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Ultrasound-Targeted Delivery of Chemotherapeutic Drug and Nucleic Acids By Gas-Filled Cationic Liposomes

Ultrasound is widely used in the medical imaging field for diagnostic purposes. Twenty years ago, their use has turned to therapeutic applications for musculoskeletal disorders mainly The invention of gas microbubble ultrasound contrast agent was the trigger of a large number of studies on extra-molecules delivery into cells by coupling ultrasound and gas microbubbles. This technique called sonoporation has the advantage to deliver locally drugs near or loaded inside microbubbles. Gas microbubble is therefore serves as a drug reservoir that could be triggered by ultrasound. In this study, we developed gas microbubbles capable of delivering both a cytotoxic agent as Paclitaxel and siRNA to promote tumour regression. Microbubbles were developed with original histidylated cationic lipids which are pH-sensitive. In vitro measurements have been done to depict the behaviour of these microbubbles in the presence of tumour cells after ultrasound activation. Confocal microscopy and flow cytometry experiments demonstrated that cationic microbubbles were able to complex siRNA. Ultrasound parameters were optimized in vitro for siRNA delivery in 4T1 cells stably expressing luciferase (luc). Gas-filled cationic microbubbles complexed with anti-luc siRNA led to specific inhibition of luciferase expression under specific ultrasound parameters. A proof of principle has been validated in vivo using 4T1 orthotopic murine mammary tumour model. Our siRNA-Paclitaxel formulations were injected either inside the tumour or in the blood circulation via tail vein followed by ultrasound application at tumour site. A significant inhibition of tumor growth were observed in mice treated weekly with these formulations repeated at least three times. In conclusion, we succeeded to produce original gas-filled liposomes made with histidylated cationic liposomes that were ultrasound-sensitive and able to co-deliver efficiently Paclitaxel and siRNA for tumor treatment.

ultrasound, sonoporation, cationic microbubbles, paclitaxel, siRNAs

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