Inhaled Gold Nano-Star Carriers for Targeted Delivery of Triple Suicide Gene Therapy and Therapeutic MicroRNAs to Lung Metastases: Development and Validation in a Small Animal Model

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-beta-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 approximate to 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.

Automated summary

A new nanosystem that can be delivered via intranasal administration has been tested in mouse models for the treatment of lung metastases in TNBC. It utilizes non-toxic gold nanoparticles coated with chitosan-beta-cyclodextrin to carry suicide genes and therapeutic miRNAs. The system predominantly accumulates in the lungs and facilitates gene therapy against TNBC lung metastases.