From Micro- to Nano-Multifunctional Theranostic Platform: Effective Ultrasound Imaging Is Not Just a Matter of Scale

Abstract

Ultrasound Contrast Agents (UCAs) consisting of gas-filled-coated Microbubbles (MBs) with diameters between 1 and 10 µm have been used for a number of decades in diagnostic imaging. In recent years, submicron contrast agents have proven to be a viable alternative to MBs for ultrasound (US)-based applications for their capability to extravasate and accumulate in the tumor tissue via the enhanced permeability and retention effect. After a short overview of the more recent approaches to ultrasound-mediated imaging and therapeutics at the nanoscale, phase-change contrast agents (PCCAs), which can be phase-transitioned into highly echogenic MBs by means of US, are here presented. The phenomenon of acoustic droplet vaporization (ADV) to produce bubbles is widely investigated for both imaging and therapeutic applications to develop promising theranostic platforms.

Influence of Nanobubble Size Distribution on Ultrasound-Mediated Plasmid DNA and Messenger RNA Gene Delivery

“…( Greenleaf et al, 1998 ; Tachibana et al, 1999 ; Moosavi Nejad et al, 2011 ; Song et al, 2019 ; Kooiman et al, 2020 ). A new approach of using nanobubbles (NBs) instead of MBs have attracted attention as an alternative means for ultrasound-mediated gene therapy ( Zullino et al, 2018 ). Nanobubbles, officially termed as ultra-fine bubbles ( ISO, 2017 ), are defined as sub-micron diameter bubbles.…”

One‐Step Microfluidic Coating of Phospholipid Microbubbles with Natural Alginate Polymer as a Delivery System for Human Epithelial Lung Adenocarcinoma

“…But they remain in the circulation until they are taken up by the spleen and the liver or they dissolve in rather short times. [ 18 ] As microbubbles cause cavitation at a rather low acoustic pressure, their action mechanisms depend on oscillations of the bubbles near the endothelium of tumors to enhance drug penetration through different mechanisms such as sonoporation, activation of endocytosis, or permeabilization of cell junctions. As for encapsulation efficiency of carboplatin, the amount of drug loading into the alginate layer was calculated by indirect evaluation of the non‐encapsulated drug quantified in the infranatant of the microbubble sample, after previous separation of the two layers by centrifugation.…”

Micro/Nanobubbles Driven Multimodal Imaging and Theragnostics of Cancer

“…Because the gaps between tumor vessels endothelium cells are smaller than 1 μm [24], MBs cannot penetrate the tumor vessels and enter the tumor microenvironment. Nano-sized ultrasound contrast agents are small enough to penetrate tumor vessels pores and interact with tumor cells directly, thus showing great potential in the field of molecular ultrasound imaging and drug/gene delivery [25][26][27]. Nanobubbles have smaller particle size, more stable performance, and longer circulation time than MBs, which leads to more accumulation in the tumor area [28].…”