Liver‐Specific and Echogenic Hyaluronic Acid Nanoparticles Facilitating Liver Cancer Discrimination

Abstract

With the increasing demand for instant real‐time ultrasound (US) imaging of a specific organ, target‐specific and long‐circulating ultrasound contrast agents are of special interest. A new species of echogenic hyaluronic acid nanoparticles is presented as an ultralong‐acting, liver‐specific, US contrast agent that is distinct from conventional gas‐filled microbubbles. Using an oil‐in‐water (O/W) emulsification method, bioinert and hydrophobic perfluoropentane (PFP) is encapsulated as an ultrasound gas precursor into hyaluronic acid nanoparticles (HANPs) using hydrophobic interactions. HANPs are formulated by self‐assembly, with amphiphilic hyaluronic acid‐5β‐cholanic acid (HA‐CA) conjugating in aqueous conditions. The resulting echogenic PFP‐encapsulated HANPs (Echo‐NPs) show solid nanostructures, differentiated from core‐empty conventional microbubbles, and exhibiting outstanding physical properties as an ultrasound contrast agent. They are more stable and robust echogenic solid bodies with an in vivo favorable hydrodynamic size and because PFPs vaporize gradually, their expansion process is very slow in body conditions. After several systemic circulations, echo‐NPs generated intense and ultralong echo signals for US imaging at the target site. The echogenic properties of Echo‐NPs show a significantly increased half‐life and echo persistence, compared with conventional microbubbles. The results clearly show that echo‐NPs outperform conventional microbubbles in terms of both physical and echogenic in vitro and in vivo properties.

Polysaccharide-Based Nanocarriers for Drug Delivery

“…Based on these results, HA micelles were proposed for hepatic cancer imaging. 185 Nevertheless, hepatic accumulation may represent a major drawback for cancer therapies directed to organs. In order to reduce the hepatic uptake of HA-cholanic acid micelles, PEGylation of the HA backbone 50,52,56,57 has been studied.…”

Cancer‐Associated, Stimuli‐Driven, Turn on Theranostics for Multimodality Imaging and Therapy

“…Commercialized contrast agents for US include Albunex (albumin shell with air), Optison (albumin shell with octafluoropropane), Definity (lipid/surfactant shell with octafluoropropane), Imagent (lipid/surfactant shell with N 2 /perfluorohexane), Sonovue (lipid shell with sulphur hexafluoride) Levovist (lipid/galactose shell with air) CARDIOsphere (PLGA polymer/albumin with N 2 ) and Sonovist (cyanoacrylate polymer shell with air) . In addition, a number of nanoparticles, as well as microparticles, that have the ability to generate gases have been developed for target specific US imaging . However, applications of US are limited by low resolution, dependency on skilled operators and difficulties in obtaining information about organs containing gas or behind bones.…”

Nanoparticle‐Loaded Protein–Polymer Nanodroplets for Improved Stability and Conversion Efficiency in Ultrasound Imaging and Drug Delivery

“…Ultrasound is one of the most widely applied clinical imaging modalities on account of its ability to provide real time images particularly of blood flow, its cost effectiveness, and high patient acceptability . Over the past two decades, research into the therapeutic applications of ultrasound has also expanded significantly for indications ranging from cancer therapy to thrombolysis .…”

“…Notwithstanding their significant potential, the development of nanodroplets still poses some considerable challenges. While nanodroplet stability is greatly enhanced compared with that of microbubbles, it is still relatively poor compared with that of solid particles, and droplets may undergo coalescence and/or premature phase transition before they reach the target region. Once in the target region, the conversion efficiency, i.e., the proportion of droplets undergoing a phase change for a given set of ultrasound exposure conditions is also often very low .…”