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"Blood volume taken as 6.5 mL/100 g body weight. bPercentage uptake at one hour. Source: From Ref. 13.

"Blood volume taken as 6.5 mL/100 g body weight. bPercentage uptake at one hour. Source: From Ref. 13.

polymerization of monomers and dispersion of preformed polymers. The former includes direct emulsion, micelle, and interfacial polymerization approaches. The emulsion polymerization method involves heating a mixture of monomer and active agent(s) in an aqueous or a nonaqueous phase that contains an initiator, a surfactant (employed usually in excess of its critical micelle concentration), and a stabilizer. Vigorous agitation is employed during the emulsion formation to produce particles smaller than 100 |im. The smaller particle size assures good tissue tolerance, uptake, and transfer, and causes no foreign body reaction. Examples of carrier systems prepared by the emulsion polymerization approach include poly(alkyl methacrylate) nanoparticles, which exhibit excellent adjuvant properties for vaccines (133), and poly(alkylcyanoacrylate) nanoparticles (134), which are biodegradable. The main advantage of emulsion polymerization is that higher molar mass polymers are usually formed at a faster rate and a lower temperature. A major disadvantage, however, is that the product cannot be readily freed from the residual monomers. Micellar polymerization differs from emulsion polymerization only in that the monomers and active agent(s) are contained within the micelles formed by a suitable concentration of a surfactant before the polymerization is commenced. This allows very little, if any, increase in particle size as polymerization proceeds. In interfacial polymerization, monomers react at the interface of two immiscible liquid phases to produce a film that encapsulates the dispersed phase. The process involves an initial emulsification step in which an aqueous phase, containing a reactive monomer and a core material, is dispersed in a nonaqueous continuous phase. This is then followed by the addition of a second monomer to the continuous phase. Monomers in the two phases then diffuse and polymerize at the interface to form a thin film. The degree of polymerization depends on the concentration of monomers, the temperature of the system, and the composition of the liquid phases.

Non-polymerization approaches commonly practiced to prepare microparticles and nanoparticles are polymer precipitation, solvent evaporation, and salting out methods. The precipitation method is used to encapsulate hydrophilic drugs and frequently yields particles with a narrow polydispersity index. The solvent evaporation approach is applicable to both hydrophobic and hydrophilic drugs. Typically, the polymer, optionally with a surface-modifying agent, is dissolved in an appropriate nonaqueous solvent (usually, methylene chloride, chloroform, or ethyl acetate). The drug is then dissolved or suspended in the solution and an oil-in-water (o/w) emulsion is prepared by mixing it with a large volume of water containing an emulsifier [e.g., polyvinyl alcohol) or a surfactant] under vigorous stirring (to produce smaller-size oil droplets). The solvent is then removed to produce the particles. To produce nanosize particles, a high-shear mixer, ultrasonicator, or microfluidizer can be used. Addition of a water-miscible organic solvent (e.g., acetone) has also been used to produce smaller-size particles. It has been suggested that the rapid diffusion of a water-miscible organic solvent into the aqueous and organic phases generates interfacial turbulence, which spontaneously results in a large interfacial area, leading to the formation of smaller-size droplets. Removal of the organic solvent produces the particles. One of the disadvantages of the o/w method is poor entrapment efficiency of the moderately and highly soluble drugs. To overcome this problem, an oil-in-oil (o/o) emulsion or a double emulsification (w/o/w) method can be used. The o/o type emulsion is prepared by using a volatile organic solvent and mineral oil. The w/o/w emulsion approach is especially useful for encapsulating large doses of hydrophilic drugs, peptides, proteins, and vaccines. The salting out/solvent displacement method eliminates the use of chlorinated organic solvents and large amounts of surfactants. The coacervation (phase separation) approach involves heating or chemical denaturation and desolvation of natural proteins or carbohydrates. As much as 85% of water-soluble drugs can be entrapped within a protein matrix by freeze drying the emulsion prepared in this manner. For water-insoluble drugs, a microsuspension emulsion procedure has been suggested as a method of choice to achieve high drug payloads. Various processing parameters that can affect the preparation of micro- or nanoparticles include the concentration and nature of the surfactant, the number of homogenization cycles, the addition of excipient to the inner water phase, the drug concentration, and the oil-water phase ratio.

