ABSTRACT
The last decade has seen substantial progress in the development and application of various strategies for the targeted delivery of therapeutic agents to the pulmonary endothelium. However, many problems remain to be solved before these strategies can be used in clinical applications. This chapter describes the in vivo and cellular barriers to pulmonary endothelium targeting. Its application in the targeted delivery of various types of therapeutics, particularly protein and gene therapeutics, is also discussed. 7.1 IntroductionPulmonary drug delivery is an important strategy for the treatment of various human diseases, including lung diseases. Drugs can be delivered to the lung via either the airway or the vascular route depending on the disease under study. Airway delivery has been
employed for the treatment of respiratory tract infections, asthma, and chronic obstructive pulmonary diseases and has an obvious advantage of concentrating the administered agents at the site of action and reducing the undesired systemic effects [1-3]. In addition to lung diseases, aerosol has also been explored as a possible route of administration for the treatment of systemic diseases (e.g., diabetes mellitus) due to the large alveolar surface area, excellent blood perfusion, and a thin alveolar-capillary barrier [3]. Recently, there has also been increased interest in developing strategies for the targeted delivery of various types of imaging and therapeutic agents to pulmonary endothelial cells (ECs), including conventional drugs, radioisotopes, protein therapeutics, therapeutic siRNA, and genes. These studies have important implications as endothelial dysfunction plays an important role in a number of pulmonary diseases, such as pulmonary hypertension, adult respiratory distress syndrome, and metastatic disease to the lung. On the other hand, lung ECs are also an attractive site as the “expression factory” for production and secretion of various types of therapeutic proteins into circulation due to their large surface area. The success of these applications, however, is largely dependent on the development of a vehicle that is capable of efficient delivery of different types of therapeutics with minimal toxicity. The delivery of therapeutic agents to the pulmonary circulation can be achieved via passive or active targeting. This chapter will discuss the pulmonary physiology that affects drug delivery to the pulmonary circulation. Special emphasis will be placed on a discussion of strategies that have been developed for the delivery of different types of therapeutics to the pulmonary circulation. 7.2 Pulmonary Endothelium as a Target for
7.2.1 Physiological Functions of Lung ECsThe pulmonary endothelium is a thin layer of ECs that lines the luminal surface of blood vessels. The ECs act as a semiper-meable barrier between blood and underlying tissue, controlling the passage of materials and the transit of white blood cells into and out of the bloodstream. The vascular endothelium is also a metabolically
active tissue that regulates the metabolism and/or generation and release of various types of biologically active substances and, therefore, is critically involved in many physiological processes such as regulation of vascular tone and maintenance of a normal balance between coagulation and fibrinolysis systems [4]. Furthermore, pulmonary ECs are also involved in the immunological and inflammatory responses in the lung [5] The function of the pulmonary endothelium is subjected to alterations in various disease conditions, including hyperoxia, hypertension, smoke, dust inhalation, pneumonia, cardiac failure, sepsis, thrombosis, diabetes, and cancer [6]. Thus, the pulmonary endothelium is an important target for the treatment of both pulmonary and systemic diseases. The targeted delivery of therapeutics to the pulmonary endothelium could improve the therapeutic effects and minimize the untoward side effects.
