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Future perspectives and challenges of exosomes as drug carriers in cancer therapy

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Future perspectives and challenges of exosomes as drug carriers in cancer therapy

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. Correct selection of the cell of the origin for targeting

. Transport drug to tumor tissue with high specificity and increasing the efficiency of the carried drugs

. More preclinical studies in cancer models are required

. Promising results in tumors expressing the MDR phenotype

. Overcome challenges before scale-up development, translation into the clinic and their application in cancer therapy

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1. COMPREHENSIVENESS: Build a comprehensive dataset on proteins and genomic sequences involved in exosome formation for cancer therapy.
2. SCALE: The genomic scale is an aspect of functional genomics which in the case of cancer takes into account the multifactoriality of the disease state. To obtain large-scale data, use computational analyzes and databases. The programs responsible for these comparisons are based on sequence alignment algorithms and involve the comparison of the sequence of interest with those present in the databases, the function of which is known.
3. TECHNOLOGY DEVELOPMENT: The study of exosomes in cancer therapy requires modern technologies to maintain high standards. State-of-the-art techniques are needed: extraction and identification of nucleic acids, gene manipulation, immunibiology, pathophysiology, etc.
4. RAPID DATA RELEASE: Large-scale data must be a common resource that can be easily consulted, so there are also databases for exosomes. Example: http://www.exocarta.org/
5. SOCIAL AND ETHICAL IMPLICATION: The study of therapies for human cancer necessarily requires previous steps of experimentation on animals, after also on humans. This creates ethical and social conflicts.

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Exosomes are 30-150 nm membrane vesicles of endocytic origin secreted by most cell types in vitro. ExoCarta, an exosome database, provides with the contents that were identified in exosomes in multiple organisms.

Perform bioinformatics analysis of your extracellular vesicle data set using FunRich, a open access standalone tool. NEW UPDATED VERSION OF FunRich available for download (12/09/2016) from here

Vesiclepedia - Compendium on extracellular vesicles

External links of interest to the extracellular vesicle researchers

Want to contribute to ExoCarta?

We will keep ExoCarta updated with new exosome studies. We would love to have scientific community participation in any of the following ways.

Send unpublished exosome proteome/RNA/lipid datasets (it can be made private until published)
Point out an exosome publication that we missed

Contact us either to upload your exosome data or point to us if we have not added any published exosome study.

ExoCarta citation:

Keerthikumar, S., Chisanga, D., Ariyaratne, D., Al Saffar, H., Anand, S., Zhao, K., Samuel, M., Pathan, M., Jois, M., Chilamkurti, N., Gangoda, L. and Mathivanan, S. ExoCarta: A web-based compendium of exosomal cargo. Journal of Molecular Biology. 2015.

Simpson, R.J., Kalra, H. and Mathivanan, S. ExoCarta as a resource for exosomal research Journal of Extracellular Vesicles. 2012.

Mathivanan, S. Fahner, C.J., Reid, G.E., and Simpson, R.J. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Research. 2012.

Mathivanan, S. and Simpson, R.J. ExoCarta: A compendium of exosomal proteins and RNA. Proteomics. 2009. 21, 4997-5000.

Exosome reviews:

1. Simpson RJ and Mathivanan S. Extracellular Microvesicles: The Need for Internationally Recognised Nomenclature and Stringent Purification Criteria J Proteomics Bioinform. 2012. PubMed

2. Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009. 8, 581-93. PubMed

3. Keller S, Sanderson MP, Stoeck A, Altevogt P. Exosomes: from biogenesis and secretion to biological function. Immunol Lett. 2006. 2, 102-8. PubMed

4. Simpson RJ, Lim JW, Moritz RL, Mathivanan S. Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics. 2009. 3, 267-83. PubMed

5. Record M, Subra C, Silvente-Poirot S, Poirot M. Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol. 2011.10, 1171-82. PubMed

6. Cocucci E, Racchetti G, Meldolesi J. Shedding microvesicles: artefacts no more. Trends Cell Biol. 2009. 2, 43-51. PubMed

7. Schorey JS, Bhatnagar S. Exosome function: from tumor immunology to pathogen biology. Traffic. 2008. 6, 871-81. PubMed

8. Mathivanan S, Ji H, Simpson RJ. Exosomes: Extracellular organelles important in intercellular communication. Journal of Proteomics. 2010. PubMed

9. van Niel G, Porto-Carreiro I, Simoes S, Raposo G. Exosomes: a common pathway for a specialized function. J Biochem. 2006. 1, 13-21. PubMed

10. Johnstone RM. Exosomes biological significance: A concise review. Blood Cells Mol Dis. 2006. 2, 315-21. PubMed

More exosome articles .....

