Abstract 4812: Arginine deiminase loaded in erythrocytes: a promising formulation for L-arginine deprivation therapy in cancers

Aguéra, Karine; Sénéchal, Karine; Bes, Julie; Chevrier, Anne-Marie; Gallix, Fanny; Guicher, Christine; Lorenzi, Philip L.; Bourgeaux, Vanessa; Berlier, Willy; Horand, Françoise; Godfrin, Yann

doi:10.1158/1538-7445.am2016-4812

Cited by 7 publications

(5 citation statements)

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“…With regard to erythrocyte encapsulated arginine deiminase, a dose of 10.4 IU/mL administered to CD1 mice was shown to completely deplete plasma arginine over a period of five days compared to the same dose of free enzyme. The depletion was sustained for 24 h, with the plasma levels returning to baseline by 2.5 days [107].…”

Section: Antitumor Therapymentioning

confidence: 95%

Erythrocytes as Carriers of Therapeutic Enzymes

Bax

2020

Pharmaceutics

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Therapeutic enzymes are administered for the treatment of a wide variety of diseases. They exert their effects through binding with a high affinity and specificity to disease-causing substrates to catalyze their conversion to a non-noxious product, to induce an advantageous physiological change. However, the metabolic and clinical efficacies of parenterally or intramuscularly administered therapeutic enzymes are very often limited by short circulatory half-lives and hypersensitive and immunogenic reactions. Over the past five decades, the erythrocyte carrier has been extensively studied as a strategy for overcoming these limitations and increasing therapeutic efficacy. This review examines the rationale for the different therapeutic strategies that have been applied to erythrocyte-mediated enzyme therapy. These strategies include their application as circulating bioreactors, targeting the monocyte–macrophage system, the coupling of enzymes to the surface of the erythrocyte and the engineering of CD34+ hematopoietic precursor cells for the expression of therapeutic enzymes. An overview of the diverse biomedical applications for which they have been investigated is also provided, including the detoxification of exogenous chemicals, thrombolytic therapy, enzyme replacement therapy for metabolic diseases and antitumor therapy.

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Section: Antitumor Therapymentioning

confidence: 95%

Erythrocytes as Carriers of Therapeutic Enzymes

Bax

2020

Pharmaceutics

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“…In 2015, ERYTECH Pharma patented the use of RBCs containing arginine deiminase (ERY-ADI) for the treatment of, in particular, hepatocarcinoma and malignant melanoma [89]. It was shown in mice that the time of arginine depletion (5 days) with ERY-ADI treatment was increased compared to the same time for the free form of ADI (24 h) [90].…”

Section: Enzymes Used In Antitumor Therapymentioning

confidence: 99%

“…Formate dehydrogenase Methanol intoxication [264] Cyanide sulfurtransferase (rhodanase) Cyanide intoxication [65][66][67][68][69][70]265,266] Catalase, PEG-catalase Antioxidant [267] l-Asparaginase Antitumor therapy [16,22,24,[83][84][85][86]237,[268][269][270][271][272][273][274][275][276][277][278][279][280][281][282][283][284] l-Methioninase [87,88,285,286] Arginine deiminase [89,90] Hexokinase, glucose oxidase To decrease blood glucose (diabetes) [287,288] Insulin [138][139][140]289,290] Inositol hexaphosphate (IHP) Sickle...…”

