Blood cells: the future of drug delivery

Author: Bai Lu

The drug delivery system is the holy grail of precision medicine aimed at reducing off-target side effects of drugs

Recent studies have shown that blood cells, the most abundant cells in our body, may be a better choice.

In addition, blood cells can exist in the blood for several days to several months, of which red blood cells live for an average of 4 months, which means they can continue to deliver drugs for a long period of time

Red blood cell drug delivery

Red blood cells are also called red blood cells.

At this stage, the technical path of companies related to red blood cell therapy is mainly focused on two ways: 1) using intact red blood cells to directly load drugs; 2) using stem cells as the source of engineered red blood cells to load drugs

With the gradual maturity of stem cell and gene editing technologies, the technology of engineered red blood cells derived from stem cells has developed rapidly

Rubius currently focuses on the field of cancer and autoimmune diseases

Rubius R&D pipeline (Source: Rubius Therapeutics official website)

The technical field of using intact red blood cells to directly load drugs started earlier.

EryDel is an Italian biotechnology company that uses human mature red blood cells to deliver drugs.

It is worth noting that the current therapies used to treat enzyme deficiencies usually trigger an immune response in the body, reduce the effect of enzymes, and cause serious side effects

At present, EryDel has a total of 8 drugs under development, mainly focusing on the development of drugs for rare diseases

EryDel product pipeline (Source: EryDex official website)

Among them, EryDex, a leading product that loads dexamethasone sodium phosphate into autologous red blood cells to treat ataxia telangiectasia, has entered phase III clinical trials (NCT02770807)

Another company dedicated to red blood cell therapy is EryTech, a French biotechnology company

EryTech has developed a series of candidate products for the unmet medical needs in the market

EryTech CEO Gil Beyen explained: "Our goal is to transform red blood cells into a'pharmaceutical factory', depriving cancer cells of an important nutrient-asparagine

EryTech product pipeline (Source: EryTech official website)

Eryaspase is in phase III clinical stage in the treatment of second-line pancreatic cancer, and is in phase II clinical stage in the treatment of triple-negative breast cancer

It should be noted that although the use of red blood cells to deliver drugs has great potential, it is not without limitations
.
First, the osmotic shock used to load the drug may irreversibly damage the cell membrane of certain cells
.
Second, the drug may diffuse out of red blood cells before reaching the target, causing side effects
.
Of course, many new methods have solved these problems, but they have not yet been clinically verified
.
These measures include loading drugs on the cell surface to avoid cell damage, and coating red blood cell fragments on synthetic nanocarriers to evade the immune system
.

Platelet drug carrier

The average life span of platelets is 10 days, and its circulation time in the blood is not as long as that of red blood cells
.
However, they have a high storage capacity and can carry a variety of goods
.
Platelets patrol the human vascular system to detect and repair leaking blood vessels, which makes them ideal candidates for targeting injury sites and releasing contents
.

Drug delivery systems that use platelets lag behind red blood cells, the most advanced of which is still in the pre-clinical development stage
.
However, thanks to the efforts of companies such as Plasfer, PlateletBio, and Cellphire Therapeutics, they are quickly catching up
.

Plasfer is an Italian biopharmaceutical company in the preclinical stage.
With its scientific knowledge centered on platelets, the company's team focuses on the production of cellular drugs to treat a series of diseases with unmet medical needs
.

Plasfe's patented technology platform Platelet Transfer Technology (PTTTM) can efficiently design human and mouse platelets to transfect genetic material (mRNA, siRNA, microRNA, plasmid DNA) and other types of molecules with very high efficiency
.

Plasfer's platelet therapy consists of autologous or allogeneic platelets
.
These platelets are engineered to efficiently express and deliver different types of therapeutic molecules inside or on the cell surface
.

Plasfer product pipeline (source: Plasfer official website)

Similarly, the use of platelets to deliver drugs has many advantages: 1) Like red blood cells, the use of platelets to deliver drugs can avoid the attack of the immune system; 2) Platelets can also deliver drugs in a smaller form similar to synthetic nanoparticles; Some types of tissues, cancers, wounds and pathogens have natural homing effects, which can reduce the off-target effects of cell therapy; 4) In addition to wounds and cancer, this technology can also be applied to regenerative medicine and cardiovascular diseases
.

But there are two potential problems that need attention
.
First, due to the role of platelets in the formation of blood clots, they are at risk of causing excessive blood clotting or further aggravating diseases that should be treated (such as certain forms of blood cancer)
.
Second, loading platelets with drugs may shorten the lifespan of platelets
.

Other blood cells and excellent carriers

White blood cells (white blood cells) are also candidate cells for drug delivery
.
They are adhesive and can adhere to the walls of blood vessels.
In addition, they have the inherent homing ability to cancer and inflammation sites, which can make drug delivery more precise
.
However, the commercial viability of this delivery method is still a distant goal because there are many differences between batches when extracting white blood cells
.
As an alternative, researchers are trying to coat nanocarriers with ingredients derived from white blood cells
.

Among the types of white blood cells, neutrophils and monocytes are particularly useful in drug delivery
.
As the first responder of the immune system, neutrophils are the first cells to reach the site of inflammation
.

On July 31, 2021, researchers from Shenyang Pharmaceutical University published an article in Acta Biomaterialia, demonstrating their construction of a drug delivery platform with neutrophils and monocytes (N/Ms) as carriers
.
The platform specifically binds N/Ms through synthetic sialic acid-stearic acid conjugates to modify the surface of liposome epirubicin, enhances the endocytosis of liposomes through circulating N/Ms, and loads lipids The N/Ms of plastid epirubicin can still maintain its inherent chemotaxis to tumors
.

In tumor-bearing mice, compared with other preparations, liposomal epirubicin significantly improved tumor targeting efficiency and therapeutic effect, and even eradicated tumors, because N/Ms containing liposomal epirubicin has Tumor aggregation and inhibition
.

Source: Acta Biomaterialia

This study shows that N/Ms as a drug delivery vehicle has huge clinical application potential
.

summary

It is undeniable that no matter what type of blood cells, the use of patients' own blood cells as drug carriers is still limited to small-scale use
.
Like other forms of cell therapy, the commercialization of blood cell-based therapy faces some major challenges, including expansion of production and long-term storage
.
It is worth looking forward to that spot-based therapies made from donor cells in the future may solve some of these problems
.

Note: The original text has been deleted

Reference materials:

1# Blood Cells: The Future of Drug Delivery (Source: LABIOTECH.
eu)

2# Junqiang Ding et al.
Sialic acid conjugate-modified liposomes enable tumor homing of epirubicin via neutrophil / monocyte infiltration for tumor therapy.
Acta Biomaterialia.
(2021)

3# The emergence of red blood cell therapy! Foreign pioneer company Rubius announces evidence of active anti-cancer, and domestic leading company obtains another 100 million yuan in financing (Source: Medical Rubik's Cube Pro)

4# Official website of each company