Limits...
Theranostic mRNA-loaded microbubbles in the lymphatics of dogs: implications for drug delivery.

Dewitte H, Vanderperren K, Haers H, Stock E, Duchateau L, Hesta M, Saunders JH, De Smedt SC, Lentacker I - Theranostics (2015)

Bottom Line: Our results indicate that both types of microbubbles are equally capable of rapidly entering the lymph vessels and nodes upon injection, and novel, valuable and detailed information on the lymphatic structure in the animals could be obtained.Importantly, neither the microbubble migration distance within the lymphatics, nor the observed contrast signal intensity was influenced by mRNA-loading.Although further optimization of acoustic parameters will be needed, this could represent a first step towards ultrasound-guided, ultrasound-triggered intranodal mRNA delivery using these theranostic microbubbles.

View Article: PubMed Central - PubMed

Affiliation: 1. Laboratory for General Biochemistry and Physical Pharmacy, Faculty of Pharmacy, Ghent University, Ghent, Belgium;

ABSTRACT
Microbubbles have shown potential as intralymphatic ultrasound contrast agents while nanoparticle-loaded microbubbles are increasingly investigated for ultrasound-triggered drug and gene delivery. To explore whether mRNA-nanoparticle loaded microbubbles could serve as theranostics for detection of and mRNA transfer to the lymph nodes, we investigate the behavior of unloaded and mRNA-loaded microbubbles using contrast-enhanced ultrasound imaging after subcutaneous injection in dogs. Our results indicate that both types of microbubbles are equally capable of rapidly entering the lymph vessels and nodes upon injection, and novel, valuable and detailed information on the lymphatic structure in the animals could be obtained. Furthermore, additional observations were made regarding the dynamics of microbubble lymph node uptake. Importantly, neither the microbubble migration distance within the lymphatics, nor the observed contrast signal intensity was influenced by mRNA-loading. Although further optimization of acoustic parameters will be needed, this could represent a first step towards ultrasound-guided, ultrasound-triggered intranodal mRNA delivery using these theranostic microbubbles.

Show MeSH
Burst destruction of intranodal microbubbles. After visualization of unloaded microbubble drainage, the scanner's burst function was used to destroy the microbubbles within the lymphatics. Images show (A) CEUS image with a ROI drawn around a lymph node filled with mRNA-loaded microbubbles and (B) the corresponding B-mode image. Burst analysis is represented in (C) as the echo mean (dB), where each burst is visible as an echo mean peak, followed by a reduction of the contrast echo mean. Time after mRNA-loaded microbubble injection is noted on the CEUS images (in min:s).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4265751&req=5

Figure 7: Burst destruction of intranodal microbubbles. After visualization of unloaded microbubble drainage, the scanner's burst function was used to destroy the microbubbles within the lymphatics. Images show (A) CEUS image with a ROI drawn around a lymph node filled with mRNA-loaded microbubbles and (B) the corresponding B-mode image. Burst analysis is represented in (C) as the echo mean (dB), where each burst is visible as an echo mean peak, followed by a reduction of the contrast echo mean. Time after mRNA-loaded microbubble injection is noted on the CEUS images (in min:s).

Mentions: Keeping in mind the final aim of the mRNA loaded microbubbles, namely the ultrasound-triggered delivery of mRNA to DCs that reside within the lymph nodes, we tested whether intranodal mRNA-loaded microbubbles could indeed be imploded by applying higher-intensity ultrasound bursts. For this, we used the scanner's preset burst function, and looked at the decrease in mean echo contrast intensity within the lymph node. As shown in Figure 7, with each burst, the microbubble echo intensity was reduced, reaching a minimum after 6 bursts. A video of this burst destruction can be found in supplementary data (Additional file 4: supplementary video 4).


Theranostic mRNA-loaded microbubbles in the lymphatics of dogs: implications for drug delivery.

Dewitte H, Vanderperren K, Haers H, Stock E, Duchateau L, Hesta M, Saunders JH, De Smedt SC, Lentacker I - Theranostics (2015)

Burst destruction of intranodal microbubbles. After visualization of unloaded microbubble drainage, the scanner's burst function was used to destroy the microbubbles within the lymphatics. Images show (A) CEUS image with a ROI drawn around a lymph node filled with mRNA-loaded microbubbles and (B) the corresponding B-mode image. Burst analysis is represented in (C) as the echo mean (dB), where each burst is visible as an echo mean peak, followed by a reduction of the contrast echo mean. Time after mRNA-loaded microbubble injection is noted on the CEUS images (in min:s).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4265751&req=5

Figure 7: Burst destruction of intranodal microbubbles. After visualization of unloaded microbubble drainage, the scanner's burst function was used to destroy the microbubbles within the lymphatics. Images show (A) CEUS image with a ROI drawn around a lymph node filled with mRNA-loaded microbubbles and (B) the corresponding B-mode image. Burst analysis is represented in (C) as the echo mean (dB), where each burst is visible as an echo mean peak, followed by a reduction of the contrast echo mean. Time after mRNA-loaded microbubble injection is noted on the CEUS images (in min:s).
Mentions: Keeping in mind the final aim of the mRNA loaded microbubbles, namely the ultrasound-triggered delivery of mRNA to DCs that reside within the lymph nodes, we tested whether intranodal mRNA-loaded microbubbles could indeed be imploded by applying higher-intensity ultrasound bursts. For this, we used the scanner's preset burst function, and looked at the decrease in mean echo contrast intensity within the lymph node. As shown in Figure 7, with each burst, the microbubble echo intensity was reduced, reaching a minimum after 6 bursts. A video of this burst destruction can be found in supplementary data (Additional file 4: supplementary video 4).

Bottom Line: Our results indicate that both types of microbubbles are equally capable of rapidly entering the lymph vessels and nodes upon injection, and novel, valuable and detailed information on the lymphatic structure in the animals could be obtained.Importantly, neither the microbubble migration distance within the lymphatics, nor the observed contrast signal intensity was influenced by mRNA-loading.Although further optimization of acoustic parameters will be needed, this could represent a first step towards ultrasound-guided, ultrasound-triggered intranodal mRNA delivery using these theranostic microbubbles.

View Article: PubMed Central - PubMed

Affiliation: 1. Laboratory for General Biochemistry and Physical Pharmacy, Faculty of Pharmacy, Ghent University, Ghent, Belgium;

ABSTRACT
Microbubbles have shown potential as intralymphatic ultrasound contrast agents while nanoparticle-loaded microbubbles are increasingly investigated for ultrasound-triggered drug and gene delivery. To explore whether mRNA-nanoparticle loaded microbubbles could serve as theranostics for detection of and mRNA transfer to the lymph nodes, we investigate the behavior of unloaded and mRNA-loaded microbubbles using contrast-enhanced ultrasound imaging after subcutaneous injection in dogs. Our results indicate that both types of microbubbles are equally capable of rapidly entering the lymph vessels and nodes upon injection, and novel, valuable and detailed information on the lymphatic structure in the animals could be obtained. Furthermore, additional observations were made regarding the dynamics of microbubble lymph node uptake. Importantly, neither the microbubble migration distance within the lymphatics, nor the observed contrast signal intensity was influenced by mRNA-loading. Although further optimization of acoustic parameters will be needed, this could represent a first step towards ultrasound-guided, ultrasound-triggered intranodal mRNA delivery using these theranostic microbubbles.

Show MeSH