A. Cellular Uptake and Processing:
Following administration, a drug frequently passes through various cells, membranes and organs to reach its target sites. These pathways offer opportunities for cell selection and access by targeted drug delivery.
Low-molecular-weight drugs can enter into, or pass through, various cells by simple diffusion processes. Targeted drug delivery systems often comprise macromolecular assemblies, and are unable to enter into cells by such simple processes. Instead, they are captured by a process called endocytosis. Endocytosis is defined as a phenomenon that involves internalization of the plasma membrane, with concomitant engulfment of the extra cellular material (particulate or fluid). This process can be constitutive or nonconstitutive. Other methods of gaining access to cells include passive diffusion, membrane fusion, and binding to either specific or nonspecific regions of the cell.
Endocytosis is divided into two types: phagocytosis and pinocytosis. The former refers to the capture of particulate matter, whereas the latter represents engulfment of fluids. Phagocytosis is carried out by specialized cells of the mononuclear phagocyte system (MPS), called phagocytes. It is mediated by the absorption of specific blood components [e.g. immunoglobulin (Ig) G, complement C3b, and fibronectin], called opsonins, and relevant receptors located on macrophages. The extent to which a drug is opsonized, and by what plasma protein depends on the size and surface characteristics of the particles. This, in turn, determines the engulfment mechanism.
Following ingestion, the phagocytic vacuole (or phagosome) fuses with one or more lyososomes to form phagolysosomes (or secondary lyososomes); It is here that the digestion of particles by lyososomes acid hydrolases (e.g. protemases, glycosidases, nucleases, phospholipases, phosphatases, and sulfatases) occurs, making the drug available to exert its therapeutic effect. The internal pH of lysozomes is between 4.5 and 5.5.
Unlike phagocytosis, which is mediated by the serum opsonin, pinocytosis does not require any external stimulus. Pinocytosis is divided into two types; fluid phase pinocytosis and adsorptive pinocytosis. Fluid-phase pinocytosis is a nonspecific, continuous process, and is a general process for transporting macromolecular constructs through epithelia, some endothelia, and into various blood cells. Adsorptive pinocytosis, in contrast, refers to internalization of macromolecules that bind to the cell surface membrane. If the macromolecule adheres to a general cell surface site, then uptake is referred to as simply nonspecific pinocytosis. However, if it binds to a specific cell receptor site, then the process is called receptor-mediated pinocytosis.
Once internalized the pinocytosis vesicles interact among themselves or with vesicles of other intracellular origins such as endosomes and lysozomes.
B. Transport across the epithelial barrier:
The oral, buccal, nasal, vaginal and rectal cavities are all internally lined with one or more layer of epithelial cells. The transport of macromolecules across the intestinal epithelium may occur by cellular vesicular process by either fluid-phase pinocytosis or specialized (receptor-mediated) endocytotic process.
C. Extravasation :
Many diseases are known that result from the dysfunction of cells located outside the cardiovascular system. Thus, for a drug to exert its therapeutic effects, it must egress from the central circulation and interact with its extravascular-extracellular or extravascular-intracellular target(s). This process of transvascular exchange is called extravasation, and it is governed by the permeability of blood capillary walls. The main biological features that control permeability of capillaries include the structure of the capillary wall, under normal and (patho) physiological conditions, and the rate of blood and lymph supply. Physicochemical factors that are of prohydrophilic-lipophilic balance (HLB) characteristics.
D. Lymphatic Uptake:
Following extravasation, the drug molecules can either reabsorb into the blood stream directly by the enlarged postcapillary interendothelial cell pores found in most tissues or enter into the lymphatic system and then return with the lymph to the blood circulation.