Ultrasound-Guided Delivery of Thymidine Kinase–Nitroreductase Dual Therapeutic Genes By PEGylated-PLGA/PEI Nanoparticles for Enhanced Triple Negative Breast Cancer Therapy

Abstract

Aim: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype. Since no targeted therapy is available, gene-directed enzyme prodrug therapy (GDEPT) could be an attractive strategy for treating TNBC. Materials & methods: Polyethylene glycol (PEG)ylated-poly(lactic-co-glycolic acid)/polyethyleneimine nanoparticles (PLGA/PEI NPs) were synthesized and complexed with TK–NTR fusion gene. Ultrasound (US) and microbubble (MB) mediated sonoporation was used for efficient delivery of the TK–NTR–DNA–NP complex to TNBC tumor in vivo for cancer therapy. Therapeutic effect was evaluated by treating TNBC cells in vitro and tumor xenograft in vivo by using prodrugs ganciclovir (GCV) and CB1954. Results: TNBC cells treated with GCV/CB1954 prodrugs after transfection of TK–NTR–DNA by PEGylated-PLGA/PEI NP resulted in high apoptotic-index. US–MB image-guided delivery of TK–NTR–DNA–NP complex displayed significant expression level of TK–NTR protein and showed tumor reduction when treated with GCV/CB1954 prodrugs in TNBC xenograft in vivo. Conclusion: US–MB image-guided delivery of TK–NTR gene by PEGylated-PLGA/PEI NPs could be a potential prodrug therapy for TNBC in the clinic.

Keywords:

• gene delivery
• gene-directed enzyme prodrug therapy (GDEPT)
• nanoparticles
• NTR
• PEG
• PEI
• PLGA
• thymidine kinase (TK)
• triple-negative breast cancer (TNBC)

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Acknowledgements

The authors would like to thank Bracco for providing BR38 microbubbles, the Stanford Center for Innovation in In vivo Imaging for help with ultrasound imaging and tumor volume measurements.

Financial & competing interests disclosure

This research was supported by NIH grants: R01CA209888, R21EB022298. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.