1. Circulatory cells as drug carriers
Nanocarriers (NCs), such as liposomes, hydrogels, nanoparticles, micelles, fibers, and dendrimers, provide several advantages in delivery applications and have been extensively applied to enhance the therapeutic efficacy of drugs [Citation1–Citation4]. However, the major challenges in NC applications are to transport the therapeutics to the target site without significant degradation, avoid rapid phagocytic clearance, prolonging the circulation time, insufficient targeting, and limited ability to cross biological barriers such as the blood–brain barrier [Citation1–Citation4]. Thus, alternative drug delivery approaches are desirable. One emerging strategy to address the above nanotechnology challenges is to select body’s own circulatory cells as drug carriers [Citation1,Citation4–Citation8].
Circulatory cells have received a significant interest as drug delivery vehicles because of several attractive and distinctive features arise from their unique structures, mechanical properties, and surface functionality [Citation1,Citation4–Citation8]. These properties include high biocompatibility (if immunologically compatible), high mobility, a longer circulation lifespan, inherent biodegradability through known clearance pathways, natural capability of cell/tissue targeting, high drug loading capacity due to their large internal volume, remarkable stability in circulation, and their ability to cross biological barriers [Citation1,Citation4–Citation7]. This editorial article provides an outline of several circulatory cells and their inherent properties () in the design of cell-mediated delivery systems ().
Figure 1. (a) Circulatory cells (erythrocyte, monocyte, macrophage, lymphocyte, neutrophil, platelets, leukocyte, dendritic cells, stem cells, and extracellular vesicles) in drug delivery approaches. (b) Fabrication and advantages of circulatory cells in cell-mediated drug delivery using free drug or drug loaded nanocarriers (NCs). Drugs or NCs can be loaded on to circulatory cells using physical, chemical, or biological methods [Citation4]. (c) Application of circulatory cells in cell-mediated drug delivery using a Trojan horse or reinfusion approaches. Circulatory cells-based carriers have a long circulation half-life in blood compared to conventional NCs and inherent targeting ability to diseased sites such as tumor. The cell-mediated delivery approach can be designed to be internalized in vivo by surface decoration with macrophage/monocytes receptor specific ligands (Trojan horse approach) or the drug/NCs can be loaded in these cells ex vivo and then re-infused into the host to target the diseased sites. (d) Cell mediated carrier’s migration in to diseased sites (e.g. tumor). Drug release from cell-carriers can be designed to be triggered using stimuli (external or internal) -responsive approaches based on the NCs biomaterials (polymer) characteristics.
![Figure 1. (a) Circulatory cells (erythrocyte, monocyte, macrophage, lymphocyte, neutrophil, platelets, leukocyte, dendritic cells, stem cells, and extracellular vesicles) in drug delivery approaches. (b) Fabrication and advantages of circulatory cells in cell-mediated drug delivery using free drug or drug loaded nanocarriers (NCs). Drugs or NCs can be loaded on to circulatory cells using physical, chemical, or biological methods [Citation4]. (c) Application of circulatory cells in cell-mediated drug delivery using a Trojan horse or reinfusion approaches. Circulatory cells-based carriers have a long circulation half-life in blood compared to conventional NCs and inherent targeting ability to diseased sites such as tumor. The cell-mediated delivery approach can be designed to be internalized in vivo by surface decoration with macrophage/monocytes receptor specific ligands (Trojan horse approach) or the drug/NCs can be loaded in these cells ex vivo and then re-infused into the host to target the diseased sites. (d) Cell mediated carrier’s migration in to diseased sites (e.g. tumor). Drug release from cell-carriers can be designed to be triggered using stimuli (external or internal) -responsive approaches based on the NCs biomaterials (polymer) characteristics.](/cms/asset/c2d572f5-95df-4636-85e9-31352cd81a96/iedd_a_1254614_f0001_oc.jpg)
2. Types of circulatory cells in drug delivery applications
Several circulatory cells have been employed in drug delivery application. Erythrocytes or red blood cells (RBCs) constitute >99% of total blood cells and transport oxygen from the respiratory organs to the rest of the body [Citation4,Citation5]. RBCs are biodegradable as the reticuloendothelial system (RES) organs rapidly remove the old, incompatible cells. Several inherent properties of RBCs such as RES targeting ability, reversible deformation, established ex vivo processing methods, and high drug loading capacity make them a promising carrier [Citation4–Citation6]. Leukocytes play a significant role in the immune system, cell interaction, and cell adhesion [Citation4]. These cells express several specialized functions such as the capability of crossing biological barriers and innate ability to migrate to tumor cells, rendering them an attractive drug carrier. Neutrophils constitute the most abundant leukocytes, and due to their rapid response to inflammatory signals, they are able to deliver therapeutics to the diseased tissues [Citation4].