Micro- or nanoparticles, for use in drug targeting, must be produced as sterile, freeze-dried, free-flowing powders. They can be administered either systemically or by an intramuscular route. Drugs can either be encapsulated or molecularly entrapped within the polymer matrix or conjugated on the particle surfaces. As is obvious from Table 5, the major use of micro- and nanoparticles, including magnetic particles, has been in tumor therapy (135-143). Particle-in-oil emulsions have been used as lysosomotropic systems. After subcutaneous administration, the oily product is readily taken up by the lymphatic system (130). Numerous examples of biodegradable polymeric micro- and nanoparticles, with potential applications in medical imaging, gene therapy, and drug targeting specific cells or tissues, have been reported (136-139,144-146). Nanoparticles can carry high doses of drug or agent (up to 45% of particle weight), with an entrapment efficiency of over 95%. Studies also show that solid lipid particles can be used to target antineoplastic and gene-therapeutic agents to the brain (143,147) and to increase the permeation of glucocorticoids through the human epidermis (148). Peracchia et al. (149) reported that PEG conjugated poly(cyanoacrylate) nanoparticles, following intravenous administration, accumulated in larger amounts in the spleen than in the liver, offering an interesting perspective for targeting drugs to tissues other than the liver. The release of drugs from particulate carriers can occur by surface erosion, disintegration, hydration, or breakdown (by a chemical or an enzymatic reaction) of the particles. These and other factors that can affect the release of drugs are presented in Table 7.

Liposomes Liposomes are versatile, efficient, and, probably, the most extensively studied class of carrier systems. Several liposomal formulations are currently either in preclinical/ clinical trials or commercially available (e.g., Doxil®/Caelyx®, Myocet®, AmBisome®, and DaunoXome®). A comprehensive review of the preparation, analysis, drug entrapment, and interactions with the biological milieu, including drug targeting, can be found in a compendium entitled Liposome Technology, edited by Gregoriadis (150,151). There are several books (152-155), book chapters (156-160), and review articles (161-168) that cover various aspects of liposome technology.

The important attributes of liposomes as a drug carrier are that (i) they are biologically inert and completely biodegradable; (if) they pose no concerns of toxicity, antigenicity, or pyrogenicity, because phospholipids are natural components of all cell membranes; (iii) they can be prepared in various sizes, compositions, surface charges, and so forth, depending on the requirements of a given application; (iv) they can be used to entrap or encapsulate a wide variety of hydrophilic and lipophilic drugs, including enzymes, hormones, vitamins, antibiotics, and cytostatic agents; (v) drugs entrapped in liposomes are physically separated from the environment and are thus less susceptible to degradation or deactivation by the action of external media (e.g., enzymes or inhibitors); and (vf) liposome-entrapped drugs offer new possibilities for drug targeting, since entrapped drugs follow the fate of liposomes and are released only at the site of liposome destruction.

The drug-loading capacities of liposomes depend on the properties of the drug, phospholipids, and other additives used. Typically, hydrophobic drugs are solubilized

Table 7 Factors Affecting the Release of Drugs from Particulate Carriers

Drugs

Position in the particle Molecular mass Physiochemical properties Concentrations Drug carrier interaction

Diffusion, desorption from surface, low exchange Particles

Type and amount of matrix material Size and density of the particle Capsular or monolithic

Extent and nature of any cross-linking, denaturation of polymer Presence of adjuvants

Surface erosion, particle diffusion and leaching Total disintegration of particles

Environmental

Hydrogen ion concentration

Polarity

Ionic strength

Presence of enzymes

Temperature

Microwave

Magnetism

Light

Source: From Ref. 3.

with lipid(s) in an organic solvent that is then dried and subsequently hydrated to yield liposomal drug formulations. The loading of hydrophilic drugs is limited by their aqueous solubility. By submitting the liposome-drug solution to several freeze-thaw cycles, the entrapment efficiency of water-soluble drugs can be increased. However, this is possible only at high lipid concentrations (169). The loading of cationic (or anionic) drugs can be significantly improved by using liposomes containing negatively (or positively) charged lipids. Gabizon (170) reported that the entrapment efficiency can be increased from 10% for neutral liposomes to 60% for charged liposomes. Other approaches to increase entrapment efficiency involve the use of transmembrane pH gradients and dehydration and rehydration of vesicles (DRV). In general, liposomes with low internal pH tend to accommodate a higher loading of cationic drugs, whereas a high intraliposomal pH enables increased entrapment of negatively charged (anionic drugs) and amphiphilic drugs (171). The dehydration-rehydration method allows entrapment of drugs in a concentration range of 50% to 85% (172,173). This method is easy to scale up, and the liposome vesicles containing drug, including protein, can be freeze dried and reconstituted with saline solution without affecting the entrapped drug. Proteins, sugar residues, and antibodies can also be incorporated into liposomes. Other approaches used include physical adsorption, incorporation during liposomal preparation, and covalent attachment (direct or through a spacer) to the active drug or an inert additive (e.g., polymer) incorporated into the liposomal membrane (167,174,175).

