Conclusions And Future Directions

The continuing development of targetable drugs to the respiratory tract looks promising. Much emphasis will probably be focused on the respiratory tract as a suitable entry point for proteins and peptides for delivery into the systemic circulation. The use of macromolecule- and monoclonal antibody-drug conjugates will almost certainly increase with the advent of new polymer technology and the availability of human monoclonal antibodies. However, these advances may well be tempered unless parallel progress is made in other important areas. One area that has received relatively little attention is establishing the distribution of metabolizing enzymes throughout the respiratory tract. An in-depth study of the distribution of pulmonary metabolizing enzymes is necessary to achieve a greater cellular selectivity by the activation of appropriately designed prodrugs or drug conjugates in the vicinity of the target cell or a more efficient inactivation to minimize the systemic absorption of the drug.

A greater emphasis will also need to be placed on elucidating epithelial membrane transport mechanisms, especially with regard to improving the epithelial transport of macromolecules. Studies are presently focusing on the microstructural aspects of macromolecular transport across pulmonary epithelia; the results of these investigations will certainly be of value in pulmonary drug-targeting strategies. The discovery of new epithelial and endothelium membrane receptors and of selective materials for binding or adhering to these receptors will also aid in the targeting of drugs to the respiratory tract.

Specific targeting of drugs to other pulmonary targets, such as the alveolar macrophages, which lie in contact with the surfactant lining of the alveoli [234] and which have well-defined surface membrane receptors for initiating particle attachment and phagocytosis [235], may also be exploitable for improving selectivity. If one considers the inhalation route as a means for delivery of drugs to the systemic circulation, then inhaled drugs must enter the circulatory system principally by diffusion or transport across the alveolar capillary membrane. Drug molecules will, therefore, come into contact with the alveolar membrane, the alveolar epithelial cells, the capillary endothelial cells, and other "residents" of the pulmonary circulation, such as the pulmonary intravascular macrophages (PIMs).

These PIMs have been considered a cellular target of potential utility for inhaled drugs [164]. These cells reside in "thick" portions of the pulmonary capillaries and are attached to the capillary endothelium by an electron-dense membrane-adhesive complex. It is likely that such cells would be exposed to high concentrations of inhaled drugs. The PIM cell density appears to increase with pathological stimuli; thus, acute lung injury or lung infection augments the lung burden of PIMs and raises the question of the role of this cell type in the development of lung injury.

Gillespie et al. [164] suggested that microparticulate delivery systems given by intravascular administration might be targeted to PIMs. This suggestion is based on these investigators' observation that particles exceeding 7 mm are often retained in the lung, while smaller particles localize in the liver and spleen. The sequestering in the lung is associated with pulmonary hypertension and lung injury, and, in some cases, it is not related to particle size. Thus, lung sequestering of particles was speculated to be a result of phagocytosis by PIMs and that this could be sued as a means of targeting conventional drug entities, synthetic genes, or antisense oligonucleotides that could perturb PIM function. Any PIMs that have sequestered particulate drug-delivery systems may serve as depots for the release of drug entities into the circulation.

Thus, the future of pulmonary drug targeting is promising, and although drug discovery efforts will no doubt lead to the development of agents with greater selectivity for pulmonary receptors, a greater emphasis will be placed on cell targeting and the development of new macromolecular vectors and cellular targets for this purpose.

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