Enhancement of Adenovirus Delivery after Ultrasound-Stimulated Therapy in a Cancer Model

Abstract

Improving the efficiency of adenovirus (Ad) delivery to target tissues has the potential to advance the translation of cancer gene therapy. Ultrasound (US)-stimulated therapy uses microbubbles (MBs) exposed to low-intensity US energy to improve localized delivery. We hypothesize that US-stimulated gene therapy can improve Ad infection in a primary prostate tumor through enhanced tumor uptake and retention of the Ad vector. In vitro studies were performed to analyze the degree of Ad infectivity after application of US-stimulated gene therapy. A luciferase-based Ad on a ubiquitous cytomegalovirus (CMV) promoter (Ad5/3-CMV-Luc) was used in an animal model of prostate cancer (bilateral tumor growth) to evaluate Ad transduction efficiency after US-stimulated therapy. Bioluminescence imaging was employed for In vivo analysis to quantify Ad infection within the tumor. In vitro studies revealed no difference in Ad transduction between groups receiving US-stimulated therapy using high, low or sham US intensity exposures at various multiplicities of infection (MOIs) (p = 0.80). In vivo results indicated that tumors receiving US-stimulated therapy after intra-tumoral injection of Ad5/3-CMV-Luc (1 × 106 plaque-forming units) exhibited a 95.1% enhancement in tumor delivery compared with control tumors receiving sham US (p = 0.03). US-stimulated therapy has significant potential to immediately affect Ad-based cancer gene therapy by improving virus bioavailability in target tissues.

Theranostic Multilayer Capsules for Ultrasound Imaging and Guided Drug Delivery

“…For diagnostic US treatment, ,− the custom setup included a single element (1.90 cm in diameter) immersion transducer (Olympus, Waltham, MA) in series with a signal generator (AFG3022B, Tektronix, Beaverton, OR) and a power amplifier (A075, Electronics and Innovation, Rochester, NY). The following acoustic parameters were used: 2.25 MHz US frequency, 2.0 MPa pressure amplitude, 1000 cycle pulse length, 1.0 s pulse repetition period, and 3, 30, 180, 300, and 900 s duration of exposure.…”

Localized Co-delivery of Serca2a and Cx43 Genes Combined With Bone Marrow Mesenchymal Stem Cells Restores Rat Ischemic Cardiac Mechano-electrical Function

“…Although viral vectors were highlighted by their satisfactory transfection e ciency, lack of tissue targeted ability limit the administration route of viral vectors to local injection, which might cause tissue damage. Previous studies have proved that a tissue targeted effective gene transfection could be achieved through binding viral vectors to the surface of MBs with the aid of ultrasound irradiation [36,37]. In our latest research, we also demonstrated that ultrasound beam could destroy the virus loading MBs, release the viral vectors at ventricular level, and realize the tissue targeted gene delivery [22].…”

Targeting of Magnetic Nanoparticle-coated Microbubbles to the Vascular Wall Empowers Site-specific Lentiviral Gene Delivery in vivo

“…Furthermore, MB sonication has been found to induce caveolae- and clathrin-dependent endocytosis in targeted cells29,30 thereby promoting uptake of i.a. viral particles31,32. Using our settings, we found transduction by lentiviral SO-Mag MMB to be mediated by caveolin-dependent endocytosis, potentially induced by sonication.…”