Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Panjab, India.
SLT Institute of Pharmaceutical Sciences, Guru Ghasidas University, Bilaspur, India.
J Colloid Interface Sci. 2015 May 1;445:219-230. doi: 10.1016/j.jcis.2014.12.092. Epub 2015 Jan 9.
9-Bromo-noscapine (9-Br-Nos) alters tubulin polymerization in non-small cell lung cancer cells differently from noscapine. However, clinical applications of 9-Br-Nos are limited owing to poor aqueous solubility and high lipophilicity that eventually lead to suboptimal therapeutic efficacy at the site of action. Hence, 9-Br-Nos loaded nanostructured lipid particles (9-Br-Nos-NLPs) were prepared by nanoemulsion method to reduce the particle size below 100 nm. To impart the inhalable and rapid release (RR) attributes, 9-Br-Nos-NLPs were treated with spray dried lactose and effervescent excipients to generate, 9-Br-Nos-RR-NLPs. The mean particle and aerodynamic size of 9-Br-Nos-NLPs were measured to be 13.4±3.2 nm and 2.3±1.5 μm, significantly (P<0.05) lower than 19.4±6.1 nm and 3.1±1.8 μm of 9-Br-Nos-RR-NLPs. In addition, zeta-potential of 9-Br-Nos-NLPs was examined to be -9.54±0.16 mV, significantly (P<0.05) lower than -7.23±0.10 mV of 9-Br-Nos-RR-NLPs. Hence, both formulations were found to be optimum for pulmonary delivery through inhalation route of administration. Next, 9-Br-Nos-RR-NLPs exhibited enhanced cytotoxicity, apoptosis and cellular uptake in A549, lung cancer cells, as compared to 9-Br-Nos-NLPs and 9-Br-Nos suspension. This may be attributed to enhanced drug delivery and internalization character of 9-Br-Nos-RR-NLPs by energy-dependent endocytosis and passive diffusion mechanism. Pharmacokinetic and distribution analysis demonstrated the superiority of 9-Br-Nos-RR-NLPs that exhibited ∼1.12 and ∼1.75-folds enhancement in half-life of the drug as compared to 9-Br-Nos-NLPs and 9-Br-Nos powder following inhalation route. Continuation to this, 9-Br-Nos-RR-NLPs also displayed ∼3.75-fold increment in half-life of the drug in lungs, as compared to 9-Br-Nos suspension following intravenous route of administration. Furthermore, enhanced drug exposure was measured in terms of AUC(last) in lungs following administration of 9-Br-Nos-RR-NLPs, as compared to 9-Br-Nos-NLPs, 9-Br-Nos powder and 9-Br-Nos suspension. This may be attributed to rapid dispersion, enhanced dissolution and deep lung deposition of nanoparticles following inhalation route. Therefore, inhalable 9-Br-Nos-RR-NLPs claims further in depth in vivo tumor regression study to scale up the technology for clinical applications.
9-溴-纳曲酮（9-Br-Nos）改变非小细胞肺癌细胞中的微管聚合的方式与纳曲酮不同。然而，由于较差的水溶性和高亲脂性，9-Br-Nos 的临床应用受到限制，最终导致在作用部位的治疗效果不理想。因此，通过纳米乳液法制备了负载 9-Br-Nos 的纳米结构脂质载体（9-Br-Nos-NLPs），将粒径降低至 100nm 以下。为了赋予吸入和快速释放（RR）特性，用喷雾干燥乳糖和泡腾赋形剂处理 9-Br-Nos-NLPs，生成 9-Br-Nos-RR-NLPs。测定 9-Br-Nos-NLPs 的平均粒径和空气动力学粒径分别为 13.4±3.2nm 和 2.3±1.5μm，显著低于 9-Br-Nos-RR-NLPs 的 19.4±6.1nm 和 3.1±1.8μm。此外，测定 9-Br-Nos-NLPs 的 zeta 电位为-9.54±0.16mV，显著低于 9-Br-Nos-RR-NLPs 的-7.23±0.10mV。因此，这两种制剂都被认为是通过吸入途径进行肺部给药的最佳选择。接下来，与 9-Br-Nos-NLPs 和 9-Br-Nos 混悬剂相比，9-Br-Nos-RR-NLPs 在 A549 肺癌细胞中表现出增强的细胞毒性、细胞凋亡和细胞摄取。这可能归因于 9-Br-Nos-RR-NLPs 通过能量依赖性内吞作用和被动扩散机制增强了药物的传递和内化特性。药代动力学和分布分析表明，与 9-Br-Nos-NLPs 和 9-Br-Nos 粉末相比，9-Br-Nos-RR-NLPs 经吸入途径给药后，药物的半衰期分别提高了约 1.12 倍和 1.75 倍。除此之外，与 9-Br-Nos 混悬剂相比，9-Br-Nos-RR-NLPs 经静脉途径给药后，药物在肺部的半衰期也提高了约 3.75 倍。此外，与 9-Br-Nos-NLPs、9-Br-Nos 粉末和 9-Br-Nos 混悬剂相比，经 9-Br-Nos-RR-NLPs 给药后，肺部的药物暴露量 AUC(last)也有所增加。这可能归因于吸入途径给药后纳米粒子的快速分散、增强的溶解和更深的肺部沉积。因此，吸入式 9-Br-Nos-RR-NLPs 需要进一步进行深入的体内肿瘤消退研究，以将该技术推向临床应用。
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