Ultrasound-guided delivery of thymidine kinase-nitroreductase dual therapeutic genes by PEGylated-PLGA/PIE 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.

• Authors: Rammohan Devulapally, Taehwa Lee, Aarohi Barghava-Shah, Thillai V Sekar, Kira Foygel, Sunitha V Bachawal, Jürgen K Willmann, Ramasamy Paulmurugan
• Journal: Nanomedicine (London, England) (Nanomedicine (Lond)) Vol. 13 Issue 9 Pg. 1051-1066 (05 2018) ISSN: 1748-6963 [Electronic] England
• PMID: 29790803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Aziridines
• Lactates
• poly(lactic acid-ethylene glycol)
• Polyethylene Glycols
• tretazicar
• Nitroreductases
• Thymidine Kinase

Topics

• Animals
• Apoptosis (drug effects)
• Aziridines (pharmacology)
• Cell Line, Tumor
• Female
• Flow Cytometry
• Humans
• Lactates (chemistry)
• Mice
• Mice, Nude
• Nanoparticles (chemistry)
• Nitroreductases (genetics)
• Polyethylene Glycols (chemistry)
• Thymidine Kinase (genetics)
• Transfection
• Triple Negative Breast Neoplasms (genetics, therapy)
• Ultrasonic Waves