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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

Passive targeting is enabled by ‘leaky’ vessels with fenestrae up to several 100 nm in tumor-associated endothelium and a poor lymphatic drainage, increasing both likelihood and retention time of nano-sized particles in the interstitium (EPR effect). After extravasation, NB/particles could also actively target specific surface molecules on cancer cells (schematic illustration, not drawn to scale).
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Figure 3: Passive targeting is enabled by ‘leaky’ vessels with fenestrae up to several 100 nm in tumor-associated endothelium and a poor lymphatic drainage, increasing both likelihood and retention time of nano-sized particles in the interstitium (EPR effect). After extravasation, NB/particles could also actively target specific surface molecules on cancer cells (schematic illustration, not drawn to scale).

Mentions: Active targeting has also been tested for NB. The principle is the same, but contrary to MB, NB can also target receptors and other molecules outside the endothelium due to their possible extravasation to the tumor tissue (Figure 3). Functional coupling of an antibody, in this case directed against the TAG-72 antigen overexpressed on several epithelial tumors, to polymer-coated NB and successful binding of those to cancer cells in vitro has been shown by Xu et al. (2010). The usefulness of such an approach for tumor treatment has also been demonstrated in vivo using HLA-G as a target for antibody-coupled polymer-NB (Zhang et al., 2014). The combination of HIFU and the local release of chemotherapeutics after bubble disruption was shown to strongly enhance apoptosis of tumor cells. Recently Jiang et al. (2015) presented a promising new construct for tumor imaging, improving the idea and the in vitro model of Liu et al. (2007). Their lipid-based NB were coupled to Herceptin® (Roche, Basel, CH), also known as trastuzumab, a therapeutic monoclonal antibody binding to Her-2, which is overexpressed in many breast tumors. They found a significant increase in NB-binding to the tumor in xenograft-models which are known to overexpress Her-2, but only little accumulation in tumor xenografts with low Her-2 expression. Targeted NB in Her-2 overexpressing tumors also had an increased washout half-time, enabling longer observation times. Additionally, their bubble-construct was found to be of a low cytotoxicity (Jiang et al., 2015). To this date, this might be the approach being the closest to clinical studies. Herceptin® has also been conjugated to mesoporous silica nanoparticles and showed tumor-specific toxicity in vitro, suggesting further development of silica particles in the field of targeted imaging and drug delivery (Milgroom et al., 2014).


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

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

Passive targeting is enabled by ‘leaky’ vessels with fenestrae up to several 100 nm in tumor-associated endothelium and a poor lymphatic drainage, increasing both likelihood and retention time of nano-sized particles in the interstitium (EPR effect). After extravasation, NB/particles could also actively target specific surface molecules on cancer cells (schematic illustration, not drawn to scale).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Passive targeting is enabled by ‘leaky’ vessels with fenestrae up to several 100 nm in tumor-associated endothelium and a poor lymphatic drainage, increasing both likelihood and retention time of nano-sized particles in the interstitium (EPR effect). After extravasation, NB/particles could also actively target specific surface molecules on cancer cells (schematic illustration, not drawn to scale).
Mentions: Active targeting has also been tested for NB. The principle is the same, but contrary to MB, NB can also target receptors and other molecules outside the endothelium due to their possible extravasation to the tumor tissue (Figure 3). Functional coupling of an antibody, in this case directed against the TAG-72 antigen overexpressed on several epithelial tumors, to polymer-coated NB and successful binding of those to cancer cells in vitro has been shown by Xu et al. (2010). The usefulness of such an approach for tumor treatment has also been demonstrated in vivo using HLA-G as a target for antibody-coupled polymer-NB (Zhang et al., 2014). The combination of HIFU and the local release of chemotherapeutics after bubble disruption was shown to strongly enhance apoptosis of tumor cells. Recently Jiang et al. (2015) presented a promising new construct for tumor imaging, improving the idea and the in vitro model of Liu et al. (2007). Their lipid-based NB were coupled to Herceptin® (Roche, Basel, CH), also known as trastuzumab, a therapeutic monoclonal antibody binding to Her-2, which is overexpressed in many breast tumors. They found a significant increase in NB-binding to the tumor in xenograft-models which are known to overexpress Her-2, but only little accumulation in tumor xenografts with low Her-2 expression. Targeted NB in Her-2 overexpressing tumors also had an increased washout half-time, enabling longer observation times. Additionally, their bubble-construct was found to be of a low cytotoxicity (Jiang et al., 2015). To this date, this might be the approach being the closest to clinical studies. Herceptin® has also been conjugated to mesoporous silica nanoparticles and showed tumor-specific toxicity in vitro, suggesting further development of silica particles in the field of targeted imaging and drug delivery (Milgroom et al., 2014).

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