Ultrasound-Responsive Cavitation Nuclei for Therapy and Drug Delivery

Abstract

Therapeutic ultrasound strategies that harness the mechanical activity of cavitation nuclei for beneficial tissue bio-effects are actively under development. The mechanical oscillations of circulating microbubbles, the most widely investigated cavitation nuclei, which may also encapsulate or shield a therapeutic agent in the bloodstream, trigger and promote localized uptake. Oscillating microbubbles can create stresses either on nearby tissue or in surrounding fluid to enhance drug penetration and efficacy in the brain, spinal cord, vasculature, immune system, biofilm or tumors. This review summarizes recent investigations that have elucidated interactions of ultrasound and cavitation nuclei with cells, the treatment of tumors, immunotherapy, the bloodÀbrain and bloodÀspinal cord barriers, sonothrombolysis, cardiovascular drug delivery and sonobactericide. In particular, an overview of salient ultrasound features, drug delivery vehicles, therapeutic transport routes and pre-clinical and clinical studies is provided. Successful implementation of ultrasound and cavitation nuclei-mediated drug delivery has the potential to change the way drugs are administered systemically, resulting in more effective therapeutics and less-invasive treatments.

Microbubbles and Nanobubbles with Ultrasound for Systemic Gene Delivery

“…Ultrasound exposure is known to increase cell membrane permeability and facilitate the delivery of drugs or genes into cells [ 18 , 19 ]. A combination of ultrasound exposure and microbubbles further increases cell membrane permeability even when using weak intensity ultrasound, leading to enhanced drug and gene uptake [ 12 , 13 , 14 , 15 , 16 , 17 ]. Stable oscillations of microbubbles are caused by exposure to low acoustic pressure, a process termed stable cavitation.…”

“…In recent years, nanoscale contrast agents have been developed. Furthermore, micro- or nanobubbles have previously been investigated as site-specific drug or gene delivery tools [ 12 , 13 , 14 , 15 , 16 , 17 ]. To exploit the combination of ultrasound and bubbles both for diagnosis and therapeutics as a theranostic system, various types of bubbles valuable for systemic administration have been well documented in recent years.…”

The Impact of Lipid Handling and Phase Distribution on the Acoustic Behavior of Microbubbles

“…Targeted microbubbles are employed for molecular imaging of inflammation, tumors, and cardiovascular disease [ 2 ]. Other types of microbubbles are being developed specifically for drug delivery [ 3 ]. All of these applications make use of the compression and expansion of the microbubble gas core upon ultrasound insonification.…”

“…The coating reduces surface tension and gas diffusion [ 7 ]. If phospholipids or polymers are used as microbubble coating, a ligand can be attached for molecular imaging [ 8 ], and they can be loaded with a drug for localized delivery [ 3 ]. The physicochemical properties of the microbubble coating, such as the shell elasticity and viscosity, are related to the acoustical properties, such as the resonance frequency and the damping coefficient [ 9 , 10 ].…”

Alleviating tumor hypoxia with perfluorocarbon-based oxygen carriers

“…[20] Administration of PFC-stabilized MBs in conjunction with US was deemed beneficial in several theranostic approaches that can combine diagnostic imaging and ablation, histotripsy, embolotherapy, radiotherapy, photo(sono)dynamic therapy, chemotherapy, gene delivery, including across the blood brain barrier, or anti-vascular therapy. [21][22][23][24][25] This short review, after briefly reminding the impeding effects of hypoxia on cancer therapies, reports recent advances that demonstrate the capacity for PFC-based NEs, P-SNEs, MBs and other PFC-based nanodevices to deliver oxygen to tumors and, thereby, efficiently fight hypoxia in O 2 -dependant cancer therapies.…”