Erythrocytes as Carriers for Drug Delivery in Blood Transfusion and Beyond

Abstract

Red blood cells (RBCs) are innate carriers that can also be engineered to improve the pharmacokinetics and pharmacodynamics of many drugs, particularly bio-therapeutics. Successful loading of drugs, both internally and on the external surface of RBCs, has been demonstrated for many drugs including anti-inflammatory, anti-microbial, and anti-thrombotic agents. Methods for internal loading of drugs within RBCs are now entering clinical use. While internal loading can result in membrane disruption that may compromise biocompatibility, surface loading using either affinity or chemical ligands offers a diverse set of approaches for the production of RBC drug carriers. A wide range of surface determinants is potentially available for this approach, although there remains a need to characterize the effects of coupling agents to these surface proteins. Somewhat surprisingly, recent data also suggest that red cell mediated delivery may confer tolerogenic immune effects. Questions remaining before widespread application of these technologies include determining the optimal loading protocol, source of RBCs, and production logistics, as well as addressing regulatory hurdles. RBC drug carriers, after many decades of progress, are now poised to enter the clinic and broaden the potential application of RBCs in blood transfusion.

Vascular Drug Delivery Using Carrier Red Blood Cells: Focus on RBC Surface Loading and Pharmacokinetics

“…Drug delivery systems based on surface loading can find utility for the prolongation and redistribution of agents that are supposed to work in the bloodstream and other sites accessible for RBCs ( Figure 1), including vascular endothelium, hepatic sinuses, pathological sites of RBC diapedesis and hemorrhages, and sites of surveillance and phagocytosis of senescent RBC. These drug cargoes include drugs regulating blood fluidity, inflammation, decoy and capture systems for pathological agents, immunological reactions, and some of the applications described above for RBCencapsulated agents [19][20][21][22]. In addition, RBC drug delivery systems can be surface-modified to confer specific affinity to therapeutic sites of interest, including those of vascular injury [13,14,23,24].…”

Biocompatible coupling of therapeutic fusion proteins to human erythrocytes

“…Drug delivery by red blood cells (RBCs) was envisioned decades ago [1][2][3] and the field has seen substantial growth, [4][5][6] spurred by advances in drug loading within cells, 7,8 approaches to coupling to the cell surface, 9,10 new technologies for genetic manipulation, 11 and clinical successes in cellular therapeutics overall. 12 Delivery by carrier RBCs enhances pharmacokinetics and, in some cases, the pharmacodynamics of the loaded agents.…”

Untitled

“…DISCUSSION: Encapsulation of biochemical substances into erythrocytes leads to the production of resealed erythrocytes that are widely used in biopharmaceutical studies as carriers [14][15] . In malaria research, resealed erythrocytes have been used to study the physiological functions of the digestive vacuole pH [17][18] , the mechanisms of antimalarial drug action and resistance 19 , the parasite attachment to and invasion of host cells 16,[25][26] , and the formation of the digestive vacuole 4 .…”

“…Although prior studies had been performed on the encapsulation of a variety of biopharmaceuticals in erythrocytes as cellular carriers [14][15] , the application of resealed erythrocytes containing high molecular weight dextran-linked fluorescent markers to track and dissect the parasite"s metabolic processes has exposed new paradigms 16 . This has evoked plenty of research projects with the goal of using the potential capabilities of these resealed erythrocytes in different experimental situations such as in the study of pH regulation of the parasite"s digestive vacuole [17][18] , the mechanisms of action and resistance of antimalarial drugs 19 , the cell attachment and invasion by the parasite 16 and the hemoglobin uptake and transport within parasiteinfected erythrocytes 4,20 .…”