Extracellular vesicles as drug delivery systems: Lessons from the liposome field

Meel, Roy van der; Fens, Marcel H.A.M.; Vader, Pieter; Solinge, Wouter W. van; Eniola‐Adefeso, Omolola; Schiffelers, Raymond M.

doi:10.1016/j.jconrel.2014.07.049

Cited by 405 publications

(286 citation statements)

References 152 publications

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“…Exosomes are acknowledged to bear advantages above synthetic nanovesicles for in vivo drug delivery, mostly related to the high stability in body fluids and their properties of "natural delivery system" (45)(46)(47). Furthermore, their elevated plasticity in terms of molecular manipulation makes exosomes more appealing than for instance liposomes, also tested for TRAIL delivery (12)(13)(14).…”

Section: Discussionmentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

Rivoltini

Chiodoni

Squarcina

et al. 2016

Clinical Cancer Research

166

120

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Purpose: Exosomes deliver signals to target cells and could thus be exploited as an innovative therapeutic tool. We investigated the ability of membrane TRAIL-armed exosomes to deliver proapoptotic signals to cancer cells and mediate growth inhibition in different tumor models.Experimental Methods and Results: K562 cells, transduced with lentiviral human membrane TRAIL, were used for the production of TRAIL þ exosomes, which were studied by nanoparticle tracking analysis, cytofluorimetry, immunoelectronmicroscopy, Western blot, and ELISA. In vitro, TRAIL þ exosomes induced more pronounced apoptosis (detected by Annexin V/ propidium iodide and activated caspase-3) in TRAIL-death receptor (DR)5 þ cells (SUDHL4 lymphoma and INT12 melanoma), with respect to the DR5 À DR4 þ KMS11 multiple myeloma. Intratumor injection of TRAIL þ exosomes, but not mock exosomes, induced growth inhibition of SUDHL4 (68%) and INT12 (51%), and necrosis in KMS11 tumors. After rapid blood clearance, systemically administered TRAIL þ exosomes accumulated in the liver, lungs, and spleen and homed to the tumor site, leading to a significant reduction of tumor growth (58%) in SUDHL4-bearing mice. The treatment of INT12-bearing animals promoted tumor necrosis and a not statistically significant tumor volume reduction. In KMS11-bearing mice, despite massive perivascular necrosis, no significant tumor growth inhibition was detected.Conclusions: TRAIL-armed exosomes can induce apoptosis in cancer cells and control tumor progression in vivo. Therapeutic efficacy was particularly evident in intratumor setting, while depended on tumor model upon systemic administration. Thanks to their ability to deliver multiple signals, exosomes thus represent a promising therapeutic tool in cancer.

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Section: Discussionmentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

Rivoltini

Chiodoni

Squarcina

et al. 2016

Clinical Cancer Research

166

120

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“…Furthermore, MSC-EVs have been successfully used to treat a steroid-resistant Graft- versus -host disease (GvHD) patient without inducing any side effects [14]. In addition to their therapeutic potential, EVs are increasingly recognised as biomarkers for a variety of different diseases such as cancer [22–24], and are considered drug-delivery vehicles for different substances [20,25,26]. …”

Section: Introductionmentioning

confidence: 99%

Precipitation with polyethylene glycol followed by washing and pelleting by ultracentrifugation enriches extracellular vesicles from tissue culture supernatants in small and large scales

Ludwig

Miroschedji

Doeppner

et al. 2018

J of Extracellular Vesicle

198

206

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Extracellular vesicles (EVs) provide a complex means of intercellular signalling between cells at local and distant sites, both within and between different organs. According to their cell-type specific signatures, EVs can function as a novel class of biomarkers for a variety of diseases, and can be used as drug-delivery vehicles. Furthermore, EVs from certain cell types exert beneficial effects in regenerative medicine and for immune modulation. Several techniques are available to harvest EVs from various body fluids or cell culture supernatants. Classically, differential centrifugation, density gradient centrifugation, size-exclusion chromatography and immunocapturing-based methods are used to harvest EVs from EV-containing liquids. Owing to limitations in the scalability of any of these methods, we designed and optimised a polyethylene glycol (PEG)-based precipitation method to enrich EVs from cell culture supernatants. We demonstrate the reproducibility and scalability of this method and compared its efficacy with more classical EV-harvesting methods. We show that washing of the PEG pellet and the re-precipitation by ultracentrifugation remove a huge proportion of PEG co-precipitated molecules such as bovine serum albumine (BSA). However, supported by the results of the size exclusion chromatography, which revealed a higher purity in terms of particles per milligram protein of the obtained EV samples, PEG-prepared EV samples most likely still contain a certain percentage of other non-EV associated molecules. Since PEG-enriched EVs revealed the same therapeutic activity in an ischemic stroke model than corresponding cells, it is unlikely that such co-purified molecules negatively affect the functional properties of obtained EV samples. In summary, maybe not being the purification method of choice if molecular profiling of pure EV samples is intended, the optimised PEG protocol is a scalable and reproducible method, which can easily be adopted by laboratories equipped with an ultracentrifuge to enrich for functional active EVs.

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“…In addition, production strategies of artificial EVs based on liposomes are more sustainble and easier to scale up [11,89]. This fact is quite important for preclinical and clinical studies and in order to manufacture products ready to be sent to the market [2].…”

Section: Top-down and Bottom-up Methods For The Development Of Full Smentioning

confidence: 99%

“…While technological progress has allowed the design, development and production of nanomedicines with high pharmaceutical grade, their clinical impact has been smaller than expected due to a lack of sufficient information about in vivo interactions and fates inside the human body [11]. Specific challenges [13] are related to the functionalization of vesicle surface with a combination of functional proteins at the same time because actual methodologies are time-consuming and because of the incorporation of nucleic acids with acceptable efficiencies.…”

Section: Top-down and Bottom-up Methods For The Development Of Full Smentioning

confidence: 99%

Therapeutic biomaterials based on extracellular vesicles: classification of bio‐engineering and mimetic preparation routes

García‐Manrique

Matos

Gutiérrez

et al. 2018

J of Extracellular Vesicle

151

153

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Extracellular vesicles (EVs) are emerging as novel theranostic tools. Limitations related to clinical uses are leading to a new research area on design and manufacture of artificial EVs. Several strategies have been reported in order to produce artificial EVs, but there has not yet been a clear criterion by which to differentiate these novel biomaterials. In this paper, we suggest for the first time a systematic classification of the terms used to build up the artificial EV landscape, based on the preparation method. This could be useful to guide the derivation to clinical trial routes and to clarify the literature. According to our classification, we have reviewed the main strategies reported to date for their preparation, including key points such as: cargo loading, surface targeting strategies, purification steps, generation of membrane fragments for the construction of biomimetic materials, preparation of synthetic membranes inspired in EV composition and subsequent surface decoration.

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Extracellular vesicles as drug delivery systems: Lessons from the liposome field

Cited by 405 publications

References 152 publications

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

TNF-Related Apoptosis-Inducing Ligand (TRAIL)–Armed Exosomes Deliver Proapoptotic Signals to Tumor Site

Precipitation with polyethylene glycol followed by washing and pelleting by ultracentrifugation enriches extracellular vesicles from tissue culture supernatants in small and large scales

Therapeutic biomaterials based on extracellular vesicles: classification of bio‐engineering and mimetic preparation routes

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