Journal articles on the topic 'EV-based therapeutics'
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Williams, Katherine B., and Nicole P. Ehrhart. "Regenerative medicine 2.0: extracellular vesicle–based therapeutics for musculoskeletal tissue regeneration." Journal of the American Veterinary Medical Association 260, no. 7 (April 1, 2022): 683–89. http://dx.doi.org/10.2460/javma.22.02.0060.
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In recent years, extracellular vesicles (EVs) have emerged as prominent mediators of the homeostasis, repair, and regeneration of musculoskeletal tissues including bone, skeletal muscle, and cartilage. Accordingly, the therapeutic potential of EVs for regenerative medicine applications has not gone unnoticed. The use of EVs for the treatment of musculoskeletal injury and disease in veterinary species is a nascent but rapidly expanding area of research. Recent studies in this area have demonstrated the safety and feasibility of EV products in dogs and horses. While early clinical responses to EV-based therapeutics in companion animals have been favorable, more rigorously designed, sufficiently powered, and placebo-controlled clinical trials are required to fully elucidate the clinical benefits and best-use scenarios for EV therapeutics in veterinary medicine. Additionally, clinical translation of EV-based therapeutics will require Good Manufacturing Practice–compliant methods to scale up and purify EV products. Despite these challenges, EVs hold great promise in the regenerative medicine landscape, particularly in the treatment of musculoskeletal injury and disease in companion animals.
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OCHIYA, Takahiro. "Development of extracellular vesicle (EV)-based diagnostics and therapeutics." Translational and Regulatory Sciences 2, no. 3 (2020): 80–83. http://dx.doi.org/10.33611/trs.2020-016.
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Klyachko, Natalia L., Camryn J. Arzt, Samuel M. Li, Olesia A. Gololobova, and Elena V. Batrakova. "Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations." Pharmaceutics 12, no. 12 (December 1, 2020): 1171. http://dx.doi.org/10.3390/pharmaceutics12121171.
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Drug nanoformulations hold remarkable promise for the efficient delivery of therapeutics to a disease site. Unfortunately, artificial nanocarriers, mostly liposomes and polymeric nanoparticles, show limited applications due to the unfavorable pharmacokinetics and rapid clearance from the blood circulation by the reticuloendothelial system (RES). Besides, many of them have high cytotoxicity, low biodegradability, and the inability to cross biological barriers, including the blood brain barrier. Extracellular vesicles (EVs) are novel candidates for drug delivery systems with high bioavailability, exceptional biocompatibility, and low immunogenicity. They provide a means for intercellular communication and the transmission of bioactive compounds to targeted tissues, cells, and organs. These features have made them increasingly attractive as a therapeutic platform in recent years. However, there are many obstacles to designing EV-based therapeutics. In this review, we will outline the main hurdles and limitations for therapeutic and clinical applications of drug loaded EV formulations and describe various attempts to solve these problems.
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Nelson, Bryant C., Samantha Maragh, Ionita C. Ghiran, Jennifer C. Jones, Paul C. DeRose, Elzafir Elsheikh, Wyatt N. Vreeland, and Lili Wang. "Measurement and standardization challenges for extracellular vesicle therapeutic delivery vectors." Nanomedicine 15, no. 22 (September 2020): 2149–70. http://dx.doi.org/10.2217/nnm-2020-0206.
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Extracellular vesicles (EVs), such as exosomes and microvesicles, are nonreplicating lipid bilayer particles shed by most cell types which have the potential to revolutionize the development and efficient delivery of clinical therapeutics. This article provides an introduction to the landscape of EV-based vectors under development for the delivery of protein- and nucleic acid-based therapeutics. We highlight some of the most pressing measurement and standardization challenges that limit the translation of EVs to the clinic. Current challenges limiting development of EVs for drug delivery are the lack of: standardized cell-based platforms for the production of EV-based therapeutics; EV reference materials that allow researchers/manufacturers to validate EV measurements and standardized measurement systems for determining the molecular composition of EVs.
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Dang, Xuan T. T., Jayasinghe Migara Kavishka, Daniel Xin Zhang, Marco Pirisinu, and Minh T. N. Le. "Extracellular Vesicles as an Efficient and Versatile System for Drug Delivery." Cells 9, no. 10 (September 29, 2020): 2191. http://dx.doi.org/10.3390/cells9102191.
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Despite the recent advances in drug development, the majority of novel therapeutics have not been successfully translated into clinical applications. One of the major factors hindering their clinical translation is the lack of a safe, non-immunogenic delivery system with high target specificity upon systemic administration. In this respect, extracellular vesicles (EVs), as natural carriers of bioactive cargo, have emerged as a promising solution and can be further modified to improve their therapeutic efficacy. In this review, we provide an overview of the biogenesis pathways, biochemical features, and isolation methods of EVs with an emphasis on their many intrinsic properties that make them desirable as drug carriers. We then describe in detail the current advances in EV therapeutics, focusing on how EVs can be engineered to achieve improved target specificity, better circulation kinetics, and efficient encapsulation of therapeutic payloads. We also identify the challenges and obstacles ahead for clinical translation and provide an outlook on the future perspective of EV-based therapeutics.
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Gilligan, Katie E., and Róisín M. Dwyer. "Extracellular Vesicles for Cancer Therapy: Impact of Host Immune Response." Cells 9, no. 1 (January 16, 2020): 224. http://dx.doi.org/10.3390/cells9010224.
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In recent times, extracellular vesicles (EVs) have come under the spotlight as potential therapeutics for cancer, due to the relative ease of manipulation of contents and potential for tumor targeting. The use of EVs as delivery vehicles may bypass some of the negative effects associated with cell-based carriers, and there has been a major focus on defining EV subtypes, establishing transparent nomenclature, and isolation and characterization techniques. EVs are believed to be a fingerprint of the secreting cell and so researchers harness the positive aspects of a particular cell of origin, and can then further modify EV contents to improve therapeutic efficacy. In this review, we highlight studies employing EVs as cancer therapeutics that have reported on immune response. As we rapidly advance towards potential application in the clinical setting, the question of immune response to EV administration in the cancer setting has become critically important.
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Abreu, Catarina M., Bruno Costa-Silva, Rui L. Reis, Subhas C. Kundu, and David Caballero. "Microfluidic platforms for extracellular vesicle isolation, analysis and therapy in cancer." Lab on a Chip 22, no. 6 (2022): 1093–125. http://dx.doi.org/10.1039/d2lc00006g.
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Ovchinnikova, Leyla A., Ioanna N. Filimonova, Maria Y. Zakharova, Dmitriy S. Balabashin, Teimour K. Aliev, Yakov A. Lomakin, and Alexander G. Gabibov. "Targeting Extracellular Vesicles to Dendritic Cells and Macrophages." Acta Naturae 13, no. 3 (November 15, 2021): 114–21. http://dx.doi.org/10.32607/actanaturae.11478.
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Targeting protein therapeutics to specific cells and tissues is a major challenge in modern medicine. Improving the specificity of protein therapeutic delivery will significantly enhance efficiency in drug development. One of the promising tools for protein delivery is extracellular vesicles (EVs) that are enveloped by a complex lipid bilayer. EVs are secreted by almost all cell types and possess significant advantages: biocompatibility, stability, and the ability to penetrate the bloodbrain barrier. Overexpression of the vesicular stomatitis virus protein G (VSV-G) was shown to promote EV formation by the producer cell. We have developed an EV-based system for targeted delivery of protein cargoes to antigen-presenting cells (APCs). In this study, we show that attachment of a recombinant llama nanobody -CD206 to the N-terminus of a truncated VSV-G increases the selectivity of EV cargo delivery mainly to APCs. These results highlight the outstanding technological and biomedical potential of EV-based delivery systems for correcting the immune response in patients with autoimmune, viral, and oncological diseases.
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Brown, Thomas J., and Victoria James. "The Role of Extracellular Vesicles in the Development of a Cancer Stem Cell Microenvironment Niche and Potential Therapeutic Targets: A Systematic Review." Cancers 13, no. 10 (May 18, 2021): 2435. http://dx.doi.org/10.3390/cancers13102435.
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Cancer stem cells (CSCs) have increasingly been shown to be a crucial element of heterogenous tumors. Although a relatively small component of the population, they increase the resistance to treatment and the likelihood of recurrence. In recent years, it has been shown, across multiple cancer types (e.g., colorectal, breast and prostate), that reciprocal communication between cancer and the microenvironment exists, which is, in part, facilitated by extracellular vesicles (EVs). However, the mechanisms of this method of communication and its influence on CSC populations is less well-understood. Therefore, the aim of this systematic review is to determine the evidence that supports the role of EVs in the manipulation of the tumor microenvironment to promote the survival of CSCs. Embase and PubMed were used to identify all studies on the topic, which were screened using PRISMA guidelines, resulting in the inclusion of 16 studies. These 16 studies reported on the EV content, pathways altered by EVs and therapeutic targeting of CSC through EV-mediated changes to the microenvironment. In conclusion, these studies demonstrated the role of EV-facilitated communication in maintaining CSCs via manipulation of the tumor microenvironment, demonstrating the potential of creating therapeutics to target CSCs. However, further works are needed to fully understand the targetable mechanisms upon which future therapeutics can be based.
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Haney, Matthew J., Yuling Zhao, Yeon S. Jin, and Elena V. Batrakova. "Extracellular Vesicles as Drug Carriers for Enzyme Replacement Therapy to Treat CLN2 Batten Disease: Optimization of Drug Administration Routes." Cells 9, no. 5 (May 20, 2020): 1273. http://dx.doi.org/10.3390/cells9051273.