Section: Active Substance Application Referencesmentioning

confidence: 99%

Erythrocytes as Carriers: From Drug Delivery to Biosensors

et al. 2020

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Drug delivery using natural biological carriers, especially erythrocytes, is a rapidly developing field. Such erythrocytes can act as carriers that prolong the drug's action due to its gradual release from the carrier; as bioreactors with encapsulated enzymes performing the necessary reactions, while remaining inaccessible to the immune system and plasma proteases; or as a tool for targeted drug delivery to target organs, primarily to cells of the reticuloendothelial system, liver and spleen. To date, erythrocytes have been studied as carriers for a wide range of drugs, such as enzymes, antibiotics, anti-inflammatory, antiviral drugs, etc., and for diagnostic purposes (e.g., magnetic resonance imaging). The review focuses only on drugs loaded inside erythrocytes, defines the main lines of research for erythrocytes with bioactive substances, as well as the advantages and limitations of their application. Particular attention is paid to in vivo studies, opening-up the potential for the clinical use of drugs encapsulated into erythrocytes.Pharmaceutics 2020, 12, 276 2 of 44 property of RBCs allows to load them with biologically active substances of different molecular weights. For these reasons, erythrocytes are promising biocompatible cells for drug delivery.The methods for incorporating various substances into red blood cells differ in the way that substances penetrate the cells. The cause of permeability may be the pores' formation in the cell membrane due to a physical exposure (high voltage electric pulse [10,11] or ultrasound [12]). Drug molecules can also enter the RBCs by endocytosis in the presence of certain chemical compounds (for example, primaquine [13], vinblastine, chlorpromazine, hydrocortisone or tetracaine [14,15]), or using the cell-penetrating peptides bounded to the compound that should be encapsulated [16]. However, the most popular are different variants of osmotic methods.In some cases, RBCs are first exposed to a hyperosmotic pulse of a low molecular weight substance that penetrates very well through the cell membrane (for example, dimethyl sulfoxide (DMSO) [17,18] or glucose [19,20]). After washing the cells, which decreases the external concentration of these compounds and creates a gradient of their concentration between both sides of the RBC membrane, the target drug is introduced into the external volume. Water with this drug begins to enter into the cells to decrease the osmotic pressure there. The process ends when the gradient of DMSO or glucose disappears. The pores close and part of the drug remains into RBCs. Other, the most popular of the osmotic methods are hypoosmotic. These methods are based on creating a hypotonic environment around RBCs, which causes swelling of the cells and opening pores in the cellular membrane, through which therapeutic compounds can penetrate RBCs. Then, a hypertonic solution is introduced into the cell suspension. The pores close, the cells restore their original size, trapping the drug molecules inside the cell. Osmotic methods are divided into severa...

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“…The same dose of free ADI strongly depleted arginine (<5 μM) for 24 hours but its plasma levels returned to baseline by 2.5 days. Higher dose (10.4 IU/mL) resulted in the complete depletion of plasmatic arginine over the 5-day period of the study without causing tolerability problems [59]. Anyway, to date there is no evidence of preclinical efficacy of this therapeutic strategy in cancer animal models; differently, ADI-loaded RBCs have been shown to be efficient in a preclinical model for Arginase-1 deficiency, where promising results been recently generated (www.erytech.com).…”

Section: Arginine Deiminase As Cancer Therapymentioning

confidence: 99%

Preclinical developments of enzyme-loaded red blood cells

Rossi

Pierigé

Bregalda

et al. 2020

Expert Opinion on Drug Delivery

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Introduction: Therapeutic enzymes are currently used in the treatment of several diseases. In most cases, the benefits are limited due to poor in vivo stability, immunogenicity, and drug-induced inactivating antibodies. A partial solution to the problem is obtained by masking the therapeutic protein by chemical modifications. Unfortunately, this is not a satisfactory solution because frequent adverse events, including anaphylaxis, can arise. Area covered: Among the delivery systems, we focused on red blood cells for the delivery of therapeutic enzymes. Erythrocytes possess a long circulation time, a reduced immunogenicity, there is no need of chemical modifications and the encapsulated enzyme remains active because it is protected by the cell membrane. Here we discuss some representative applications of the preclinical developments of the field. Some of these are currently in clinic, others are approaching the clinic and others are illustrative of the development process. The selected examples are not always the most recent, but they are the most useful for a comparative approach. Expert opinion: The results discussed confirm the central role that red blood cells can play in the treatment of several conditions and suggest the benefit in using a natural cellular carrier in terms of pharmacokinetic, biodistribution, safety, and efficacy.

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Abstract 4812: Arginine deiminase loaded in erythrocytes: a promising formulation for L-arginine deprivation therapy in cancers

Cited by 7 publications

References 0 publications

Erythrocytes as Carriers of Therapeutic Enzymes

Erythrocytes as Carriers of Therapeutic Enzymes

Erythrocytes as Carriers: From Drug Delivery to Biosensors

Preclinical developments of enzyme-loaded red blood cells

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