Extracellular Vesicles Mediate the Intercellular Exchange of Nanoparticles

Wu, Xian; Tang, Tang; Wei, Yushuang; Cummins, Katherine A; Wood, David K.; Pang, Henrianna

doi:10.1002/advs.202102441

Cited by 12 publications

(19 citation statements)

References 68 publications

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“…We then adapted this assay into a collagenbased 3D assay. [13] With this assay, we confirmed that these are extracellular vesicles (EVs), but not direct cell-cell contacts, that are these membrane-enclosed structures for the intercellular exchange. We also demonstrated that EV-mediated intercellular exchange plays an important role in extravasation and penetration of NPs in vivo.…”

Section: Introductionmentioning

confidence: 60%

“…[10,11] We termed the exit from one cell (donor) and the re-entry into another (recipient) together as intercellular exchange, and developed cellular assays to monitor and quantify the intercellular exchange events in vitro. [12,13] In the first version of our assay, donor and recipient cells were simply mixed in ultralow binding plates to form spheroids (termed "spheroid" model). [12] Our results with this assay revealed that a significant portion of NPs are transferred intercellularly in membraneenclosed structures.…”

Section: Introductionmentioning

confidence: 99%

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Identification of an ALK‐2 Inhibitor as an Agonist for Intercellular Exchange and Tumor Delivery of Nanomaterial

Guo

Zhao

et al. 2022

Advanced Therapeutics

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Inefficient extravasation and penetration in solid tissues hinder the clinical outcome of nanoparticles (NPs). Recent studies have shown the extravasation and penetration of NPs in solid tumor are mostly achieved via an active transcellular route. Numerous efforts are devoted to elucidate the endocytosis and subcellular trafficking of NPs. However, how they exit from one cell and re-enter into neighboring ones (termed intercellular exchange) remains poorly understood. The previous study showed that a significant portion of NPs are transferred inside extracellular vesicles (EVs). Inhibition of EV biogenesis significantly reduces tumor accumulation and vascular penetration of various NPs in vivo. Here, a manual chemical screen is performed with this assay, which identifies that LDN-214117 (an inhibitor for activin receptor-like kinase-2, ALK-2) as an agonist of NP intercellular exchange. LDN-214117 is showed to regulate the intercellular exchange by increasing the EV biogenesis via bone morphogenetic protein-mitogen-activated protein kinase (BMP-MAPK) signaling pathway. LDN-214117 treatment further enhances tumor accumulation and vascular penetration of a variety of NPs in multiple tumor models, which improves their antitumor efficacy. Overall, the identification of a novel chemical compound with intercellular exchange assay is showcase to modulate EV-mediated transport, thus boosting the delivery and therapeutic efficacy of nanomaterials.

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Section: Introductionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Identification of an ALK‐2 Inhibitor as an Agonist for Intercellular Exchange and Tumor Delivery of Nanomaterial

Guo

Zhao

et al. 2022

Advanced Therapeutics

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“…The NM surface parameters (e.g., size and surface coating) determine cellular uptake and subsequent sorting into EVs. Another exciting aspect is that EVs can also mediate the intercellular exchange of nanoparticles [ 53 ]. Theoretically, transcellular transport consists of four steps: entry into one cell, intracellular transport, cargo export or exocytosis, and the re-entry of released cargo into another cell.…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, while freely released nanoparticles engage with the same cellular receptors for re-entry, EV-enclosed ones bypass this dependence. These studies provided an easy and precise system to investigate the intercellular exchange stage of NMs delivery and shed the first light on the importance of EV transport between cells and across complex tissues [ 53 ]. Trojan exosome hypothesis where virus uses exosome biogenesis pathway for the formation of infectious particles.…”

Section: Discussionmentioning

confidence: 99%

Nanomaterial Exposure, Extracellular Vesicle Biogenesis and Adverse Cellular Outcomes: A Scoping Review

