Localized drug delivery to lung cancer can overcome the limitations of systemic nanocarriers including low drug amounts reaching lung tissues and severe off-target toxicity. The current work presented novel inhalable nanocomposites as noninvasive platforms for lung cancer therapy. Nanoparticulate liquid crystals (LCNPs) based on monoolein were developed for synergistic co-encapsulation of the cytotoxic chemotherapeutic drug, pemetrexed, and the phytoherbal drug, resveratrol (PEM-RES-LCNPs). For active tumor targeting, lactoferrin (LF) and chondroitin sulfate (CS), natural polymers with intrinsic tumor-targeting capabilities, were exploited to functionalize the surface of LCNPs using a layer-by-layer (LbL) self-assembly approach. To maximize their deep lung deposition, LF/CS-coated PEM-RES-LCNPs were then microencapsulated within various carriers to obtain inhalable nanocomposites via spray-drying techniques. The inhalable dry powder nanocomposites prepared using a mannitol–inulin–leucine (1:1:1 wt) mixture displayed superior in vitro aerosolization performance (2.72 μm of MMAD and 61.6% FPF), which ensured deep lung deposition. In lung cancer-bearing mice using urethane as a chemical carcinogen, the inhalable LF/CS-coated PEM-RES-LCNP nanocomposites showed superior antitumor activity as revealed by a considerable decrease of the average lung weight, reduced number and diameter of cancerous lung foci, decreased expression of VEGF-1, and increased expression of active caspase-3 as well as reduced Ki-67 expression compared to the spray-dried free PEM/RES powder mixture and positive control. Moreover, the in vivo fluorescence imaging confirmed successful lung deposition of the inhalable nanocomposites. Conclusively, the inhalable liquid crystalline nanocomposites elaborated in the current work could open new avenues for noninvasive lung cancer treatment.

中文翻译：

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可吸入的乳铁蛋白/软骨素功能化的单油精纳米复合材料靶向肺癌

向肺癌的局部给药可以克服全身性纳米载体的局限性，包括到达肺组织的药物量少和严重的脱靶毒性。当前的工作提出了新颖的可吸入纳米复合材料作为肺癌治疗的非侵入性平台。基于单油精的纳米颗粒液晶（LCNP）被开发用于协同协同包封培美曲塞的细胞毒性化疗药物和白藜芦醇的植物草药药物（PEM-RES-LCNPs）。为了有效地靶向肿瘤，乳铁蛋白（LF）和硫酸软骨素（CS）是具有固有肿瘤靶向能力的天然聚合物，被利用来使用逐层（LbL）自组装方法来功能化LCNP的表面。为了最大化其深层肺部沉积，然后将包有LF / CS的PEM-RES-LCNP微囊化在各种载体中，以通过喷雾干燥技术获得可吸入的纳米复合材料。使用甘露醇-菊粉-亮氨酸（1：1：1 wt）混合物制备的可吸入干粉纳米复合材料显示出优异的体外雾化性能（2.72μmMMAD和61.6％FPF），可确保深层肺部沉积。在使用氨基甲酸乙酯作为化学致癌物的肺癌小鼠中，可吸入的LF / CS涂层PEM-RES-LCNP纳米复合材料表现出了优异的抗肿瘤活性，这通过平均肺重量的显着降低，癌性肺病灶的数量和直径的减少而得以揭示。与喷雾干燥的游离PEM / RES粉末混合物和阳性对照相比，VEGF-1的表达降低，而活性caspase-3的表达增加，Ki-67的表达降低。此外，体内荧光成像证实了可吸入纳米复合材料在肺部的成功沉积。结论是，当前工作中阐述的可吸入液晶纳米复合材料可以为无创肺癌治疗开辟新的途径。