Drug Targeting Organ-Specific Strategies

82 3 Pulmonary Drug Delivery: Delivery To and Through the Lung
i.v. injection, all drug conjugates will encounter the endothelial lining of the lungs. Using a
carrier consisting of a cationic polymer polyethylenimine and anti-PECAM-1 antibody, Li
and colleagues were able to selectively deliver model plasmid DNA into pulmonary endothelium.This
was associated with a decrease in circulating TNFα levels as compared to the
levels seen with the injection of polyethylenimine/plasmid, indicating less toxic side-effects of
the targeted strategy [142]. Using a similar approach with anti-PECAM-1 antibody, the enzyme
glucose oxidase was selectively delivered to the pulmonary endothelium serving as a
model for oxidative pulmonary vascular injury [143].
In general, when the cells of the endothelium in the lungs are the target cells of interest
(see Chapters 7 and 9 on aspects of targeting drugs to endothelium in inflammatory diseases
and cancer, respectively), systemic administration seems the route of choice. Bronchial epithelium
on the other hand can more easily be reached via the pulmonary route. The accessibility
of other cells in the lungs is most likely governed by disease conditions, factors that can
affect epithelial permeability and vascular permeability, and others as described earlier.
3.13 Final Conclusions and Perspectives
Pulmonary drug administration is likely to become a rapidly growing field in drug delivery
over the next two decades. Its potential to serve as a port of entry for the systemic administration
of peptides and proteins makes this route an attractive choice for many of the compounds
evolving from the rapidly growing field of biotechnology. However, many of the exciting
possibilities that have been described over past years, lack sufficient substantiation at
this time. Much experimental work is still required for many products in development before
they can be introduced as a pulmonary dosage form that guarantees reproducible delivery
through the lung.
Too often results are compromised by a poor experimental set-up of the studies and nontransparent
data. Even essential information such as the relevant physicochemical characteristics
of the drug in relation to the chosen aerosol system or the fraction that is deposited
in the alveoli is often not provided. This makes it impossible to evaluate the impact of such
studies. As a result, it is unclear until now to what extent and at what rate macromolecular
drugs (> 20 kDa) can be absorbed by the lung. Moreover, the routes by which macromolecules
pass through the different pulmonary membranes, especially the alveolar membrane,
are unknown. Appropriate experiments and models that provide adequate answers to these
questions are required in the coming years.
With regard to the systemic administration of smaller proteins (