et al. 2022

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The progressively increasing use of nanomaterials (NMs) has awakened issues related to nanosafety and its potential toxic effects on human health. Emerging studies suggest that NMs alter cell communication by reshaping and altering the secretion of extracellular vesicles (EVs), leading to dysfunction in recipient cells. However, there is limited understanding of how the physicochemical characteristics of NMs alter the EV content and their consequent physiological functions. Therefore, this review explored the relevance of EVs in the nanotoxicology field. The current state of the art on how EVs are modulated by NM exposure and the possible regulation and modulation of signaling pathways and physiological responses were assessed in detail. This review followed the manual for reviewers produced by The Joanna Brigs Institute for Scoping Reviews and the PRISMA extension for Scoping Reviews (PRISMA-ScR): checklist and explanation. The research question, “Do NMs modulate cellular responses mediated by EVs?” was analyzed following the PECO model (P (Population) = EVs, E (Exposure) = NMs, C (Comparator) = EVs without exposure to NMs, O (Outcome) = Cellular responses/change in EVs) to help methodologically assess the association between exposure and outcome. For each theme in the PECO acronym, keywords were defined, organized, and researched in PubMed, Science Direct, Scopus, Web of Science, EMBASE, and Cochrane databases, up to 30 September 2021. In vitro, in vivo, ex vivo, and clinical studies that analyzed the effect of NMs on EV biogenesis, cargo, and cellular responses were included in the analysis. The methodological quality assessment was conducted using the ToxRTool, ARRIVE guideline, Newcastle Ottawa and the EV-TRACK platform. The search in the referred databases identified 2944 articles. After applying the eligibility criteria and two-step screening, 18 articles were included in the final review. We observed that depending on the concentration and physicochemical characteristics, specific NMs promote a significant increase in EV secretion as well as changes in their cargo, especially regarding the expression of proteins and miRNAs, which, in turn, were involved in biological processes that included cell communication, angiogenesis, and activation of the immune response, etc. Although further studies are necessary, this work suggests that molecular investigations on EVs induced by NM exposure may become a potential tool for toxicological studies since they are widely accessible biomarkers that may form a bridge between NM exposure and the cellular response and pathological outcome.

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“…has shown that docetaxel resistant variants of DU145 and 22Rv1 cells transfer the docetaxel resistance to sensitive cells (DU145, 22Rv1 and LNCaP) partly through MDR-1/P-gp transfer, suggesting the role of exosomes in the propagation of chemoresistance [ 54 ] . Moreover, other studies have reported the inhibition of EVs secretion in cell culture and/or suppression of tumor growth in mice after GW4869 treatment [ 53 , 55 - 57 ] . In vivo experiment in the present study indicated that GW4869 treatment decreases the tumor growth significantly without affecting the overall bodyweight of the mice.…”

Section: Discussionmentioning

confidence: 99%

Role of extracellular vesicles secretion in paclitaxel resistance of prostate cancer cells

Kumar¹,

Kumar²,

Sharma³

et al. 2022

Cancer Drug Resist

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Aim: The development of chemotherapy resistance is the major obstacle in the treatment of advanced prostate cancer (PCa). Extracellular vesicles (EVs) secretion plays a significant role among different mechanisms contributing to chemoresistance. Hence, inhibition of EVs release may increase the efficacy of chemotherapeutic drugs against PCa. Methods: Paclitaxel (PTX) resistant PCa cells (PC3-R and DU145-R) were treated with GW4869, a known exosome biogenesis inhibitor. EVs were isolated from the conditioned media by ExoQuick-based precipitation method and characterized for concentration and size distribution by nanoparticle tracking analysis. The effect of GW4869 treatment on the survival and growth of PCa cells was assessed by MTT, and colony formation assays in vitro, and ectopic PC3-R xenografts in male athymic nude mice in vivo. The effect of other EV biogenesis inhibitors, imipramine and dimethyl amiloride (DMA), treatment was also analyzed on the survival of PC3-R cells. Results: GW4869 (10-20 µM) treatment of PTX resistant PCa cells significantly reduced the release of small EVs (50-100 nm size range) while increasing the release of larger EVs (> 150 nm in size), and inhibited their clonogenicity. Moreover, GW4869 (5-20 µM) treatment (24-72h) significantly inhibited the survival of PC3-R cells in a dose-dependent manner. We observed a similar growth inhibition with both imipramine (5-20 µg/mL) and DMA (5-20 µg/mL) treatment in PC3-R cells. Furthermore, GW4869 treatment (IP) in mice bearing PC3-R xenografts significantly reduced the tumor weight (65% reduction, P = 0.017) compared to the vehicle-treated control mice without causing any noticeable toxicity. Conclusion: Inhibiting the release of EVs could sensitize the resistant PCa cells to chemotherapy.

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Extracellular Vesicles Mediate the Intercellular Exchange of Nanoparticles

Cited by 12 publications

References 68 publications

Identification of an ALK‐2 Inhibitor as an Agonist for Intercellular Exchange and Tumor Delivery of Nanomaterial

Identification of an ALK‐2 Inhibitor as an Agonist for Intercellular Exchange and Tumor Delivery of Nanomaterial

Nanomaterial Exposure, Extracellular Vesicle Biogenesis and Adverse Cellular Outcomes: A Scoping Review

Role of extracellular vesicles secretion in paclitaxel resistance of prostate cancer cells

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