Abstract
Recently, we have developed novel polyethylene glycol modified liposomes (bubble liposomes; BL) entrapping an ultrasound (US) imaging gas, which can work as a gene delivery tool with US exposure. In this study, we investigated the usefulness of US-mediated gene transfer systems with BL into synoviocytes in vitro and joint synovium in vivo. Highly efficient gene transfer could be achieved in the cultured primary synoviocytes transfected with the combination of BL and US exposure, compared to treatment with plasmid DNA (pDNA) alone, pDNA plus BL, or pDNA plus US. When BL was injected into the knee joints of mice, and US exposure was applied transcutaneously to the injection site, highly efficient gene expression could be observed in the knee joint transfected with the combination of BL and US exposure, compared to treatment with pDNA alone, pDNA plus BL, or pDNA plus US. The localized and prolonged gene expression was also shown by an in vivo luciferase imaging system. Thus, this local gene delivery system into joint synovium using the combination of BL and US exposure may be an effective means for gene therapy in joint disorders.
Highlights
Intra-articular gene therapy is considered a feasible technique to deliver therapeutic proteins to suppress inflammation and destruction of the joints in rheumatoid arthritis and osteoarthritis, because it could minimize extra-articular adverse effects linked to the systemic injection of drugs [1, 2]
To solve the above-mentioned issues of microbubbles, we previously developed polyethylene glycol- (PEG-) modified liposomes entrapping echo contrast, bubble liposomes (BL), which can function as a novel gene delivery tool by applying them with US exposure [22,23,24,25,26,27]
We first tried to transfect naked plasmid DNA (pDNA) into primary synoviocytes (HFLS), which are primary fibroblast-like cells derived from the inflamed synovial tissue of rheumatoid arthritis patients, by BL and/or US (Figure 1)
Summary
Intra-articular gene therapy is considered a feasible technique to deliver therapeutic proteins to suppress inflammation and destruction of the joints in rheumatoid arthritis and osteoarthritis, because it could minimize extra-articular adverse effects linked to the systemic injection of drugs [1, 2]. Previous studies using viral vectors reported the successful transfer of therapeutic genes into the target cells in joint diseases [1, 2], but because of the considerable immunogenicity related to the use of viruses, nonviral gene transfer still needs to be developed [3]. Low-intensity US in combination with microbubbles has recently acquired much attention as a safe method of gene delivery [12,13,14,15,16]; microbubbles have problems with size, stability, and targeting function. The establishment of a method to deliver genes into joints by the combination of BL and US exposure may facilitate the development of a safe and efficient gene therapy for joint disorders. We investigated the usefulness of US-mediated gene transfer systems with BL into synoviocytes in vitro and the joint synovium in vivo
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