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CLN2 Batten disease (BD) is one of a broad class of lysosomal storage disorders that is characterized by the deficiency of lysosomal enzyme, TPP1, resulting in a build-up of toxic intracellular storage material in all organs and subsequent damage. A major challenge for BD therapeutics is delivery of enzymatically active TPP1 to the brain to attenuate progressive loss of neurological functions. To accomplish this daunting task, we propose the harnessing of naturally occurring nanoparticles, extracellular vesicles (EVs). Herein, we incorporated TPP1 into EVs released by immune cells, macrophages, and examined biodistribution and therapeutic efficacy of EV-TPP1 in BD mouse model, using various routes of administration. Administration through intrathecal and intranasal routes resulted in high TPP1 accumulation in the brain, decreased neurodegeneration and neuroinflammation, and reduced aggregation of lysosomal storage material in BD mouse model, CLN2 knock-out mice. Parenteral intravenous and intraperitoneal administrations led to TPP1 delivery to peripheral organs: liver, kidney, spleen, and lungs. A combination of intrathecal and intraperitoneal EV-TPP1 injections significantly prolonged lifespan in BD mice. Overall, the optimization of treatment strategies is crucial for successful applications of EVs-based therapeutics for BD.
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Andrade, André Cronemberger, Martin Wolf, Heide-Marie Binder, Fausto Gueths Gomes, Felix Manstein, Patricia Ebner-Peking, Rodolphe Poupardin, Robert Zweigerdt, Katharina Schallmoser, and Dirk Strunk. "Hypoxic Conditions Promote the Angiogenic Potential of Human Induced Pluripotent Stem Cell-Derived Extracellular Vesicles." International Journal of Molecular Sciences 22, no. 8 (April 9, 2021): 3890. http://dx.doi.org/10.3390/ijms22083890.
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Stem cells secrete paracrine factors including extracellular vesicles (EVs) which can mediate cellular communication and support the regeneration of injured tissues. Reduced oxygen (hypoxia) as a key regulator in development and regeneration may influence cellular communication via EVs. We asked whether hypoxic conditioning during human induced pluripotent stem cell (iPSC) culture effects their EV quantity, quality or EV-based angiogenic potential. We produced iPSC-EVs from large-scale culture-conditioned media at 1%, 5% and 18% air oxygen using tangential flow filtration (TFF), with or without subsequent concentration by ultracentrifugation (TUCF). EVs were quantified by tunable resistive pulse sensing (TRPS), characterized according to MISEV2018 guidelines, and analyzed for angiogenic potential. We observed superior EV recovery by TFF compared to TUCF. We confirmed hypoxia efficacy by HIF-1α stabilization and pimonidazole hypoxyprobe. EV quantity did not differ significantly at different oxygen conditions. Significantly elevated angiogenic potential was observed for iPSC-EVs derived from 1% oxygen culture by TFF or TUCF as compared to EVs obtained at higher oxygen or the corresponding EV-depleted soluble factor fractions. Data thus demonstrate that cell-culture oxygen conditions and mode of EV preparation affect iPSC-EV function. We conclude that selecting appropriate protocols will further improve production of particularly potent iPSC-EV-based therapeutics.
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Yan, Biying, and Yaxuan Liang. "New Therapeutics for Extracellular Vesicles: Delivering CRISPR for Cancer Treatment." International Journal of Molecular Sciences 23, no. 24 (December 12, 2022): 15758. http://dx.doi.org/10.3390/ijms232415758.
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Cancers are defined by genetic defects, which underlines the prospect of using gene therapy in patient care. During the past decade, CRISPR technology has rapidly evolved into a powerful gene editing tool with high fidelity and precision. However, one of the impediments slowing down the clinical translation of CRISPR-based gene therapy concerns the lack of ideal delivery vectors. Extracellular vesicles (EVs) are nano-sized membrane sacs naturally released from nearly all types of cells. Although EVs are secreted for bio-information conveyance among cells or tissues, they have been recognized as superior vectors for drug or gene delivery. Recently, emerging evidence has spotlighted EVs in CRISPR delivery towards cancer treatment. In this review, we briefly introduce the biology and function of the CRISPR system and follow this with a summary of current delivery methods for CRISPR applications. We emphasize the recent progress in EV-mediated CRISPR editing for various cancer types and target genes. The reported strategies for constructing EV-CRISPR vectors, as well as their limitations, are discussed in detail. The review aims to throw light on the clinical potential of engineered EVs and encourage the expansion of our available toolkit to defeat cancer.
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Chong, Suet Yen, Choon Keong Lee, Chenyuan Huang, Yi Hsuan Ou, Christopher J. Charles, Arthur Mark Richards, Yub Raj Neupane, et al. "Extracellular Vesicles in Cardiovascular Diseases: Alternative Biomarker Sources, Therapeutic Agents, and Drug Delivery Carriers." International Journal of Molecular Sciences 20, no. 13 (July 3, 2019): 3272. http://dx.doi.org/10.3390/ijms20133272.
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Cardiovascular diseases (CVD) represent the leading cause of morbidity and mortality globally. The emerging role of extracellular vesicles (EVs) in intercellular communication has stimulated renewed interest in exploring the potential application of EVs as tools for diagnosis, prognosis, and therapy in CVD. The ubiquitous nature of EVs in biological fluids presents a technological advantage compared to current diagnostic tools by virtue of their notable stability. EV contents, such as proteins and microRNAs, represent specific signatures of cellular activation or injury. This feature positions EVs as an alternative source of biomarkers. Furthermore, their intrinsic activity and immunomodulatory properties offer EVs unique opportunities to act as therapeutic agents per se or to serve as drug delivery carriers by acting as miniaturized vehicles incorporating bioactive molecules. In this article, we aim to review the recent advances and applications of EV-based biomarkers and therapeutics. In addition, the potential of EVs as a drug delivery and theranostic platform for CVD will also be discussed.
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Ovchinnikova, Leyla A., Stanislav S. Terekhov, Rustam H. Ziganshin, Dmitriy V. Bagrov, Ioanna N. Filimonova, Arthur O. Zalevsky, and Yakov A. Lomakin. "Reprogramming Extracellular Vesicles for Protein Therapeutics Delivery." Pharmaceutics 13, no. 6 (May 21, 2021): 768. http://dx.doi.org/10.3390/pharmaceutics13060768.
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Delivering protein therapeutics specifically into target cells and tissues is a promising avenue in medicine. Advancing this process will significantly enhance the efficiency of the designed drugs. In this regard, natural membrane-based systems are of particular interest. Extracellular vesicles (EVs), being the bilayer lipid particles secreted by almost all types of cells, have several principal advantages: biocompatibility, carrier stability, and blood–brain barrier penetrability, which make them a perspective tool for protein therapeutic delivery. Here, we evaluate the engineered genetically encoded EVs produced by a human cell line, which allow efficient cargo loading. In the devised system, the protein of interest is captured by self-assembling structures, i.e., “enveloped protein nanocages” (EPN). In their turn, EPNs are encapsulated in fusogenic EVs by the overexpression of vesicular stomatitis virus G protein (VSV-G). The proteomic profiles of different engineered EVs were determined for a comprehensive evaluation of their therapeutic potential. EVs loading mediated by bio-safe Fos–Jun heterodimerization demonstrates an increased efficacy of active cargo loading and delivery into target cells. Our results emphasize the outstanding technological and biomedical potential of the engineered EV systems, including their application in adoptive cell transfer and targeted cell reprogramming.
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Yim, Kevin Ho Wai, Ala’a Al Hrout, Simone Borgoni, and Richard Chahwan. "Extracellular Vesicles Orchestrate Immune and Tumor Interaction Networks." Cancers 12, no. 12 (December 9, 2020): 3696. http://dx.doi.org/10.3390/cancers12123696.
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Extracellular vesicles (EVs) are emerging as potent and intricate intercellular communication networks. From their first discovery almost forty years ago, several studies have bolstered our understanding of these nano-vesicular structures. EV subpopulations are now characterized by differences in size, surface markers, cargo, and biological effects. Studies have highlighted the importance of EVs in biology and intercellular communication, particularly during immune and tumor interactions. These responses can be equally mediated at the proteomic and epigenomic levels through surface markers or nucleic acid cargo signaling, respectively. Following the exponential growth of EV studies in recent years, we herein synthesize new aspects of the emerging immune–tumor EV-based intercellular communications. We also discuss the potential role of EVs in fundamental immunological processes under physiological conditions, viral infections, and tumorigenic conditions. Finally, we provide insights on the future prospects of immune–tumor EVs and suggest potential avenues for the use of EVs in diagnostics and therapeutics.
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Heath, Nikki, Xabier Osteikoetxea, Taiana Mia de Oliveria, Elisa Lázaro-Ibáñez, Olga Shatnyeva, Christina Schindler, Natalie Tigue, et al. "Endosomal escape enhancing compounds facilitate functional delivery of extracellular vesicle cargo." Nanomedicine 14, no. 21 (November 2019): 2799–814. http://dx.doi.org/10.2217/nnm-2019-0061.
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Aim: Extracellular vesicles (EVs) are desirable delivery vehicles for therapeutic cargoes. We aimed to load EVs with Cre recombinase protein and determine whether functional delivery to cells could be improved by using endosomal escape enhancing compounds. Materials & methods: Overexpressed CreFRB protein was actively loaded into EVs by rapalog-induced dimerization to CD81FKBP, or passively loaded by overexpression in the absence of rapalog. Functional delivery of CreFRB was analysed using a HEK293 Cre reporter cell line in the absence and presence of endosomal escape enhancing compounds. Results: The EVs loaded with CreFRB by both active and passive mechanisms were able to deliver functional CreFRB to recipient cells only in the presence of endosomal escape enhancing compounds chloroquine and UNC10217832A. Conclusion: The use of endosomal escape enhancing compounds in conjunction with EVs loaded with therapeutic cargoes may improve efficacy of future EV based therapeutics.
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Khawar, Muhammad Babar, Muddasir Hassan Abbasi, Zerwa Siddique, Amin Arif, and Nadeem Sheikh. "An Update on Novel Therapeutic Warfronts of Extracellular Vesicles (EVs) in Cancer Treatment: Where We Are Standing Right Now and Where to Go in the Future." Oxidative Medicine and Cellular Longevity 2019 (July 25, 2019): 1–21. http://dx.doi.org/10.1155/2019/9702562.
