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

Abstract

Red blood cells (RBC) have great potential as drug delivery systems, capable of producing unprecedented changes in pharmacokinetics, pharmacodynamics, and immunogenicity. Despite this great potential and nearly 50 years of research, it is only recently that RBC-mediated drug delivery has begun to move out of the academic lab and into industrial drug development. RBC loading with drugs can be performed in several ways-either via encapsulation within the RBC or surface coupling, and either ex vivo or in vivo-depending on the intended application. In this review, we briefly summarize currently used technologies for RBC loading/coupling with an eye on how pharmacokinetics is impacted. Additionally, we provide a detailed description of key ADME (absorption, distribution, metabolism, elimination) changes that would be expected for RBC-associated drugs and address unique features of RBC pharmacokinetics. As thorough understanding of pharmacokinetics is critical in successful translation to the clinic, we expect that this review will provide a jumping off point for further investigations into this area.Pharmaceutics 2020, 12, 440 2 of 21 of the research enterprise encompassing the design of drug delivery systems (DDS)-liposomes, antibody-drug conjugates, and polymeric nanocarriers, to name a few.Nevertheless, approaches to use RBCs as carriers for pharmacological agents have recently gained significant and rapidly growing attention. Progress in this field is rapidly diversifying and accelerating towards potentially clinically useful products. Many groups are now investigating the use of RBCs in drug delivery and are making significant contributions, leading to breakthrough findings and upbeat investments. Several RBC-based drug delivery approaches have entered clinical trials, including RBC-encapsulated asparaginase (Erytech, Phase 3) and dexamethasone (EryDel, Phase 3). Novel advanced strategies are emerging, including genetic molecular modifications of RBC [2,3], modulation of the immune system by RBC-coupled antigens [3,4], and vascular transfer of RBC-coupled nanocarriers (RBC hitchhiking) [5][6][7].Both encapsulation into and coupling to the surface of RBC fundamentally transform the key parameters of absorption, distribution, metabolism, and elimination (ADME) of drugs and drug delivery systems (DDS), including diverse nanocarriers. To our knowledge, studies of the pharmacokinetics (PK) and pharmacodynamics (PD) of RBC-based DDS are lacking, despite great relevance for industrial development and clinical utility.In order to help to close this gap of knowledge, in this paper we undertook the first attempt to define specific, salient parameters controlling behavior of RBC/DDS in the body. Our goal is to provide the modular framework for experimental and theoretical pre-clinical and clinical investigations of ADME-PK-PD features of RBC-based drug delivery.

Injectables and Depots to Prolong Drug Action of Proteins and Peptides

“…An emerging technology is coupling drugs to carriers, such as erythrocytes/red blood cells (RBCs), which has been reported as a unique carrier for drug delivery [ 94 , 95 ] of peptides, receptors and antibodies [ 96 , 97 ]. RBC conjugation can avoid complications associated with transfusion of RBCs and ex vivo manipulations [ 98 ]; and can help alter pharmacokinetic profiles [ 99 ]. RBC-encapsulated asparaginase is currently in Phase III clinical trials [ 99 ].…”

“…RBC conjugation can avoid complications associated with transfusion of RBCs and ex vivo manipulations [ 98 ]; and can help alter pharmacokinetic profiles [ 99 ]. RBC-encapsulated asparaginase is currently in Phase III clinical trials [ 99 ].…”

Preclinical developments of enzyme-loaded red blood cells

“…The reader will find information on preclinical progress in different fields that could be representative of the many areas were enzymeloaded red blood cells can have a place. Finally, we would like to mention that enzymes targeted to selected red blood cell membrane proteins by fusion with single-chain fragment antibodies could provide an alternative to enzyme-loading for selected applications [90].…”

Immunocyte Membrane-Coated Nanoparticles for Cancer Immunotherapy

“…It is feasible and would be significant to use cell membranes to coat nanomaterials for more effective drug delivery. Numerous nanomaterials coated with cell membrane have been fabricated from many different types of cells, such as red blood cells [ 16 , 17 , 18 , 19 , 20 ], cancer cells, immunocytes, stem cells, platelets [ 21 ], and bacteria. These cell membrane-based biomimetic nanomaterials not only retain the complex biological functions of natural cell membranes, but they also maintain the highly adjustable physicochemical properties of the synthesized nanomaterials [ 22 , 23 , 24 ].…”