After intravenous administration, liposomes are rapidly removed from blood, primarily by cells of the RES, and, foremost, by the liver (Kupffer cells). The half-lives of liposomes in the bloodstream may range from a few minutes to many hours (up to 72 hours) (176), depending on the nature and compositions of the lipids, surface properties, and size of the liposomal vesicles. In general, smaller unilamellar vesicles (SUVs) show much longer half-lives in the blood than multilamellar vesicles (MLVs) and large unilamellar vesicles (LUVs). Negatively charged liposomes are cleared more rapidly from the circulation than corresponding neutral or positively charged liposomes. Also, the uptake by the spleen is greater for negatively charged liposomes than for positive or neutral liposomes. The SUVs can penetrate 0.1-|im fenestrations located in the endothelium of discontinuous (sinusoidal) capillaries lining the liver, spleen, and bone marrow (177) and reach the underlying parenchymal cells. The endothelium of the hepatic sinusoid contains openings larger than 0.1 |im in diameter, and this may allow penetration of MLVs and LUVs. An increase in the liposome dose causes a relative decrease in liver uptake and, consequently, an increase in blood levels and, to some extent, in spleen and bone marrow uptake (177). Prolongation of the blood clearance times of the liposomes by blocking the RES uptake has been used to increase the likelihood of liposomes to interact with vascular endothelial cells and circulating blood cells.

Irrespective of size, liposomes, when injected intraperitoneally, partially accumulate in the liver and spleen. It has been suggested that transport of liposomes from the peritoneal cavity to the systemic circulation and eventually to tissues occurs by lymphatic pathways. Local injection of larger liposomes leads to quantitative accumulation at the site of injection. The slow disintegration of the carrier releases the drug, which then diffuses into the blood circulation. Smaller liposomes, on the other hand, enter the lymph nodes and blood circulation and eventually accumulate in the liver and spleen.

Since the RES is the natural target, liposomes have been extensively investigated as carriers for the treatment of liver and RES organ diseases (passive targeting). Belchetz et al. (178) reported that liposome-entrapped glucocerebroside, when administered intravenously in patients suffering with Gaucher's disease, reduced the liver size significantly. The effect is attributed to the penetration ability of the liposomal drug into the cells. The native enzyme had no effects because of its inability to penetrate the cells. A similar finding was reported in patients suffering with glycogenesis type II disease following administration of amyloglycosidase entrapped in liposomes (179). Encapsulation of antimonial drugs within liposomes has increased the efficacy by 800- to 1000-fold compared with the free drug against experimental visceral and cutaneous leishmaniasis in rats (180-182). Bakker-Woudenberg et al. (183) found an about-90-fold increase in the therapeutic efficacy following administration of liposome-encapsulated ampicillin compared with free ampicillin against Listeria monocytogenes infection.

The rapid clearance of liposomes by cells of the RES system can be avoided by creating a highly hydrated layer on the surface of the liposomes by coating/grafting with water-soluble polymers [e.g., PEG, surfactants (e.g., poloxamers)] or by including phosphatidylinositol or gangliosides to create a highly hydrated shell. Moghimi (74) reported that the inclusion of methoxypoly(ethylene glycol) into the liposomal bilayer can control the rate of drainage as well as lymphatic distribution following subcutaneous administration. Liposomal vesicles containing 6.7 mol% PEG (molar mass 2000) were noted to drain faster from the site of application than 15mol% PEG (molar mass 350). The latter, however, showed greater retention in the regional lymph nodes. Conjugation of nonspecific IgG to the distal end of PEG, however, dramatically increased the lymph node retention of the faster-draining PEG-containing vesicle.

