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Inhaled Gold Nano-star Carriers for Targeted Delivery of Triple Suicide Gene Therapy and Therapeutic MicroRNAs to
Yi Liu1, Uday Kumar Sukumar1, Natacha Jugniot1
1Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford University, CA.
Abstract:
Pulmonary metastases pose significant treatment challenges for many cancers, including triple-negative breast cancer (TNBC). We developed and tested a novel suicide gene and therapeutic microRNAs (miRs) combination therapy against lung metastases in vivo in mouse models after intranasal delivery using nontoxic gold nanoparticles (AuNPs) formulated to carry these molecular therapeutics. We used AuNPs coated with chitosan-β-cyclodextrin (CS-CD) 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). We synthesized three AuNPs: 20nm nanodots (AuND), and 20nm or 50nm nanostars (AuNS), then surface coated these with CS-CD using a microfluidic-optimized method. We sequentially coated the resulting positively charged AuNP-CS-CD core with synthetic miRNAs followed by TK-p53-NTR via electrostatic interactions, and added uPA peptide through CD-adamantane host-guest chemistry. A comparison of transfection efficiencies for different AuNPs showed that the 50nm AuNS allowed ∼4.16-fold higher gene transfection than other NPs. The intranasal delivery of uPA-AuNS-TK-p53-NTR-microRNAs NPs (pAuNS@TK-p53-NTR-miRs) in mice predominantly accumulated in lungs and facilitated ganciclovir and CB1954 prodrug-mediated gene therapy against TNBC lung metastases. This new nanosystem may 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.
Insights
We developed a novel gold nanoparticle (AuNP) system for intranasal delivery of suicide genes and therapeutic microRNAs to treat triple-negative breast cancer lung metastases. This adaptable platform shows promise for future inhalational combination therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Pulmonary metastases, particularly from triple-negative breast cancer (TNBC), present significant therapeutic challenges.
- Current treatments for lung metastases often have limited efficacy and severe side effects.
Purpose of the Study:
- To develop and evaluate a novel combination therapy using suicide genes and therapeutic microRNAs (miRs) delivered via gold nanoparticles (AuNPs) for treating lung metastases.
- To assess the efficacy of intranasal delivery of these AuNPs in mouse models of TNBC lung metastases.
Main Methods:
- Synthesized AuNPs (nanodots and nanostars) coated with chitosan-β-cyclodextrin (CS-CD) and functionalized with urokinase plasminogen activator (uPA) peptide.
- Loaded AuNPs with triple cancer suicide genes (thymidine kinase-p53-nitroreductase: TK-p53-NTR) and therapeutic miRNAs (antimiR-21, antimiR-10b, miR-100).
- Administered AuNPs intranasally in mouse models and evaluated gene transfection efficiency, lung accumulation, and therapeutic efficacy using prodrugs.
Main Results:
- The 50nm AuNS formulation demonstrated approximately 4.16-fold higher gene transfection efficiency compared to other nanoparticle types.
- Intranasal delivery of the uPA-AuNS-TK-p53-NTR-microRNAs nanoparticles (pAuNS@TK-p53-NTR-miRs) showed predominant lung accumulation.
- The treatment facilitated prodrug-mediated gene therapy against TNBC lung metastases in mice.
Conclusions:
- The developed nanosystem is a promising platform for inhalational suicide gene-microRNA combination therapy against pulmonary metastases.
- This approach offers an adaptable, facile, and potentially clinically scalable strategy for various cancer types with lung metastasis.