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Extracellular vesicles (EVs) are a heterogeneous group of membrane-bounded vesicles that are believed to be produced and secreted by presumably all cell types under physiological and pathological conditions, including tumors. EVs are very important vehicles in intercellular communications for both shorter and longer distances and are able to deliver a wide range of cargos including proteins, lipids, and various species of nucleic acids effectively. EVs have been emerging as a novel biotherapeutic platform to efficiently deliver therapeutic cargos to treat a broad range of diseases including cancer. This vast potential of drug delivery lies in their abilities to carry a variety of cargos and their ease in crossing the biological membranes. Similarly, their presence in a variety of body fluids makes them a potential biomarker for early diagnosis, prognostication, and surveillance of cancer. Here, we discuss the relatively least and understudied aspects of EV biology and tried to highlight the obstacles and limitations in their clinical applications and also described most of the new warfronts to beat cancer at multiple stages. However, much more challenges still remain to evaluate EV-based therapeutics, and we are very much hopeful that the current work prompts further discovery.
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Fujita, Yu, Tsukasa Kadota, Jun Araya, Takahiro Ochiya, and Kazuyoshi Kuwano. "Clinical Application of Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapeutics for Inflammatory Lung Diseases." Journal of Clinical Medicine 7, no. 10 (October 14, 2018): 355. http://dx.doi.org/10.3390/jcm7100355.
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It is currently thought that extracellular vesicles (EVs), such as exosomes and microvesicles, play an important autocrine/paracrine role in intercellular communication. EVs package proteins, mRNA and microRNA (miRNA), which have the ability to transfer biological information to recipient cells in the lungs. Depending on their origin, EVs fulfil different functions. EVs derived from mesenchymal stem cells (MSCs) have been found to promote therapeutic activities that are comparable to MSCs themselves. Recent animal model-based studies suggest that MSC-derived EVs have significant potential as a novel alternative to whole-cell therapies. Compared to their parent cells, EVs may have a superior safety profile and can be stored without losing function. It has been observed that MSC-derived EVs suppress pro-inflammatory processes and reduce oxidative stress, pulmonary fibrosis and remodeling in a variety of in vivo inflammatory lung disease models by transferring their components. However, there remain significant challenges to translate this therapy to the clinic. From this view point, we will summarize recent studies on EVs produced by MSCs in preclinical experimental models of inflammatory lung diseases. We will also discuss the most relevant issues in bringing MSC-derived EV-based therapeutics to the clinic for the treatment of inflammatory lung diseases.
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Kaddour, Hussein, Malik Tranquille, and Chioma M. Okeoma. "The Past, the Present, and the Future of the Size Exclusion Chromatography in Extracellular Vesicles Separation." Viruses 13, no. 11 (November 13, 2021): 2272. http://dx.doi.org/10.3390/v13112272.
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Extracellular vesicles (EVs) are cell-derived membranous particles secreted by all cell types (including virus infected and uninfected cells) into the extracellular milieu. EVs carry, protect, and transport a wide array of bioactive cargoes to recipient/target cells. EVs regulate physiological and pathophysiological processes in recipient cells and are important in therapeutics/drug delivery. Despite these great attributes of EVs, an efficient protocol for EV separation from biofluids is lacking. Numerous techniques have been adapted for the separation of EVs with size exclusion chromatography (SEC)-based methods being the most promising. Here, we review the SEC protocols used for EV separation, and discuss opportunities for significant improvements, such as the development of novel particle purification liquid chromatography (PPLC) system capable of tandem purification and characterization of biological and synthetic particles with near-single vesicle resolution. Finally, we identify future perspectives and current issues to make PPLC a tool capable of providing a unified, automated, adaptable, yet simple and affordable particle separation resource.
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Royo, Felix, Clotilde Théry, Juan M. Falcón-Pérez, Rienk Nieuwland, and Kenneth W. Witwer. "Methods for Separation and Characterization of Extracellular Vesicles: Results of a Worldwide Survey Performed by the ISEV Rigor and Standardization Subcommittee." Cells 9, no. 9 (August 25, 2020): 1955. http://dx.doi.org/10.3390/cells9091955.
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Research on extracellular vesicles (EVs) is growing exponentially due to an increasing appreciation of EVs as disease biomarkers and therapeutics, an expanding number of EV-containing materials under study, and application of new preparation, detection, and cargo analysis methods. Diversity of both sources and methodologies imposes challenges on the comparison of measurement results between studies and laboratories. While reference guidelines and minimal requirements for EV research have achieved the important objective of assembling community consensus, it is also essential to understand which methodologies and quality controls are currently being applied, and how usage trends are evolving. As an initial response to this need, the International Society for Extracellular Vesicles (ISEV) performed a worldwide survey in 2015 on “Techniques used for the isolation and characterization of extracellular vesicles” and published the results from this survey in 2016. In 2019, a new survey was performed to assess the changing state of the field. The questionnaire received more than 600 full or partial responses, and the present manuscript summarizes the results of this second worldwide survey. The results emphasize that separation methods such as ultracentrifugation and density gradients are still the most commonly used methods, the use of size exclusion chromatography has increased, and techniques based on tangential flow and microfluidics are now being used by more than 10% of respondents. The survey also reveals that most EV researchers still do not perform sample quality controls before or after isolation of EVs. Finally, the majority of EV researchers emphasize that separation and characterization of EVs should receive more attention.
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Villata, Simona, Marta Canta, and Valentina Cauda. "EVs and Bioengineering: From Cellular Products to Engineered Nanomachines." International Journal of Molecular Sciences 21, no. 17 (August 22, 2020): 6048. http://dx.doi.org/10.3390/ijms21176048.
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Extracellular vesicles (EVs) are natural carriers produced by many different cell types that have a plethora of functions and roles that are still under discovery. This review aims to be a compendium on the current advancement in terms of EV modifications and re-engineering, as well as their potential use in nanomedicine. In particular, the latest advancements on artificial EVs are discussed, with these being the frontier of nanomedicine-based therapeutics. The first part of this review gives an overview of the EVs naturally produced by cells and their extraction methods, focusing on the possibility to use them to carry desired cargo. The main issues for the production of the EV-based carriers are addressed, and several examples of the techniques used to upload the cargo are provided. The second part focuses on the engineered EVs, obtained through surface modification, both using direct and indirect methods, i.e., engineering of the parental cells. Several examples of the current literature are proposed to show the broad variety of engineered EVs produced thus far. In particular, we also report the possibility to engineer the parental cells to produce cargo-loaded EVs or EVs displaying specific surface markers. The third and last part focuses on the most recent advancements based on synthetic and chimeric EVs and the methods for their production. Both top-down or bottom-up techniques are analyzed, with many examples of applications.
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De Luca, Thomas, Robert E. Stratford, Madison E. Edwards, Christina R. Ferreira, and Eric A. Benson. "Novel Quantification of Extracellular Vesicles with Unaltered Surface Membranes Using an Internalized Oligonucleotide Tracer and Applied Pharmacokinetic Multiple Compartment Modeling." Pharmaceutical Research 38, no. 10 (October 2021): 1677–95. http://dx.doi.org/10.1007/s11095-021-03102-z.
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Abstract Purpose We developed an accessible method for labeling small extracellular vesicles (sEVs) without disrupting endogenous ligands. Using labeled sEVs administered to conscious rats, we developed a multiple compartment pharmacokinetic model to identify potential differences in the disposition of sEVs from three different cell types. Methods Crude sEVs were labeled with a non-homologous oligonucleotide and isolated from cell culture media using a commercial reagent. Jugular vein catheters were used to introduce EVs to conscious rats (n = 30) and to collect blood samples. Digital PCR was leveraged to allow for quantification over a wide dynamic range. Non-linear mixed effects analysis with first order conditional estimation – extended least squares (FOCE ELS) was used to estimate population-level parameters with associated intra-animal variability. Results 86.5% ± 1.5% (mean ± S.E.) of EV particles were in the 45–195 nm size range and demonstrated protein and lipid markers of endosomal origin. Incorporated oligonucleotide was stable in blood and detectable over five half-lives. Data were best described by a three-compartment model with one elimination from the central compartment. We performed an observation-based simulated posterior predictive evaluation with prediction-corrected visual predictive check. Covariate and bootstrap analyses identified cell type having an influence on peripheral volumes (V2 and V3) and clearance (Cl3). Conclusions Our method relies upon established laboratory techniques, can be tailored to a variety of biological questions regarding the pharmacokinetic disposition of extracellular vesicles, and will provide a complementary approach for the of study EV ligand-receptor interactions in the context of EV uptake and targeted therapeutics.
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Chitti, Sai V., Christina Nedeva, Raja Manickam, Pamali Fonseka, and Suresh Mathivanan. "Extracellular Vesicles as Drug Targets and Delivery Vehicles for Cancer Therapy." Pharmaceutics 14, no. 12 (December 16, 2022): 2822. http://dx.doi.org/10.3390/pharmaceutics14122822.
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Extracellular vesicles (EVs) are particles that are released from cells into the extracellular space both under pathological and normal conditions. It is now well established that cancer cells secrete more EVs compared to non-cancerous cells and that, captivatingly, several proteins that are involved in EV biogenesis and secretion are upregulated in various tumours. Recent studies have revealed that EVs facilitate the interaction between cancer cells and their microenvironment and play a substantial role in the growth of tumours. As EVs are involved in several aspects of cancer progression including angiogenesis, organotropism, pre-metastatic niche formation, fostering of metastasis, and chemoresistance, inhibiting the release of EVs from cancer and the surrounding tumour microenvironment cells has been proposed as an ideal strategy to treat cancer and associated paraneoplastic syndromes. Lately, EVs have shown immense benefits in preclinical settings as a novel drug delivery vehicle. This review provides a brief overview of the role of EVs in various hallmarks of cancer, focusing on (i) strategies to treat cancer by therapeutically targeting the release of tumour-derived EVs and (ii) EVs as valuable drug delivery vehicles. Furthermore, we also outline the drawbacks of the existing anti-cancer treatments and the future prospective of EV-based therapeutics.
