Introduction

Exosomes denote a family of nano-sized membrane extracellular vesicles with a diameter in the range of 40 ∼ 130 nm that are secreted by most cell types of the body [1]. Initial studies suggested that this extracellular vesicle is a metabolic waste that cells secrete. However, more and more studies have shown that exosomes act as mediators of cell-to-cell signaling and participate in a variety of physiological and pathological activities in organisms [2]. Due to such characteristics, analyzing the specific biomarkers [3] carried therein is expected to be a non-invasive method for diagnosis and monitoring of tumors. Additionally, exosomes are not only important for tumor immunity, tumor invasion, metastasis and tumor resistance, but also has important value in the diagnosis and treatment of tumor.

Exosomes can exert important effects in various disease models [4]. Overall studies give an idea that exosomes play both cancer-promoting and malignant functions in malignant tumors [5]. In order to clarify the potential value of exosomes in tumors, further study of exosome complexity and functional heterogeneity is needed. Exosomes have important conversion values in the diagnosis of tumors, such as the value of liquid biopsy and the value of biomarkers. At the same time, exosomes also have important biological functions in tumorigenesis and development. Tumor cell-derived exosomes may be involved in the host's mesenchymal transfer reaction and participate in the antitumor activity of proto-oncogenes and the formation of the internal environment during the anti-tumor process, promoting or limiting the progression of tumors.

Nanocarriers have been extensively investigated for the targeted-delivery of drugs/genes to tumor and inflammatory tissues [6]. In particular for tumor tissue, nanocarriers take advantage of the enhanced permeability and retention effect to passively accumulate into tumors [7]. Despite decades of intensive investigation of nanocarriers for cancer therapies, there has been limited success in clinical trials due to the lack of safety and inefficient active targeting carriers. Exosomes are novel nanoparticle drug carriers that retain critical nanoparticle characteristics, such as the enhanced permeability and retention effect and passive targeting, but possess additional unique characteristics, such as targeting specificity as well as their intrinsic biological effects on the targeted cells due to the exosome cellular origin [8].

Malignant tumors are one of the most difficult diseases in the world today, which have a high mortality rate and a low survival rate. Malignant tumors are treated in a variety of ways, including radiotherapy and chemotherapy, targeting, biological and immunotherapy [9]. These methods greatly extend the survival time of patients. At present, chemotherapy and radiotherapy are the most commonly used methods. Although chemotherapy and radiotherapy may cause differences in efficacy due to the type and course of malignancy, chemotherapy resistance and radiotherapy tolerance after radiotherapy in tumors have been the major obstacles to cancer therapy [10]. Tumors are prone to recurrence and metastasis, which in turn affects patient survival [11]. Therefore, to study the causes and mechanisms of drug resistance, and to overcome or reverse drug resistance and radiotherapy tolerance accordingly has been the focus of current research on cancer therapy.

This article will review the recent progress of exosomes as a drug carrier application in clinic, briefly discuss the effects of these factors on the transport system of the exosome-based drug carriers. We also review the role of exosomes in chemotherapy, summarized the mechanism of exosome resistance in chemotherapy, and discussed some ways to eliminate chemoresistant caused by exosomes. At the same time, we also succinctly compared some of the applications of exosomes in radiotherapy. The aim of this view is to summarize recent progress in exosomes with an emphasis of tumor-associated exsomes and their potential applications in tumor treatment, and we will look forward to the challenges and possible solutions to the exosomes drug delivery system, chemotherapy and radiotherapy of exosomes in clinic.

Discovery of exosomes

In 1983, Johnstone et al. [12] first discovered that sheep mature reticulocytes can release a membranous vesicle, which was originally thought to be used to excrete excess transferrin receptors. In a further study in 1987 these vesicles were named "exosomes", and the researchers began to focus on these functional vesicles. The rapid development of exosome-related research has benefited mainly from two breakthroughs. First, in 1996 Raposo et al. [13] found that B-lymphocyte-derived vesicles can activate the immune system and participate in the adaptive immune process. Subsequently, the further study of functional proteins in exosomal vesicles established the concept of exosomes as intercellular signaling mediators. Second, the discovery of RNA in exosomal vesicles has facilitated the development of exosomal studies. In 2010, studies showed that miRNAs are present in exosomal vesicles and can inhibit the expression of target genes [14]. Subsequent studies have demonstrated that exosomes are widely involved in intercellular communication and can act on target cells to regulate physiological processes [15].

