Extracellular Vescicles

Exosome vesicles

Recently, extracellular vesicles are attracting considerable interest from the scientific community due to their multiple applications including therapeutics; drug delivery, and biomarkers. Considering that in today’s era of personalized medicine, wherein targeted delivery of drugs is crucial for effective therapeutic outcomes; the role of exosomes in drug delivery has been a recent topic of interest in the field of nanotechnology.

Special interests were raised, when researchers all over the world understood that extracellular communication help in transmitting messages through intracellular communication. Traditionally, it was well known that cells secrete certain vesicles during their growth period, but previously it was thought that during cellular communication, signals were sent to promote apoptosis in the form of extracellular vesicles. However, with the recent investigation, it is well-known that healthy cells also secrete extracellular vesicles to promote a healthy growth environment in the tissue.

Exosomes Micro vesicles Apoptotic Bodies
Origin Endocytic Pathways Plasma Membrane Plasma Membrane
Size 40-120 nm 50-1,000 nm 500-2,000 nm
Function Intercellular Communication Intercellular Communication Facilitate Phagocytosis
Markers CD 81, CD 63, CD 9 Integrin, selectin Annexin V
Contents Proteins and nucleic acids Proteins and nucleic acids Nuclear fractions, cell organelles

Exosomes and microvesicles (MVs) are released by both healthy and diseased cells. Although, it should be noted that exosomes secreted by both cell types differ in several factors. While in the neurogenic system, EVs have been proposed to participate in cell-to-cell transit systems by mediating short- and long-distance communication, affecting various aspects of cell biology.
Considering their functional importance, currently, exosomes are being explored for their therapeutic benefits, as potential biomarkers, and as an effective drug delivery system.
Kosheeka has come up with a range of therapeutic exosomes and oncogenic exosomes, derived from good quality, growing primary cells and cancer cells.

Overview

With recent advancements in the diagnostic industry, biomarkers are being referred to as the new innovative signatures to understand disease pathophysiology; further supporting drug screening and drug discovery. Given the fact that exosomes play a critical role in cellular communications while being loaded with important information in the form of proteins, lipids, and messengers; the same can be referred to as diagnostic checkpoints of abnormalities at the cellular levels when compared with healthy control.

Thus, exosomes mediated detection technologies are emerging currently in the field of diagnostics, as the early detection of disease status may lead to efficient treatment for various chronic diseases including cancer, autoimmune disorders, and inflammatory diseases. Accordingly, many studies have confirmed the relevant importance of diagnostics. The details of the same can be obtained herewith:

  • A study confirmed that circulating Exo -DNA with higher mutational probability in KRAS genes can be used as a confirmatory test for the entry-stage development of pancreatic cancer (Allenson K., et.al; 2017). 
  • Another study confirmed increasing levels of GPC1+ circulating exosomes to be referred to as an indication of pancreatic ductal carcinoma and colorectal cancers (Melo, et.al; 2015). 
  • In lung cancers, the detection of circulating exosomes EGFRT790M has great potential as a confirmatory test, further avoiding unnecessary tumor biopsies (Castellanos, et.al; 2018)
  • A study also confirmed that the expression of proteins can potentially discriminate between cancerous and non-cancerous growth. A study has revealed that the expression of CD151, CD171, and tetraspanin 8 can be considered the most significant to separate patients with lung cancer and cancer-free individuals (Sandfeld-Paulsen, et.al; 2016). 
  • In lung cancer the FLI1 exonic circular RNAs were identified as the novel carcinogenic driver, further contributing to the metastasis of cancer; can be used as an effective biomarker confirming cancer metastasis (Li L, et.al; 2019). 
As discussed above, EVs possess inherent properties of tissue repair and overall remodeling, which can further be exploited for therapeutic benefits.  In the context of regenerative medicine and cell-based therapies, EVs show significant benefits in comparison to their source, EVs may be less immunogenic. Unlike cellular components, EVs have a longer shelf life and can be circulated in the blood system for approximately 3 months. EVs do not replicate after injection and can cross the blood-brain barrier very easily. Thus, since the time of their discoveries, EVs have served as potential therapeutic agents in the liver, neurodegenerative as well as cardiovascular disorders. 

