Recent trends in the use of polysaccharides for improved delivery of therapeutic agents: pharmacokinetic and pharmacodynamic perspectives.

New and innovative methods of delivery of therapeutic agents using polysaccharides have been recently developed, which target site of action, increase the intensity and/or prolong pharmacologic action, and/or reduce toxicity of small molecule drugs, proteins, or enzymes. This review is focused on the role of dextran, pullulan, and mannan polysaccharides in such applications. While dextran and pullulan are glucose polymers with different glucosidic linkages, mannan is composed of mannose units. In terms of pharmacokinetics of the carriers themselves, molecular weight (MW), electric charge, various chemical modifications, and degree of polydispersity and/or branching would mostly determine their fate in vivo. Generally, large MW polysaccharides (MWs > or = 40 kD) have low clearance and relatively long plasma half life, resulting in accumulation in reticuloendothelial or tumor tissues. The tumor accumulation in most cases is a passive targeting due to "enhanced permeation and retention" of macromolecules by tumors. Additionally, drugs such as anticancer agents may be actively targeted to specific cells by polysaccharides to which appropriate ligands are attached. In terms of mode of use, polysaccharides have been utilized in a variety of innovative ways for improvement of drug delivery. Their most important application has been as carriers for preparation of macromolecular prodrugs that are normally inactive and need to release the active drug at the site(s) of interest. Also, they have been used for preparation of macromolecule-protein conjugates, which may retain the activity of the proteins, in order to increase the duration of effect and decrease the immunogenicity of proteins. Several other new applications, such as polysaccharide-anchored liposomal formulations, have also been gained attention recently and are briefly reviewed here. Finally, four recent examples of polysaccharide-based delivery systems involving specific drugs/imaging agents are reviewed in detail in terms of their development, pharmacokinetics, and pharmacodynamics. Collectively, these data suggest that macromolecular polysaccharides are promising agents for improving drug delivery.