Gene Therapy of Carcinoma Using Ultrasound-Targeted Microbubble Destruction

Abstract

When microbubble contrast agents are loaded with genes and systemically injected, ultrasound-targeted microbubble destruction (UTMD) facilitates focused delivery of genes to target tissues. A mouse model of squamous cell carcinoma was used to test the hypothesis that UTMD would specifically transduce tumor tissue and slow tumor growth when treated with herpes simplex virus thymidine kinase (TK) and ganciclovir. UTMD-mediated delivery of reporter genes resulted in tumor expression of luciferase and green fluorescent protein (GFP) in perivascular areas and individual tumor cells that exceeded expression in control tumors (p = 0.02). The doubling time of TK-treated tumors was longer than GFP-treated tumors (p = 0.02), and TK-treated tumors displayed increased apoptosis (p = 0.04) and more areas of cellular drop-out (p = 0.03). These data indicate that UTMD gene therapy can transduce solid tumors and mediate a therapeutic effect. UTMD is a promising nonviral method for targeting gene therapy that may be useful in a spectrum of tumors.

Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles

“…These were safe and had excellent penetration ability, strong specificity, and potential for clinical translation. 39,40 This study can not only provide a basis for ultrasound molecular imaging of prostate cancer, but can also provide methods for constructing targeted ultrasound probes carrying aptamers. In addition, because the aptamer is a gene fragment in itself, it can be intercalated with anthracyclines or can be connected to other gene fragments, which can lay the foundation for future construction of targeted NBs carrying drugs (or genes) in targeted therapy under ultrasound irradiation.…”

“…Currently, there are still no in vivo reports on this type of targeted NB. 39 We will continue in-depth studies on the following subjects and improve the effect of this targeted NB in experimental animals with the goal of clinical translation. 1) The PSMA-positive and -negative cells used with the same in vitro concentrations of the two types of NBs were used for imaging in the mice.…”

Cell mechanics in biomedical cavitation

“…Upon arriving at a targeted site, the microbubbles are activated by ultrasound leading to violent collapse. This releases the drug/gene cargo and also causes cell membranes nearby to become temporarily leaky, a phenomenon known as sonoporation [9,10]. The mechanism aids the gene/drug to enter the target cells via diffusion and also convection if microjets arise [11 -13].…”

Enhanced delivery of PEAL nanoparticles with ultrasound targeted microbubble destruction mediated siRNA transfection in human MCF-7/S and MCF-7/ADR cells in vitro

“…The protonated amino group of PLL could electrostatically interact with the polyanionic siRNA and negatively charged cell membrane to increase the transportation of siRNA to the cytosol. [14][15][16] UTMD, a safe and effective gene transfer method, can protect nanocarriers against nonspecific recognition in the systemic circulation, [17][18][19][20] whereas, directional rupture of microbubbles (MB) with the help of ultrasound (US) can transiently lead to the formation of repairable pores on cell membrane, which is conducive to increase the permeability of biological macromolecules and can assist nanocarriers in penetrating cell membrane and entering into cells. [21][22][23] In this work, the siRNA-loaded PEAL NPs were prepared by emulsification-solvent evaporation method 24 and characterized in terms of morphology, size, ζ potential, and encapsulation efficiency (EE).…”