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Bednova, Olga, and Jeffrey V. Leyton. "Targeted Molecular Therapeutics for Bladder Cancer—A New Option beyond the Mixed Fortunes of Immune Checkpoint Inhibitors?" International Journal of Molecular Sciences 21, no. 19 (October 1, 2020): 7268. http://dx.doi.org/10.3390/ijms21197268.
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The fact that there are now five immune checkpoint inhibitor (ICI) monoclonal antibodies approved since 2016 that target programmed cell death protein 1 or programmed death ligand-1 for the treatment of metastatic and refractory bladder cancer is an outstanding achievement. Although patients can display pronounced responses that extend survival when treated with ICIs, the main benefit of these drugs compared to traditional chemotherapy is that they are better tolerated and result in reduced adverse events (AEs). Unfortunately, response rates to ICI treatment are relatively low and, these drugs are expensive and have a high economic burden. As a result, their clinical efficacy/cost-value relationship is debated. Long sought after targeted molecular therapeutics have now emerged and are boasting impressive response rates in heavily pre-treated, including ICI treated, patients with metastatic bladder cancer. The antibody-drug conjugates (ADCs) enfortumab vedotin (EV) and sacituzumab govitecan (SG) have demonstrated the ability to provide objective response rates (ORRs) of 44% and 31% in patients with bladder tumor cells that express Nectin-4 and Trop-2, respectively. As a result, EV was approved by the U.S. Food and Drug Administration for the treatment of patients with advanced or metastatic bladder cancer who have previously received ICI and platinum-containing chemotherapy. SG has been granted fast track designation. The small molecule Erdafitinib was recently approved for the treatment of patients with advanced or metastatic bladder cancer with genetic alterations in fibroblast growth factor receptors that have previously been treated with a platinum-containing chemotherapy. Erdafitinib achieved an ORR of 40% in patients including a proportion who had previously received ICI therapy. In addition, these targeted drugs are sufficiently tolerated or AEs can be appropriately managed. Hence, the early performance in clinical effectiveness of these targeted drugs are substantially increased relative to ICIs. In this article, the most up to date follow-ups on treatment efficacy and AEs of the ICIs and targeted therapeutics are described. In addition, drug price and cost-effectiveness are described. For best overall value taking into account clinical effectiveness, price and cost-effectiveness, results favor avelumab and atezolizumab for ICIs. Although therapeutically promising, it is too early to determine if the described targeted therapeutics provide the best overall value as cost-effectiveness analyses have yet to be performed and long-term follow-ups are needed. Nonetheless, with the arrival of targeted molecular therapeutics and their increased effectiveness relative to ICIs, creates a potential novel paradigm based on ‘targeting’ for affecting clinical practice for metastatic bladder cancer treatment.
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Zhang, Jiayi, Annie Brown, Brendan Johnson, David Diebold, Kyle Asano, Gerard Marriott, and Biao Lu. "Genetically Engineered Extracellular Vesicles Harboring Transmembrane Scaffolds Exhibit Differences in Their Size, Expression Levels of Specific Surface Markers and Cell-Uptake." Pharmaceutics 14, no. 12 (November 23, 2022): 2564. http://dx.doi.org/10.3390/pharmaceutics14122564.
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Background: Human cell-secreted extracellular vesicles (EVs) are versatile nanomaterials suitable for disease-targeted drug delivery and therapy. Native EVs, however, usually do not interact specifically with target cells or harbor therapeutic drugs, which limits their potential for clinical applications. These functions can be introduced to EVs by genetic manipulation of membrane protein scaffolds, although the efficiency of these manipulations and the impacts they have on the properties of EVs are for the most part unknown. In this study, we quantify the effects of genetic manipulations of different membrane scaffolds on the physicochemical properties, molecular profiles, and cell uptake of the EVs. Methods: Using a combination of gene fusion, molecular imaging, and immuno-based on-chip analysis, we examined the effects of various protein scaffolds, including endogenous tetraspanins (CD9, CD63, and CD81) and exogenous vesicular stomatitis virus glycoprotein (VSVG), on the efficiency of integration in EV membranes, the physicochemical properties of EVs, and EV uptake by recipient cells. Results: Fluorescence imaging and live cell monitoring showed each scaffold type was integrated into EVs either in membranes of the endocytic compartment, the plasma membrane, or both. Analysis of vesicle size revealed that the incorporation of each scaffold increased the average diameter of vesicles compared to unmodified EVs. Molecular profiling of surface markers in engineered EVs using on-chip assays showed the CD63-GFP scaffold decreased expression of CD81 on the membrane surface compared to control EVs, whereas its expression was mostly unchanged in EVs bearing CD9-, CD81-, or VSVG-GFP. The results from cell uptake studies demonstrated that VSVG-engineered EVs were taken up by recipient cells to a greater degree than control EVs. Conclusion: We found that the incorporation of different molecular scaffolds in EVs altered their physicochemical properties, surface protein profiles, and cell-uptake functions. Scaffold-induced changes in the physical and functional properties of engineered EVs should therefore be considered in engineering EVs for the targeted delivery and uptake of therapeutics to diseased cells.
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Koul, Sneh, Victoria L. Schaal, Subhash Chand, Steven T. Pittenger, Neetha Nanoth Vellichirammal, Vikas Kumar, Chittibabu Guda, Rick A. Bevins, Sowmya V. Yelamanchili, and Gurudutt Pendyala. "Role of Brain Derived Extracellular Vesicles in Decoding Sex Differences Associated with Nicotine Self-Administration." Cells 9, no. 8 (August 11, 2020): 1883. http://dx.doi.org/10.3390/cells9081883.
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Smoking remains a significant health and economic concern in the United States. Furthermore, the emerging pattern of nicotine intake between sexes further adds a layer of complexity. Nicotine is a potent psychostimulant with a high addiction liability that can significantly alter brain function. However, the neurobiological mechanisms underlying nicotine’s impact on brain function and behavior remain unclear. Elucidation of these mechanisms is of high clinical importance and may lead to improved therapeutics for smoking cessation. To fill in this critical knowledge gap, our current study focused on identifying sex-specific brain-derived extracellular vesicles (BDEV) signatures in male and female rats post nicotine self-administration. Extracellular vesicles (EVs) are comprised of phospholipid nanovesicles such as apoptotic bodies, microvesicles (MVs), and exosomes based on their origin or size. EVs are garnering significant attention as molecules involved in cell–cell communication and thus regulating the pathophysiology of several diseases. Interestingly, females post nicotine self-administration, showed larger BDEV sizes, along with impaired EV biogenesis compared to males. Next, using quantitative mass spectrometry-based proteomics, we identified BDEV signatures, including distinct molecular pathways, impacted between males and females. In summary, this study has identified sex-specific changes in BDEV biogenesis, protein cargo signatures, and molecular pathways associated with long-term nicotine self-administration.
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Neri, Paola, Kathy Gratton, Li Ren, Jordan Johnson, Jiri Slaby, Peter Duggan, Douglas A. Stewart, and Nizar J. Bahlis. "Role of Mir-30e in Multiple Myeloma Cells Resistance to Lenalidomide and Bortezomib." Blood 120, no. 21 (November 16, 2012): 323. http://dx.doi.org/10.1182/blood.v120.21.323.323.
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Abstract Abstract 323 Background: miRNAs are non-coding small RNAs that modulate protein expression at the post-transcriptional level and are implicated in the pathogenesis of a variety of cancers. In Multiple Myeloma (MM) a global elevation of miRNAs was previously correlated with poor disease outcomes and response to therapy. Using miRNome profiling of MM patients, we have recently established a miRNA-based risk score that is predictive of response to lenalidomide (Neri P, Blood 2011). In particular, we identified significant upregulation of miR-30 family members (a, b, c and e) in lenalidomide resistant patients. In the present study, we evaluated the biological functions of miR-30e in MM and its role in plasma cells resistance to lenalidomide as well as other anti-MM therapeutics. Methods and Results: Microarray profiling (Affymetrix miRNA GeneChip) of total RNA extracted from bone marrow plasma cells from lenalidomide sensitive and resistant MM patients (n=40), coupled with quantitative short stem-loop PCR (TaqMan, Applied Biosystems), confirmed the upregulation of miR-30e in lenalidomide resistant patients. Functionally, we sought to determine if overexpression of miR-30e would modify MM cells sensitivity to lenalidomide and bortezomib. Lentiviral-mediated stable expression (pLKO.1 retroviral plasmid) of miR-30e, and relative to empty vector (EV), significant increased MM1S and OPM2 cells growth (1.3 fold) as determined by MTT assay. In addition, miR-30e overexpressing cells (MM1S-30e and OPM2-30e vs MM1-EV and OPM2-EV) were more resistant to the cytotoxic effects of lenalidomide as well as bortezomib with approximately 15 to 20% reduction in cells death (Annexin V staining and MTT assay). Computational target prediction analysis (TargetScan 6.0 and miRanda) identified CRBN and BLIMP1 as potential target of miR-30e with a miRNA seed region that matches 8 or 7mer sites within Cereblon and BLIMP1 3'UTR regions. In a panel of MM cell lines (MM1S, OPM2, H929, INA-6, U266, 8226, KMS11) CRBN mRNA levels were indeed inversely correlated with miR-30e and stable mir-30e overexpression significantly reduced CRBN mRNA in these cells (MM1S-30e and OPM2-30e). In addition to CRBN, BLIMP1 mRNA and protein levels were also reduced in miR-30e overexpressing cells. In plasma cells, BLIMP1 drives XBP1 expression while supressing c-myc. In MM1S-30e and OPM2-30e (relative to empty vector), and consistent with their reduced BLIMP1 expression, XBP1 mRNA and protein levels were reduced. Furthermore, treatment with lenalidomide (10μM) significantly reduced c-MYC protein levels in MM1S-EV cells after 4 hours while it had no effect on C-MYC expression in MM1S-30e cells. Conclusions: miR-30e is overexpressed in resistant MM cells and is here shown to regulate cereblon expression, plasma cells differentiation axis (BLIMP1, XBP1) and cell growth (c-MYC). Disclosures: Neri: Johnson ans Johnson: Research Funding. Bahlis:Johnson and Johnson: Honoraria, Research Funding; Celgene: Honoraria.
