Drug-loaded erythrocytes: on the road toward marketing approval

Bourgeaux, Vanessa; Lanao, José M.; Bax, Bridget E.; Godfrin, Yann

doi:10.2147/dddt.s96470

Cited by 67 publications

(52 citation statements)

References 61 publications

(58 reference statements)

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“…Drug encapsulation into RBCs for use in humans is currently achieved either in vitro or ex vivo using either autologous blood or matching donor blood as a source for RBCs. Washed RBCs are loaded with drugs via transient pores formed in the membrane of RBC during osmotic swelling in hypotonic buffer containing a high concentration of drugs, with subsequent washing with an excess amount of drug [10,11]. Notably, this process does release some hemoglobin from the RBCs [10,11].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…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.…”

Section: Introductionmentioning

confidence: 99%

Biocompatible coupling of therapeutic fusion proteins to human erythrocytes

et al. 2018

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Key Points• Thrombomodulin was fused to scFvs targeting RhCE (Rh17 epitope) and band 3/GPA (Wr b epitope).• Fusion proteins were efficacious in a humanized microfluidic model of inflammatory thrombosis. fibrin deposition induced by tumor necrosis factor-a in an endothelialized microfluidic model using human whole blood. RhCE-bound hTM-scFv more effectively reduced platelet and leukocyte adhesion, whereas anti-Wr b scFv appeared to promote platelet adhesion.These data provide a translational framework for the development of engineered affinity ligands to safely couple therapeutics to human RBCs.

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“…Increasing demand due to aging populations, challenges of adventitious agent screening, or requirement for specific immuno-phenotypes, has created a growing search for alternative sources to public donation. New uses for red blood cells (RBCs) such as targeted drug delivery may increase this demand further (Bourgeaux et al, 2016). There is evidence that transfusion of homogenously young RBCs may have clinical benefit by decreasing the transfusion frequency of chronically transfused patients (Bosman, 2013;Luten et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The productivity limit of manufacturing blood cell therapy in scalable stirred bioreactors

Bayley

Ahmed

Glen

et al. 2017

J Tissue Eng Regen Med

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Manufacture of red blood cells (RBCs) from progenitors has been proposed as a method to reduce reliance on donors. Such a process would need to be extremely efficient for economic viability given a relatively low value product and high (2 × 1012) cell dose. Therefore, the aim of these studies was to define the productivity of an industry standard stirred‐tank bioreactor and determine engineering limitations of commercial red blood cells production. Cord blood derived CD34+ cells were cultured under erythroid differentiation conditions in a stirred micro‐bioreactor (Ambr™). Enucleated cells of 80% purity could be created under optimal physical conditions: pH 7.5, 50% oxygen, without gas‐sparging (which damaged cells) and with mechanical agitation (which directly increased enucleation). O2 consumption was low (~5 × 10–8 μg/cell.h) theoretically enabling erythroblast densities in excess of 5 × 108/ml in commercial bioreactors and sub‐10 l/unit production volumes. The bioreactor process achieved a 24% and 42% reduction in media volume and culture time, respectively, relative to unoptimized flask processing. However, media exchange limited productivity to 1 unit of erythroblasts per 500 l of media. Systematic replacement of media constituents, as well as screening for inhibitory levels of ammonia, lactate and key cytokines did not identify a reason for this limitation. We conclude that the properties of erythroblasts are such that the conventional constraints on cell manufacturing efficiency, such as mass transfer and metabolic demand, should not prevent high intensity production; furthermore, this could be achieved in industry standard equipment. However, identification and removal of an inhibitory mediator is required to enable these economies to be realized. Copyright © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd.

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Drug-loaded erythrocytes: on the road toward marketing approval

Cited by 67 publications

References 61 publications

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

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

Biocompatible coupling of therapeutic fusion proteins to human erythrocytes

The productivity limit of manufacturing blood cell therapy in scalable stirred bioreactors

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