A „NUMERICAL“STUDY OF PULMONARY DRUG DELIVERY

The lungs are the vital organs in charge of delivering oxygen to the cells. At the same time they also protect the organism from many threats contained in the air such as pollutants and pathogens. The mechanism by which these functions are achieved is extraordinarily complex to be explained in short, nevertheless, some numbers might aid to highlight the process that is taking place, right now, within your lungs.

An average adult human breathes 15 times per minute and inhales approximately500 mililiters of air with each breath, meaning that at least 10.800 liters of air are inhaled (and exhaled) every day by each of us(note that this just refers to resting conditions). With each breath the inhaled air-stream goes through the upper airways (nose, mouth and throat) and reaches the trachea, which branches dichotomously into the two main bronchi, which divide as well into two further bronchi, and so on over more than 20 generations of conducting airways.Finally, the air-stream reaches the alveoli in the deep lung, where the gas exchange occurs. There are approximately 300 million alveoli in the lung andeach one has a radius of about 0.05milimeters (mm).  Adding the surface area of each alveolus will result in a total gas exchange area of about 100 square meters, which represents, more or less, the surface area of a tennis court. Besides a large area, the so called air-blood barrier is very thin. In the alveoli, the air and the blood are just separated by 0.0002 mm, a thickness 50 times smaller than that of a regular paper sheet. By this mechanism the partial pressures of oxygen and carbon dioxide remain constant in our arteries in a range of 80-110 and 35-45 mm of mercury respectively(check these values if you get a gasometry!).

With such a huge surface area the lungs represent an appealing route for drug delivery. With current aerosol generating devices particles in the range between 1-5 micrometers (0.001-0.005 mm)are transported together with the air-stream into the deep lung. However, only 10-20% of the produced microparticles deposit within the lungs and the remaining 80-90% impacts on the mouth and throat, or is released to the ambient air.

In addition, the lungs are equipped with efficient defense mechanisms that filter and remove many of the inhaled particles. The conducting airways are coated with a layer of pulmonary mucus that varies in thickness from 8 micrometers (0.008 mm) in the trachea to 3 micrometers (0.003 mm) in the terminal bronchiand acts as a potent filter for inhaled particulates. The alveoli, on the other hand, are coated with a very thin surfactant layer of 0,07 micrometers (0.00007 mm)and eachone is patrolled by 10-12 macrophages, which are defensive cells with the ability to efficiently phagocytize and remove microparticles in the range between 1-5 micrometers (0.001-0.005 mm).  Multiplying the number of macrophages by the number of alveoli the approximate macrophage army consists of 3,000 million units.

Unfortunately, the defense mechanism of the lungs cannot distinguish between good and bad particulates and tends to clear them form the airways irrespective of if they are pathogens or therapeutics. A new approach in pulmonary drug delivery proposes the use of nanotechnology as a tool to design “intelligent” particles that might in part sidestep the pulmonary defenses.  With this technology very small particles with a size ranging between 10 and 500 nanometers (0.00001 mm and 0.0005 mm) can be developed and loaded with therapeutic molecules. This way, modifying their size, shape and/or they coating, therapeutic nanoparticles have the potential to improve the efficacy of many inhaled therapeutics as well as to settle the basis for new treatments designed to pulmonary and non-pulmonary diseases.

In this regard, one of our aims within the PathChooser project is to investigate the complex pulmonary barriers as we believe that understanding the way that these defense mechanisms work, a path through the pulmonary barriers can be found for novel therapeutic nanopharmaceuticals, while the lungs take good care by itself of the potential threats contained in the inhaled air.

Xabier Murgia Esteve, PathChooser Fellow, HZI

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