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Jain, Rohit K., Youngchul Kim, Jennifer Rembisz, Richard Piekarz, Timothy W. Synold, Jingsong Zhang, and Guru P. Sonpavde. "Phase Ib trial of erdafitinib (E) combined with enfortumab vedotin (EV) following platinum and PD-1/L1 inhibitors for metastatic urothelial carcinoma (mUC) with FGFR2/3 genetic alterations (GAs)." Journal of Clinical Oncology 40, no. 6_suppl (February 20, 2022): TPS595. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.tps595.
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TPS595 Background: Erdafitinib and enfortumab vedotin are available treatment options in mUC patients with somatic FGFR2/3 GAs after progression on platinum-based chemotherapy and PD-1/L1 inhibitors. However, due to decline in their clinical condition, the sequential delivery of these agents is challenging. Tubulin antagonists induce a G2-M cell-cycle block, while FGFR inhibitors cause a G1 block, with studies suggesting that their combination may be additive or synergistic. Retrospective studies suggest that the activity of EV is not compromised by somatic FGFR2/3 GAs. Hence, there is rationale to evaluate the feasibility of the combination of EV and E, to overcome the difficulties of resistance and sequencing these agents in mUC patients with FGFR2/3 GAs. Methods: This is a phase Ib, single arm, multicenter study in patients with mUC harboring somatic FGFR2/3 GAs who have progressed after platinum and PD-1/L1 inhibitor therapies with enrollment of up to 30 patients. Pts are required to have predominant urothelial component, ECOG-PS 0-2, neuropathy ≤ grade 1 and no ophthalmologic conditions precluding treatment with E. FGFR2/3 GAs may be identified by tumor tissue or circulating tumor (ct)-DNA profiling. The primary objective is feasibility and establishing a recommended phase-2 dose (RP2D). Secondary objectives include objective response rate, duration of response, progression-free survival and overall survival. The dose-escalation component will enroll up to 18 pts with 3+3 design (dosing cohorts in table), followed by dose-expansion component of 12 pts. The dose limiting toxicities (DLTs) will be evaluated using a sequential Bayesian toxicity monitoring that allows a maximum DLT rate of 0.33 during the dose-expansion phase. Exploratory biomarker analyses will be performed including 1) tumor PD-L1, Nectin-4 assessment by immunohistochemistry and association with response 2) ct-DNA evaluation at baseline and progression to evaluate resistance pathways 3) pharmacokinetic studies will assess plasma levels of E and free monomethyl auristatin-E (MMAE). This is led by North American Star Consortium as part of Experimental Therapeutics. Clinical trial information: NCT04963153. [Table: see text]
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Nwizu, Chibuikem Chukwudalu, Lorin Crawford, Theo Borgovan, Sicheng Wen, Mark S. Dooner, Pamela C. Egan, John L. Reagan, Adam J. Olszewski, Laura R. Goldberg, and Peter J. Quesenberry. "Using Machine Learning to Classify the "Goodness" of Hmsc-Derived and AML-Derived EV's." Blood 132, Supplement 1 (November 29, 2018): 5244. http://dx.doi.org/10.1182/blood-2018-99-120183.
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Abstract Introduction Extracellular vesicles (EVs) form a unique class of messengers for intercellular communication. Depending on their cell of origin, EVs have the ability to induce a phenotypic change in the recipient cell. For example, EVs from explant prostate cancer induce a neoplastic phenotype in normal prostate cell lines. Conversely, EVs from human mesenchymal stem cells (hMSC) reverse the malignant phenotype in prostate and colorectal cancer and mitigate radiation damage to the marrow. Characterization of EVs as "good" or "bad" has the potential to be a very important diagnostic tool in regard to direct therapy and biomarker identification. Currently, there is no way of characterizing the "goodness" of an EV sample. We leveraged advances in the area of machine learning to develop a novel therapeutic tool that can classify the goodness of an EV particle distribution in a serum sample. Methods EVs were harvested from three sources: hMSC primary progenitor cells, Kasumi Acute Myeloid Leukemia (AML) cells lines, and patient samples. Using a standard centrifugation isolation, EVs were isolate, resuspended in 1% DMSO, and frozen. All samples were analyzed using the NanoSight N500. We collected biophysical properties of the EVs such as diameter and diffusion coefficient. The results were summarized in a distribution based on either size or diffusion coefficient. Summary statistics from each distributions were calculated. Summary statistics included mean, mode, and the diameter at which 10%, 50%, and 90% of size or diffusion coefficient is comprised of smaller particles (D10, D50, and D90, respectively). These served as inputs into a softmax Multilayer Perceptron. This neural network classifier was trained on only the hMSC-derived EVs and Kasumi AML-derived EVs, which served to represent a healthy patient and leukemic patient respectively. Results/Conclusion The mean accuracy after 10 fold cross validation was 90.16% ± 9.26%. For each validation run, a Receiver Operating Characteristic (ROC) curve was drawn and the area under the curve (AUC) was calculated. The mean AUC (after 10 fold cross validation) was 95.97% ± 5.38%. We programmed the algorithm, when given a patient sample, to calculate and return similarity to the Kasumi AML-derived EVs. The algorithm was given three patient sample representing three leukemic disease processes: AML, Chronic Myelomonocytic Leukemia (CMML), and Multiple myeloma (MM). The result was a calculate % similarity of 100%, 100%, and 66% for AML, CMML, and MM respectively. These results are promising and have prompted us to begin collecting and test the algorithms on normal, active leukemic, and recovered leukemic patients. We endeavor to evolve our predictive algorithms to include disease and patient specific information, allowing us to adapt our learning models towards clinically relevant endpoints. Disclosures Reagan: Alexion: Honoraria; Pfizer: Research Funding; Takeda Oncology: Research Funding. Olszewski:Spectrum Pharmaceuticals: Consultancy, Research Funding; TG Therapeutics: Research Funding; Genentech: Research Funding.
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Huntington, Scott F., Stephen J. Schuster, Wei He, Tong Shen, Heather Walker, Laura Leary, Kylie Boyhen, et al. "Phase I Study of First-in-Class Oral Triplet Therapy DTRM-555 in Relapsed/Refractory Lymphoma Patients through Fixed-Dose Combination and Synthetic Lethality." Blood 132, Supplement 1 (November 29, 2018): 5384. http://dx.doi.org/10.1182/blood-2018-99-112944.
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Abstract Background: Synthetic lethality (SL) is characterized by the chemical inhibition of multiple aberrant genes to differentially kill malignant cells. We investigated small-molecule combinations for SL through in vitro and in vivo screening and optimization studies (as in the granted patents in USA and China) and demonstrated the synergistic potential of best-in-class combinations of targeted agents, drug repositioning, immune modulation and low-dose combinations. We hypothesize that BTK and mTOR inhibition coupled with an IMID will target multiple key signaling pathways, improve differential apoptosis and target acquired drug resistance. DTRM-555, an optimized mechanism-based combination, consists of the clinically differentiated BTK inhibitor DTRMWXHS-12 (or DTRM-12), everolimus (EV) and pomalidomide (POM). In xenograft tumor models, DTRM-555 administered orally has demonstrated superior efficacy over monotherapy at very low dose combinations of the three agents (1/18 of DTRM-12, 1/6 of EV, and 1/6 of POM). DTRM-12 monotherapy has been safe and well tolerated in simultaneous phase Ia trials (US and China) with preliminary efficacy across 50 mg through 400 mg once daily (QD). Here we report the US clinical results of the oral combination therapies DTRM-505 (DTRM-12 plus EV) and DTRM-555 (DTRM-12 plus EV plus POM) for the first time (NCT02900716). Methods: The safety and anti-tumor activity of the oral doublet therapy DTRM-505 and the oral triplet therapy DTRM-555 are evaluated using a "3+3" study design. Enrollment was conducted concurrently with a phase Ia study of DTRM-12 monotherapy; with DTRM-505 opened for accrual when monotherapy DTRM-12 cleared the 200-mg dose level. Eligible patients are at least 18 years old, having ECOG performance status less than 2 with relapsed/refractory chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL) or classical Hodgkin lymphoma (cHL). Study treatment is administered daily for 21 consecutive days over a 28-day cycle. The dose-limiting toxicity (DLT) period was defined during the first cycle of therapy, and treatment was continued until disease progression or unacceptable toxicity. Patients underwent tumor evaluations every 2 months and response was recorded using revised response criteria (IWCLL and Cheson 2014). Results: Between 9/2016 and 7/2018, 19 patients have been treated with DTRM-12 monotherapy in the USA (6 pts, 50-300 mg) and China (13 pts, 50-400 mg). Patients have tolerated up to 23+ cycles of DTRM-12 monotherapy. Seven patients, including DLBCL, CLL, MCL, FL and cHL, have been treated with oral doublet therapy DTRM-505 for 2 to 12 cycles. Three patients (2 DLBCL, 1 FL) have been treated with oral triplet therapy DTRM-555, including one patient transitioned from the doublet DTRM-505 under an exploratory arm. No patient has discontinued due to an adverse event (AE) and no DLT has occurred. Recurring AEs are mostly grade 1 or 2 and responses have been seen with DTRM-505 and DTRM-555 across diverse lymphoma histologies (See Tables). All patients evaluable for response demonstrated partial response to DTRM-505 and DTRM-555, with 2/7 (doublet) and 3/3 (triplet) patients remaining on therapy. Conclusion: The maximum tolerated dose has not been reached for DTRM-12 monotherapy and for the current fixed dose doublet and triplet combinations. Toxicities have been mild and repeated cycles of study treatment have been well tolerated without delays of subsequent treatment cycles. Enrollment continues for refractory lymphoma patients to demonstrate the safety and efficacy for the first-in-class oral triplet therapy DTRM-555. Disclosures Huntington: Janssen: Consultancy; Bayer: Consultancy; Celgene: Consultancy. Schuster:Merck: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria; Dava Oncology: Consultancy, Honoraria; Physician's Education Source, LLC: Honoraria; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees. He:Zhejiang DTRM Biopharma Co. Ltd.: Other: Founder and CEO; Zhejiang DTRM Biopharma LLC: Other: Founder and CEO. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Kennard:AbbVie, Gilead, Verastem: Consultancy. Dwivedy Nasta:Incyte: Research Funding; Takeda/Millenium: Research Funding; Debiopharm: Research Funding; Pharmacyclics: Research Funding; Rafael/WF: Research Funding; Aileron: Research Funding; Roche: Research Funding; Merck: Other: DSMC; Celgene: Membership on an entity's Board of Directors or advisory committees. Landsburg:Takeda: Consultancy; Curis: Consultancy, Research Funding. Porter:Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Genentech: Other: Spouse employment; Kite Pharma: Other: Advisory board. Svoboda:Bristol-Myers Squibb: Consultancy, Research Funding; TG Therapeutics: Research Funding; Kyowa: Consultancy; Regeneron: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; KITE: Consultancy. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhu:Beijing Cancer Hospital: Employment. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Ding:Merck: Research Funding. Mato:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AstraZeneca: Consultancy; Regeneron: Research Funding; Celgene: Consultancy; Acerta: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Portola: Research Funding; Johnson & Johnson: Consultancy; Prime Oncology: Honoraria; Medscape: Honoraria.
