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Breathing New Life into TRAIL for Breast Cancer Therapy: Co-Delivery of pTRAIL and Complementary siRNAs Using
Bindu Thapa1, Remant Kc2, Markian Bahniuk2
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Abstract:
Preclinical studies showed that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy is safe and effective to combat cancers, but clinical outcomes have been less than optimal due to short half-life of TRAIL protein, insufficient induction of apoptosis, and TRAIL resistance displayed in many tumors. In this study, we explored co-delivery of a TRAIL expressing plasmid (pTRAIL) and complementary small interfering RNAs (siRNAs) (silencing Bcl2-like 12 [BCL2L12] and superoxide dismutase 1 [SOD1]) to improve the response of breast cancer cells against TRAIL therapy. It is desirable to co-deliver the pDNA along with siRNA using a single delivery agent, but this is challenging given different structures of long/flexible pDNA and short/rigid siRNA. Toward this goal, we identified an aliphatic lipid-grafted low-molecular weight polyethylenimine (PEI) that accommodated both pDNA and siRNA in a single complex. The co-delivery of pTRAIL with BCL2L12- or SOD1-specific siRNAs resulted more significant cell death in different breast cancer cells compared with separate delivery without affecting nonmalignant cells viability. Ternary complexes of lipopolymer with pTRAIL and BCL2L12 siRNA significantly retarded the growth of breast cancer xenografts in mice. The enhanced anticancer activity was attributed to increased in situ secretion of TRAIL and sensitization of breast cancer cells against TRAIL by the co-delivered siRNAs. The lipid-grafted PEIs capable of co-delivering multiple types of nucleic acids can serve as powerful carriers for more effective complementary therapeutics. Graphical Abstract [Figure: see text].
Insights
This study introduces a novel lipid-grafted polyethylenimine (PEI) for co-delivering tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plasmid and siRNAs to enhance breast cancer therapy, improving cell death and tumor growth retardation.
Area of Science:
- Biotechnology and Nanomedicine
- Cancer Therapeutics
- Molecular Biology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy shows promise for cancer treatment but faces challenges like short half-life and tumor resistance.
- Existing delivery methods struggle to co-deliver plasmid DNA (pDNA) and small interfering RNA (siRNA) effectively due to their differing structures.
Purpose of the Study:
- To develop a single delivery agent for co-delivering pTRAIL and complementary siRNAs (BCL2L12 or SOD1) to enhance breast cancer cell response to TRAIL therapy.
- To investigate the efficacy of this co-delivery system in vitro and in vivo.
Main Methods:
- Development of an aliphatic lipid-grafted low-molecular weight polyethylenimine (PEI) capable of complexing both pDNA and siRNA.
- Co-delivery of pTRAIL with BCL2L12- or SOD1-specific siRNAs in breast cancer cell lines.
- Evaluation of cell viability and tumor growth in xenograft models.
Main Results:
- The developed PEI successfully co-delivered pTRAIL and siRNAs, leading to significantly increased breast cancer cell death compared to separate deliveries.
- Non-malignant cells remained largely unaffected.
- Co-delivery of pTRAIL and BCL2L12 siRNA significantly inhibited breast cancer xenograft growth in mice.
Conclusions:
- Lipid-grafted PEIs are effective carriers for co-delivering multiple nucleic acid types, enhancing TRAIL-based cancer therapy.
- Co-delivery increases in situ TRAIL secretion and sensitizes cancer cells to TRAIL, offering a promising strategy for improved cancer treatment.
