Advances in Ultrasound Mediated Gene Therapy Using Microbubble Contrast Agents

Abstract

Microbubble ultrasound contrast agents have the potential to dramatically improve gene therapy treatments by enhancing the delivery of therapeutic DNA to malignant tissue. The physical response of microbubbles in an ultrasound field can mechanically perturb blood vessel walls and cell membranes, enhancing drug permeability into malignant tissue. In this review, we discuss literature that provided evidence of specific mechanisms that enhance in vivo gene delivery utilizing microbubble contrast agents, namely their ability to 1) improving cell membrane permeability, 2) modulate vascular permeability, and 3) enhance endocytotic uptake in cells. Additionally, we review novel microbubble vectors that are being developed in order to exploit these mechanisms and deliver higher gene payloads with greater target specificity. Finally, we discuss some future considerations that should be addressed in the development of next-generation microbubbles in order to improve in vivo microbubble gene delivery. Overall, microbubbles are rapidly gaining popularity as efficient gene carriers, and combined with their functionality as imaging contrast agents, they represent powerful theranostic tools for image guided gene therapy applications.

A bibliometric analysis of micro/nano-bubble related research: current trends, present application, and future prospects

“…8, the three most frequently used keywords are ''Ultrasound'' (767; 15.9 %), ''Contrast Agent(s)'' (295; 6.1 %), and ''Ultrasound Contrast Agent(s)'' (287; 5.9 %). These top 3 most frequently used substantives reflect the large amount of literature dealing with the introduction of microbubbles into a new era for personalized diagnostics, therapy, and theranostics by ultrasound contrast agents (Blomley et al 2001;Klibanov 2006;Kiessling (Delalande et al 2012;Sirsi and Borden 2012;Unger et al 2014). Without targeted microbubbles as ultrasound contrast agents in the three main clinical applications including molecular imaging, drug delivery and gene delivery, their principles and methods are as follows.…”

Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles

“…Over the years, it has undergone significant development from an initial proof of concept to a localized membrane perforation technique with spatio-temporal control [3], and it has achieved early success in facilitating drug delivery [4], gene therapy [5], intracellular biomarker extraction [6] and cancer treatment [7]. In fostering localized induction of sonoporation, one technical advance that has played an important role is the advent of targeted microbubbles with binding affinity to antigen receptors on the cell type of interest [8,9], such as vascular endothelial growth factor (VEGF) receptors expressed on cancerous cells [10] or hypoxic endothelial cells [11]. These targeted microbubbles, often composed of a perfluorocarbon gas core encapsulated within an antibody-conjugated shell material [12], are in effect artificial gas bodies that would cavitate in response to ultrasound excitation, which could be as short as a single pulse firing [13].…”

Pseudomonas aeruginosa exotoxin T induces potent cytotoxicity against a variety of murine and human cancer cell lines

“…Gene therapy using this technology has gained significant momentum in recent years (Smith et al, 2011;Chen et al, 2012;Sirsi & Borden, 2012;Smith & Land, 2012). In summary, we propose that P. aeruginosa ExoT possesses attractive anti-cancer properties that make it an attractive cancer drug candidate.…”