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Advanced Drug Delivery Reviews Dec 2021
Topics: Diagnostic Imaging; Drug Delivery Systems; Drug Development; Extracellular Vesicles; Humans; In Vitro Techniques; Neoplasms
PubMed: 34710528
DOI: 10.1016/j.addr.2021.114026 -
Cell Proliferation Jan 2021Metastasis refers to the progressive dissemination of primary tumour cells and their colonization of other tissues and is associated with most cancer-related... (Review)
Review
Metastasis refers to the progressive dissemination of primary tumour cells and their colonization of other tissues and is associated with most cancer-related mortalities. The disproportional and systematic distribution pattern of distant metastasis in different cancers has been well documented, as is termed metastatic organotropism, a process orchestrated by a combination of anatomical, pathophysiological, genetic and biochemical factors. Extracellular vesicles (EVs), nanosized cell-derived membrane-bound particles known to mediate intercellular communication, are now considered crucial in organ-specific metastasis. Here, we review and summarize recent findings regarding EV-associated organotropic metastasis as well as some of the general mechanisms by which EVs contribute to this important process in cancer and provide a future perspective on this emerging topic. We highlight studies that demonstrate a role of tumour-derived EVs in organotropic metastasis via pre-metastatic niche modulation. The bioactive cargo carried by EVs is of diagnostic and prognostic values, and counteracting the functions of such EVs may be a novel therapeutic strategy targeting metastasis. Further investigations are warranted to better understand the functions and mechanisms of EVs in organotropic metastasis and accelerate the relevant clinical translation.
Topics: Animals; Extracellular Vesicles; Humans; Neoplasm Metastasis; Neoplasms
PubMed: 33145869
DOI: 10.1111/cpr.12948 -
ACS Nano Feb 2021The ability to track extracellular vesicles (EVs) without influencing their biodistribution is a key requirement for their successful development as drug delivery...
The ability to track extracellular vesicles (EVs) without influencing their biodistribution is a key requirement for their successful development as drug delivery vehicles and therapeutic agents. Here, we evaluated the effect of five different optical and nuclear tracers on the biodistribution of EVs. Expi293F EVs were labeled using either a noncovalent fluorescent dye DiR, or covalent modification with indium-DTPA, or bioengineered with fluorescent (mCherry) or bioluminescent (Firefly and NanoLuc luciferase) proteins fused to the EV marker, CD63. To focus specifically on the effect of the tracer, we compared EVs derived from the same cell source and administered systemically by the same route and at equal dose into tumor-bearing BALB/c mice. Indium and DiR were the most sensitive tracers for imaging of EVs, providing the most accurate quantification of vesicle biodistribution by imaging of organs and analysis of tissue lysates. Specifically, NanoLuc fused to CD63 altered EV distribution, resulting in high accumulation in the lungs, demonstrating that genetic modification of EVs for tracking purposes may compromise their physiological biodistribution. Blood kinetic analysis revealed that EVs are rapidly cleared from the circulation with a half-life below 10 min. Our study demonstrates that radioactivity is the most accurate EV tracking approach for a complete quantitative biodistribution study including pharmacokinetic profiling. In conclusion, we provide a comprehensive comparison of fluorescent, bioluminescent, and radioactivity approaches, including dual labeling of EVs, to enable accurate spatiotemporal resolution of EV trafficking in mice, an essential step in developing EV therapeutics.
Topics: Animals; Extracellular Vesicles; Kinetics; Mice; Mice, Inbred BALB C; Radioactive Tracers; Tissue Distribution
PubMed: 33470092
DOI: 10.1021/acsnano.0c09873 -
ACS Applied Bio Materials Mar 2023Extracellular vesicles (EVs)─including exosomes and microvesicles─are involved in cell-cell communication. EVs encapsulate different types of molecules such as...
Extracellular vesicles (EVs)─including exosomes and microvesicles─are involved in cell-cell communication. EVs encapsulate different types of molecules such as proteins or nucleotides and are long-lasting contenders for the establishment of personalized drug delivery systems. Recent studies suggest that the intrinsic capacities for uptake and cargo delivery of basic EVs might be too limited to serve as a potent delivery system. Here, we develop two synergistic methods to, respectively, control EV cargo loading and enhance EV cargo delivery through fusion without requirement for any viral fusogenic protein. Briefly, cargo loading is enabled through a reversible drug-inducible system that triggers the interaction between a cargo of interest and CD63, a well-established transmembrane EV marker. Enhanced cargo delivery is promoted by overexpressing Syncytin-1, an endogenous retrovirus envelop protein with fusogenic properties encoded by the human genome. We validate our bioengineered EVs in a qualitative and quantitative manner. Finally, we utilize this method to develop highly potent killer EVs, which contain a lethal toxin responsible for protein translation arrest and acceptor cell death. These advanced methods and future downstream applications may open promising doors in the manufacture of virus-free and EV-based delivery systems.