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Exosomes are 30-150 nm membrane vesicles of endocytic origin secreted by most cell types in vitro. ExoCarta, an exosome database, provides with the contents that were identified in exosomes in multiple organisms. Perform bioinformatics analysis of your extracellular vesicle data set using FunRich, a open access standalone tool.

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Naturally derived exosomes for cancer therapy (2)

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Naturally derived exosomes for cancer therapy (2)

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- Dendritic cells (DC) act as the initial link between oncogenesis and the host's immune system.
-The exosomes secreted by DC are called Dex and are nano-vesicles that have a size between 30-100 nm.
-Dex contain many bioactive fillers, responsible for the presentation of antigens, being ideal for the treatment of cancer.
-The clinical progress of cancer therapies involving DC and DEX is still in its infancy.

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Differences between Dex therapy and CD therapy

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Differences and Advantages of Dex therapy over CD therapy (4)

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Differences and Advantages of Dex therapy over CD therapy (4)

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Advantages:
-Exosomes have immunostimulatory characteristics identical to DC.
-Due to the stable nature of their membranes, Dex are able to be stored at low temperatures for at least 6 months without losing their main characteristics.
-Dex is also easier to produce and can be replicated in vivo without major problems.
-Treatment using Dex is more resistant to immunomodulatory events that usually occur in tumors.

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-MHC-I and MHC-II molecules
-α and β integrin chains (αMβ2)
-member of the ICAM-1 immunoglobulin family
-EGF factor 8 milk fat globule (MFG-E8)
-family of tetraspanin proteins, including CD9, CD63, and CD81
- cytosolic proteins derived from the donor DC
-mRNA and small RNA molecules (including miR)

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Ways of acting of Dex in cancer therapy (6)

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Ways of acting of Dex in cancer therapy (6)

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Interfering with cancer cell-derived exosomes for cancer therapy (7)

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Interfering with cancer cell-derived exosomes for cancer therapy (7)

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There are a number of chemical messengers that help the progression of tumors. It can interfere in several ways:
1- Inhibit the synthesis of cancer cell-derived exosomes (Rab27a)
2- Inhibit the release of cancer cell-derived exosomes (miR-494)
3- Inhibit the absorption of exosomes by tumor cells and destined for surrounding cells (Hemofiltration and HS)

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Exosomes as miRNA carrier for cancer therapy (8)

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Exosomes as miRNA carrier for cancer therapy (8)

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microRNAs

endogenous, small, non-coding RNAs

important roles in regulating gene expression

act as either tumor supressors or oncogenes

assist in the promotion or suppression of cancer growth

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Exosomes enriched with the anti-glioma miRNA can suppress glioma growth in vitro and reduce remarkably glioma xenograft growth in rats.

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Development of extracellular vesicles-mediated miRNA delivery strategies for cancer therapy (EV – Extracellular vesicle) (di Rocco et al., 2017).

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miRNA as therapeutic agents: EVs-mediated miRNA replacement therapy

miRNA as therapeutic target: EV-mediated miRNA inhibition therapy

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Exosomes as protein carrier for cancer therapy (15)

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Exosomes as protein carrier for cancer therapy (15)

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Exosomes

TRAIL (TNF-alpha-related-apoptosis-inducing-ligand)-armed exosomes

Effects:

·    promote apoptosis in cancer cells

·    control tumor progression in vivo

IL-18 enriched exosomes

Effects:

·  enhance Th1 cytokine release

·  proliferation of peripheral blood mononuclear cells

What gives them the capability to induce more specific anti-tumor immunity as they trigger a bigger immune response

IL-2 enriched exosomes
Effects:

·  induce the antigen-specific Th1-polarized immune response

·  cytotoxic T lymphocyte response more efficiently

This leads to a significant inhibition of tumor growth in mice.

