Chapter category: Drug Design
Streptavidin-Mediated Coupling of Therapeutic Proteins to Carrier Erythrocytes
Erythrocyte Engineering for Drug Delivery and Targeting
Edited by: Mauro MagnaniISBN: 0-306-47691-6
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Chapter authors:
Vladimir R. Muzykantov and Juan-Carlos Murciano
Red blood cells (RBC) can provide a natural, safe and abundant carrier to prolong the life-time in the bloodstream and thus enhance the efficacy of certain therapeutic agents, while restricting their accessibility to the extravascular compartment and thus reducing side effects. Methods for coupling diverse therapeutic proteins to the RBC surface have been proposed, including coupling via streptavidin-biotin cross-linker. RBC-coupled proteins retain biological activity and effectively interact with either free or immobilized ligands. However, preservation of the biocompatibility of RBC-drug complexes represents a significant challenge. As with other RBC-mediated drug delivery paradigms, complement activation and uptake by macrophages in the reticuloendothelial system (RES, e.g., spleen and liver) represent major pathways for destruction and elimination of RBC carriers modified with biotin and avidin. An extensive biotinylation of RBC and coupling of avidin inactivate complement regulators DAF and CD59 in RBC, thus leading to C3b fixation. This results in phagocytosis and hemolysis, which greatly compromise RBC biocompatibility. However, coupling of streptavidin monovalently to modestly biotinylated RBC obviates these problems and permits stable attachment of 104-105 molecules of antibodies or enzymes to biocompatible RBC. RBC-drug complexes do not fix complement, avoid uptake by macrophages and circulate in a functionally active form in the bloodstream without hemolysis or elimination by reticuloendothelial system. Therefore, the monovalent streptavidin-mediated coupling to RBC allows prolongation of the functional half-life of therapeutic proteins in the circulation by orders of magnitude and markedly alters their pharmacokinetics in rodent models. This approach may be utilized for the site-selective delivery of diverse agents to the intravascular targets (e.g., immunotargeting of drugs to blood and vascular cells), as well as sustained circulation of drugs, which should exert their activity in blood (e.g., RBC carriage of anti-thrombotic enzymes). Further animal and human studies will test the validity, practical feasibility and therapeutic effectiveness of this approach.
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