Liposomes have also been used for delivering immunomodulating agents to macrophages, the immunologically competent extravascular cells that contribute to host defense mechanisms. Activated macrophages are capable of selectively killing tumor cells, thereby leaving normal cells unharmed. Fidler et al. (184) have shown that lymphokines (e.g., interferon), muramyl dipeptide, and a lipophilic derivative of muramyl tripeptide, encapsulated within liposomes, are highly effective in activating antitumor functions in rodent and human macrophages in vitro and in mouse and rat in vivo. Dose-response measurements show that these preparations induce maximum levels of macrophage activation at a significantly lower dose than needed for equivalent activation by the nonencapsulated preparation (185-187). Roerdnik et al. (157) reported a 50% to 60% increase in the tumoricidal activity of muramyl dipeptide when encapsulated within liposomes compared with free drug against B-16 melanoma cells in vitro. The free drug gave a maximum activity of 30% cytotoxicity versus a 250- to 1000-fold increase in potentiation of muramyl-induced cytotoxicity because of encapsulation within liposomes. Saiki et al. (188,189) and Sone et al. (190) have found that encapsulation of more than one agent within the same liposome produces synergistic activation of macrophages in vitro and in vivo. The activation of macrophages, in general, requires phagocytosis of the liposome, followed by a lag period of four to eight hours before tumoricidal activity is expressed (186). Since no participation of macrophage surface receptors is required, the tumoricidal activity of macrophages results from the interaction of immunomodulating agents with intracellular targets (191).

Liposomes have been extensively studied as carriers for a variety of antineoplastic drugs. Mayhew and Rustum (192) demonstrated that liposomes containing doxorubicin [adriamycin (ADR)] are 100 times more effective compared with free drug against the liver metastasis of the M5076 tumor. Liposomal encapsulation of amphotericin B, a potent, but extremely toxic, antifungal drug, also resulted in much reduced toxicity, while it maintained potency (193). Rosenberg et al. (194) and Burkhanov et al. (195) have reported that liposomes prepared by using autologous phospholipids obtained from tumor cells are taken up by the tumor cells two to six times better than a control egg lecithin liposome.

Liposomes containing specific targeting molecules, such as tumor-specific antibodies or cell receptor-specific ligands (e.g., glycolipids, lipoproteins, lectin, folic acid, and amino sugars), have been prepared to provide liposomes with increased direct transport properties (115,167,176,196,197). These cell-specific targeting molecules can be either adsorbed on or covalently attached, directly or by a spacer, to the outer surface of the liposomal membrane. The use of spacers enables binding of considerable quantities of targeting molecules without affecting its specific binding properties or the integrity of the liposomes.

Temperature- and pH-sensitive liposomes have been investigated for targeting drugs to primary tumors and metastases or sites of infection and inflammation (198). The basis for the temperature-sensitive drug delivery is that at elevated temperatures, above the gel to liquid crystalline phase transition temperature (Tc), the permeability of liposomes markedly increases, causing the release of the entrapped drug. The release rate depends on the temperature and the action of the serum components, principally the lipoproteins. Weinstein et al. (199) investigated the effect of heating on incorporation of [3H]methotrexate, administered in the free form and encapsulated in 7:3 (w/w) dipalmitoyl and distearoyl phosphatidylcholine liposomal vesicles, in L1210 tumors implanted in the hind feet of mice. They found about a 14% increase in [3H]methotrexate incorporation from the liposomal form, compared with the free drug, after heating. This approach has been extended to a bladder transitional cell carcinoma, implanted in the hind legs of C3H/Bi mice (200), and for delivery of cisplatin (cis-diamminedichloroplatinum) selectively to tumors (201).

The pH-sensitive liposomes consist of mixtures of several saturated egg phosphatidylcholines and several Af-acylamino acids. The release of drug is suggested to be a function of acid-base equilibrium effected by the interaction between ionizable amino acids and Af-acylamino acid headgroups of the liposomes. There appears to be a close relation between Tc and pH effect (198). Recently, long-circulating pH-sensitive liposomal formulations have been prepared using PEG and a terminally alkylated poly(N-isopropylacrylamide)-methacrylic copolymer. Incorporation of PEG renders hydro-philicity, causing liposomes to avoid RES uptake and, consequently, stay in circulation for a longer period (202). The fusogenic peptide-based pH-sensitive liposomes containing folate and transferrin ligands have been described for intracellular targeting (113).

