Bacteriophage-mediated therapy of chondrosarcoma by selective delivery of the tumor necrosis factor alpha (TNFα) gene.
Aitthiphon ChongchaiSajee WaramitKeittisak SuwanMariam Al-BahraniSasimol UdomrukThanyaluck PhitakPrachya KongtawelertPeraphan PothacharoenAmin HajitouPublished in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (2021)
Chondrosarcoma is a cartilage-forming bone tumor, well known for intrinsic resistance to chemotherapy and radiotherapy. We have designed a targeted chondrosarcoma gene therapy using a bacteriophage (phage) particle to deliver therapeutic genes. Phage has no tropism for mammalian cells, allowing engineered phage to be targeted to specific cell surface receptors in cancer. We modified the phage capsid to display the RGD4C ligand on the pIII minor coat proteins to specifically bind to αvβ3 or αvβ5 integrin receptors. The endosomal escape peptide, H5WYG, was also displayed on recombinant pVIII major coat proteins to enhance gene delivery. Finally, a human tumor necrosis factor alpha (TNFα) therapeutic transgene expression cassette was incorporated into the phage genome. First, we found that human chondrosarcoma cells (SW1353) have high expression of αvβ3, αvβ5 integrin receptors, and both TNFα receptors. Targeted particle encoding a luciferase reporter gene efficiently and selectively mediated gene delivery to these cells. When SW1353 cells were treated with the targeted particle encoding a TNFα transgene, significant cell killing was evident and was associated with high expression of TNFα and apoptosis-related genes. In vivo, mice with established human chondrosarcoma showed suppression of tumors upon repetitive intravenous administrations of the targeted phage. These data show that our phage-based particle is a promising, selective, and efficient tool for targeted chondrosarcoma therapy.
Keyphrases
- rheumatoid arthritis
- pseudomonas aeruginosa
- cell cycle arrest
- induced apoptosis
- cancer therapy
- endothelial cells
- poor prognosis
- endoplasmic reticulum stress
- gene therapy
- cell death
- genome wide
- cell surface
- stem cells
- radiation therapy
- locally advanced
- gene expression
- induced pluripotent stem cells
- genome wide identification
- machine learning
- long non coding rna
- bone mineral density
- crispr cas
- cell therapy
- type diabetes
- bone marrow
- papillary thyroid
- insulin resistance
- skeletal muscle
- body composition
- high dose
- genome wide analysis
- smoking cessation
- low dose