Circulation of a drug encapsulated in a vehicle or conjugated with a carrier creates a relatively homogenous level in the blood. Only a small fraction accumulates in the area of therapeutic interest. One approach to improve delivery of a drug to vascular areas of interest is to load it into large vehicles (e.g., microspheres with diameters 20 to 50 mm) that mechanically lodge in the precapillary arterioles, creating an elevated local level of a drug or imaging agent. For example, clinically used albumin microspheres labeled with technetium-99, indium-111, or other isotopes can be visualized in a gamma-camera and thus help to image perfusion of blood vessels downstream from the injection site: pulmonary circulation after injection via intravenous route, coronary or cerebral vasculature after injection via the coronary or carotid artery routes, or other microvascular beds after infusion into afferent arteries.
A similar principle, lodging in the precapillary and capillary vascular bed in an organ of interest, is being also explored in the context of gene therapy. Thus, cationic liposomes complexed with negatively charged plasmid DNA rapidly form multimicrometer aggregates in blood, which lodge downstream the injection site. This technique has been employed for a transgene expression in the lungs and in angiogenic endothelial cells in tumors . Further, infusion via vascular catheters inserted in the arteries supplying a pathologically altered organ creates a high local level of therapeutics or genetic materials, promoting their delivery to or beyond endothelium in the area of interest.
However, mechanical or electrostatic retention of small aggregates affords no selective delivery of cargoes into certain cell types (e.g., endothelial cells), nor any control over subcellular localization of the delivered cargoes. In addition, perfusion rapidly removes drugs released from a lodged vehicle or carrier, reducing the time of contact with target cells that is necessary for binding and uptake. In some cases, use of the catheters permitting temporarily cessation of perfusion in the site of delivery helps to circumvent this problem. However, interruption of blood flow creates ischemia and activates flow-sensitive endothelium, causing potentially harmful side effects.
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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.