Changing perspective: Can we use our Immune System cells as drug carriers?

Improving drug therapeutics via the drug or the mechanism of delivery has been a priority. Although some drugs have the potential to effectively treat diseases in vitro, they are unable to fulfill their function once they enter the patient, as they become degraded too quickly, or are eliminated by the immune system, or are too dilute to be effective. Synthetic nanoparticles have been developed to overcome these limitations, as the drug release can be controlled by the environment. In this regard, micelles are attractive for hydrophobic drugs due to their ability to self-assemble in aqueous solutions into monolayer vesicles with hydrophobic cores; however, in vivo micelles begin to disassemble, releasing the drug cargo. Combination of micelles and polymers can increase its stability, but most polymers are not biocompatible or biodegradable, becoming toxic to healthy cells [1, 2]. The cytotoxic limitation, together with the potential immunological problems [3], can be overcome by using biocompatible and biodegradable polymers [4, 5], although they are not easy to produce. Moreover, micelles have other shortcomings such as their poor targeting ability and their tendency to be rapidly cleared from blood circulation. Liposomes constitute an alternative for carrying hydrophilic drugs since they have bilayer membranes and a good in vivo stability; nevertheless, they also face problems of cytotoxicity, inefficient delivery [6], rapid clearance by the immune system, and their synthesis is typically expensive and complicated, with poor storage stability. 

Examples of several synthetic nanoparticles. Smith JD, Morton LD, Ulery BD. Nanoparticles as synthetic vaccines. Curr Opin Biotechnol. 2015 Aug; 34:217-24. doi: 10.1016/j.copbio.2015.03.014. 

Due to the incompatibility of synthetic nanoparticles, they produced as many problems as they solved. In the present, researchers are investigating how immune system cells (and their derivatives) could be used as drug carriers to effectively drop therapeutic cargoes to target cells.

Immune cells were quickly identified as promising delivery systems due to their fast migration, biocompatibility (they comprise our defense system), their minimal interaction with normal or healthy cells [2], and the ability to actively target specific cells and sites [7]. Let's take a tour through the different types of cells of the immune and hematopoietic systems and their possible use as drug carriers.

- Macrophages: They are phagocytic cells mostly recognized for their role in travelling to and clearing an injury site of foreign debris as part of the innate immune system. They are also able to cross the blood-brain barrier (BBB) [8], making them attractive for targeting and treating neurodegenerative disorders, inflammatory diseases and cancers. Natural phagocytosis and active migration in response to cell signaling menas that drug uptake and transport would be greatly improved, especially in comparison to the passive diffusion by which synthetic nanoparticles are restricted. 

Macrophages also face certain shortcomings, as high loads of drugs or drugs encapsulated in nanoparticles can interfere with cell survival, migration and function, limiting the drug load. They can also digest most drug carriers, degrading the drugs and then reducing drug release and efficacy. To overcome this limitation, researchers developed ‘cellular backpacks’ that encapsulate drugs that adhere to macrophages. Although drugs were successfully transported, backpack covers the plasma membrane and functions such as signaling, adhesion and migration are restricted [7]. Another strategy is to create drug-loaded capsules designed to withstand macrophage enzymatic and oxidative degradation. Slow drug release from the capsules minimized adverse effects on macrophages, allowing time for migration and drug delivery to the target site [7]. 

- T cells: They naturally produce receptors for a large variety of antigens, making them excellent targeting cells. Cell specificity and induced apoptosis of target cells make T cells very attractive for carrying drugs to target and eliminate tumors. T cells can be reprogrammed by modifying their antigen receptor (TCR) through the generation of chimeric antigen receptors (CARs) and modifying their secretions, thus changing their original target to cancer cells evading the immune system.

Efforts have been made to develop backpacking nanogels that can carry proteins on the tumor targeting T cell membranes, and only release the proteins when the CAR-T cell binds to the cancer cell and initiates T cell surface redox activity [9]. Although CAR-T cells are very promising for cancer treatment, sometimes they are extremely efficient, resulting in a cytokine release syndrome or B cell aplasia, neither of which yet have sustainable solutions [10].

Erythrocytes as carriers. RBCs can be used for several purposes. Koleva, L. et al. (2020). Erythrocytes as Carriers: From Drug Delivery to Biosensors. Pharmaceutics, 12(3), 276. https://doi.org/10.3390/pharmaceutics12030276

- Platelets: Platelets prevent blood leakage from injured blood vessels by aggregating to form a clot, being able to precisely target specific sites and cells [11, 12]. Platelets are ideal drug carriers due to their long lifespans, abundancy, high drug loading efficiencies, immune system evasion and the fact that a patient´s own platelets can be used for treatment. They have been used for wound healing, hemostasis, to combat inflammation and to treat vascular diseases such as lymphoma and lung adenocarcinoma. 

Platelets naturally release their cargo at faster rates in more acidic environments [13]; since cancerous sites are more acidic than healthy tissues, drug release can be controlled by the presence of tumor cells. Furthermore, as metastatic cells naturally activate platelets, they can aggregate around tumor cells, helping them to spread to new tissues through blood circulation [12]. Loading platelets with cancer therapeutics means that tumors can be targeted and then not be able to metastasize. 

- Erythrocytes and their mimics: Red blood cells (RBCs) have emerged as superior drug carriers, as they exhibit many of the same characteristics as immune cells: biocompatibility, biodegradability and targeting ability. RBCs are already being identified as clinically safe for transfusions and the cargo can be loaded onto their surface or inside them. RBCs have been shown to be effective carriers for alleviating symptoms of inflammation and pulmonary embolism, and a recent study determined that RBCs could become organ-targeted drug carriers based on the injection site [14]. 

RBC mimics maintains the RBC membrane and its proteins, differing from them only in their core, which is composed of a drug-encapsulated nanoparticle. RBC mimics have been used in cancer, acute liver failure and myocardial infarction models, but they have the potential to be applied to other vascular diseases [12, 15, 16]. The immunogenicity of the nanoparticle held within is minimized, which prolongs the blood circulation of the nanoparticles. Production of the mimics is fast, straightforward and safe, having better stability storage [16, 17].

Solely in terms of delivery, RBCs, their mimics and immune cells hold the most promise as drug carriers, since they do not induce cytotoxicity or unfavorable immune activity. Nevertheless, there is still a long way to go in the development of these therapies. It is likely that in the coming years we will see how these tools are adapted to other types of infectious and autoimmune diseases as well.

References:

Kim, M.S., et al., Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine, 2016. 12(3): p. 655-664.

2. Xu, P., et al., Doxorubicin-loaded platelets conjugated with anti-CD22 mAbs: a novel targeted delivery system for lymphoma treatment with cardiopulmonary avoidance. Oncotarget, 2017. 8(35): p. 58322-58337.

3. Xu, P., et al., Doxorubicin-loaded platelets as a smart drug delivery system: An improved therapy for lymphoma. Sci Rep, 2017. 7: p. 42632.

4. Shu, Y., et al., RNA-based micelles: A novel platform for paclitaxel loading and delivery. J Control Release, 2018. 276: p. 17-29.

5. Sarkar, S., et al., Drug delivery using platelet cancer cell interaction. Pharm Res, 2013. 30(11): p. 2785-94.

6. Layek, B., et al., Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting. Mol Cancer Ther, 2018. 17(6): p. 1196-1206.

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