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Massaro, Crescenzo, Giulia Sgueglia, Victoria Frattolillo, S. Rubina Baglio, Lucia Altucci, and Carmela Dell'Aversana. "Extracellular Vesicle-Based Nucleic Acid Delivery: Current Advances and Future Perspectives in Cancer Therapeutic Strategies." Pharmaceutics 12, no. 10 (October 16, 2020): 980. http://dx.doi.org/10.3390/pharmaceutics12100980.
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Extracellular vesicles (EVs) are sophisticated and sensitive messengers released by cells to communicate with and influence distant and neighboring cells via selective transfer of bioactive content, including protein lipids and nucleic acids. EVs have therefore attracted broad interest as new and refined potential therapeutic systems in many diseases, including cancer, due to their low immunogenicity, non-toxicity, and elevated bioavailability. They might serve as safe and effective vehicles for the transport of therapeutic molecules to specific tissues and cells. In this review, we focus on EVs as a vehicle for gene therapy in cancer. We describe recent developments in EV engineering to achieve efficient intracellular delivery of cancer therapeutics and avoid off-target effects, to provide an overview of the potential applications of EV-mediated gene therapy and the most promising biomedical advances.
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Sherman, Cherrie D., Shweta Lodha, and Susmita Sahoo. "EV Cargo Sorting in Therapeutic Development for Cardiovascular Disease." Cells 10, no. 6 (June 15, 2021): 1500. http://dx.doi.org/10.3390/cells10061500.
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Cardiovascular disease remains the leading cause of morbidity and mortality in the world. Thus, therapeutic interventions to circumvent this growing burden are of utmost importance. Extracellular vesicles (EVs) actively secreted by most living cells, play a key role in paracrine and endocrine intercellular communication via exchange of biological molecules. As the content of secreted EVs reflect the physiology and pathology of the cell of their origin, EVs play a significant role in cellular homeostasis, disease pathogenesis and diagnostics. Moreover, EVs are gaining popularity in clinics as therapeutic and drug delivery vehicles, transferring bioactive molecules such as proteins, genes, miRNAs and other therapeutic agents to target cells to treat diseases and deter disease progression. Despite our limited but growing knowledge of EV biology, it is imperative to understand the complex mechanisms of EV cargo sorting in pursuit of designing next generation EV-based therapeutic delivery systems. In this review, we highlight the mechanisms of EV cargo sorting and methods of EV bioengineering and discuss engineered EVs as a potential therapeutic delivery system to treat cardiovascular disease.
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Couto, Nuno, Julia Elzanowska, Joana Maia, Silvia Batista, Catarina Esteves Pereira, Hans Christian Beck, Ana Sofia Carvalho, et al. "IgG+ Extracellular Vesicles Measure Therapeutic Response in Advanced Pancreatic Cancer." Cells 11, no. 18 (September 8, 2022): 2800. http://dx.doi.org/10.3390/cells11182800.
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(1) Background: Pancreatic ductal adenocarcinoma (PDAC) is expected to be the second-leading cause of cancer deaths by 2030. Imaging techniques are the standard for monitoring the therapy response in PDAC, but these techniques have considerable limits, including delayed disease progression detection and difficulty in distinguishing benign from malignant lesions. Extracellular vesicle (EV) liquid biopsy is an emerging diagnosis modality. Nonetheless, the majority of research for EV-based diagnosis relies on point analyses of EVs at specified times, while longitudinal EV population studies before and during therapeutic interventions remain largely unexplored. (2) Methods: We analyzed plasma EV protein composition at diagnosis and throughout PDAC therapy. (3) Results: We found that IgG is linked with the diagnosis of PDAC and the patient’s response to therapy, and that the IgG+ EV population increases with disease progression and reduces with treatment response. Importantly, this covers PDAC patients devoid of the standard PDAC seric marker CA19.9 expression. We also observed that IgG is bound to EVs via the tumor antigen MAGE B1, and that this is independent of the patient’s inflammatory condition and IgG seric levels. (4) Conclusions: We here propose that a population analysis of IgG+ EVs in PDAC plasma represents a novel method to supplement the monitoring of the PDAC treatment response.
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Kamal, Asif, Urooj Haroon, Hakim Manghwar, Khalid H. Alamer, Ibtisam M. Alsudays, Ashwaq T. Althobaiti, Anila Iqbal, et al. "Biological Applications of Ball-Milled Synthesized Biochar-Zinc Oxide Nanocomposite Using Zea mays L." Molecules 27, no. 16 (August 22, 2022): 5333. http://dx.doi.org/10.3390/molecules27165333.
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Nanotechnology is one of the vital and quickly developing areas and has several uses in various commercial zones. Among the various types of metal oxide-based nanoparticles, zinc oxide nanoparticles (ZnO NPs) are frequently used because of their effective properties. The ZnO nanocomposites are risk-free and biodegradable biopolymers, and they are widely being applied in the biomedical and therapeutics fields. In the current study, the biochar-zinc oxide (MB-ZnO) nanocomposites were prepared using a solvent-free ball-milling technique. The prepared MB-ZnO nanocomposites were characterized through scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) spectroscopy, X-ray powder diffraction (XRD), and thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), and ultraviolet–visible (UV) spectroscopy. The MB-ZnO particles were measured as 43 nm via the X-ray line broadening technique by applying the Scherrer equation at the highest peak of 36.36°. The FTIR spectroscope results confirmed MB-ZnO’s formation. The band gap energy gap values of the MB-ZnO nanocomposites were calculated as 2.77 eV by using UV–Vis spectra. The MB-ZnO nanocomposites were tested in various in vitro biological assays, including biocompatibility assays against the macrophages and RBCs and the enzymes’ inhibition potential assay against the protein kinase, alpha-amylase, cytotoxicity assays of the leishmanial parasites, anti-inflammatory activity, antifungal activity, and antioxidant activities. The maximum TAC (30.09%), TRP (36.29%), and DPPH radicals’ scavenging potential (49.19%) were determined at the maximum dose of 200 µg/mL. Similarly, the maximum activity at the highest dose for the anti-inflammatory (76%), at 1000 μg/mL, alpha-amylase inhibition potential (45%), at 1000 μg/mL, antileishmanial activity (68%), at 100 μg/mL, and antifungal activity (73 ± 2.1%), at 19 mg/mL, was perceived, respectively. It did not cause any potential harm during the biocompatibility and cytotoxic assay and performed better during the anti-inflammatory and antioxidant assay. MB-ZnO caused moderate enzyme inhibition and was more effective against pathogenic fungus. The results of the current study indicated that MB-ZnO nanocomposites could be applied as effective catalysts in various processes. Moreover, this research provides valuable and the latest information to the readers and researchers working on biopolymers and nanocomposites.
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Zhao, Yuling, Matthew J. Haney, John K. Fallon, Myosotys Rodriguez, Carson J. Swain, Camryn J. Arzt, Philip C. Smith, et al. "Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease." Cells 11, no. 12 (June 15, 2022): 1933. http://dx.doi.org/10.3390/cells11121933.
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Extracellular vesicles (EVs) are cell-derived nanoparticles that facilitate transport of proteins, lipids, and genetic material, playing important roles in intracellular communication. They have remarkable potential as non-toxic and non-immunogenic nanocarriers for drug delivery to unreachable organs and tissues, in particular, the central nervous system (CNS). Herein, we developed a novel platform based on macrophage-derived EVs to treat Parkinson disease (PD). Specifically, we evaluated the therapeutic potential of EVs secreted by autologous macrophages that were transfected ex vivo to express glial-cell-line-derived neurotrophic factor (GDNF). EV-GDNF were collected from conditioned media of GDNF-transfected macrophages and characterized for GDNF content, size, charge, and expression of EV-specific proteins. The data revealed that, along with the encoded neurotrophic factor, EVs released by pre-transfected macrophages carry GDNF-encoding DNA. Four-month-old transgenic Parkin Q311(X)A mice were treated with EV-GDNF via intranasal administration, and the effect of this therapeutic intervention on locomotor functions was assessed over a year. Significant improvements in mobility, increases in neuronal survival, and decreases in neuroinflammation were found in PD mice treated with EV-GDNF. No offsite toxicity caused by EV-GDNF administration was detected. Overall, an EV-based approach can provide a versatile and potent therapeutic intervention for PD.
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Hua, Shu, Peter Mark Bartold, Karan Gulati, Corey Stephen Moran, Sašo Ivanovski, and Pingping Han. "Periodontal and Dental Pulp Cell-Derived Small Extracellular Vesicles: A Review of the Current Status." Nanomaterials 11, no. 7 (July 19, 2021): 1858. http://dx.doi.org/10.3390/nano11071858.
