Retargeted adenoviruses for radiation-guided gene delivery

Abstract

The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage to improve therapeutic results in glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78-kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus-mediated gene delivery by selectively targeting adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to endeavor a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated reporter gene expression of fiber modified adenoviruses in vitro using a panel of glioma cells and the human D54MG tumor xenograft model. Obtained results demonstrated that employment of GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses compared to untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognize tumor cells responding to radiation treatment.

Clinical landscape of oncolytic virus research in 2020

“…There has been considerable preclinical studies supporting expression of a variety of genes that help promote cytotoxic killing of tumor cells, induction of immune responses, inhibition of tumor neoangiogenesis, enhancing radiosensitization and other strategies. [8][9][10] Other considerations in OV development includes selection of how to deliver the virus to the patient with cancer and, while initial studies used direct intratumoral (IT) injections, this may be logistically challenging for visceral and central nervous system (CNS) tumors. Other strategies have included intravenous administration which is logistically simple and allows targeting of multiple metastatic lesions but may be complicated by rapid dilution in the circulation, neutralization by antiviral antibodies and other serum proteins, and ultimately limited biodistribution to tumors.…”

Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors

“… 60 Ionizing radiation is known to upregulate multiple endocytosis pathways as well as increase surface antigens and receptors that could potentially facilitate endocytosis of AMONs. 24 , 61 The cell membrane lipid bilayer is naturally impermeable to complexes >1 kDa, alternate strategies involving the modulation of endocytosis using lipid-based drug delivery systems, nanoscale carriers and synthetic receptor targeting adapted for high affinity binding of targeting molecules and clathrin-dependent uptake are not novel and some of these are currently being evaluated in clinical trials. 62 , 63 , 64 Radiation-mediated enhanced intracellular uptake as well as microbubble oscillation using ultrasound to deliver adeno-viral vectors, plasmid DNA or siRNA have been previously described by upregulation of the physiological endocytosis pathways and our study for the first time demonstrate the use of a priming dose of non-ablative ionizing radiation-enhanced delivery of unmodified morpholino oligomers to effectively knockdown target proteins.…”

RNA interference-mediated gene silencing of cyclophilin A enhances the radiosensitivity of PAa human lung adenocarcinoma cells in vitro

“…Radiotherapy is a common therapeutic choice for lung adenocarcinoma ( 4 ). Gene-radiotherapy, the combination of traditional radiation and targeted gene therapy is a recent breakthrough in cancer treatment ( 22 ). In a previous study, proteomic analysis of pulmonary adenocarcinoma demonstrated an upregulation of CyPA following radiotherapy ( 14 ).…”