Development of Dry Powder Inhaler formulation for site specific delivery of nanoconjugates loaded with Curcumin and BCL2 siRNA in Lung Cancer

IF 2.8 3区医学 Q2 PHARMACOLOGY & PHARMACY

Pulmonary pharmacology & therapeutics Pub Date : 2025-06-03 DOI:10.1016/j.pupt.2025.102361

Madhuchandra Lahan , Trideep Saikia , Rinku Baishya , Alakesh Bharali , Sunayana Baruah , Shatabdi Ghose , Nikhil Biswas , Damiki Laloo , Subhash Medhi , Bhanu P Sahu

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Abstract

Lung cancer remains one of the leading causes of cancer-related deaths, with current chemotherapy limited by poor drug delivery, toxicity, and resistance. To overcome these challenges, we developed a dry powder inhaler (DPI) system incorporating a PLGA-PEG-LHRH (PPL) nanoconjugate (NC) for enhanced delivery. Curcumin (CUR), with known anticancer and P-gp inhibition properties, was co-loaded with bcl2 siRNA (bclsR) to target bcl2 protein and combat resistance mechanisms.

The CUR and bclsR-loaded PLGA NC (172.12 ± 24.23 nm) were prepared using double emulsion solvent evaporation (DESE) method and converted into DPI using a carbohydrate carrier, showing a mass mean aerodynamic diameter of 4.62 μm and fine particle fraction of 65.39 ± 0.19 %, ideal for lung delivery. Animal studies showed that DPI delivered via tracheal administration in lung cancer models exhibited superior anticancer effects compared to free CUR, particularly in terms of pathological improvements and upregulation of cancer markers like P53 and TNF-α.

In vivo biodistribution studies in tumor-bearing mice revealed higher CUR concentrations in plasma (326.85 ± 6.17 μg) and lungs (207.03 ± 4.11 μg), with enhanced systemic exposure as indicated by higher AUC and Cmax values. These findings suggest that CUR-siRNA loaded DPI could provide an effective therapeutic approach for lung cancer.

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用于肺癌中姜黄素和BCL2 siRNA负载纳米偶联物位点特异性递送的干粉吸入剂配方的开发

肺癌仍然是癌症相关死亡的主要原因之一，目前的化疗受到药物输送不良、毒性和耐药性的限制。为了克服这些挑战，我们开发了一种包含PLGA-PEG-LHRH （PPL）纳米偶联物（NC）的干粉吸入器（DPI）系统，以增强给药能力。姜黄素（Curcumin， CUR）具有抗癌和抑制P-gp的特性，与bcl2 siRNA （bclsR）共负载，以bcl2蛋白为靶点，对抗bcl2的耐药机制。采用双乳液溶剂蒸发法（DESE）制备了cnr和bclsr负载的PLGA NC(172.12±24.23 nm)，并通过碳水化合物载体转化为DPI，其质量平均气动直径为4.62 μm，细颗粒分数为65.39±0.19%，适合肺输送。动物研究表明，在肺癌模型中，与游离CUR相比，经气管给药的DPI具有更好的抗癌作用，特别是在病理改善和P53和TNF-α等癌症标志物上调方面。荷瘤小鼠的体内生物分布研究显示，CUR在血浆（326.85±6.17 μg）和肺部（207.03±4.11 μg）中的浓度较高，AUC和Cmax值较高，表明全身暴露增强。这些发现表明，携带CUR-siRNA的DPI可以为肺癌提供有效的治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pulmonary pharmacology & therapeutics 医学-呼吸系统

CiteScore

6.20

自引率

0.00%

发文量

审稿时长

42 days

期刊介绍： Pulmonary Pharmacology and Therapeutics (formerly Pulmonary Pharmacology) is concerned with lung pharmacology from molecular to clinical aspects. The subject matter encompasses the major diseases of the lung including asthma, cystic fibrosis, pulmonary circulation, ARDS, carcinoma, bronchitis, emphysema and drug delivery. Laboratory and clinical research on man and animals will be considered including studies related to chemotherapy of cancer, tuberculosis and infection. In addition to original research papers the journal will include review articles and book reviews. Research Areas Include: • All major diseases of the lung • Physiology • Pathology • Drug delivery • Metabolism • Pulmonary Toxicology.