Liposomes also offer potential for use as carriers to transfer genetic materials to cells. Nicolau et al. (203) reported that a recombinant plasmid containing the rat preproinsulin I gene, encapsulated in large liposomes, when injected intravenously, resulted in the transient expression of this gene in the liver and spleen of the recipient animals. A significant fraction of the expressed hormone was in physiologically active form. Recently, liposomes have also been used to block the initial binding of human immunodeficiency virus (HIV) to host cells (157). This binding takes place between a glycoprotein (gp 120) on the virus coat and the CD4 receptor on the surface of T-helper lymphocytes and other cells. Antiviral drugs, such as zalcitabine (2',3'-dideoxycytidine)-5'-triphosphate (204) and AZT (205), have also been incorporated into liposomes and studied for their antiviral activities.

The incorporation of magnetic particles in liposomes, combined with an externally applied magnetic field, has recently demonstrated in vivo the ability to selectively target a specific organ, that is, one kidney over the other (206). The use of liposomes for targeting and to increase the bioavailability of antibiotics has been recently reviewed (207). Ocular drug targeting by liposomes is another important area of research (208). Several oral liposomal formulations for drug delivery and immunization have also been described (209-213).

Niosomes Niosomes are globular submicroscopic vesicles composed of nonionic surfactants. They can be formed by techniques analogous to those used to prepare liposomes (214). To predict whether the surfactant being used will produce micelles or bilayer niosome vesicles, an arbitrary critical packing parameter (CPP) can be used, that is, via • I, where v and I are specific volume and length of the hydrophilic portion of the surfactant and a is the area of the hydrophobic segment of the surfactant (215). A CPP value of 0.5 or less favors the formation of micelles, whereas a value between 0.5 and 1.0 favors the formation of vesicles. The various types of nonionic surfactants used to prepare niosomes include polyglycerol alkylethers (216), glucosyl dialkyl ethers (217), crown ethers (218), and polyoxyethylene alkylethers (218). Similar to liposomes, niosome vesicles can be unilamellar, oligolamellar, or multilamellar. A variety of lipid additives, such as cholesterol, can be incorporated in the niosome bilayer. Incorporation of cholesterol in the niosome bilayer enhances the stability of niosomes against the destabilizing effects of plasma and serum proteins and decreases the permeability of the vesicle to the entrapped solute (219). Niosomes are osmotically active and require no special conditions for handling and storage.

Niosomes have been investigated as drug carriers in experimental cancer chemotherapy and in murine visceral leishmaniasis (219). When compared with free drug, niosomal forms of methotrexate, after intravenous administration by the tail vein in mice, exhibited prolonged lifetimes in the plasma and produced increased methotrexate levels in the liver and the brain. In addition, encapsulation within niosomes caused a reduction in the metabolism and urinary and fecal excretion of methotrexate (220,221). Polysorbate 80, a nonionic surfactant that does not form niosomes, when coadministered with free methotrexate, provided reduced efficacy compared with methotrexate encapsulated in niosomes (221). This suggests that it is essential for surfactants to have a vesicular structure to effect enhanced targeting of drugs. Niosomal delivery has also been reported for 5-fluorouracil (222).

The delivery of doxorubicin to the S180 sarcoma (tumor) in mice by using niosomes as a carrier has been studied by Rogerson (223). Much higher tumor drug levels were reported with niosomes containing 50% cholesterol than with free drug or drug encapsulated in cholesterol-free niosomes. The initial serum drug concentrations were higher following administration of free drug, but between two and six hours after administration, the concentrations dropped and were lower than those observed by using niosomal drugs, suggesting a rapid metabolism or distribution of free drug from the vascular system.

Niosomes containing stibogluconate have been found to be as effective as the corresponding liposomal drugs in the visceral leishmaniasis model. Free drug showed reduced efficacy (224).

Lipoproteins A lipoprotein is an endogenous macromolecule consisting of an inner apolar core of cholesteryl esters and triglycerides surrounded by a monolayer of phospholipid embedded with cholesterol and apoproteins. The functions of lipoproteins are to transport lipids and to mediate lipid metabolism. There are four main types of lipoproteins (classified on the basis of their flotation rates in salt solutions): chylomicrons, very-low-density lipoprotein (VLDL), LDL, and high-density lipoprotein (HDL). These differ in size, molar mass, and density, and have different lipid, protein, and apoprotein compositions. The apoproteins are important determinants in the metabolism of lipoproteins—they serve as ligands for lipoprotein receptors and as mediators in lipoprotein interconversion by enzymes.

