Pulmonary metastases pose treatment challenges for many cancers, including triple-negative breast cancer (TNBC). A novel suicide gene and therapeutic microRNAs (miRs) combination therapy against lung metastases in vivo is tested in mouse models after intranasal delivery using nontoxic gold nanoparticles (AuNPs) formulated to carry these molecular therapeutics. AuNPs coated with chitosan-β-cyclodextrin (CS-CD) are used and functionalized with a urokinase plasminogen activator (uPA) peptide to carry triple cancer suicide genes (thymidine kinase-p53-nitroreductase: TK-p53-NTR) plus therapeutic miRNAs (antimiR-21, antimiR-10b and miR-100). Three AuNPs are synthesized: 20 nm gold nanodots (AuND), and 20 nm or 50 nm nanostars (AuNS), all surface coated with CS-CD using a microfluidic-optimized method. These positively charged AuNP-CS-CD cores are sequentially coated with synthetic miRNAs followed by TK-p53-NTR via electrostatic interactions, and uPA peptide is added through CD-adamantane hostguest chemistry. Transfection efficiency comparisons for different AuNPs shows 50 nm AuNS allows ≈4.16-fold higher gene transfection than other AuNPs. Intranasal delivery of uPA-AuNS-TK-p53-NTR-microRNAs NPs (pAuNS@TK-p53-NTR-miRs) in mice predominantly accumulates in lungs and facilitates ganciclovir and CB1954 prodrug-mediated gene therapy against TNBC lung metastases. This new nanosystem can serve as an adaptable-across-cancer-type, facile, and clinically scalable platform to allow future inhalational suicide gene-miR combination therapy for patients harboring pulmonary metastases.

中文翻译：

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吸入金纳米星载体用于向肺转移瘤靶向递送三重自杀基因疗法和治疗性 MicroRNA：在小动物模型中的开发和验证

肺转移给许多癌症的治疗带来挑战，包括三阴性乳腺癌（TNBC）。使用配制为携带这些分子治疗剂的无毒金纳米颗粒 (AuNP) 进行鼻内递送后，在小鼠模型中测试了一种新型自杀基因和治疗性 microRNA (miR) 体内针对肺转移的联合疗法。使用壳聚糖-β-环糊精 (CS-CD) 包被的 AuNP，并通过尿激酶纤溶酶原激活剂 (uPA) 肽进行功能化，以携带三重癌症自杀基因（胸苷激酶 -p53-硝基还原酶：TK-p53-NTR）和治疗性 miRNA（ antimiR-21、antimiR-10b 和 miR-100)。合成了三种 AuNP：20 nm 金纳米点 (AuND) 和 20 nm 或 50 nm 纳米星 (AuNS)，所有表面均采用微流体优化方法涂有 CS-CD。这些带正电荷的 AuNP-CS-CD 核心依次包被合成 miRNA，然后通过静电相互作用包被 TK-p53-NTR，并通过 CD-金刚烷主客体化学添加 uPA 肽。不同 AuNP 的转染效率比较显示，50 nm AuNS 的基因转染率比其他 AuNP 高约 4.16 倍。小鼠鼻内递送 uPA-AuNS-TK-p53-NTR-microRNA NP (pAuNS@TK-p53-NTR-miRs) 主要在肺部积聚，促进更昔洛韦和 CB1954 前药介导的针对 TNBC 肺转移的基因治疗。这种新的纳米系统可以作为一个适应性强、跨癌症类型、简便且临床可扩展的平台，允许未来对肺转移患者进行吸入性自杀基因-miR联合治疗。