Preclinical developments of enzyme-loaded red blood cells

Abstract

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.

Engineering new metabolic pathways in isolated cells for the degradation of guanidinoacetic acid and simultaneous production of creatine

“…In fact, the presence of glucose in the medium fuels the glycolytic pathway, while extracellular methionine at physiological concentrations supports the intracellular production of SAM. Moreover, previous preclinical and clinical studies 10 , 33 on protein-loaded RBCs confirm that engineered erythrocytes maintain a vitality, such as to be a viable therapeutic product, despite some differences existing between untreated native and loaded RBCs, which justify their slightly reduced survival in circulation but do not compromise their therapeutic efficacy. 34 , 35 , 36 The key physiologic mechanisms controlling the in vivo behavior of RBCs engineered as drug delivery system, as well as the design parameters developed to overcome the main critical steps, have been recently reviewed.…”

Artificial Cells: Past, Present and Future

“…Artificial cells containing thymidine phosphorylase can be used to treat mitochondrial neurogastrointestinal encephalomyopathy, and a phase II clinical trial is under development. Additionally, artificial cells containing alcohol oxidase are undergoing preclinical research for alcohol detoxification treatment. − …”

Erythrocyte‐Inspired Functional Materials for Biomedical Applications

“…[ 22 ] A mass of enzymes, proteins, micromolecular drugs, macromolecules, NPs, and even bacteria has been loaded to the surface or interior of erythrocytes, as mentioned in Section 2.1. [ 8,142–144 ] Their applications involve chemo/phototherapy for cancer, [ 15 ] therapeutic delivery for antidotes, [ 145 ] and binding of bacteria to membranes for anti‐infection. [ 142,146 ] They aim to modulate immune responses and to improve and alter pharmacokinetics of therapeutic.…”