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Exosomes can also be used as carriers of protein antagonists
Exemple:
Exosomes carrying SIRPα ( signal regulatory protein that  can interact with CD47, a  signal that limits the ability of macrophages to engulf tumor cells α) antagonists could significantly increase tumor phagocytosis

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Exosomes as a Drug Delivery System in Cancer Therapy (11)

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Exosomes as a Drug Delivery System in Cancer Therapy (11)

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. exosomes potential in drug carriers

. biogenesis of exosomes

. key points in exosomes as drug delivery systems

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Exosome-Based Drug Delivery Systems (12)

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Exosome-Based Drug Delivery Systems (12)

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. different loading strategies into exosomes
. direct loading
. indirect parental cells

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 MSCs-Derived Exosomes as Drug Carriers (13)

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 MSCs-Derived Exosomes as Drug Carriers (13)

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. Application of MSCs-Derived Exosomes as Drug Carrier

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Munich, Stephan, Andrea Sobo-Vujanovic, William J. Buchser, Donna Beer-Stolz, and Nikola L. Vujanovic. 2012. “Dendritic Cell Exosomes Directly Kill Tumor Cells and Activate Natural Killer Cells via TNF Superfamily Ligands.” OncoImmunology 1 (7): 1074–83. https://doi.org/10.4161/onci.20897.

Pitt, Jonathan M., Fabrice André, Sebastian Amigorena, Jean Charles Soria, Alexander Eggermont, Guido Kroemer, and Laurence Zitvogel. 2016. “Dendritic Cell-Derived Exosomes for Cancer Therapy.” Journal of Clinical Investigation 126 (4): 1224–32. https://doi.org/10.1172/JCI81137.

Schulze, Alex Von, and Fengyan Deng. 2020. “A Review on Exosome-Based Cancer Therapy.” Journal of Cancer Metastasis and Treatment 2020. https://doi.org/10.20517/2394-4722.2020.79.

Nicolini, A.; Ferrari, P.; Biava, P.M. Exosomes and Cell Communication: From Tumour-Derived Exosomes and Their Role in Tumour Progression to the Use of Exosomal Cargo for Cancer Treatment. Cancers 2021, 13, 822. https://doi.org/10.3390/cancers13040822

Li J, Chen J, Wang S, Li P, Zheng C, Zhou X, Tao Y, Chen X, Sun L, Wang A, Cao K, Tang S, Zhou J. Blockage of transferred exosome-shuttled miR-494 inhibits melanoma growth and metastasis. J Cell Physiol. 2019 Feb 5. Epub ahead of print. PMID: 30723916. doi: 10.1002/jcp.28234.

Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M. Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci U S A. 2013;110(43):17380-17385. doi:10.1073/pnas.1304266110

Kibria, G.; Ramos, E.K.; Wan, Y.; Gius, D.R.; Liu, H. Exosomes as a Drug Delivery System in Cancer Therapy: Potential and Challenges. Mol. Pharm. 2018, 15, 3625–3633. https://doi.org/10.1021/acs.molpharmaceut.8b00277

Gowda R, Robertson BM, Iyer S, et al. The role of exosomes in metastasis and progression of melanoma. Cancer Treat Rev. 2020;85: 101975.https://doi.org/10.1016/j.ctrv.2020.101975

Ortega, A., Martinez-Arroyo, O., Forner, M. J., and Cortes, R. (2020). Exosomes as Drug Delivery Systems: Endogenous Nanovehicles for Treatment of Systemic Lupus                    Erythematosus. Pharmaceutics 13 (1), 3. https://doi.org/10.3390/pharmaceutics13010003

Ferreira, D.; Moreira, J.N.; Rodrigues, L.R. "New advances in exosome-based targeted drug delivery systems". Critical Reviews in Oncology/Hematology 172 (2022): 103628. http://dx.doi.org/10.1016/j.critrevonc.2022.103628

Chen L, Wang L, Zhu L, Xu Z, Liu Y, Li Z, Zhou J and Luo F (2022) Exosomes as Drug Carriers in Anti-Cancer Therapy. Front. Cell Dev. Biol. 10:728616. https://doi.org/10.3389/fcell.2022.728616

von Schulze, A., & Deng, F. (2020). A review on exosome-based cancer therapy. Journal of Cancer Metastasis and Treatment, 2020. https://doi.org/10.20517/2394-4722.2020.79

di Rocco, G., Baldari, S., & Toietta, G. (2017). Exosomes and other extracellular vesicles-mediated microRNA delivery for cancer therapy. In Translational Cancer Research (Vol. 6, pp. S1321–S1330). AME Publishing Company. https://doi.org/10.21037/tcr.2017.09.29

Hannafon, B. N., & Ding, W. Q. (2013). Intercellular communication by exosome-derived microRNAs in cancer. In International Journal of Molecular Sciences (Vol. 14, Issue 7, pp. 14240–14269). https://doi.org/10.3390/ijms140714240