebulization (MMAD of 4.21 ± 0.53 µm and FPF > 75%). The BQLC displayed enhanced cellular internalization and cytotoxicity with a ~ 3-fold reduction in IC50 compared to free BQ in NSCLC (A549) cells, after 48 h treatment. The BQLC suppressed cell proliferation via apoptotic pathway, further inhibited colony formation, and cancer metastasis in vitro. Additionally, 3D-tumor simulation studies established the anti-cancer efficacy of cubosomal nanocarriers as compared to free BQ. This is the first study exploring the potential of cubosomes as inhalation therapy of repurposed drug, BQ and the results suggest that BQLC may be a promising NSCLC therapy due to excellent aerosolization performance and enhanced anti-cancer activity.



中文翻译:

用于治疗非小细胞肺癌 (NSCLC) 的可吸入贝达喹啉负载立方体

非小细胞肺癌 (NSCLC) 是全球癌症死亡的主要原因。治疗相关的不良反应和耐药性的发展限制了大多数患者可用的治疗选择。因此,需要具有有限的副作用和显着的抗癌功效的更新的候选药物和药物递送系统。对于 NSCLC 治疗,通过吸入给药是非常有益的,因为它需要较低的剂量并限制全身毒性。贝达喹啉 (BQ) 是一种 FDA 批准的抗结核药物,此前已显示出优异的抗癌功效。然而,较差的水溶性限制了其通过肺的递送。在这个项目中,我们开发了可吸入的 BQ 负载立方体 (BQLC) 纳米载体,用于治疗 NSCLC。BQLC 是使用溶剂蒸发技术制备的,立方体纳米载体的粒径为 150.2 ± 5.1 nm,zeta 电位为 (+) 35.4 ± 2.3 mV,封装效率为 51.85 ± 4.83%。固态表征(DSC 和 XRD)证实了药物包封并且在立方体内以无定形形式存在。BQLC 纳米载体在雾化后表现出优异的空气动力学特性(MMAD 为 4.21 ± 0.53 µm,FPF > 75%)。BQLC 显示出增强的细胞内化和细胞毒性,IC 降低了约 3 倍 BQLC 纳米载体在雾化后表现出优异的空气动力学特性(MMAD 为 4.21 ± 0.53 µm,FPF > 75%)。BQLC 显示出增强的细胞内化和细胞毒性,IC 降低了约 3 倍 BQLC 纳米载体在雾化后表现出优异的空气动力学特性(MMAD 为 4.21 ± 0.53 µm,FPF > 75%)。BQLC 显示出增强的细胞内化和细胞毒性,IC 降低了约 3 倍50与 NSCLC (A549) 细胞中的游离 BQ 相比,处理 48 小时后。BQLC 通过凋亡途径抑制细胞增殖,进一步抑制集落形成和体外癌症转移。此外,与游离 BQ 相比,3D 肿瘤模拟研究确定了立方体纳米载体的抗癌功效。这是第一项探索立方体作为再利用药物 BQ 吸入疗法潜力的研究,结果表明 BQLC 可能是一种有前途的 NSCLC 疗法,因为它具有出色的雾化性能和增强的抗癌活性。

更新日期:2021-08-31
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