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Extracellular vesicles (EVs) are membrane-bound lipid particles that are secreted by all cell types and function as cell-to-cell communicators through their cargos of protein, nucleic acid, lipids, and metabolites, which are derived from their parent cells. There is limited information on the isolation and the emerging therapeutic role of periodontal and dental pulp cell-derived small EVs (sEVs, <200 nm, or exosome). In this review, we discuss the biogenesis of three EV subtypes (sEVs, microvesicles and apoptotic bodies) and the emerging role of sEVs from periodontal ligament (stem) cells, gingival fibroblasts (or gingival mesenchymal stem cells) and dental pulp cells, and their therapeutic potential in vitro and in vivo. A review of the relevant methodology found that precipitation-based kits and ultracentrifugation are the two most common methods to isolate periodontal (dental pulp) cell sEVs. Periodontal (and pulp) cell sEVs range in size, from 40 nm to 2 μm, due to a lack of standardized isolation protocols. Nevertheless, our review found that these EVs possess anti-inflammatory, osteo/odontogenic, angiogenic and immunomodulatory functions in vitro and in vivo, via reported EV cargos of EV–miRNAs, EV–circRNAs, EV–mRNAs and EV–lncRNAs. This review highlights the considerable therapeutic potential of periodontal and dental pulp cell-derived sEVs in various regenerative applications.
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Simeone, Pasquale, Christian Celia, Giuseppina Bologna, Eva Ercolino, Laura Pierdomenico, Felisa Cilurzo, Rossella Grande, et al. "Diameters and Fluorescence Calibration for Extracellular Vesicle Analyses by Flow Cytometry." International Journal of Molecular Sciences 21, no. 21 (October 23, 2020): 7885. http://dx.doi.org/10.3390/ijms21217885.
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Extracellular vesicles (EVs) play a crucial role in the intercellular crosstalk. Mesenchymal stem cell-derived EVs (MSC-EVs), displaying promising therapeutic roles, contribute to the strong rationale for developing EVs as an alternative therapeutic option. EV analysis still represents one of the major issues to be solved in order to translate the use of MSC-EV detection in clinical settings. Even if flow cytometry (FC) has been largely applied for EV studies, the lack of consensus on protocols for FC detection of EVs generated controversy. Standard FC procedures, based on scatter measurements, only allows the detection of the “tip of the iceberg” of all EVs. We applied an alternative FC approach based on the use of a trigger threshold on a fluorescence channel. The EV numbers obtained by the application of the fluorescence triggering resulted significantly higher in respect to them obtained from the same samples acquired by placing the threshold on the side scatter (SSC) channel. The analysis of EV concentrations carried out by three different standardized flow cytometers allowed us to achieve a high level of reproducibility (CV < 20%). By applying the here-reported method highly reproducible results in terms of EV analysis and concentration measurements were obtained.
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Jabalee, James, Rebecca Towle, and Cathie Garnis. "The Role of Extracellular Vesicles in Cancer: Cargo, Function, and Therapeutic Implications." Cells 7, no. 8 (August 1, 2018): 93. http://dx.doi.org/10.3390/cells7080093.
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Extracellular vesicles (EVs) are a heterogeneous collection of membrane-bound structures that play key roles in intercellular communication. EVs are potent regulators of tumorigenesis and function largely via the shuttling of cargo molecules (RNA, DNA, protein, etc.) among cancer cells and the cells of the tumor stroma. EV-based crosstalk can promote proliferation, shape the tumor microenvironment, enhance metastasis, and allow tumor cells to evade immune destruction. In many cases these functions have been linked to the presence of specific cargo molecules. Herein we will review various types of EV cargo molecule and their functional impacts in the context of oncology.
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Du, Rong, Chen Wang, Ling Zhu, and Yanlian Yang. "Extracellular Vesicles as Delivery Vehicles for Therapeutic Nucleic Acids in Cancer Gene Therapy: Progress and Challenges." Pharmaceutics 14, no. 10 (October 19, 2022): 2236. http://dx.doi.org/10.3390/pharmaceutics14102236.
Full textAbstract:
Extracellular vesicles (EVs) are nanoscale vesicles secreted by most types of cells as natural vehicles to transfer molecular information between cells. Due to their low toxicity and high biocompatibility, EVs have attracted increasing attention as drug delivery systems. Many studies have demonstrated that EV-loaded nucleic acids, including RNA-based nucleic acid drugs and CRISPR/Cas gene-editing systems, can alter gene expressions and functions of recipient cells for cancer gene therapy. Here in this review, we discuss the advantages and challenges of EV-based nucleic acid delivery systems in cancer therapy. We summarize the techniques and methods to increase EV yield, enhance nucleic acid loading efficiency, extend circulation time, and improve targeted delivery, as well as their applications in gene therapy and combination with other cancer therapies. Finally, we discuss the current status, challenges, and prospects of EVs as a therapeutic tool for the clinical application of nucleic acid drugs.
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Kee, Li Ting, Chiew Yong Ng, Maimonah Eissa Al-Masawa, Jhi Biau Foo, Chee Wun How, Min Hwei Ng, and Jia Xian Law. "Extracellular Vesicles in Facial Aesthetics: A Review." International Journal of Molecular Sciences 23, no. 12 (June 16, 2022): 6742. http://dx.doi.org/10.3390/ijms23126742.
Full textAbstract:
Facial aesthetics involve the application of non-invasive or minimally invasive techniques to improve facial appearance. Currently, extracellular vesicles (EVs) are attracting much interest as nanocarriers in facial aesthetics due to their lipid bilayer membrane, nanosized dimensions, biological origin, intercellular communication ability, and capability to modulate the molecular activities of recipient cells that play important roles in skin rejuvenation. Therefore, EVs have been suggested to have therapeutic potential in improving skin conditions, and these highlighted the potential to develop EV-based cosmetic products. This review summarizes EVs’ latest research, reporting applications in facial aesthetics, including scar removal, facial rejuvenation, anti-aging, and anti-pigmentation. This review also discussed the advanced delivery strategy of EVs, the therapeutic potential of plant EVs, and clinical studies using EVs to improve skin conditions. In summary, EV therapy reduces scarring, rejuvenates aging skin, and reduces pigmentation. These observations warrant the development of EV-based cosmetic products. However, more efforts are needed to establish a large-scale EV production platform that can consistently produce functional EVs and understand EVs’ underlying mechanism of action to improve their efficacy.
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Wang, Jing, Alain Wuethrich, Abu Ali Ibn Sina, Rebecca E. Lane, Lynlee L. Lin, Yuling Wang, Jonathan Cebon, Andreas Behren, and Matt Trau. "Tracking extracellular vesicle phenotypic changes enables treatment monitoring in melanoma." Science Advances 6, no. 9 (February 2020): eaax3223. http://dx.doi.org/10.1126/sciadv.aax3223.
Full textAbstract:
Monitoring targeted therapy in real time for cancer patients could provide vital information about the development of drug resistance and improve therapeutic outcomes. Extracellular vesicles (EVs) have recently emerged as a promising cancer biomarker, and EV phenotyping shows high potential for monitoring treatment responses. Here, we demonstrate the feasibility of monitoring patient treatment responses based on the plasma EV phenotypic evolution using a multiplex EV phenotype analyzer chip (EPAC). EPAC incorporates the nanomixing-enhanced microchip and the multiplex surface-enhanced Raman scattering (SERS) nanotag system for direct EV phenotyping without EV enrichment. In a preclinical model, we observe the EV phenotypic heterogeneity and different phenotypic responses to the treatment. Furthermore, we successfully detect cancer-specific EV phenotypes from melanoma patient plasma. We longitudinally monitor the EV phenotypic evolution of eight melanoma patients receiving targeted therapy and find specific EV profiles involved in the development of drug resistance, reflecting the potential of EV phenotyping for monitoring treatment responses.
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Driscoll, Julia, Irene K. Yan, and Tushar Patel. "Development of a Lyophilized Off-the-Shelf Mesenchymal Stem Cell-Derived Acellular Therapeutic." Pharmaceutics 14, no. 4 (April 13, 2022): 849. http://dx.doi.org/10.3390/pharmaceutics14040849.
Full textAbstract:
The therapeutic activities elicited by mesenchymal stem cells (MSC) are in part mediated through paracrine action by the release of extracellular vesicles (EV) and secreted proteins. Collectively, these MSC-derived factors, referred to as the secretome product (SP), are intrinsically therapeutic and represent an attractive alternative to cell-based therapies. Herein, we developed a lyopreservation protocol to extend the shelf-life of the MSC-SP without compromising the structural or functional integrity of the vesicular components. The SP isolated from normoxia- and anoxia-exposed MSC elicited protective effects in an in vitro model of oxidative injury and the bioactivity was retained in the lyophilized samples. Three separate formulations of MSC-SP were isolated by tangential flow filtration using sucrose, trehalose, and mannitol as lyoprotectant agents. The MSC-SPs were lyophilized using a manifold protocol and the structural and functional integrity were assessed. The trehalose formulation of SP exhibited the highest EV and protein recovery after manifold-based lyophilization. To facilitate development as a therapeutic, a shelf lyophilization protocol was developed which markedly enhanced the recovery of EV and proteins. In conclusion, lyophilization represents an efficient method to preserve the structural and functional integrity of the MSC-SP and can be used to develop an off-the-shelf therapeutic.
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Jung, Youn Jae, Hark Kyun Kim, Yoonsuk Cho, Ji Suk Choi, Chang Hee Woo, Kyoung Soo Lee, Jae Hoon Sul, et al. "Cell reprogramming using extracellular vesicles from differentiating stem cells into white/beige adipocytes." Science Advances 6, no. 13 (March 2020): eaay6721. http://dx.doi.org/10.1126/sciadv.aay6721.
