Targeted treatment of chondrosarcoma with a bacteriophage-based particle delivering a secreted tumor necrosis factor-related apoptosis-inducing ligand

Abstract

Chondrosarcoma is a malignant cartilage-forming bone tumor which is inherently resistant to chemotherapy and radiotherapy leaving surgery as the only treatment option. We have designed a tumor-targeted bacteriophage (phage)-derived particle (PDP), for targeted systemic delivery of cytokine-encoding transgenes to solid tumors. Phage has no intrinsic tropism for mammalian cells; therefore, it was engineered to display a double cyclic RGD4C ligand on the capsid to target tumors. To induce cancer cell death, we constructed a transgene cassette expressing a secreted form of the cytokine tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL). We detected high expression of αvβ3 and αvβ5 integrin receptors of the RGD4C ligand, and of the TRAIL receptor-2 in human chondrosarcoma cells (SW1353) but not in primary normal chondrocytes. The RGD4C.PDP-Luc particle carrying a luciferase reporter gene, Luc, effectively and selectively mediated gene delivery to SW1353 cells but not primary chondrocytes. Transduction of SW1353 cells with RGD4C.PDP-sTRAIL encoding a human sTRAIL, resulted in expression of TRAIL and subsequent cell dead without harming the normal chondrocytes. Intravenous administration of RGD4C.PDP-sTRAIL to mice with established human chondrosarcoma resulted in reduction of tumor size and tumor viability. Altogether, RGD4C.PDP-sTRAIL can be used to target systemic treatment of chondrosarcoma with the sTRAIL.