The potential of monocytes and macrophages to cross biological barriers, ability to phagocytose drugs/NCs, and carry therapeutics from circulation in hypoxic tumor areas is of great interest in cell-based delivery systems. Macrophages play versatile roles in inflammation and bacteria/cellular debris clearance [Citation1]. Macrophages are found in various tissues, regularly recruited to diseased sites, and have the potential to be activated by a variety of stimuli, which can trigger the drug release. NCs can be loaded in macrophages ex vivo and then reinfused into the host or designed to be internalized in vivo by surface decoration with macrophage receptor-specific ligands (Trojan horse approach) [Citation8].
T cells and B cells are the major lymphocytes play critical roles in cell-mediated and humoral immunities, respectively, with the potential of tissue targeting [Citation1,Citation4]. Antigen-presenting cells (APCs) recognize an antigen to the T cells which secrete cytokines and stimulate cytotoxic T cells to kill the target/abnormal cells. The potential of T cells in cancer therapy has been explored owing to their intrinsic ability to migrate to the tumor site [Citation9].
Platelets provide integrity to the capillary endothelium, activate coagulation, and support vascular regeneration in addition to the antimicrobial host defense, inflammation, and tumor growth [Citation1]. Platelets can be used as a vehicle for biomolecule delivery since they are natural carriers of biologically active proteins in their cytoplasmic granules which can be released upon activation to achieve hemostasis and tissue repair [Citation8].
Stem cells in drug delivery applications have versatile advantages including their natural targeting capability, self-renewability, high potency, potential of migrating towards tumor microenvironment, easy harvesting and in vitro culture, hypo-immunogenicity, and differentiability into specialized cells [Citation4,Citation6]. Mesenchymal stem cells have been employed for tissue regeneration vehicles in gene therapy [Citation10].
Dendritic cells (DCs) are APCs and play an important role in the adaptive immune response with potential application in the development of immunotherapeutic vaccines [Citation6]. DCs can be transduced to express and release different molecules. These cells have been used in vaccine delivery for cancer therapy [Citation11].
Extracellular lipid vesicles (EVs) such as exosomes and microvesicles are secreted as a result of several triggering events. EVs have the potential to serve as a next-generation drug vehicle owing to their low immunogenicity, tissue targeting capability, ability to evade phagocytic clearance, and stability in circulation [Citation12]. Because of their small size, exosomes take advantage of the enhanced permeability and retention effect for tumor targeting. Exosomes have been explored in the brain delivery of siRNA for the Alzheimer’s disease [Citation13].
Several investigations using living cells as drug vehicles are underway and summarized in [Citation1,Citation7,Citation14]. Two distinct approaches are utilized in cell-mediated drug delivery. Cell carriers are either genetically modified to produce therapeutic molecules or loaded with drugs to deliver them to the disease site. In the former approach, the cell carrier should be stable in culture, capable of sustained expression of therapeutic molecules, and have a long survival time in vivo. In the second application, the drug or NCs can be encapsulated or conjugated to circulatory cells using physical, chemical or biological methods and directed to the specific site using cells intrinsic targeting capabilities.
