Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: New nanotools for cancer treatment

Kooijmans, Sander A.A.; Schiffelers, Raymond M.; Zarovni, Nataša; Vago, Riccardo

doi:10.1016/j.phrs.2016.07.006

Cited by 168 publications

(116 citation statements)

References 136 publications

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“…Exosomes have different receptors or membranous proteins, depending on the cell of origin, and accordingly have different tropism in the body. 5 In fact, we hypothesize that different exosomes with cell-specific surface proteins may have distinct routes and circulation pattern all over the body. The use of exosomes as nanovehicles in the field of cancer therapy requires the recognition of the tumor tropism of the extracted exosomes.…”

Section: Introductionmentioning

confidence: 95%

Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo

Naseri

Oskuee

Jaafari

et al. 2018

IJN

205

116

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BackgroundExosomes, widely recognized natural nanovesicles, represent one of the recently discovered modes of intercellular communication due to their ability to transmit crucial cellular information that can be engineered to have robust delivery and targeting capacity. MiR-142-3p, one of the upregulated microRNAs (miRNAs) in many types of breast cancer, activates the canonical Wnt signaling pathway and transactivates the miR-150 expression, and results in the hyperproliferation of cancer cells in vitro and mammary glands in vivo.Materials and methodsIn this study, we exploited the exosomes isolated from bone marrow-derived mesenchymal stem cells (MSCs-Exo) to deliver LNA (locked nucleic acid)-modified anti-miR-142-3p oligonucleotides to suppress the expression level of miR-142-3p and miR-150 in 4T1 and TUBO breast cancer cell lines.ResultsThe in vitro results showed that the MSCs-Exo can efficiently deliver anti-miR-142-3p to reduce the miR-142-3p and miR-150 levels and increase the transcription of the regulatory target genes, APC and P2X7R. We also evaluated in vivo distribution of the MSCs-Exo in tumor-bearing mice. The in vivo result indicated that MSCs-Exo can penetrate the tumor site and are suitable nanovehicles to deliver the inhibitory oligonucleotides into the tumor tissues to downregulate the expression levels of miR-142-3p and miR-150.ConclusionWe showed that MSCs-derived exosomes could be used as a feasible nanovehicle to deliver drug molecules like LNA-anti-miR-142-3p in both in vitro and in vivo studies.

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Section: Introductionmentioning

confidence: 95%

Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo

Naseri

Oskuee

Jaafari

et al. 2018

IJN

205

116

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“…Therefore, detargeting from macrophages or targeting of EVs to specific tissues may enhance their therapeutic efficacy and reduce possible off-target effects. In order to achieve targeted delivery different strategies to modify EVs' natural tropism have been developed (Table 2) [119–121]. Some approaches require the functionalization of the cellular source to generate “tailored” EVs (Figure 2).…”

Section: Targeting Extracellular Vesicles Deliverymentioning

confidence: 99%

Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis

Rocco¹,

Baldari²,

Toietta³

2016

Stem Cells International

120

101

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Extracellular vesicles (EVs), such as microvesicles and exosomes, are membranous structures containing bioactive material released by several cells types, including mesenchymal stem/stromal cells (MSCs). Increasing lines of evidences point to EVs as paracrine mediators of the beneficial effects on tissue remodeling associated with cell therapy. Administration of MSCs-derived EVs has therefore the potential to open new and safer therapeutic avenues, alternative to cell-based approaches, for degenerative diseases. However, an enhanced knowledge about in vivo EVs trafficking upon delivery is required before effective clinical translation. Only a few studies have focused on the biodistribution analysis of exogenously administered MSCs-derived EVs. Nevertheless, current strategies for in vivo tracking in animal models have provided valuable insights on the biodistribution upon systemic delivery of EVs isolated from several cellular sources, indicating in liver, spleen, and lungs the preferential target organs. Different strategies for targeting EVs to specific tissues to enhance their therapeutic efficacy and reduce possible off-target effects have been investigated. Here, in the context of a possible clinical application of MSC-derived EVs for tissue regeneration, we review the existing strategies for in vivo tracking and targeting of EVs isolated from different cellular sources and the studies elucidating the biodistribution of exogenously administered EVs.

