Publications by authors named "Joy Wolfram"

65 Publications

Considerations for extracellular vesicle and lipoprotein interactions in cell culture assays.

J Extracell Vesicles 2022 Apr;11(4):e12202

Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida, USA.

With an exponential increase in extracellular vesicle (EV) studies in the past decade, focus has been placed on standardization of experimental design to ensure inter-study comparisons and validity of conclusions. In the case of in vitro assays, the composition of cell culture media is important to consider for EV studies. In particular, levels of lipoproteins, which are critical components of the interstitial fluid, should be taken into consideration. Results from this study reveal that lipoprotein levels in cell culture medium impact the effects that EVs have on recipient cells. Additionally, evidence of EV binding and fusion to lipoprotein-like structures in plasma is provided. However, it is unclear whether the impact of lipoproteins in cell culture is due to direct interactions with EVs, indirect effects, or a combination of both mechanisms. Taken together, cell culture studies performed in the absence of physiological levels of lipoproteins are unlikely to reflect interactions that occur between EVs and recipient cells in an in vivo environment.
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http://dx.doi.org/10.1002/jev2.12202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971175PMC
April 2022

Extracellular vesicle glucose transporter-1 and glycan features in monocyte-endothelial inflammatory interactions.

Nanomedicine 2022 Jun 22;42:102515. Epub 2022 Jan 22.

Department of Biochemistry and Molecular Biology, Department of Physiology and Biomedical Engineering, Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA; Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA; Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD, Australia (present affiliation); School of Chemical Engineering, University of Queensland, Brisbane, QLD, Australia (present affiliation). Electronic address:

Monocyte-induced endothelial cell inflammation is associated with multiple pathological conditions, and extracellular vesicles (EVs) are essential nanosized components of intercellular communication. EVs derived from endotoxin-stimulated monocytes were previously shown to carry pro-inflammatory proteins and RNAs. The role of glucose transporter-1 (GLUT-1) and glycan features in monocyte-derived EV-induced endothelial cell inflammation remains largely unexplored. This study demonstrates that EVs derived from endotoxin-stimulated monocytes activate inflammatory pathways in endothelial cells, which are partially attributed to GLUT-1. Alterations in glycan features and increased levels of GLUT-1 were observed in EVs derived from endotoxin-stimulated monocytes. Notably, inhibition of EV-associated GLUT-1, through the use of fasentin, suppressed EV-induced inflammatory cytokines in recipient endothelial cells.
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http://dx.doi.org/10.1016/j.nano.2022.102515DOI Listing
June 2022

Effects of Adipose-Derived Biogenic Nanoparticle-Associated microRNA-451a on Toll-like Receptor 4-Induced Cytokines.

Pharmaceutics 2021 Dec 22;14(1). Epub 2021 Dec 22.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA.

Extracellular vesicles (EVs) are cell-released nanoparticles that transfer biomolecular content between cells. Among EV-associated biomolecules, microRNAs (miRNAs/miRs) represent one of the most important modulators of signaling pathways in recipient cells. Previous studies have shown that EVs from adipose-derived mesenchymal stromal cells (MSCs) and adipose tissue modulate inflammatory pathways in macrophages. In this study, the effects of miRNAs that are abundant in adipose tissue EVs and other biogenic nanoparticles (BiNPs) were assessed in terms of altering Toll-like receptor 4 (TLR4)-induced cytokines. TLR-4 signaling in macrophages is often triggered by pathogen or damage-induced inflammation and is associated with several diseases. This study demonstrates that miR-451a, which is abundant in adipose tissue BiNPs, suppresses pro-inflammatory cytokines and increases anti-inflammatory cytokines associated with the TLR4 pathway. Therefore, miR-451a may be partially responsible for immunomodulatory effects of adipose tissue-derived BiNPs.
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http://dx.doi.org/10.3390/pharmaceutics14010016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780819PMC
December 2021

Extracellular vesicle therapeutics from plasma and adipose tissue.

Nano Today 2021 Aug 27;39. Epub 2021 Apr 27.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL, USA.

Extracellular vesicles (EVs) are cell-released lipid-bilayer nanoparticles that contain biologically active cargo involved in physiological and pathological intercellular communication. In recent years, the therapeutic potential of EVs has been explored in various disease models. In particular, mesenchymal stromal cell-derived EVs have been shown to exert anti-inflammatory, anti-oxidant, anti-apoptotic, and pro-angiogenic properties in cardiovascular, metabolic and orthopedic conditions. However, a major drawback of EV-based therapeutics is scale-up issues due to extensive cell culture requirements and inefficient isolation protocols. An emerging alternative approach to time-consuming and costly cell culture expansion is to obtain therapeutic EVs directly from the body, for example, from plasma and adipose tissue. This review discusses isolation methods and therapeutic applications of plasma and adipose tissue-derived EVs, highlighting advantages and disadvantages compared to cell culture-derived ones.
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http://dx.doi.org/10.1016/j.nantod.2021.101159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104307PMC
August 2021

A Simple and Quick Method for Loading Proteins in Extracellular Vesicles.

Pharmaceuticals (Basel) 2021 Apr 13;14(4). Epub 2021 Apr 13.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL 32224, USA.

