AbstractOver the past three decades intensive efforts have been made to design novel systems able to deliver the drug more effectively to the target site. The ongoing intense search for novel and innovative drug delivery systems is predominantly a consequence of the wellestablished fact that the conventional dosage forms are not sufficiently effective in conveying the drug compound to its site of action and once in the target area, in releasing the active agent over a desired period of time. The potential use of macromolecular prodrugs as a means of achieving targeted drug delivery has attracted considerable interest in recent years. Macromolecules such as antibodies, lipoproteins, lectins, proteins, polypeptides, polysaccharides, natural as well as synthetic polymers offer potential applicabilities as high molecular weight carriers for various therapeutically active compounds. Dextrans serve as one of the most promising macromolecular carrier candidates for a wide variety of therapeutic agents due to their excellent physicochemical properties and physiological acceptance. The present contribution attempts to review various features of the dextran carrier like its source, structural and physicochemical characteristics, pharmacokinetic fate and its applications as macromolecular carrier with special emphasis on dextran prodrugs. The ongoing intense search for novel and innovative drug delivery systems is predominantly a consequence of the well-established fact that the conventional dosage forms are not sufficiently effective in conveying the drug to its site of action and once in the target area, in releasing the active agent over a desired period of time. In order to achieve controlled and site-specific drug delivery two approaches have been attempted. One of these approaches is pharmaceutical approach, which involves coating the drugs with pH-dependent polymers, time-dependent delivery systems, biodegradable coatings and embedding the drugs in therapeutic systems like liposomes or microspheres[1]. The other approach involves chemically based delivery systems like prodrug approach, in which a latentiated drug derivative is prepared, which is inactive as such but yields active drug after activation in mammalian systems by chemical or enzymatic pathway[2]. The potential use of macromolecular prodrugs as a means of achieving targeted drug delivery has attracted considerable interest in recent years. Macromolecules such as antibodies, lipoproteins, lectins, proteins, polypeptides, polysaccharides, natural as well as synthetic polymers offer potential applicabilities as high molecular weight carriers for various therapeutically active compounds.

Basic

concept

Since the 1950s, a variety of drugs have been covalently attached to many natural and synthetic polymers. Initially, the only rationale was that converting the drug into macromolecular prodrug might reduce renal excretion and hence increase the duration of activity. At that time there was little concern about the cellular uptake and processing of these conjugates. In 1975, Ringsdorf[3] proposed a more rationalized model for macromolecular prodrugs [Figure - 1]. He upgraded the potential of this concept by calling attention to the possibility of introducing onto the polymer carrier not only the drug moiety but also groups that can influence the solubility properties as well as groups that can alter the body distribution and promote cell selectivity.

In this model, the polymeric carrier can be either an inert or a biodegradable polymer. The drug can be fixed directly or via spacer group onto the polymer backbone. If the polymeric conjugate is pharmacologically active as a whole, the product can be regarded as polymer drug. Conjugates that are active after release of parent drug are termed as macromolecular prodrugs. Proper selection of the spacer provides the possibility of controlling the site and rate of release of active drug from conjugate by hydrolytic or enzymatic cleavage. The most interesting aspect of this model is the possibility of altering body distribution and cell uptake by attaching cell specific or non-specific uptake enhancers (homing device). This model has been an important milestone in the history of polymeric prodrug design.

DextranDextran is a complex, branched glucan (polysaccharide) made of many glucose molecules joined into chains of varying lengths (from 10 to 150 kilodaltons), used as an antithrombotic (anti-platelet), and to reduce blood viscosity. The straight chain consists of 1->6 glycosidic linkages between glucose molecules, while branches begin from 1->4 linkages (and in some cases, 1->2 and 1->3 linkages as well). Dextrans, which belong to the group of polysaccharide macromolecular carriers devoid of selective transport properties, may serve as one of the most promising carrier candidates for a wide variety of therapeutic agents due to their excellent physico-chemical properties and physiological acceptance. The important objectives that may be achieved by utilizing these soluble drug carrier conjugates include drug targeting, improvement of circulation time, stabilization of therapeutic agent, solubilization of drugs, reduction of side effects, sustained release action and depot properties[4]. Origins of dextran:

Dextrans of different chemical composition are synthesized by a large number of bacteria confined to the family Lactobacillaceae and mainly from Leuconostoc mesenteroids, Leuconostoc dextranicum and Streptobacterium dextranicum. The medium for synthesis contains low molecular weight dextran, sucrose or other carbohydrates containing anhydro-D-glucopyranose units[5]. Of particular pharmaceutical interest are dextrans derived from Leuconostoc mesenteroids NRRL B-152. These are characterized by their content of 95% a-1,6-glucopyranosidic linkages and 5% 1,3-linkages. The product of microbiological synthesis is termed 'native-dextran'. Clinical dextrans are obtained from high molecular weight native dextrans after their partial depolymerisation by acid hydrolysis and fractionation[6]. Physical properties:

Dextrans obtained from different sources differ in their structure and properties i.e.

