Erythrocyte membrane-bound hemoglobin-loaded drugs

A new generation of drugs is erythrocyte membrane-loaded hemoglobin-loaded drugs, which leverage the advantages of RBCs and the curative power of hemoglobin. Red blood cells, which come innately with a highly effective and biocompatible membrane, have long been analyzed for potential as carriers of medications. The RBC membrane is also extremely versatile: it can be designed to trap or bind any type of drug – protein, peptide, nucleic acid, small-molecule. Inserting hemoglobin (Hb), RBCs' oxygen-transporting protein, into this membrane network, scientists have come up with a new way to pack drugs for delivery and therapeutic effect. Its delivery mechanism exploits erythrocytes' inherent biocompatibility and circulatory abilities to circumvent many of the challenges of conventional drug delivery mechanisms (premature degradation, immune recognition, low release profile, etc. Erythrocyte membrane-bound hemoglobin-loaded drugs based on the fact that RBCs are able to survive in the blood longer because they're not immunogenic and are therefore "stealthy". Once the payload is delivered on the erythrocyte, hemoglobin (or a payload of hemoglobin) stabilizes the drug and guards against enzymatic breakdown in the bloodstream. Even hemoglobin has been identified as carrying other healing properties such as antioxidant action and the ability to remove reactive oxygen species (ROS) that reduce oxidative stress in tissues. This is what makes hemoglobin-loaded erythrocyte-based drug delivery systems very attractive for the treatment of inflammation, oxidative stress and tissue ischemia diseases. What's more, erythrocytes' ability to undergo biocompatible modifications and still retain their innate properties – flexibility– mean they are able to through capillary systems and deliver drugs to tissues precisely. The advantage of erythrocyte membrane-loaded hemoglobin-laden drug systems is their controlled, long-term release. Not only is hemoglobin an useful treatment, it can also be a cargo vehicle, guiding the timing and release of other loaded drugs. The inclusion of haemoglobin in the erythrocyte cell membrane might provide a reservoir of oxygen or other small molecules that could be released on site depending on the environmental pH or hypoxia. For instance, in the case of cancer treatment, where tumours tend to generate hypoxic microenvironments, the system's haemoglobin component might provide localised oxygenation that might help to boost cytotoxicity of certain chemotherapy drugs. There's also the possibility to change the RBC membrane so that the drug has a gradual, regulated release, by tailoring interactions between the drug and the hemoglobin or the RBC membrane. This allows the drugs to be dispersed over time, thus increasing therapy and decreasing drug dosage. Combining the advantages of hemoglobin and erythrocyte-based drug delivery technologies provides an effective platform for increased drug bioavailability, targeted delivery and controlled release.

Figure 1. Preparation and characterization of EMNVs. (Tao SC, et al.; 2018)

What drives erythrocyte membrane-bound hemoglobin-loaded drug delivery is some of the most important physiological and biochemical properties. Above all, red blood cell membrane consists of a lipid bilayer that can be tailored to hold other medications. This bilayer is highly malleable, and can be deformed as RBCs pass through the smallest of capillaries. This adaptability is what allows drug-loaded erythrocytes to deliver drugs to tissues most effectively, especially in microvascular contexts that are difficult for other systems to access. The lipid bilayer also protects against enzymatic degradation, which is usually the Achilles heel of liposome- or nanoparticle-based drug delivery. When the researchers introduce hemoglobin into the membrane, they harness both its intrinsic oxygen-binding power and its capacity as a stabiliser for the erythrocyte wall and the payload of a drug. One of the best things about erythrocytes as a carrier for drugs is that they have a long circulatory half-life, which is enhanced even further if the membrane of the erythrocyte is altered with hemoglobin or other biological substances. : Erythrocytes stay in the bloodstream for an average of 100-120 days before being excreted through the spleen. This longevity is in part a function of the cell's lack of nucleus (its immunity is sluggish), and the special surface glycocalyx that guards against immune detection. This stealth property has been tapped into drug delivery by attaching drugs to RBCs or their membranes. Hemoglobin grafted onto the RBC membrane can further protect the drug against recognition and clearance by the immune system. This works especially well for drugs that would otherwise be eliminated or immune neutralized rapidly, such as biologics or gene therapies. Hemoglobin's insertion into the erythrocyte surface also allows for a new mode of tissue-specific drug delivery. Because hemoglobin binds oxygen, it's especially useful when the blood must carry local oxygen — in ischemic tissue, wounds or tumours. In such situations, the hemoglobin-packed erythrocytes can act as carriers that carry the drug but also restore the normality of the oxygen field that can prove essential for the efficacy of some treatment therapies, such as chemotherapy drugs, angiogenesis inhibitors and regenerative drugs. In addition, hemoglobin release itself can increase blood supply and oxygen supply to hypoxic tissues, which lowers therapies' toxicity by curbing off-target effects. The capacity of hemoglobin to excrete oxygen at lower partial pressures of oxygen can be used to release drugs site-specifically under hypoxia – the standard scenario for solid tumours or inflamed tissues. The potential of erythrocyte membrane-bound hemoglobin-based drug delivery systems is unexplored but there are still a few hurdles to overcome before the systems can become fully clinically efficient. Preparing stable and efficient erythrocyte-based delivery systems is the first hurdle. When loading hemoglobin on the erythrocyte surface or encapsulating drugs inside RBCs, you need to be able to control exactly how your product will form and remain stable. The loading process of hemoglobin – whether it be chemical conjugation, physical encapsulation or fusion – must be chosen carefully in order to preserve both the hemoglobin and the drug. And of course, in vivo stability of such systems should be guaranteed, since early degradation or leakage of the drug would reduce therapeutic effect. Another hurdle is whether the manipulated RBCs are immunogenic or immune cleared. Erythrocytes themselves are immune-privileged, but their membranes could still be modified with hemoglobin or other bioactive molecules and the immune system would recognize them. The surface modification of RBCs must be controlled so that there's no immune clearance and the carrier system continues to work. Techniques like PEGylation (the addition of polyethylene glycol chains) have been used to minimize immunogenicity and prolong the lifetime of nanoparticles and liposomes, and similar techniques might be needed to extend the life of hemoglobin-packed erythrocytes in the bloodstream. The future for erythrocyte membrane-associated hemoglobin-loaded delivery systems is bright in this respect — particularly in the areas of personalized medicine and precision drug delivery. Researchers are working on modifying these systems for more particular therapeutic uses, including cancer, cardiovascular disease and regenerative medicine. These systems could be targeted to create extremely specific and efficacious treatments with smaller side-effects if their targeting and drug-release properties could be improved. Besides, nanotechnology, surface modification and bioconjugation chemistry will keep increasing the efficacy and safety of erythrocyte-based drug delivery systems. Furthermore, if hemoglobin-loaded carriers could be combined with other therapies – gene therapy or immunotherapy, for example – they could become powerful systems for treating many complex disorders.

Alternate Names:
Drug-Loaded Exosome-Mimetic Nanoparticles
Drug-Loaded EMNs
Exosome-Mimetic Nanovesicles
Exosome-Mimicking Nanovesicles
Exosome-Like Nanoparticles
Exosome-Mimetic Drug Nanovesicles
Nanovesicle-Based Drug Delivery Systems
Drug-Encapsulated Exosome-Mimetic Vesicles

References:
1. Tao SC, et al.; Extracellular vesicle-mimetic nanovesicles transport LncRNA-H19 as competing endogenous RNA for the treatment of diabetic wounds. Drug Deliv. 2018, 25(1):241-255.

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