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Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery.

Paefgen V, Doleschel D, Kiessling F - Front Pharmacol (2015)

Bottom Line: Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent.Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability.Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen Germany.

ABSTRACT
Ultrasound (US) is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents (CAs). There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular CAs enable functional analyses, e.g., to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles' shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent. Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of US CAs and introduces the current clinical applications of contrast-enhanced US. Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given.

No MeSH data available.


Related in: MedlinePlus

Targeted MBs with entrapped drug/nucleic acids rupture under the US-induced acoustic pressure and release their loading specifically at the side of a tumor (schematic illustration, not drawn to scale).
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Figure 4: Targeted MBs with entrapped drug/nucleic acids rupture under the US-induced acoustic pressure and release their loading specifically at the side of a tumor (schematic illustration, not drawn to scale).

Mentions: The second application field for bubble-enhanced sonoporation is US-mediated drug release (Figure 4). Using drug-loaded MB, it is possible to spatiotemporally apply LOFU pulses at certain organs to increase the membrane permeability, and at the same time increase the energy to promote bubble collapse and particle release (Tzu-Yin et al., 2013). This way, the group around Kiessling and co-workers used USPIO containing PBCA-MB (USPIO-MB) as a proof of principle approach to demonstrate drug delivery across the BBB in mice (Figure 5). For the experiment, mice were scanned by MRI before and after injection of USPIO-MB and successive US treatment in the head region using destructive pulses. In comparison to control groups, the USPIO brain incorporation was significantly increased in the group receiving US treatment. Drug delivery across the BBB was additionally confirmed by histology, and significantly enhanced FITC-dextran extravasation and deposition within the brain was detected in animals receiving USPIO-MB and sonification. The temporal and spatial BBB-opening offers a new perspective to treat gliomas, but also neurodegenerative disorders like Alzheimer or Parkinson’s disease, where macromolecular drugs or growth factors have to be locally accumulated (Lammers et al., 2015). However, also outside of the brain US-supported drug delivery is promising. In an animal model of incomplete tumor resection, cetuximab-loaded MB and US stimulation had stronger therapeutic effects on the remaining tumor mass than cetuximab-only treated animals, which was confirmed by in vivo fluorescence and bioluminescence, as well as caliper measurements (Sorace et al., 2014). Co-delivery of paclitaxel and siRNA to inhibit anti-apoptotic protein production also showed very promising results in a murine HepG2 tumor model. Here, tumor growth was strongly inhibited in animals which received NB with paclitaxel entrapped in and siRNA-containing micelles attached to the shell, additionally to US application. Furthermore those animals showed longer survival (Yin et al., 2014). Despite those promising results further animal studies need to be done before similar setups can go into clinical trials.


Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery.

Paefgen V, Doleschel D, Kiessling F - Front Pharmacol (2015)

Targeted MBs with entrapped drug/nucleic acids rupture under the US-induced acoustic pressure and release their loading specifically at the side of a tumor (schematic illustration, not drawn to scale).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4584939&req=5

Figure 4: Targeted MBs with entrapped drug/nucleic acids rupture under the US-induced acoustic pressure and release their loading specifically at the side of a tumor (schematic illustration, not drawn to scale).
Mentions: The second application field for bubble-enhanced sonoporation is US-mediated drug release (Figure 4). Using drug-loaded MB, it is possible to spatiotemporally apply LOFU pulses at certain organs to increase the membrane permeability, and at the same time increase the energy to promote bubble collapse and particle release (Tzu-Yin et al., 2013). This way, the group around Kiessling and co-workers used USPIO containing PBCA-MB (USPIO-MB) as a proof of principle approach to demonstrate drug delivery across the BBB in mice (Figure 5). For the experiment, mice were scanned by MRI before and after injection of USPIO-MB and successive US treatment in the head region using destructive pulses. In comparison to control groups, the USPIO brain incorporation was significantly increased in the group receiving US treatment. Drug delivery across the BBB was additionally confirmed by histology, and significantly enhanced FITC-dextran extravasation and deposition within the brain was detected in animals receiving USPIO-MB and sonification. The temporal and spatial BBB-opening offers a new perspective to treat gliomas, but also neurodegenerative disorders like Alzheimer or Parkinson’s disease, where macromolecular drugs or growth factors have to be locally accumulated (Lammers et al., 2015). However, also outside of the brain US-supported drug delivery is promising. In an animal model of incomplete tumor resection, cetuximab-loaded MB and US stimulation had stronger therapeutic effects on the remaining tumor mass than cetuximab-only treated animals, which was confirmed by in vivo fluorescence and bioluminescence, as well as caliper measurements (Sorace et al., 2014). Co-delivery of paclitaxel and siRNA to inhibit anti-apoptotic protein production also showed very promising results in a murine HepG2 tumor model. Here, tumor growth was strongly inhibited in animals which received NB with paclitaxel entrapped in and siRNA-containing micelles attached to the shell, additionally to US application. Furthermore those animals showed longer survival (Yin et al., 2014). Despite those promising results further animal studies need to be done before similar setups can go into clinical trials.

Bottom Line: Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent.Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability.Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental Molecular Imaging, RWTH Aachen University Hospital, Aachen Germany.

ABSTRACT
Ultrasound (US) is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents (CAs). There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular CAs enable functional analyses, e.g., to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles' shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent. Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of US CAs and introduces the current clinical applications of contrast-enhanced US. Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given.

No MeSH data available.


Related in: MedlinePlus