molecular weight, degree of branching, relative quantity of particular type of glycosidic links, solubility, optical activity and physiological action. Dextrans are soluble in water, formamide and dimethylsulfoxide and insoluble in alcohol and acetone. Native dextran is a polymer of high molecular weight ranging between 10 7 to 10 8. Its molecular weight can be reduced by acid hydrolysis irrespective of the nature of acid used. Native dextran also possesses high degree of polydispersibility. The value of optical rotation for aqueous solutions of various dextrans varies from +199 to +235. The intrinsic viscosity is affected by the nature and pH of solvent, degree of branching, number of intermolecular bonds and temperature[7]. Chemistry: Dextran [Figure - 2] is the generic name applied to a large class of a-D-glucans with anhydro-D-glucopyranose units as a part of their main molecular chain. The predominance of a-1,6-linkages is a common feature of dextrans[8]. Pharmaceutically, the most important dextrans are composed of 95% a-1,6-glucopyranosidic linkages and 5% 1,3-linkages. The 1,3-linkages are points of attachment of side chains, of which about 85% are 1 or 2 glucose residues in length and the remaining 15% of side chain may have an average length of 33 glucose residues, which may not be uniformly distributed in the molecule. Dextrans may also contain variable quantities of a-1,2-, a-1,3- and a-1,4glycosidic bonds, by means of which side chains are usually attached to the main chains. Being very reactive towards chemical reactions, dextran can be extensively exploited as a carrier for attaching the drugs. With alkali and alkaline earth metals, dextrans form alkoxides dextranate[9]. Oxidation products of dextrans are useful in preparation of several new derivatives of dextrans. Periodic acid and lead tetraacetate in DMSO can be used to oxidize dextran partially[10]. A water-soluble chlorodeoxydextran has been prepared by treating dextran with thionyl chloride in DMF. Aminodeoxy derivatives have been obtained by nucleophilic substitution[10]. A deoxymercapto derivative has been obtained by pyrolysis of oxidation-product of dextran-xanthate with sodium nitrite followed by treatment of resulting polymer with alkali[11]. Pharmacokinetic fate of dextran:

Several physico-chemical properties like molecular size and shape, flexibility, charge, hydrophilic lipophilic balance are determinants for pharmacokinetic fate of dextran[12]. When given parenterelly, intravascular persistence of dextran varies dramatically with molecular weight. Dextrans of the molecular weight less than 70,000 have rapid elimination rates during the first hour after injection followed by a slower decrease in concentration[13]. Dextrans with molecular weight in the range 70,000-2, 50, 000 show prolonged survival in circulatory system. The high polarity of dextrans excludes their transcellular passage and their size prevents their passage through gastrointestinal tract. Dextrans are depolymerised by the enzyme dextranase present in intestine.

UsesMicrosurgery uses

These agents are used commonly by microsurgeons to decrease vascular thrombosis. The antithrombotic effect of dextran is mediated through its binding of erythrocytes, platelets, and vascular endothelium, increasing their electronegativity and thus reducing erythrocyte aggregation and platelet adhesiveness. Dextrans also reduce factor VIII-Ag Von Willebrand factor, thereby decreasing platelet function. Clots formed after administration of dextrans are more easily lysed due to an altered thrombus structure (more evenly distributed platelets with coarser fibrin). By inhibiting -2 antiplasmin, dextran serves as a plasminogen activator and therefore possesses thrombolytic features. Outside from these features, larger dextrans, which do not pass out of the vessels, are potent osmotic agents, and thus have been used urgently to treat hypovolemia. The hemodilution caused by volume expansion with dextran use improves blood flow, thus further improving patency of microanastomoses and reducing thrombosis. Still, no difference has been detected in antithrombotic effectiveness in comparison of intraarterial and intravenous administration of dextran. Dextrans are available in multiple molecular weights ranging from 10,000 Da to 150,000 Da. The larger dextrans are excreted poorly from the kidney and therefore remain in the blood for as long as weeks until they are metabolized. Subsequently, they have prolonged antithrombotic and colloidal effects. In this family, dextran-40 (MW: 40,000 Da), has been the most popular member for anticoagulation therapy. Close to 70% of dextran-40 is excreted in urine within the first 24 hours after intravenous infusion while the remaining 30% will be retained for several more days. Other medical uses

It is used in some eye drops as a lubricant, and in certain intravenous fluids to solubilise other factors, e.g. iron (=iron dextran). Dextran in intravenous solution provides an osmotically neutral fluid that once in the body is digested by cells into glucose and free water. It is occasionally used to replace lost blood in emergency situations, when replacement blood is not available, but must be used with caution as it does not provide necessary electrolytes and can cause hyponatremia or other electrolyte disturbances. It also increases blood sugar levels.

Overdosage/Toxicology Symptoms of overdose include fluid overload, pulmonary edema, increased bleeding time, and decreased platelet function. Treatment is supportive. Blood products containing clotting factors may be necessary. Anesthesia and Critical Care Concerns/Other Considerations Dextran should be used with extreme caution in patients with restrictive cardiovascular disease and renal or hepatic impairment. Patients should be observed closely during the first several minutes of the infusion in case anaphylactoid reaction occurs.

Dextran 40 is known as low molecular weight dextran (LMD) and has an average molecular weight of 40,000. Dextran 75 has an average molecular weight of 75,000. Dextran 70 has an average molecular weight of 70,000. Laboratory uses Dextran is used in the osmotic stress technique for applying osmotic pressure to biological molecules. It is also used in some size-exclusion chromatography matrices; an example is Sephadex'. Dextran has also been used in bead form to aid in bioreactor applications. Dextran has been used in immobilization in Biosensors. Dextran preferentially binds to early endosomes; fluorescently-labelled dextran can be used to visualize these endosomes under a fluorescent microscope. Dextran can be used as a stabilising coating to protect metal nanoparticles from oxidation and improve biocompatibility.

Side effectsAlthough there are relatively few side-effects associated with dextran use, these sideeffects can be very serious. These include anaphylaxis, volume overload, pulmonary oedema, cerebral oedema, or platelet dysfunction. An uncommon but significant complication of dextran osmotic effect is acute renal failure. The pathogenesis of this renal failure is the subject of many debates with direct toxic effect on tubules and glomerulus versus intraluminal hyperviscosity being some of the proposed mechanisms. Patients with history of diabetes mellitus, renal insufficiency, or vascular disorders are most at risk. Brooks and others recommend the avoidance of dextran therapy in patients with chronic renal insufficiency and CrCl