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WIREs Nanomed Nanobiotechnol
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Reengineering red blood cells for cellular therapeutics and diagnostics

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Recently optimized technologies that permit the reversible opening of nanopores across the red blood cell membrane, give the extraordinary opportunity for reengineering human erythrocytes to be used in different biomedical applications, both for therapeutic and diagnostic purposes. Engineered erythrocytes have been exploited as a system for the controlled release of drugs in circulation upon encapsulation of prodrugs or small molecules; as bioreactors when they are endowed of recombinant enzymes able to catalyze the conversion of toxic metabolite into inert products; as drug targeting system for the delivery of compounds to the reticuloendothelial system inducing proper senescent signals on the drug‐loaded erythrocyte membrane; as carrier of contrasting agents for diagnostic procedures. Preclinical development of these different applications has taken advantage from the use of proper animal models whose erythrocytes can be reengineered as the human ones or the encapsulation procedures can be adapted on the basis of their specific erythrocyte biological features. Successful results, obtained both in vitro and in preclinical studies, have prompted several clinicians to start pilot clinical investigations in different conditions and some new companies to start the industrialization of selected loading technologies and to initiate clinical development programs. This short review summarizes the key features that, to the best of our knowledge, have been crucial to advance the products toward regulatory clinical approval making reengineering of erythrocytes a modality to treat patients with limited or absent therapeutic options. WIREs Nanomed Nanobiotechnol 2017, 9:e1454. doi: 10.1002/wnan.1454 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Different applications of carrier RBC as drug delivery system. (a) RBC can act as a slow release system able to convert, by resident enzymes, a nondiffusible loaded prodrug into a diffusible active drug: this approach may be useful when slow and prolonged release of the drug into the circulation is needed and the drug concentration should be maintained within the therapeutic window. (b) RBC can act as long circulating bioreactors transporting entrapped enzymes that metabolize cell membrane permeating substrates to correct congenital metabolic disorders or to clear undesired toxic molecules from the bloodstream. (c) RBC can act as drug targeting system to selectively release loaded drug into specific districts of the body. Modified engineered erythrocytes expose on their membrane some antigenic sites that are recognized by autologous immunoglobulin G (IgG) and opsonized in order to be removed from circulation by the cells of the reticuloendothelial system (RES). (d) RBC can act as carriers of a large number of nanomaterials and contrast agents useful in diagnostic applications, especially in the visualization of the vascular system by fluorescent techniques or MPI and MRI.
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Representation of two different RBC drug loading systems by automated processes optimized for industrial application. (a) ERYcaps platform technology use a hypotonic dialysis method performed by contact of the RBC of healthy donors with a hypotonic buffer to allow pores opening and drug entry inside them. These swelled cells are successively resealed by adding hypertonic solution obtaining as final product drug‐loaded RBC to be administered to homologous patients. The whole procedure starts from about 250 to 350 mL of packed RBC (i.e., 500–700 mL of whole blood) and is carried out by using a medical apparatus termed ERY caps in about 3 h. (b) EryDel proprietary method is based on hypotonic preswelling process that is a controlled swelling of RBC placed in hypotonic environment by two‐step technique that induces the temporary opening of pores on the red cell membrane and consequently drug internalization. Resulting loaded RBC are readily infused to the patient that has previously donate his own blood. The whole procedure is performed by using 50 mL of whole blood processed in a fully automated biomedical equipment termed Red Cell Loader in about 90 min.
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Diagnostic Tools > In Vivo Nanodiagnostics and Imaging
Therapeutic Approaches and Drug Discovery > Emerging Technologies

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