Topics: Humans; Biological Transport; Extracellular Vesicles; Exosomes; Drug Delivery Systems
PubMed: 36781171
DOI: 10.1021/acsabm.2c00955 -
Frontiers in Cellular and Infection... 2022Tuberculosis (TB) remains a public health issue causing millions of infections every year. Of these, about 15% ultimately result in death. Efforts to control TB include... (Review)
Review
Tuberculosis (TB) remains a public health issue causing millions of infections every year. Of these, about 15% ultimately result in death. Efforts to control TB include development of new and more effective vaccines, novel and more effective drug treatments, and new diagnostics that test for both latent TB Infection and TB disease. All of these areas of research benefit from a good understanding of the physiology of (Mtb), the primary causative agent of TB. Mtb secreted protein antigens have been the focus of vaccine and diagnosis research for the past century. Recently, the discovery of extracellular vesicles (EVs) as an important source of secreted antigens in Mtb has gained attention. Similarly, the discovery that host EVs can carry Mtb products during and infection has spiked interest because of its potential use in blood-based diagnostics. Despite advances in understanding the content of Mtb and Mtb-infected host extracellular vesicles, our understanding on the biogenesis and role of Mtb and host extracellular vesicles during Mtb infection is still nascent. Here, we explore the current literature on extracellular vesicles regarding Mtb, discuss the host and Mtb extracellular vesicles as distinct entities, and discuss current gaps in the field.
Topics: Extracellular Vesicles; Humans; Latent Tuberculosis; Mycobacterium tuberculosis; Tuberculosis; Tuberculosis Vaccines
PubMed: 35719351
DOI: 10.3389/fcimb.2022.912831 -
Biomolecules Apr 2022Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and... (Review)
Review
Proteasomes are traditionally considered intracellular complexes that play a critical role in maintaining proteostasis by degrading short-lived regulatory proteins and removing damaged proteins. Remarkably, in addition to these well-studied intracellular roles, accumulating data indicate that proteasomes are also present in extracellular body fluids. Not much is known about the origin, biological role, mode(s) of regulation or mechanisms of extracellular transport of these complexes. Nevertheless, emerging evidence indicates that the presence of proteasomes in the extracellular milieu is not a random phenomenon, but rather a regulated, coordinated physiological process. In this review, we provide an overview of the current understanding of extracellular proteasomes. To this end, we examine 143 proteomic datasets, leading us to the realization that 20S proteasome subunits are present in at least 25 different body fluids. Our analysis also indicates that while 19S subunits exist in some of those fluids, the dominant proteasome activator in these compartments is the PA28α/β complex. We also elaborate on the positive correlations that have been identified in plasma and extracellular vesicles, between 20S proteasome and activity levels to disease severity and treatment efficacy, suggesting the involvement of this understudied complex in pathophysiology. In addition, we address the considerations and practical experimental methods that should be taken when investigating extracellular proteasomes. Overall, we hope this review will stimulate new opportunities for investigation and thoughtful discussions on this exciting topic that will contribute to the maturation of the field.
Topics: Cytoplasm; Extracellular Vesicles; Proteasome Endopeptidase Complex; Proteins; Proteomics
PubMed: 35625547
DOI: 10.3390/biom12050619 -
International Journal of Molecular... Apr 2021Extracellular vesicles (EVs) derived from mesenchymal stem cells isolated from both bone marrow (BMSCs) and adipose tissue (ADSCs) show potential therapeutic effects....
Differential Therapeutic Effect of Extracellular Vesicles Derived by Bone Marrow and Adipose Mesenchymal Stem Cells on Wound Healing of Diabetic Ulcers and Correlation to Their Cargoes.