Table 2. Cell carrier-based drug delivery systems in clinical trials and under in vivo studies [Citation1,Citation7,Citation14].
3. Expert opinion
Circulatory cell-based approaches hold promises in improving drug therapeutic effects, but with specific advantages and limitations. Although current techniques allow effective isolation/expansion in vitro, followed by reinjection into the circulation, cell carriers are susceptible to contamination that can produce side effects and may influence the integrity of the cellular functions. The low cell-drug loading capacity, a premature drug release, triggered/controlled drug release limitations, protection of drugs against intracellular degradation and of cell carriers from drug cytotoxic effects, risk of blood contamination, and efficient migration of cell carriers to the disease site are other major challenges. Moreover, the cost-effectiveness of cell-based therapies and harvesting of cells in sufficient quantities are important issues. Furthermore, the translation of preclinical experimental results in labs to humans to confirm whether cell-based delivery will have real impacts on safe translational medicine needs to be evaluated. Also, in order to trace the efficacy of a cell-based therapy, cell trafficking tracking methods are needed.
Besides the above challenges, circulatory cells have their own specific issues. RBCs have been used in targeting of RES organs; however, other targets such as tumors and brain are inaccessible to RBCs. Moreover, restricted space of activity of RBCs within blood vessels, short ex vivo shelf-life, variability in composition, and decreased RBC plasticity during drug/NC loading (may affect its resistance to osmotic/mechanical damages), are considerable limitations. The short lifespan and poor transduction efficiency of leukocytes are their major limitations. The expansion of T-cells in large numbers, difficulty in harvesting, and preservation of their integrity are major issues. The difficulties in DC isolation due to the lack of standardized techniques, complicated purification process, potential contamination with other cells, and their long-term safety issues need further evaluation. Heterogeneity and short circulation half-life of EVs, non-optimized purification techniques, low amount released from cells, and little understanding about how EVs cross biological barriers remain to be elucidated. Platelets may cause thrombogenesis in addition to their storage and contamination issues. The use of stem cells is promising, but it is tough to maintain their potency in vitro. Despite the fact that macrophage/monocyte-based delivery has shown potential for cancer treatment, several key challenges remain unmet. The free drug loading may cause cytotoxicity and hamper macrophage function in addition to the premature drug release [Citation1,Citation7]. Moreover, the off-target effects and the potential drug degradation in the presence of intracellular enzymes are critical issues in macrophages clinical applications.
Several NC design parameters (size, shape, orientation, chemistry, surface charge, mechanical properties, flexibility, and release mechanism) should be considered and requires precise tuning in effective cell-based therapy. The drug or NCs must be nontoxic to the cells and prevent cell alteration after drug encapsulation process. A rational selection of appropriate cells is also necessary to achieve high therapeutic efficiency. Moreover, combining the cell-mediated delivery with a stimuli-responsive mechanism is a promising area to explore and may have a significant impact on next-generation delivery applications to ensure safe and beneficial therapeutic effects [Citation4]. Very few studies have used this concept in cell-based delivery; for example, intracellular glutathione level is applied as a stimulus for L-asparaginase release in RBCs [Citation15]. Thus, the development of smart biomaterials are important in fabrication of effective cell-based delivery systems.
In summary, the concept of using circulatory cells as drug vehicles is promising but needs improvement in several areas. Many of these limitations can be addressed by combining nanotechnology with cell-based delivery for effective clinical translation. Regardless of numerous challenges, circulatory cell-based carriers hold great promises to improve overall diagnostic and therapeutic benefits. Experimental results suggested that particularly RBCs have the capacity to serve as an efficient and safe drug delivery system. However, more research in this direction is needed in order to further confirm the therapeutic benefits of these living cell carriers. The current advances in this research area are exciting and hold the potential to change the way of administering medicines to patients.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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