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New imaging technology for optimization of pulmonary drug delivery in patients

Inhalation therapy is widely used for the treatment of lung diseases. Targeting of drugs to the site of disease is a major goal to improve drug efficacy and minimize side effects. Scientists at the Helmholtz Zentrum München and the Technical University of Munich have now shown that combined insight from various imaging methods allows for real-time monitoring of the dynamic process of drug delivery and high-resolution visualization of the pulmonary drug distribution in murine lungs. This new technology provides guidance on optimizing pulmonary delivery techniques and designing novel nanoparticle-based therapeutics. The paper was published in SMALL journal.

Depiction of targeted drug delivery to the left half of the lung visualized by propagation-based phase contrast imaging using brilliant X-ray from the Munich Compact Light Source (PB-PCXI) and light sheet fluorescence imaging (LSFM). If required, we can also provide an LSFM with much higher resolution (down to cellular resolution). © Helmholtz Zentrum München, ILBD / CPC, Dr. Otmar Schmid

Optimizing drug delivery to the lung begins with understanding the dynamic process of drug delivery.  While the underlying mechanisms are generally well known for aerosol inhalation, this is not the case for non-aerosol based methods, which are even more widely used in preclinical lung research. By visualizing the process of drug delivery in real-time, the team of researchers unveiled the specific mechanisms of drug delivery and their implications for drug distribution in a preclinical animal model. These findings open new avenues for optimization of pulmonary drug delivery in patients.          

The imaging platform presented in this new technique consists of five preclinical imaging methods relying on propagation-based phase contrast X-ray imaging (PB-PCXI; two modes) and fluorescence imaging techniques (three modes). When delivering a mixture of nanoparticle-based contrast agents for X-ray and fluorescent imaging, the former can be used to visualize in real-time the dynamic delivery process in living mice, while the latter reveals the quantitative, three-dimensional drug/nanoparticle distribution profile at cellular resolution in ex vivo lungs.

Targeted and accelerated testing
The complementary information obtained from this imaging platform has revealed the previously unknown exact mechanisms of pulmonary drug delivery for intratracheal instillation and nasal aspiration. Moreover, it has revealed the reason for unexpected dose “hot-spots” in murine lungs after ventilator-assisted aerosol inhalation. With this technology novel concepts of targeting drugs to specific regions of the lung can be studied on live animals. It optimizes drug delivery techniques due to immediate information on the success (or failure) of novel drug delivery methods such as nanoparticle-based therapeutics. This is expected to expedite preclinical testing. After optimization in animal models these concepts will be translated into improved therapeutic outcome of inhalation therapy in patients. 

Marriage of two cutting edge technologies
This research demonstrates successful marriage of two cutting edge imaging technologies for preclinical studies of the lung, namely propagation-based phase contrast X-ray imaging (PB-PCXI) utilizing the Munich Compact Light Source (MuCLS) and light sheet fluorescence imaging (LSFM) which was established at the Munich School of BioEngineering at TUM lead by Prof. Franz Pfeiffer and the Helmholtz Zentrum München lead by Dr. Otmar Schmid, respectively. This research was partially supported through the EU Horizon 2020 project SmartNanoTox, grant agreement no. 686098

 

Original publication:
Yang, L. et al., 2019: Multimodal precision imaging of pulmonary nanoparticle delivery in mice: Dynamics of application, spatial distribution, and dosimetry. SMALL, DOI: 10.1002/smll.201904112

Video (Instillation2-crop.gif)
Real-time monitoring of the dynamic process of drug delivery via intratracheal of bulk liquid into the lungs of mice (fast motion). Initially, a small volume of bulk liquid is dripping (or squirted) into the upper bronchial region where it accumulates until it eventually blocks one of the main airways. Once this happens (here at ca. 20 s), the bulk liquid gets sucked into the lung with the next breath yielding a relatively uniformly distributed throughout the lung (here no regional targeting was intended). Visualization is based on propagation-based phase contrast imaging using brilliant X-ray from the Munich Compact Light Source (PB-PCXI) © Gradl & Pfeiffer, TUM

 

 

 

 

 

 

 

 

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