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28.02.2020

New imaging technology for optimization of pulmonary drug delivery in patients

Lung diseases such as COPD, asthma or infections have long been efficiently treated with drugs inhaled by patients. In future, other drugs will be administered in this way. Anti-cancer drugs for example in which the active substance is bound in nanoparticles.

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). © Helmholtz Zentrum München

"Such nanoparticle-based drugs have numerous advantages," explains Otmar Schmid, group leader at the ILBD. "For example, the active ingredients are not so easily broken down enzymatically because they are embedded in the nanoparticle. In addition, the nanoparticles can be directed specifically to the diseased cells if ligands are attached to them that dock to these cells". This would enable the drug's effect to be better focused on the diseased tissue, which would considerably reduce the side effects.
Researchers in Otmar Schmid's research group, together with colleagues at the Munich School of BioEngineering (MSB) at the Technical University of Munich (TUM), have now presented a combination of imaging methods that can be used to show in detail how the distribution of drugs in the lungs of a mouse depends on the way the drugs have been administered. The results of such investigations should provide important insights for the development of pulmonary drugs for humans. The findigs were published in SMALL journal.

Targeted and accelerated testing
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. 
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

Further information:As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,500 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.

The Comprehensive Pneumology Center (CPC) is a joint research project of the Helmholtz Zentrum München, the Ludwig-Maximilians-Universität Clinic Complex and the Asklepios Fachkliniken München-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnosis and therapy strategies. The CPC maintains a focus on experimental pneumology with the investigation of cellular, molecular and immunological mechanisms involved in lung diseases. The CPC is a site of the Deutsches Zentrum für Lungenforschung (DZL).