Radiation improves gene delivery by a novel transferrin-lipoplex nanoparticle selectively in cancer cells

Abstract

Selective gene transfer to tumor is critical in cancer gene therapy. We previously used ionizing radiation to improve adenovirus uptake in intrahepatic tumors but liver cytotoxicity associated with the viral administration still occurred. Here, we explore the potential of radiation for improving gene delivery by a virus-mimicking nanoparticle, transferrin (Tf)-cationic liposome-DNA complex (Tf-lipoplex). Transduction by Tf-lipoplex was highly efficient in various cell lines and further increased by radiation in a dose-and time-dependent manner. This radiation induction, which was associated with an increase in Tf-lipoplex uptake (3-to 4-folds in hepatocytes WB and lung cancer cells, LLC1), was absent when a Tf-deficient complex was used or abolished by the presence of free Tf, suggesting that Tf receptor (TfR) interaction is required for radiation induction. Radiation (10-20 Gy) markedly induced transgene (LacZ) expression in LLC1 xenografts (3.5-to 7.4-folds), correlating with increased plasmid content and TfR expression in irradiated tumors. Moreover, Tf-lipoplex-mediated gene expression was not observed in the liver or other normal tissues regardless of radiation treatment. We conclude that radiation improves Tf-lipoplex gene delivery selectively to tumor cells both in vitro and in vivo. Our findings may provide insight in developing ligand-specific lipoplex for molecularly targeted cancer gene therapy.

Improving cellular uptake and in vivo tumor suppression efficacy of liposomal oligonucleotides by urea as a chemical penetration enhancer

“…The present data clearly show that urea, and possibly other chemical penetration enhancers, are able to increase liposomal AsODN delivery and its antitumoral effect both in vivo and in vitro . In comparison with other enhancement methods, such as sonophoresis , electroporation, complex formation or radiation , which are reported for the enhancement of liposomal or nonliposomal ODN delivery, chemical penetration enhancers are considered to be less invasive, readily available, easy to apply and less expensive. This strategy may open a new era in the field of liposomal gene delivery to cancer cells (especially at subcellular levels).…”

Polymeric nanomedicine for cancer MR imaging and drug delivery

“…Non-viral gene delivery remains an active area of research with the main focus being improvement of delivery and transfection efficiency. Recently, Abela et al reported the preparation of a virus-mimicking nanoparticle, transferrin (Tf)-cationic liposome-DNA complex (Tf-lipoplex) by encapsulating plasmid DNA cytomegalovirus-green fluorescent protein (CMV-GFP) inside the core of liposomes 53. They reported that Tf-lipoplex achieved high gene delivery efficacy in C57BL mice carrying subcutaneous LLC1 tumor xenografts.…”

Targeted drug delivery in pancreatic cancer

“…Addition of the transferrin (Tf) ligand to a cationic liposome complex resulted in significantly increased in vitro and in vivo transfection efficiency in squamous cell carcinoma of the head and neck (SCCHN, 70-80% transfection rate compared with only 5–20% by liposome alone). Both p53 gene and siRNAs have been successfully delivered to the target organs using TfR conjugated liposomes or nanoparticles in treating many types of cancers including pancreatic cancer [9, 73-76]. …”