Particle-mediated transport, delivery

In addition to passive diffusion, channels, and carrier proteins, a fourth mechanism of breaching biological membranes is provided by vesicle-mediated transport, which can also be used for drug delivery. Endocytosis refers to the uptake of cell surface constituents by the formation of vesicles from the plasma membrane. This process can be subclassified into phagocytosis, the engulfment of particles, and pinocytosis, the engulfment of fluid. 

The TAT peptide derived from HIV-TAT is a frequently used CPP (Torchilin, 2008) that has been conjugated to Uposomes to improve the intercellifiar delivery of therapeutic loads (Kale and Torchilin 2007 Marty et al., 2004 Oba et al., 2007 Torchilin et al., 2003 Tseng et al., 2002). For example. Kale and Torchilin formulated a stealth liposomal delivery system with TAT conjugated on the sirr-face of the particles. TTie liposomes were delivered to the tirmor sites by the EPR effect and lost their PEG coating in the low pH tumor environment thus exposing the underlying TAT peptides, which were then able to mediate transport into the tumor cells (Kale and Torchihn, 2007). 

The first purified and characterized drug substances were administered as aerosols as a topical treatment for asthma approximately 50 years ago. More recently, drugs have been evaluated for systemic delivery. For each category of drug the mechanism of clearance from the airways must be considered. These mechanisms may be listed as mucociliary transport, absorption, and cell-mediated translocation. The composition and residence time of the particle will influence the mechanism of clearance. 

Since the uptake of particles in nasal epithelial tissue is known to be mostly mediated by M cells, nasal administration has been investigated as a noninva-sive delivery of vaccines [37], However, since the uptake of naked DNA by endocytocis is limited, use of either nanoparticles as mucosal delivery systems [37] or hypotonic shock [38] is reported for the efficient transfection of gene and vaccine into the nasal epithelium. It was also reported that polypeptides and polypeptide-coated nanospheres (diameter about 500 nm) are transported through endocytic process in rat M cells [39],... 

HDL, like LDL, is a cholesterol-rich particle, and is distinct from the other lipoprotein classes in that it does not contain apoB. HDL levels are inversely correlated with risk for atherosclerosis (Wilson et al., 1988). Nascent HDL particles are produced by direct synthesis (Hamilton, 1984), and excess surface remnants from chylomicrons and VLDL produced during the action of lipoprotein lipase (as noted above) enter the HDL density class. HDL appears to be involved in delivery of cholesterol to steroidogenic tissues as well as the removal of excess cholesterol from peripheral tissues and excretion from the system. This HDL-mediated removal of cholesterol has been termed reverse cholesterol transport (Glomset, 1968). Although apolipoproteins present in HDLs are cleared by the liver, the reverse cholesterol transport pathway has never been directly demonstrated. HDL can remove cholesterol from tissues, a process that may be partially mediated by interaction with a putative HDL receptor, with apoA-I as the ligand for that receptor (Oram el ai, 1983). The existence of an HDL receptor remains controversial saturable HDL binding may not be mediated by a specific apolipoprotein ligand and may not even be required for transfer of cholesterol from cells to... 

As far as HDL levels and metabolism are concerned, one result of the LCAT- and transfer protein-catalyzed reactions is the production of a dynamic spectrum of particles with a wide range of sizes and lipid compositions (Chapter 19). Nascent HDL particles contain mostly apo A1 and phospholipids, and undergo modulation and maturation in the circulation. For instance, the unesterified cholesterol incorporated into plasma HDL is converted to cholesteryl esters by LCAT, creating a concentration gradient of cholesterol between HDL and cell membranes, which is required for efficient cholesterol efflux from cells to HDL. In addition, cholesteryl ester transfer protein transfers a significant amount of HDL cholesteryl ester to VLDL, IDL, and LDL for further transport, primarily to the liver. Thus, a substantial fraction of cell-derived cholesterol is delivered as part of HDL indirectly to the liver via hepatic endocytic receptors for IDL and LDL this process is termed reverse cholesterol transport . However, receptor-mediated delivery of HDL cholesterol to cells is fundamentally different from the classic LDL receptor-mediated endocytic pathway, as described in Section 7.3.2. 

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