Bacteriophage-mediated therapy of chondrosarcoma by selective delivery of the tumor necrosis factor alpha (TNFα) gene

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 alpha v beta 3 or alpha v beta 5 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 (TNF alpha) therapeutic transgene expression cassette was incorporated into the phage genome. First, we found that human chondrosarcoma cells (SW1353) have high expression of alpha v beta 3, alpha v beta 5 integrin receptors, and both TNF alpha 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 TNF alpha transgene, significant cell killing was evident and was associated with high expression of TNF alpha 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.

Automated summary

A targeted chondrosarcoma gene therapy using engineered phage particles showed promising, selective, and efficient delivery of therapeutic genes to chondrosarcoma cells. In vitro studies demonstrated significant cell killing and high expression of TNF alpha and apoptosis-related genes when treated with the targeted particles. In vivo experiments on mice with chondrosarcoma further supported the potential of this phage-based therapy for chondrosarcoma.