Lipoproteins have been suggested as potential drug carriers (225) because (i) they are natural macromolecules and thus pose no threats of any anti-immunogenic response; (lï) unlike other particulate carriers, lipoproteins are not rapidly cleared from the circulation by the reticuloendothelial system; (lïi) the cellular uptake of lipoproteins is by high-affinity receptors; (iv) the inner core of a lipoprotein, which comprises triglycerides and cholesterol, provides an ideal domain for transporting highly lipophilic drugs, whereas amphiphilic drugs can be incorporated in the outer phospholipid coat of the core; (v) drugs incorporated in the core are protected from the environment during transport, and the environment is protected from the drug; and (vi) drugs located in the core do not affect the specificity of the ligand(s) present on the surface of the particle for binding to various cells.

Several methods are known to entrap or incorporate drugs into lipoproteins. The three most commonly practiced procedures include (225) (i) direct addition of an aqueous solution of a drug to the lipoprotein; (lï) transfer of a drug from a solid surface (e.g., the wall of a glass tube, glass beads, or small siliceous earth crystals) to the lipoprotein; and (ill) delipidation of lipoprotein with sodium desoxycholate or an organic solvent, followed by reconstitution with drug-phospholipid microemulsion or drug alone.

The use of LDL and other lipoproteins in drug targeting has been reviewed (225,226). Damle et al. (227) have shown that radiopharmaceuticals, such as iopanoic acid, a cholecystographic agent, could be incorporated in chylomicron remnants by esterification with cholesterol and used for liver imaging. About 87% of the chylomicron remnant-loaded iopanoic acid accumulated in the liver within 0.5 hours after administration, compared with 31% accumulated by using a saline solution containing the same amount of the drug. The LDLs have been used as a carrier to selectively deliver chemotherapeutic agents to neoplastic cells. The rationale is that tumor cells, compared with normal cells, express higher amounts of LDL receptors and can thus be selectively targeted with LDL. Thus, Samadi-Baboli et al. (228) have shown that LDL loaded with 9-methoxyellipticin incorporated in an emulsion containing dimyristoylphosphatidylcholine and cholesteryl oleate exhibited much higher activity than free drug against L1210 and P388 murine leukemia cells in vitro. The eradication of the L1210 cells by the drug-LDL complex occurred exclusively by an LDL receptor mechanism. The LDL-drug complex showed higher cytotoxicity against cells preincubated with lipoprotein-deficient serum than those incubated in fetal serum, confirming that higher LDL expression on the cells leads to a higher uptake of LDL. Another study (229) indicated that acrylophenon antineoplastic molecules, when incorporated within LDL, can be delivered selectively to cancer cells without being entrapped in other blood proteins and cleared by the reticuloendothelial cells.

Kempen et al. (230) synthesized a water-soluble cholesteryl-containing trigalacto-side, tris-gal-chol, which when incorporated in lipoproteins allowed the utilization of active receptors for galactose-terminated macromolecules as a trigger for the uptake of lipoproteins.

LDL and HDL have also been chemically modified to provide new recognition markers so that they can be selectively targeted to various types of cells in the liver (225,226). Lactosylated LDL and HDL, which contain D-galactose residues as a ligand, can be prepared by incubating the corresponding protein with lactose (D-galactosyl-D-glucose) and sodium cyanoborohydride. Incubation of LDL with acetic anhydride produces the acetylated LDL. When injected intravenously in rats, both lactosylated LDL and HDL and acetylated LDL are rapidly cleared from the circulation by the liver (Table 8). Lactosylated LDL is specifically taken up by the Kupffer cells, whereas lactosylated HDL is mainly cleared by the parenchymal cells. Acetylated LDL shows a higher accumulation in endothelial and parenchymal cells than in Kupffer cells. Thus, lactosylated HDL can be used to deliver antiviral drugs to parenchymal cells, whereas lactosylated LDL may serve as a carrier for immunomodulators, antivirals, and antiparasitic drugs to Kupffer and parenchymal cells. Acetylated LDL, on the other hand, is suitable for targeting anti-infective drugs to parenchymal and endothelial liver cells. Both Kupffer and endothelial cells have been implicated in HTV infections (231).

Activated carbon (charcoal) Activated carbon is commonly used as an adsorbent. It has a microporous structure and possesses a large surface area for adsorption. Drugs or chemicals adsorbed on activated carbon particles exist in dynamic equilibrium with nonadsorbed drugs. The aqueous suspensions of activated carbon, available commercially

Table 8 Distribution of Acetylated LDL, Lactosylated LDL, and Lactosylated HDL over Liver Cell Types
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