Exosomes often inherit properties of their parent cells, and hence for therapeutic benefits stem cell-derived exosomes are identified to be potential candidates to redefine the future of medicine. Many preclinical animal models have successfully confirmed the therapeutic potential of EVs derived from mesenchymal stem cells. 

  • At the preclinical setup, it has been confirmed that progressive liver fibrosis can be ameliorated with the infusion of UCMSC-derived exosomes that are 30-150 nm in the range (Li et.al; 2013)
  • Another study confirmed through preclinical mouse models that hUCMSC-derived exosomes can ameliorate experimental autoimmune uveoretinitis through the inhibition of inflammatory cellular migration (Bai et.al; 2017)
  • EVs from hUCMSCs are also known to inherit therapeutic potential in multiple neurodegenerative ailments including Alzheimer’s disease, Huntington’s Disease, etc. (Cho et.al; 2018)

There are also few published studies that have demonstrated the effectiveness of exosomes in clinical setups.

  • Currently, hUCMSC-EVs are being explored as potential cell-free therapeutic options with characteristic protective and immunomodulatory properties (Gowen et.al; 2020)
  • Another study further highlighted the broad-spectrum therapeutic properties of MSC-derived EVs, introducing their ability to reduce damage associated with chronic kidney injuries; a disease characteristically featured by its strong fibrotic, inflammatory, and apoptotic components (Ramirez-Bajo et.al; 2020). 

Over the past couple of years, multiple research projects are ongoing to improve methods for targeted drug delivery; especially in the case of cancer. Out of various methods that have been investigated, a targeted exosome-based drug delivery system has been proven to be highly effective. Their natural designation as cargo transporters lends a credence to the belief that exosomes are naturally occurring extracellular particles; specifically involved in the targeted delivery of various biological materials. Researchers can hijack this inherent property of exosomes for effective therapeutic applications, including drug delivery at the site of injury. Other than exosomes, other nanoparticles like liposomes, as well as polymeric NPs are also used as targeted delivery systems with good stability as well as long-circulating capabilities. However, using these nanoparticles also has regulatory obligations; hence, exosomes can be the most preferred choice. 

  • A study was conducted to analyze the drug delivery property of exosomes, wherein MSC-derived exosomes were complexed with curcumin. The therapeutic outcome of the exosome-curcumin complex was compared with that of free curcumin in mice models. The study further confirmed that the exosomes-curcumin complex enhanced clinical efficiency (Aggarwal et.al; 2009). 
  • Another in vitro experimental model confirmed that complexes of drugs formed with exosomes can significantly reduce inflammatory cytokine levels than native drugs only (Dhillon et.al; 2008)  

  • Aggarwal, B.B.; Harikumar, K.B. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune, and neoplastic diseases. Int. J. Biochem. Cell Biol. 2009, 41, 40–59.
  • Allenson, K. et al. High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. Ann. Oncol.28, 741–747 (2017).
  • Dhillon, N.; Aggarwal, B.B.; Newman, R.A.; Wolff, R.A.; Kunnumakkara, A.B.; Abbruzzese, J.L.; Ng, C.S.; Badmaev, V.; Kurzrock, R. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin. Cancer Res. 2008, 14, 4491–4499
  • Melo, S. A. et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature523, 177–182 (2015).
  • Li, J. et al. GPC1 exosome and its regulatory miRNAs are specific markers for the detection and target therapy of colorectal cancer. J. Cell. Mol. Med.21, 838–847 (2017).
  • Castellanos-Rizaldos, E. et al. Exosome-based detection of EGFR T790M in plasma from non–small cell lung cancer patients. Clin. Cancer Res.24, 2944–2950 (2018).
  • Sandfeld-Paulsen, B. et al. Exosomal proteins as diagnostic biomarkers in lung cancer. J. Thorac. Oncol.11, 1701–1710 (2016).
  • Li, L. et al. FLI1 exonic circular RNAs as a novel oncogenic driver to promote tumor metastasis in small cell lung cancer. Clin. Cancer Res.25, 1302–1317 (2019).
  • Li, T., Yan, Y., Wang, B., Qian, H., Zhang, X., Shen, L., et al. (2013). Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 22, 845–854. DOI: 10.1089/scd.2012.0395