Drag targeting has been classified into three types: (i) first-order targeting—this describes delivery to a discrete organ or tissue, (»') second-order targeting—this represents targeting a specific cell type(s) within a tissue or organ (e.g., tumor cells versus normal cells and hepatocytic cells versus Kupffer cells), and (hi) third-order targeting—this implies delivery to a specific intracellular organelle in the target cells (e.g., lysosomes) (4). Basically, there are three approaches for drag targeting. The first approach involves the use of biologically active agents that are both potent and selective to a particular site in the body (magic bullet approach of Ehrlich). The second approach involves the preparation of pharmacologically inert forms of active drags, which, upon reaching the active sites, become activated by a chemical or enzymatic reaction (prodrug approach). The third approach utilizes a biologically inert macromolecular carrier system that directs a drag to a specific site in the body where it is accumulated and effects its response (magic gun or missile approach). Regardless of the approach, the therapeutic efficacy of targeted drug delivery systems depends on the timely availability of the drag in active form at the target site(s) and its intrinsic pharmacological activity. It is important that the intrinsic pharmacokinetic properties of the targeted delivery system be the same as that of the free drag. Figure 2 shows a schematic representation of possible anatomical and physiological pathways that a drug may follow to reach its target site(s) (5). As is depicted by this figure, a drag can selectively access, and interact with, its pharmacological receptors, either passively or by active processes. Passive processes rely on the normal distribution pattern of a drag-drag carrier system, whereas the active pathways use cell receptor-recognizing ligand(s) or antibodies ("homing" or "vector" devices) to access specific cells, tissues, or organs in the body. Various biological processes and events that govern drag targeting are briefly discussed in the following sections.
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