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“…Their membranous shell prevents degradation of their contents, which comprise primarily soluble factors, proteins and RNAs, making possible long-duration and long-distance actions 17 . During cell binding and uptake, EVs induce a sort of functional expansion in the cell, transferring their functional transcriptome, proteome and lipidome to recipient cells and also inducing epigenetic modifications 18, 19 . Overall, there are plenty of evidence indicating that EV-shuttled biomolecules can profoundly affect the phenotype and activity of their target cells 20 .…”

Section: Introductionmentioning

confidence: 99%

Secretome of in vitro cultured human embryos contains extracellular vesicles that are uptaken by the maternal side

Giacomini

Vago

Sánchez

et al. 2017

Sci Rep

Self Cite

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135

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Communication between embryo and maternal endometrium occurs during a specific time frame in which implantation is possible. Here we demonstrate for the first time that conditioned media from non-manipulated human embryos cultured in vitro for 3 days or up to the blastocyst stage contain extracellular vesicles (EVs) with a diameter of 50 to 200 nm and bearing the traditional microvesicle and exosome marker proteins CD63, CD9 and ALIX. The embryonic origin of these EVs has been confirmed by the presence of stemness gene transcripts and their enrichment in the non-classical HLA-G protein. NANOG and POU5F1 transcripts were shown to be contained in vesicles deriving from embryos at different stages of development. In line with a higher detection rate of the HLA-G protein in blastocysts compared to cleavage stage embryos, a significantly higher amount of HLA-G was found in vesicles accumulated in spent media from day 3 to day 5 of development compared to those isolated from the earlier stage. Uptake of dye-labeled embryo-derived EVs by human primary endometrial epithelial and stromal cells was also demonstrated with a fluorescence intensity signal significantly higher for cells treated with vesicles derived from blastocysts. Based on these findings, EV exchange may be suggested as an emerging way of communication at the maternal-fetal interface.Since the first gestation reported in 1976 1 , more than five million pregnancies have been achieved worldwide by in vitro fertilization and its modifications, known generically as assisted reproductive technologies (ARTs). Currently, ART accounts for 1 to 3 percent of live births in the United States and Europe. Despite significant advances in the understanding of infertility mechanisms and the overcoming of many deficiencies in human fertility by evolving ART, the number of 'take-home' babies still remains low 2 . Research in this area is moving toward the improvement of success rates through a better understanding of embryo and uterine physiology 3 .Embryo implantation and consequent pregnancy is thought to involve a two-way communication between maternal uterus and the blastocyst, a dialogue whose success seems essential for the progression through the processes of embryo apposition, adhesion, attachment and penetration [4][5][6] . Some embryonic signals modulating this dialogue have been identified 7-9 . Among them, human chorionic gonadotrophin synthesized early by the trophoblast cells acts on the uterine environment via the luteinizing hormone/hCG receptor and exerts both autocrine effects, promoting differentiation 10 and migration of trophoblasts 11 , and paracrine effects on the maternal endometrium 12 . Another molecule identified in embryo culture media and supposed to be involved in the regulation of local maternal immune response is represented by sHLA-G 13 . HLA-G1/G5 protein expression has been detected in human preimplantation embryos in association with β2-microglobulin and the soluble spliced isoform has been proposed as a noninvasive tool for embryo select...

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Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: New nanotools for cancer treatment

Cited by 168 publications

References 136 publications

Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo

Exosome-mediated delivery of functionally active miRNA-142-3p inhibitor reduces tumorigenicity of breast cancer in vitro and in vivo

Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis

Secretome of in vitro cultured human embryos contains extracellular vesicles that are uptaken by the maternal side

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