Biogenesis of exosomes

Cellular communication is generally achieved through soluble regulatory molecules or cell contacts. In recent years, it has been found that extracellular vesicles also play an important role in cell communication and package delivery. Extracellular vesicles mainly include apoptotic bodies, microvesicles and exosomes. Exosomes are a type of extracellular vesicles that people are currently paying close attention to, and the specific process of its formation is shown in Figure 1 [16]. First, the cytoplasmic membrane dents to form intracellular vesicles; Secondly, intracellular vesicles further develop into multivesicular bodies; Finally, the multivesicular bodies fuse with the plasma membrane to release exosomes. The receipt of exosomes by recipient cells can be achieved by ligand/receptor interactions, endocytosis/phagocytosis, or membrane fusion.

Exosomes as drug carriers for clinical application

All authors

Cuixia Di, Qianjing Zhang, Yupei Wang, Fang Wang, Yuhong Chen, Lu Gan, Rong Zhou, Chao Sun, Hongyan Li, Xuetian Zhang, Hongying Yang & Hong Zhang

https://doi.org/10.1080/21691401.2018.1501381

Published online:

15 November 2018

Figure 1. Schematic of formation and composition of exosomes. The different steps and particles involved are depicted. Exosomes contain a range of molecules, transmembrane transporters: CD9, CD63, CD81, CD82; heat shock proteins: HSP70, HSP90; fusion proteins: Rab, annexin; integrin, MHC II proteins, et al.

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Composition of exosomes

The lipid components of exosomes include cholesterol, sphingomyelin, phosphatidylserine and saturated fatty acids, most of which are a biofilm component in plasma [17]. The main compositions of exosomes are shown in Figure 1. Exosomal proteins include intracellular, plasma, cytoplasmic proteins and nucleoprotein [18]. Exosome-enriched proteins include membrane transport related proteins and fusion proteins such as Rab, annexin, transmembrane transporters (CD9, CD63, CD81 and CD82), and also rich in heat shock proteins (HSP70, HSP90), integrin, MHC II protein, human epidermal receptor family and other exosome biosynthesis related proteins [19]. The protein composition and content of exosomes depend on the cell type from which it is derived. The earliest reported exosomes contained nucleic acids are microRNAs and mRNAs [20]. Subsequently, other types of RNA in exosomes were found, including tRNA, lncRNA and virus RNA [21]. By carrying different types of RNA, it exerts different functions and influences to the transcription process of the recipient cells, and exerts regulatory functions in signal exchange, organ development, and physiological functions among tissue embryonic cells [22].

Exosome as drug carriers

Traditional drugs often have defects of poor solubility in water, easy to be removed quickly by the human body, poor biocompatibility, poor distribution in the body and low permeability to cells [23]. Exosomes as a natural liposome as ideal drug carriers are widely used at present [24], which have many advantages over conventional nanocarriers for drug and gene delivery (Figure 2). Exosomes, whose sizes are between 40 ∼ 130 nm, are preferable carriers of genetic drugs, anticancer drugs and other drugs, taking the advantage of their low immunogenicity certain target capability (Figure 2).What kind of exosomes are ideal drug carriers? Johnsen et al. [3] pointed out that the use of exosomes for drug delivery requires consideration of the origin of exosomes, methods of purification, types of drug loading, drug loading, and how the final drug delivery system is used. What kind of drugs can exosomes carry? The details are showed in Table 1.

Exosomes as drug carriers for clinical application

All authors

Cuixia Di, Qianjing Zhang, Yupei Wang, Fang Wang, Yuhong Chen, Lu Gan, Rong Zhou, Chao Sun, Hongyan Li, Xuetian Zhang, Hongying Yang & Hong Zhang

https://doi.org/10.1080/21691401.2018.1501381

Published online:

15 November 2018

Figure 2. Exosomes are preferable carriers of genetic drugs, anticancer drugs and other drugs.

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Exosome in chemoresistance

Chemotherapy is the main means of cancer treatment, but the chemoresistance is one of the most intractable problems affecting the curative effect. Extensive studies showed that exosomes play a pivotal role in the drug-resistance of tumors (Figure 3). Studies have found that both tumor cells and stromal cells in tumor microenvironment can secrete exosomes that carry drug-resistance-related molecules, which could also deliver drug resistance molecules by the interaction of exosomes, thereby enhancing the tolerance of tumor cells to drugs.

