Design of most drug or gene delivery strategies pursues protection of therapeutic cargoes from inactivation en route, reduction of interaction with nontarget cells, and providing a sufficient circulation time to permit accumulation in the target . These goals can be achieved by loading of therapeutic cargoes into vehicles, either natural (blood cells, albumin, lipoproteins, viruses) or artificial (polymers, liposomes, nanoparticles). Vehicles separating cargoes from blood (polymer shells, liposomes) help to minimize their systemic adverse effects. In general, the diameter of vehicles and carriers for drug and gene delivery in microvascu-lature is less than 300 to 500nm, that is, a size that provides free circulation through capillaries in the vascular system and, in some cases, permits intracellular delivery into endothelial cells.
Liposomes, bilayer vesicles formed from phospholipids, represent versatile vehicles (size from 50 nm to microns) and are good carriers for small hydrophobic drugs [1, 2]. Liposomes containing positively charged phospholipids (cationic liposomes) are potentially useful for gene delivery, since they form condensed complexes with DNA, thus protecting it from inactivation and facilitating intracellular delivery [1, 3]. Micro- (0.5- to 50-|mm diameter) and nano-(100 to 500 nm diameter) vehicles and carriers consisting of biocompatible, biodegradable polymers [e.g., poly (lactic acid)] are being designed for drug delivery . Delivery of anticancer agents due to enhanced permeation of tumor vas-culature and prolonged retention of extravasated materials in the tumor due to poor lymphatic drainage is an active area of exploration for polymer nanocarriers loaded with antibiotics. Loading of large doses of active large hydrophilic drugs (e.g., proteins) into liposomal or polymer vehicles is a more challenging and not fully accomplished goal.
Unless specific countermeasures are undertaken, some drugs and most drug vehicles and carriers are rapidly cleared from the bloodstream and activate host defense systems. For example, complement activation may cause liposome destruction, uptake by phagocytes, and generation of proinflammatory mediators (e.g., cytokines). These concerns are especially acute when antibodies are used for vascular targeting, since their Fc fragments initiate defense reactions including activation of complement, blood cells, and phagocytes. Macrophages have receptors for Fc fragments of immunoglobulins and components of complement that serve for docking and endocytosis of objects coated (opsonized) with antibodies or complement. Macrophages in the liver, bone, and spleen have good access to circulation and effectively eliminate liposomes, viral particles, and even larger drug vehicles (several micrometers in diameter).
Elimination of interaction with Fc receptors, attainable by utilization of antigen-binding domains of antibodies (Fab and single-chain, scFv fragments) helps to reduce some of these untoward effects and prolong circulation time. On the other hand, attachment of poly(ethylene glycol) (PEG, a hydrophilic linear polymer) to proteins, liposomes, polymers, and viral particles creates a "PEG brush" on the surface of these carriers. PEG attracts water, which prevents aggregation of particles and reduces their accessibility for antibodies, complement, phagocytes, and immune cells. PEG-ylation markedly prolongs circulation time of drugs and drug-carrier complexes and minimizes immune reactions and other side effects associated with recognition by host defense—"stealth technologies" . A few types of FDA-approved stealth PEG liposomes are currently in clinical studies. The stealth effect increases proportionally to length and number of PEG molecules attached to a protein, DNA, or liposome; the more dense the PEG brush, the more profound the stealth effect. However, an excessive PEG coupling inactivates protein and genetic therapeutic agents, whereas incorporation of PEG moieties into more than 10 percent of liposomal phospholipids destabilizes lipid bilayer and destroys liposomes. Design of synthetic, totally PEG-coated vesicles consisting of di-block PEG copolymers with structural biocompatible polymers such as poly(lactic acid) is an attractive novel technological avenue to produce inert, long-circulating vehicles for drug delivery.
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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.