Development of Optimized, Inhalable, Gemcitabine-Loaded Gelatin Nanocarriers for Lung Cancer.
Development of Optimized, Inhalable, Gemcitabine-Loaded Gelatin Nanocarriers for Lung Cancer.
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用于肺癌的优化、可吸入、负载吉西他滨的明胶纳米载体的开发。
DOI：
10.1089/jamp.2015.1286
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发表时间：
2017
影响因子：
3.4
通讯作者：
Chougule,MahavirB
中科院分区：
文献类型：
--
作者：
Youngren-Ortiz,SusanneR;Hill,DavidB;Hoffmann,PeterR;Morris,KennethR;Barrett,EdwardG;Forest,MGregory;Chougule,MahavirB
背景：化疗纳米载体的气雾剂给药是肺癌治疗的一种很有前途的替代方案。本研究对吉西他滨(Gem)明胶纳米载体(Gem-GNCs)进行了优化，以评价其雾化治疗肺癌的潜力。方法：采用两步去溶法制备Gem-GNCs，并通过田口设计优化GEM-GNCs的理化性质。通过扫描和透射电子显微镜对Gem-GNCs的颗粒大小和形貌进行了表征。在Dulbecco的磷酸盐缓冲液和模拟肺液中进行了Gem-GNCs的体外释放实验，以确定释放机制。考察了不同pH条件下的颗粒尺寸稳定性。用差示扫描量热法和粉末X射线衍射法分别测定了Gem-GNC组分的存在和稳定性以及Gem的非晶化。用四甲基偶氮唑盐比色法检测GEM-GNC对A549和H460细胞的杀伤作用。测定Gem-GNCs、乳糖和生理盐水对照组治疗后的粘液流变学。结果：GEM-GNCs的粒径为178 ± 7.1 nm，−为18.9 MV，包封率为92.5%，载药率为9.1%。宝石和配方辅料，分子分散，构型无定形。GEM-GNCs在pH 5.4~7.4条件下稳定72小时。由于基质纳米载体的扩散/侵蚀，Gem-GNCs中GEM的释放受非Fickian控制释放的控制。GEM-GNCS可使含有3ηwt%固体的人支气管上皮细胞黏液的复数粘度 *(1 赫兹)降低40%，以模拟轻度呼吸道疾病。雾化后的GEM-GNCs的质量中位空气动力学直径为2.0 ± 0.16 μm，几何标准偏差为2.7 ± 0.16，细颗粒分数为75.2% ± 2.4%。Gem-GNC制剂在A549细胞中的表现并不优于Gem溶液。在H460细胞中，Gem-GNCs在48小时和72小时内的∼IC50分别是Gem-GNCs的5倍和10倍。结论：建立了稳定、有效、缓释的Gem-GNCs。雾化的Gem-GNCs具有令人满意的MMAD、GSD和FPF，并且该制剂降低了粘液的动态复粘度，这与纳米颗粒流动性的增加相一致。
Background:Aerosol delivery of chemotherapeutic nanocarriers represents a promising alternative for lung cancer therapy. This study optimized gemcitabine (Gem)-loaded gelatin nanocarriers (GNCs) cross-linked with genipin (Gem-GNCs) to evaluate their potential for nebulized lung cancer treatment.Methods:Gem-GNCs were prepared by two-step desolvation and optimized through Taguchi design and characterized for physicochemical properties. Particle size and morphology were confirmed by scanning and transmission electron microscopy.In vitrorelease of Gem from Gem-GNCs performed in Dulbecco's phosphate-buffered saline and simulated lung fluid was evaluated to determine release mechanisms. Particle size stability was assessed under varying pH. Differential scanning calorimetry and powder X-ray diffraction were used to determine the presence and stability of Gem-GNC components and amorphization of Gem, respectively. Gem-GNC efficacy within A549 and H460 cells was evaluated using MTT assays. Mucus rheology upon treatment with Gem-GNCs, lactose, and normal saline control was measured. Andersen cascade impaction identified the aerodynamic particle size distribution of the nebulized formulation.Results:Gem-GNCs had particle size, zeta potential, entrapment efficiency, and loading efficiency of 178 ± 7.1 nm, −18.9 mV, 92.5%, and 9.1%, respectively. The Gem and formulation excipients where molecularly dispersed and configured amorphously. Gem-GNCs were stable at pH 5.4–7.4 for 72 hours. Gem release from Gem-GNCs was governed by non-Fickian controlled release due to diffusion/erosion from a matrix-based nanocarrier. Gem-GNCs elicited a 40% reduction of the complex viscosityη*(1 Hz) of human bronchial epithelial cell mucus containing 3 wt% solids to mimic mild airway disease. The nebulized Gem-GNCs had a mass median aerodynamic diameter (MMAD) of 2.0 ± 0.16 μm, geometric standard deviation (GSD) of 2.7 ± 0.16, and fine particle fraction (FPF) of 75.2% ± 2.4%. The Gem-GNC formulation did not outperform the Gem solution in A549 cells. However, in H460, Gem-GNCs outperformed the Gem IC50 reduction by ∼5-fold at 48 and 10-fold 72 hours.Conclusion:Stable, effective, and sustained-release Gem-GNCs were developed. The nebulized Gem-GNCs had satisfactory MMAD, GSD, and FPF and the formulation reduced the dynamic complex viscosity of mucus consistent with increased mobility of nanoparticles.