Exosomes as drug carriers for clinical application

All authors

Cuixia Di, Qianjing Zhang, Yupei Wang, Fang Wang, Yuhong Chen, Lu Gan, Rong Zhou, Chao Sun, Hongyan Li, Xuetian Zhang, Hongying Yang & Hong Zhang

https://doi.org/10.1080/21691401.2018.1501381

Published online:

15 November 2018

Figure 3. Exosomes can cause chemoresistance by transporting proteins, RNAs, or mediating drug efflux. According to this, resistance can be reversed by inhibiting the release of exosomes or changing the composition of exosomes, et al.

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Exosome in radiotherapy

Tumor cells can produce anti-radiation effects through hypoxia, tumor cell genetic heterogeneity and DNA repair, et al. After irradiation, tumor cells can secrete exosomes and affect the surrounding cells to produce radiotherapy tolerance [55]. Khan et al. [56] reported that radiotherapy can induce the increase of the exosomes containing apoptosis inhibitory factor secretion from tumor cells, by which can increase the survival rate of tumor cells and result in radiotherapy tolerance. Soon after, Arscott et al. [57] suggested that exosomes derived from irradiated cells enhanced the migration of recipient cells, and their molecular profiling revealed an abundance of molecules related to signaling pathways important for cell migration, their further studies indicated that radiation influences exosome abundance, specifically alters their molecular composition, and on uptake, promotes a migratory phenotype, due to which tumor cells produce radiotherapy tolerance. In addition, Boelens et al. [58] found that stromal and breast cancer cells utilize paracrine and juxtacrine signaling to drive chemotherapy and radiation resistance, in which the paracrine antiviral and juxtacrine NOTCH3 pathways converge as STAT1 facilitates transcriptional responses to NOTCH3 and expands therapy-resistant tumor-initiating cells, and further primary human and/or mouse breast cancer analysis support the role of antiviral/NOTCH3 pathways in NOTCH signaling and stroma-mediated resistance.

Similarly, revealing the mechanism of radiotherapy tolerance, from a certain point of view helps to improve or solve cancer radiotherapy tolerance in cancer. Richards et al. [59] showed that exogenetic inhibitors have great potential in the treatment in pancreatic ductal adenocarcinoma with radiotherapy.

Future directions and concluding remarks

At present, the study of exosomes is gradually applied in clinical practice, but there are still many problems that need to be solved. For example, it is necessary to further verify the safety of exosomes for clinical application, and to clarify the composition and mechanism of various substances in exosomes, and how to quickly obtain the high purity of exosomes and the dosage of clinical use. The study of exosomes has made great progress in drug carriers, chemotherapy and drug resistance mechanisms, radiotherapy, et al. However, the tumor and its microenvironment in the body are a very complicated system. Success in treatment against complex cancers is dependent on our full understanding of the intricacies of interactions between different components within tumors. With the deepening of the research on the role of the exosomes in the tumor, it is bound to expand the understanding of the human body and provide new ideas for cancer therapy.

This article discusses the role of exosomes in clinical application. The resistance of tumor cells includes intrinsic resistance and acquired resistance. Intrinsic resistance can be partially overcome by multidrug combination. However, more than 90% of patients with failed advanced cancer treatment are due to acquired resistance. The mechanisms of therapy resistance are numerous and complicated, and the transmission of many therapy -resistant molecules is not completely dependent on exosomes. There are other pathways. Exosomes play an invaluable role in the formation and transmission of therapy resistance. Not only exosomes of tumor cells can transmit therapy resistance, exosomes of stromal cells also participate in therapy resistance. Therefore, while studying the mechanism of exosome transmission, it also provides new ideas for overcoming therapy resistance. In-depth study of exosomes carrying information molecules, according to which can be targeted at specific targets, and then effectively inhibit the messenger of exosomes, thereby improving therapy efficacy. Although great progress has been made in the study of therapy resistance mechanisms, tumors and their microenvironment in vivo is a very complex system. With the deepening of the research on the role of exosomes in tumors, it is bound to further expand. People's understanding of the molecular mechanism of tumor resistance will also provide new and more basis for overcoming drug resistance. It is hoped that researchers will dwell deeper into this emerging field of research and devise newer context dependent exosome based strategies to overcome therapeutic resistance, which happens to be the toughest and most challenging issue in cancer therapy.