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Bacteriophage-based particles carrying the TNF-related apoptosis-inducing ligand (TRAIL) gene for targeted delivery
Pattaralawan Sittiju1,2, Benjawan Wudtiwai1, Aitthiphon Chongchai1
1Thailand Excellence Center for Tissue Engineering and Stem Cells, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. peraphan.pothacharoen@gmail.com.
Abstract:
The TRAIL (Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand) is a promising candidate for cancer treatment due to its unique ability to selectively induce programmed cell death, or apoptosis, in cancer cells while sparing healthy ones. This selectivity arises from the preferential binding of the TRAIL to death receptors on cancer cells, triggering a cascade of events that lead to their demise. However, significant limitations in using the TRAIL for cancer treatment are the administration of the TRAIL protein that can potentially lead to tissue toxicity (off-target) and the short half-life of the TRAIL in the body which may necessitate frequent and sustained administration; these can pose logistical challenges for long-term treatment regimens. We have devised a novel approach for surmounting these limitations by introducing the TRAIL gene directly into cancer cells, enabling them to produce the TRAIL locally and subsequently trigger apoptosis. A novel gene delivery system such as a bacteriophage-based particle TPA (transmorphic phage/AAV) was utilized to address these limitations. TPA is a hybrid M13 filamentous bacteriophage particle encapsulating a therapeutic gene cassette with inverted terminal repeats (ITRs) from adeno-associated viruses (AAVs). The particle also showed a tumour targeting ligand, CDCRGDCFC (RGD4C), on its capsid (RGD4C.TPA) to target the particle to cancer cells. RGD4C selectively binds to αvβ3 and αvβ5 integrins overexpressed on the surface of most of the cancer cells but is barely present on normal cells. Hepatocellular carcinoma (HCC) was chosen as a model because it has one of the lowest survival rates among cancers. We demonstrated that human HCC cell lines (Huh-7 and HepG2) express αvβ5 integrin receptors on their surface. These HCC cells also express death receptors and TRAIL-binding receptors. We showed that the targeted TPA particle carrying the transmembrane TRAIL gene (RGD4C.TPA-tmTRAIL) selectively and efficiently delivered the tmTRAIL gene to HCC cells resulting in the production of tmTRAIL from transduced cells and subsequently induced apoptotic death of HCC cells. This tumour-targeted particle can be an excellent candidate for the targeted gene therapy of HCC.
Insights
A novel gene therapy approach uses a bacteriophage-based particle to deliver the TRAIL gene directly into liver cancer cells, enabling targeted apoptosis induction and overcoming limitations of traditional TRAIL protein therapy.
Area of Science:
- Oncology
- Gene Therapy
- Nanotechnology
Background:
- Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) protein shows promise for cancer treatment due to selective cancer cell apoptosis induction.
- Limitations of TRAIL protein therapy include potential tissue toxicity and short in vivo half-life, complicating treatment regimens.
Purpose of the Study:
- To develop a novel gene delivery system to overcome TRAIL protein therapy limitations.
- To enable targeted, localized production of TRAIL within cancer cells for enhanced therapeutic efficacy.
Main Methods:
- A hybrid bacteriophage/AAV particle (TPA) was engineered with a tumor-targeting ligand (RGD4C) to bind cancer cell integrins (αvβ3 and αvβ5).
- The RGD4C.TPA particle delivered the transmembrane TRAIL (tmTRAIL) gene into hepatocellular carcinoma (HCC) cells.
- HCC cell lines (Huh-7, HepG2) expressing target integrins and death receptors were used as a model.
Main Results:
- The RGD4C.TPA-tmTRAIL particle selectively targeted and transduced HCC cells.
- Transduced HCC cells produced tmTRAIL, leading to efficient apoptosis induction.
- The targeted gene delivery system demonstrated potential for selective cancer cell killing.
Conclusions:
- A bacteriophage-based gene delivery system (RGD4C.TPA) effectively delivers the tmTRAIL gene to HCC cells.
- This targeted gene therapy approach induces selective apoptosis in cancer cells, overcoming TRAIL protein limitations.
- The RGD4C.TPA-tmTRAIL system represents a promising strategy for targeted gene therapy of HCC.
