CommentariesFunctionalized exosome harboring bioactive molecules for cancer therapy
Introduction
Exosomes are spherical vesicles, 30–150 nm in diameter, produced by most cells in our body, and present in the blood, urine, and cerebrospinal fluid [1]. The biogenesis of exosomes is currently known to occur through the fusion of intracellular multivesicular bodies (MVBs), formed by the inward budding of the late endosome, with the plasma membrane [2]. Exosomes mediate intercellular communication by transporting bioactive molecules, such as nucleic acids, proteins, lipids, and glycoconjugates, which makes exosomes attractive as a potential delivery tool [3,4].
Several studies have been conducted to enhance the delivery of anticancer drugs using nanoparticles, such as synthetic polymers and liposomes [5]. Various drug delivery platforms are under preclinical trials, and there have been very few clinical trials because of inherent limitations, including poor bioavailability and tumor selectivity [6]. Exosomes have superior physical properties relative to other nanoparticles in biocompatibility, stability, and lower immunogenicity [7]. For these reasons, loading or expressing a therapeutic substance in or on exosomes increases its half-life, thereby producing remarkable efficacy by delivering the drugs to the desired target [8,9]. Moreover, since the exosomes generated from cells naturally express parent cell membrane proteins and maintain the cell membrane structure, the efficacy of the therapeutic membrane proteins can be maximized when exposed on the surface of the exosomes [10].
Based on these properties, exosomes have garnered much attention as a promising therapeutic delivery platform for cancer treatment (Fig. 1). Multiple attempts are being made in the production of exosomes as cancer therapy, and several experimental studies indicate that exosomes induce a potent anti-tumor effect over other delivery platforms (Table 1). This review summarizes the relevant examples of exosomes as drug delivery carriers for the treatment of cancer and describes the issues to be addressed in the biotechnology industry for clinical entry.
Section snippets
Nucleic acid delivery
Although nucleic acid drugs are known to have high potential as therapeutic agents, they have a limited clinical application owing to the absence of optimized delivery systems. Delivery of nucleic acids is limited by short half-life, immunogenicity, inability to penetrate physical barriers, insufficient cellular uptake, and delivery to undesired cells leading to off-target gene silencing-mediated toxicity [[11], [12], [13]]. Recently, exosomes have garnered much attention as a suitable platform
Protein delivery
Macromolecular protein therapeutics have been demonstrated to be efficient in the treatment of cancer [32]. Although used widely, protein-based drugs are difficult to purify, with potential solvent toxicity, with the added difficulty in preserving protein activity and stability [33]. The short half-life of therapeutic proteins in vivo also limits efficient cancer therapy [34]. Exosomes can overcome these challenges, with their ability to transport proteins generated from parent cells, long-term
Chemotherapy delivery
Although chemotherapeutic drugs such as doxorubicin and paclitaxel are efficient tumor-suppressors, they have low intratumoral delivery, poor bioavailability, and off-site toxicities [60,61]. Therefore, a new therapeutic approach for targeting and delivering chemotherapy to tumors is desired. Recent studies have shown that exosomes may be used as a therapeutic platform to deliver chemotherapeutics loaded exogenously, such as co-incubation or electroporation [62].
Toffoli et al. also demonstrated
Factors that affect the clinical use of exosomes
Several clinical trials have been attempted over the past decade, using exosomes for cancer therapy (Table 2). However, several questions on the optimization of exosomes for clinical usage remain unanswered, such as how to increase the yield of exosomes specific to cell types and optimize production. Furthermore, it is unclear how to store large therapeutic substances in and on exosomes and how to design a better delivery scheme to specific tissues, in a clinical setting.
Conclusion
Much attention has recently been paid to functionalized exosomes as a drug delivery platform owing to the following. First, exosomes commonly show high stability, high biocompatibility, and low immunogenicity than other drug delivery platforms, leading to a prolonged half-life of therapeutic targets. Second, the lipid bilayer membrane structure of exosomes preserves the function of membrane proteins. Third, nano-sized exosomes that bear specific surface proteins, such as integrins, can
Author contributions
Y.K.K. G.-H.N. and I.-S.K. designed manuscript; Y.K.K. G.-H.N. collated literatures and drafted the manuscript; Y.C. edited the manuscript; I.-S.K. provided oversight and reviewed the manuscript. All authors read and approved the final manuscript.
Declaration of competing interest
The authors declare no competing interests.
Acknowledgements
This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government [2017R1A3B1023418 and 2018H1A2A1062948]; the KIST Institutional Program; the KU-KIST Graduate School of Converging Science and Technology Program. We would like to thank Editage (www.editage.co.kr) for English language editing.
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