Full textAbstract:
Stem cell–derived extracellular vesicles (EVs) offer alternative approaches to stem cell–based therapy for regenerative medicine. In this study, stem cell EVs derived during differentiation are developed to use as cell-free therapeutic systems by inducing tissue-specific differentiation. EVs are isolated from human adipose-derived stem cells (HASCs) during white and beige adipogenic differentiation (D-EV and BD-EV, respectively) via tangential flow filtration. D-EV and BD-EV can successfully differentiate HASCs into white and beige adipocytes, respectively. D-EV are transplanted with collagen/methylcellulose hydrogels on the backs of BALB/c mice, and they produce numerous lipid droplets in injected sites. Treatments of BD-EV attenuate diet-induced obesity through browning of adipose tissue in mice. Furthermore, high-fat diet–induced hepatic steatosis and glucose tolerance are improved by BD-EV treatment. miRNAs are responsible for the observed effects of BD-EV. These results reveal that secreted EVs during stem cell differentiation into white adipocytes or beige adipocytes can promote cell reprogramming.
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Ollen-Bittle, Nikita, Austyn D. Roseborough, Wenxuan Wang, Jeng-liang D. Wu, and Shawn N. Whitehead. "Mechanisms and Biomarker Potential of Extracellular Vesicles in Stroke." Biology 11, no. 8 (August 18, 2022): 1231. http://dx.doi.org/10.3390/biology11081231.
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Stoke is a prevalent and devastating neurologic condition with limited options for therapeutic management. Since brain tissue is rarely accessible clinically, peripheral biomarkers for the central nervous system’s (CNS’s) cellular response to stroke may prove critical for increasing our understanding of stroke pathology and elucidating novel therapeutic targets. Extracellular vesicles (EVs) are cell-derived, membrane-enclosed vesicles secreted by all cell types within the CNS that can freely pass the blood-brain barrier (BBB) and contain unique markers and content linked to their cell of origin. These unique qualities make brain-derived EVs novel candidates for non-invasive blood-based biomarkers of both cell specificity and cell physiological state during the progression of stroke and recovery. While studies are continuously emerging that are assessing the therapeutic potential of EVs and profiling EV cargo, a vast minority of these studies link EV content to specific cell types. A better understanding of cell-specific EV release during the acute, subacute, and chronic stages of stroke is needed to further elucidate the cellular processes responsible for stroke pathophysiology. Herein, we outline what is known about EV release from distinct cell types of the CNS during stroke and the potential of these EVs as peripheral biomarkers for cellular function in the CNS during stroke.
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McLaughlin, Caroline, Pallab Datta, Yogendra P. Singh, Alexis Lo, Summer Horchler, Irina A. Elcheva, Ibrahim T. Ozbolat, Dino J. Ravnic, and Srinivas V. Koduru. "Mesenchymal Stem Cell-Derived Extracellular Vesicles for Therapeutic Use and in Bioengineering Applications." Cells 11, no. 21 (October 25, 2022): 3366. http://dx.doi.org/10.3390/cells11213366.
Full textAbstract:
Extracellular vesicles (EVs) are small lipid bilayer-delimited particles that are naturally released from cells into body fluids, and therefore can travel and convey regulatory functions in the distal parts of the body. EVs can transmit paracrine signaling by carrying over cytokines, chemokines, growth factors, interleukins (ILs), transcription factors, and nucleic acids such as DNA, mRNAs, microRNAs, piRNAs, lncRNAs, sn/snoRNAs, mtRNAs and circRNAs; these EVs travel to predecided destinations to perform their functions. While mesenchymal stem cells (MSCs) have been shown to improve healing and facilitate treatments of various diseases, the allogenic use of these cells is often accompanied by serious adverse effects after transplantation. MSC-produced EVs are less immunogenic and can serve as an alternative to cellular therapies by transmitting signaling or delivering biomaterials to diseased areas of the body. This review article is focused on understanding the properties of EVs derived from different types of MSCs and MSC–EV-based therapeutic options. The potential of modern technologies such as 3D bioprinting to advance EV-based therapies is also discussed.
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Wiklander, Oscar P. B., Meadhbh Á. Brennan, Jan Lötvall, Xandra O. Breakefield, and Samir EL Andaloussi. "Advances in therapeutic applications of extracellular vesicles." Science Translational Medicine 11, no. 492 (May 15, 2019): eaav8521. http://dx.doi.org/10.1126/scitranslmed.aav8521.
Full textAbstract:
Extracellular vesicles (EVs) are nanometer-sized, lipid membrane–enclosed vesicles secreted by most, if not all, cells and contain lipids, proteins, and various nucleic acid species of the source cell. EVs act as important mediators of intercellular communication that influence both physiological and pathological conditions. Given their ability to transfer bioactive components and surmount biological barriers, EVs are increasingly being explored as potential therapeutic agents. EVs can potentiate tissue regeneration, participate in immune modulation, and function as potential alternatives to stem cell therapy, and bioengineered EVs can act as delivery vehicles for therapeutic agents. Here, we cover recent approaches and advances of EV-based therapies.
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Zhang, Haiyang, Qi Zhang, Yuanyuan Deng, Mengxi Chen, and Chenxi Yang. "Improving Isolation of Extracellular Vesicles by Utilizing Nanomaterials." Membranes 12, no. 1 (December 31, 2021): 55. http://dx.doi.org/10.3390/membranes12010055.
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Extracellular vesicles (EVs) as the new form of cellular communication have been demonstrated their potential use for disease diagnosis, prognosis and treatment. EVs are vesicles with a lipid bilayer and are present in various biofluids, such as blood, saliva and urine. Therefore, EVs have emerged as one of the most appealing sources for the discovery of clinical biomarkers. However, isolation of the target EVs from different biofluids is required for the use of EVs as diagnostic and therapeutic entities in clinical settings. Owing to their unique properties and versatile functionalities, nanomaterials have been widely investigated for EV isolation with the aim to provide rapid, simple, and efficient EV enrichment. Herein, this review presents the progress of nanomaterial-based isolations for EVs over the past five years (from 2017 to 2021) and discusses the use of nanomaterials for EV isolations based on the underlying mechanism in order to offer insights into the design of nanomaterials for EV isolations.
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Batool, Syeda Maheen, Tiffaney Hsia, Sirena K. Khanna, Austin S. Gamblin, Yulia Rosenfeld, Dong Gil You, Bob S. Carter, and Leonora Balaj. "Decoding vesicle-based precision oncology in gliomas." Neuro-Oncology Advances 4, Supplement_2 (November 11, 2022): ii53—ii60. http://dx.doi.org/10.1093/noajnl/vdac035.
Full textAbstract:
Abstract Extracellular vesicles (EVs) represent a valuable tool in liquid biopsy with tremendous clinical potential in diagnosis, prognosis, and therapeutic monitoring of gliomas. Compared to tissue biopsy, EV-based liquid biopsy is a low-cost, minimally invasive method that can provide information on tumor dynamics before, during, and after treatment. Tumor-derived EVs circulating in biofluids carry a complex cargo of molecular biomarkers, including DNA, RNA, and proteins, which can be indicative of tumor growth and progression. Here, we briefly review current commercial and noncommercial methods for the isolation, quantification, and biochemical characterization of plasma EVs from patients with glioma, touching on whole EV analysis, mutation detection techniques, and genomic and proteomic profiling. We review notable advantages and disadvantages of plasma EV isolation and analytical methods, and we conclude with a discussion on clinical translational opportunities and key challenges associated with the future implementation of EV-based liquid biopsy for glioma treatment.
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Phan, Thanh Kha, Dilara Ceyda Ozkocak, and Ivan Ka Ho Poon. "Unleashing the therapeutic potential of apoptotic bodies." Biochemical Society Transactions 48, no. 5 (September 1, 2020): 2079–88. http://dx.doi.org/10.1042/bst20200225.
Full textAbstract:
Extracellular vesicles (EVs), membrane-bound vesicles that are naturally released by cells, have emerged as new therapeutic opportunities. EVs, particularly exosomes and microvesicles, can transfer effector molecules and elicit potent responses in recipient cells, making them attractive therapeutic targets and drug delivery platforms. Furthermore, containing predictive biomarkers and often being dysregulated in various disease settings, these EVs are being exploited for diagnostic purposes. In contrast, the therapeutic application of apoptotic bodies (ApoBDs), a distinct type of EVs released by cells undergoing a form of programmed cell death called apoptosis, has been largely unexplored. Recent studies have shed light on ApoBD biogenesis and functions, promisingly implicating their therapeutic potential. In this review, we discuss many strategies to develop ApoBD-based therapies as well as highlight their advantages and challenges, thereby positioning ApoBD for potential EV-based therapy.
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Nair, Ashita, Jiyoon Bu, Piper A. Rawding, Steven C. Do, Hangpeng Li, and Seungpyo Hong. "Cytochalasin B Treatment and Osmotic Pressure Enhance the Production of Extracellular Vesicles (EVs) with Improved Drug Loading Capacity." Nanomaterials 12, no. 1 (December 21, 2021): 3. http://dx.doi.org/10.3390/nano12010003.
Full textAbstract:
Extracellular vesicles (EVs) have been highlighted as novel drug carriers due to their unique structural properties and intrinsic features, including high stability, biocompatibility, and cell-targeting properties. Although many efforts have been made to harness these features to develop a clinically effective EV-based therapeutic system, the clinical translation of EV-based nano-drugs is hindered by their low yield and loading capacity. Herein, we present an engineering strategy that enables upscaled EV production with increased loading capacity through the secretion of EVs from cells via cytochalasin-B (CB) treatment and reduction of EV intravesicular contents through hypo-osmotic stimulation. CB (10 µg/mL) promotes cells to extrude EVs, producing ~three-fold more particles than through natural EV secretion. When CB is induced in hypotonic conditions (223 mOsm/kg), the produced EVs (hypo-CIMVs) exhibit ~68% less intravesicular protein, giving 3.4-fold enhanced drug loading capacity compared to naturally secreted EVs. By loading doxorubicin (DOX) into hypo-CIMVs, we found that hypo-CIMVs efficiently deliver their drug cargos to their target and induce up to ~1.5-fold more cell death than the free DOX. Thus, our EV engineering offers the potential for leveraging EVs as an effective drug delivery vehicle for cancer treatment.