混合脂质/聚合物纳米颗粒在 siRNA 递送到肺部时解决囊性纤维化粘液屏障：聚乙二醇化会产生影响吗？,ACS Applied Materials & Interfaces

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混合脂质/聚合物纳米颗粒在 siRNA 递送到肺部时解决囊性纤维化粘液屏障：聚乙二醇化会产生影响吗？
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2022-02-02 , DOI: 10.1021/acsami.1c14975
Gemma Conte ₁ , Gabriella Costabile ₂ , Domizia Baldassi ₃ , Valeria Rondelli ₄ , Rosaria Bassi ₄ , Diego Colombo ₄ , Giulia Linardos ₅ , Ersilia V Fiscarelli ₅ , Raffaella Sorrentino ₆ , Agnese Miro ₂ , Fabiana Quaglia ₂ , Paola Brocca ₄ , Ivana d'Angelo ₁ , Olivia M Merkel ₃ , Francesca Ungaro ₂

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吸入 siRNA 疗法在治疗严重肺部疾病方面具有独特的潜力，例如囊性纤维化 (CF)。然而，解决肺屏障的药物输送系统对于增强气道上皮细胞中的基因沉默功效是强制性的。我们最近证明了脂质-聚合物杂化纳米粒子 (hNPs)，包括聚乳酸-乙醇酸 (PLGA) 核和二棕榈酰磷脂酰胆碱 (DPPC) 的脂质壳，可以帮助核酸货物通过粘液运输-覆盖的人气道上皮。为了深入研究 hNPs 将 siRNA 输送到肺部的潜力并研究 PEG 化的假设益处，在这里，针对核因子-κB (siNFκB) 的 siRNA 库被封装在 hNPs 内，赋予非 PEG 化 (DPPC) ) 或聚乙二醇化 (1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-聚（乙二醇）或DSPE-PEG）脂质壳。测试了所得 hNP 在人工 CF 粘液、从 CF 细胞收集的粘液以及来自异质和有代表性的一组 CF 患者的痰样本中的稳定性和转运特性。通过人工和细胞 CF 粘液中的小角 X 射线散射 (SAXS) 研究获得了有关控制其与气道粘液相互作用的 hNP 特性的初步信息。hNPs 通过 CF 痰的扩散曲线表明相应供体患者的肺定植具有关键作用，影响样本的粘蛋白类型和含量。值得注意的是，聚乙二醇化不会促进复杂和粘性样品中的粘液渗透，例如来自多微生物定植患者的 CF 痰。在平行下，对在气液界面 (ALI) 上生长的粘液衬里的 Calu-3 细胞进行的体外细胞摄取研究证实了非聚乙二醇化 hNPs 克服粘液和细胞肺屏障的能力有所提高。此外，有效在LPS 刺激的 16HBE14o- 细胞中实现了体外NFκB 基因沉默。总体而言，结果突出了非聚乙二醇化 hNP 作为 siRNA 肺部递送载体用于局部治疗 CF 肺病的潜力。此外，这项研究提供了对不同模型如何提供有关纳米粒子与粘液屏障相互作用的不同信息的详细理解。

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Hybrid Lipid/Polymer Nanoparticles to Tackle the Cystic Fibrosis Mucus Barrier in siRNA Delivery to the Lungs: Does PEGylation Make the Difference?

Inhaled siRNA therapy has a unique potential for treatment of severe lung diseases, such as cystic fibrosis (CF). Nevertheless, a drug delivery system tackling lung barriers is mandatory to enhance gene silencing efficacy in the airway epithelium. We recently demonstrated that lipid-polymer hybrid nanoparticles (hNPs), comprising a poly(lactic-co-glycolic) acid (PLGA) core and a lipid shell of dipalmitoyl phosphatidylcholine (DPPC), may assist the transport of the nucleic acid cargo through mucus-covered human airway epithelium. To study in depth the potential of hNPs for siRNA delivery to the lungs and to investigate the hypothesized benefit of PEGylation, here, an siRNA pool against the nuclear factor-κB (siNFκB) was encapsulated inside hNPs, endowed with a non-PEGylated (DPPC) or a PEGylated (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol) or DSPE-PEG) lipid shell. Resulting hNPs were tested for their stability profiles and transport properties in artificial CF mucus, mucus collected from CF cells, and sputum samples from a heterogeneous and representative set of CF patients. Initial information on hNP properties governing their interaction with airway mucus was acquired by small-angle X-ray scattering (SAXS) studies in artificial and cellular CF mucus. The diffusion profiles of hNPs through CF sputa suggested a crucial role of lung colonization of the corresponding donor patient, affecting the mucin type and content of the sample. Noteworthy, PEGylation did not boost mucus penetration in complex and sticky samples, such as CF sputa from patients with polymicrobial colonization. In parallel, in vitro cell uptake studies performed on mucus-lined Calu-3 cells grown at the air–liquid interface (ALI) confirmed the improved ability of non-PEGylated hNPs to overcome mucus and cellular lung barriers. Furthermore, effective in vitro NFκB gene silencing was achieved in LPS-stimulated 16HBE14o- cells. Overall, the results highlight the potential of non-PEGylated hNPs as carriers for pulmonary delivery of siRNA for local treatment of CF lung disease. Furthermore, this study provides a detailed understanding of how distinct models may provide different information on nanoparticle interaction with the mucus barrier.

更新日期：2022-02-02

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