Extracellular vesicles (EVs) derived from mesenchymal stem cells isolated from both bone marrow (BMSCs) and adipose tissue (ADSCs) show potential therapeutic effects. These vesicles often show a similar beneficial effect on tissue regeneration, but in some contexts, they exert different biological properties. To date, a comparison of their molecular cargo that could explain the different biological effect is not available. Here, we demonstrated that ADSC-EVs, and not BMSC-EVs, promote wound healing on a murine model of diabetic wounds. Besides a general similarity, the bioinformatic analysis of their protein and miRNA cargo highlighted important differences between these two types of EVs. Molecules present exclusively in ADSC-EVs were highly correlated to angiogenesis, whereas those expressed in BMSC-EVs were preferentially involved in cellular proliferation. Finally, in vitro analysis confirmed that both ADSC and BMSC-EVs exploited beneficial effect on cells involved in skin wound healing such as fibroblasts, keratinocytes and endothelial cells, but through different cellular processes. Consistent with the bioinformatic analyses, BMSC-EVs were shown to mainly promote proliferation, whereas ADSC-EVs demonstrated a major effect on angiogenesis. Taken together, these results provide deeper comparative information on the cargo of ADSC-EVs and BMSC-EVs and the impact on regenerative processes essential for diabetic wound healing.
Topics: Adipose Tissue; Animals; Bone Marrow Cells; Diabetes Complications; Exosomes; Extracellular Vesicles; Flow Cytometry; Gene Expression Profiling; Immunohistochemistry; Mesenchymal Stem Cells; Mice; Ulcer; Wound Healing
PubMed: 33917759
DOI: 10.3390/ijms22083851 -
Aging Oct 2019
Topics: Caveolin 1; Extracellular Vesicles; Gene Expression Regulation; Humans; MicroRNAs
PubMed: 31652419
DOI: 10.18632/aging.102370 -
Cells Sep 2022In this review, we will discuss the current status of extracellular vesicle (EV) delivery via biopolymeric scaffolds for therapeutic applications and the challenges... (Review)
Review
In this review, we will discuss the current status of extracellular vesicle (EV) delivery via biopolymeric scaffolds for therapeutic applications and the challenges associated with the development of these functionalized scaffolds. EVs are cell-derived membranous structures and are involved in many physiological processes. Naïve and engineered EVs have much therapeutic potential, but proper delivery systems are required to prevent non-specific and off-target effects. Targeted and site-specific delivery using polymeric scaffolds can address these limitations. EV delivery with scaffolds has shown improvements in tissue remodeling, wound healing, bone healing, immunomodulation, and vascular performance. Thus, EV delivery via biopolymeric scaffolds is becoming an increasingly popular approach to tissue engineering. Although there are many types of natural and synthetic biopolymers, the overarching goal for many tissue engineers is to utilize biopolymers to restore defects and function as well as support host regeneration. Functionalizing biopolymers by incorporating EVs works toward this goal. Throughout this review, we will characterize extracellular vesicles, examine various biopolymers as a vehicle for EV delivery for therapeutic purposes, potential mechanisms by which EVs exert their effects, EV delivery for tissue repair and immunomodulation, and the challenges associated with the use of EVs in scaffolds.
Topics: Biocompatible Materials; Extracellular Vesicles; Tissue Engineering; Wound Healing
PubMed: 36139426
DOI: 10.3390/cells11182851 -
Frontiers in Endocrinology 2023MicroRNAs (miRNA) are small non-coding RNA molecules that regulate posttranscriptional gene expression by repressing messengerRNA-targets. MiRNAs are abundant in many... (Review)
Review
MicroRNAs (miRNA) are small non-coding RNA molecules that regulate posttranscriptional gene expression by repressing messengerRNA-targets. MiRNAs are abundant in many cell types and are secreted into extracellular fluids, protected from degradation by packaging in extracellular vesicles. These circulating miRNAs are easily accessible, disease-specific and sensitive to small changes, which makes them ideal biomarkers for diagnostic, prognostic, predictive or monitoring purposes. Specific miRNA signatures can be reflective of disease status and development or indicators of poor treatment response. This is especially important in malignant diseases, as the ease of accessibility of circulating miRNAs circumvents the need for invasive tissue biopsy. In osteogenesis, miRNAs can act either osteo-enhancing or osteo-repressing by targeting key transcription factors and signaling pathways. This review highlights the role of circulating and extracellular vesicle-derived miRNAs as biomarkers in bone-related diseases, with a specific focus on osteoporosis and osteosarcoma. To this end, a comprehensive literature search has been performed. The first part of the review discusses the history and biology of miRNAs, followed by a description of different types of biomarkers and an update of the current knowledge of miRNAs as biomarkers in bone related diseases. Finally, limitations of miRNAs biomarker research and future perspectives will be presented.
Topics: Humans; MicroRNAs; Biomarkers; Extracellular Vesicles; Circulating MicroRNA; Osteosarcoma; Bone Neoplasms
PubMed: 37293498
DOI: 10.3389/fendo.2023.1168898