Stealth liposomes, protein carriers, and other delivery systems prolong the circulation time of drugs and may enhance their cellular uptake, but do not confer an affinity to vascular endothelium. Thus, the major fraction of injected materials ends up in the liver, not in the endothelial cells. In order to facilitate targeting, cargoes or their carriers can be conjugated with affinity moieties that bind to endothelial cells. Immunostaining of tissues, in vivo selection of peptide ligands using phage display, and tracing labeled antibodies in animals helped to identify endothelial determinants potentially useful as targets [4-6].
No universal or ideal affinity carrier, however, suits all therapeutic needs. Specific therapeutic goals require different secondary effects mediated by binding to the endothelium, drug targeting to different subpopulations of endothelial cells (e.g., resting versus inflammation-engaged endothelium), and to diverse cellular compartments. Targeted delivery of antioxidants, antithrombotics, or NO donors to normal or resting endothelial cells can be useful for either prophylaxis or therapies. On the other hand, specific recognition and drug delivery to abnormally activated or pathologically altered endothelium might permit more specific means for treatment of such maladies as localized tumor growth and inflammation. Inhibition of some endothelial antigens leads to harmful adverse effects. For example, blocking a constitutive endothelial antigen throm-bomodulin may aggravate thrombosis. In addition, pathological conditions suppress expression of some endothelial antigens.
The pulmonary vasculature comprises a preferred target for vascular drug delivery to endothelium, because (i) it is the first major capillary network encountered by intravenously injected drugs; (ii) it contains roughly one-third of the endothelium in the body; (iii) it is exposed to the entire cardiac output of venous blood; and (iv) a relatively slow blood perfusion rate through high-capacity, low-resistance pulmonary vessels kinetically favors binding of ligands to endothelium. Therefore, affinity carriers recognizing panendothelial determinants (e.g., antibodies directed against constitutive cell adhesion molecules) tend to accumulate in the lungs after systemic administration. Because of its accessibility to external insults from the airways and its function as a filter for blood clots, debris, activated white blood cells, drugs, and toxins, pulmonary vasculature represents an important therapeutic target [S].
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.