Extracellular vesicles (EVs) mediate intercellular transport of biomolecular cargo in the body, making them promising delivery vehicles for bioactive compounds. Genetic engineering of producer cells has enabled encapsulation of therapeutic proteins in EVs. However, genetic engineering approaches can be expensive, time-consuming, and incompatible with certain EV sources, such as human plasma and bovine milk. The goal of this study was to develop a quick, versatile, and simple method for loading proteins in EVs post-isolation. Proteins, including CRISPR associated protein 9 (Cas9), were bound to cationic lipids that were further complexed with MDA-MB-231 cell-derived EVs through passive incubation. Size-exclusion chromatography was used to remove components that were not complexed with EVs. The ability of EVs to mediate intracellular delivery of proteins was compared to conventional methods, such as electroporation and commercial protein transfection reagents. The results indicate that EVs retain native features following protein-loading and obtain similar levels of intracellular protein delivery as conventional methods, but display less toxicity. This method opens up opportunities for rapid exploration of EVs for protein delivery.
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http://dx.doi.org/10.3390/ph14040356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069621PMC
April 2021

Education and Outreach in Physical Sciences in Oncology.

Trends Cancer 2021 01 7;7(1):3-9. Epub 2020 Nov 7.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL, USA; Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA; Center for Immunotherapeutic Transport Oncophysics, Houston Methodist Research Institute, Houston, TX, USA. Electronic address:

Physical sciences are often overlooked in the field of cancer research. The Physical Sciences in Oncology Initiative was launched to integrate physics, mathematics, chemistry, and engineering with cancer research and clinical oncology through education, outreach, and collaboration. Here, we provide a framework for education and outreach in emerging transdisciplinary fields.
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http://dx.doi.org/10.1016/j.trecan.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895467PMC
January 2021

Brain metastases-derived extracellular vesicles induce binding and aggregation of low-density lipoprotein.

J Nanobiotechnology 2020 Nov 7;18(1):162. Epub 2020 Nov 7.

Department of Biochemistry and Molecular Biology, Department of Physiology and Biomedical Engineering, Department of Transplantation, Mayo Clinic, Jacksonville, FL, 32224, USA.

Background: Cancer cell-derived extracellular vesicles (EVs) have previously been shown to contribute to pre-metastatic niche formation. Specifically, aggressive tumors secrete pro-metastatic EVs that travel in the circulation to distant organs to modulate the microenvironment for future metastatic spread. Previous studies have focused on the interface between pro-metastatic EVs and epithelial/endothelial cells in the pre-metastatic niche. However, EV interactions with circulating components such as low-density lipoprotein (LDL) have been overlooked.

Results: This study demonstrates that EVs derived from brain metastases cells (Br-EVs) and corresponding regular cancer cells (Reg-EVs) display different interactions with LDL. Specifically, Br-EVs trigger LDL aggregation, and the presence of LDL accelerates Br-EV uptake by monocytes, which are key components in the brain metastatic niche.

Conclusions: Collectively, these data are the first to demonstrate that pro-metastatic EVs display distinct interactions with LDL, which impacts monocyte internalization of EVs.
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http://dx.doi.org/10.1186/s12951-020-00722-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648399PMC
November 2020

Extracellular Vesicles in Cancer Detection: Hopes and Hypes.

Trends Cancer 2021 02 30;7(2):122-133. Epub 2020 Sep 30.

Cancer Biomarkers Research Group, National Cancer Institute, Rockville, MD, USA. Electronic address:

Early cancer diagnosis is critical for improving patient survival and mortality rates, but most diagnostics on solid tumors rely on imaging tests with limited sensitivity and specificity to identify potential cases, which are then confirmed by tissue biopsies. However, this process is usually not suitable for cancer screening or evaluation of tumor responses to treatment. Liquid biopsies have the potential to bridge this gap, but few such assays have been approved for cancer applications. Extracellular vesicles hold particular promise for liquid biopsy diagnostics but are currently limited by the lack of robust methods for isolation and analysis. New isolation and analysis techniques, however, show promise to improve the clinical utility of extracellular vesicle-based cancer diagnosis.
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http://dx.doi.org/10.1016/j.trecan.2020.09.003DOI Listing
February 2021

Glycan Node Analysis of Plasma-Derived Extracellular Vesicles.

Cells 2020 08 22;9(9). Epub 2020 Aug 22.

Department of Biochemistry and Molecular Biology, Department of Physiology and Biomedical Engineering, Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, USA.

Blood plasma is a readily accessible source of extracellular vesicles (EVs), i.e., cell-secreted nanosized carriers that contain various biomolecules, including glycans. Previous studies have demonstrated that glycans play a major role in physiological and pathological processes, and certain plasma glycans have been associated with disease conditions. However, glycome studies have been limited by a lack of analytical techniques with the throughput capacity necessary to study hundreds of clinical samples. This study is the first to characterize the EV plasma glycome based on all major glycan classes. The results based on glycan node analysis revealed, as expected, that plasma-derived EVs have distinct glycan features from donor-matched whole plasma. Specifically, glycan nodes corresponding to those observed in chondroitin sulfate, dermatan sulfate, type I keratan sulfate, and type II keratan sulfate were enriched on EVs. The identification of specific differences in glycan features in plasma vs. plasma-derived EVs is relevant for understanding the physiological role of EVs and as a reference for future diagnostic studies. Additionally, the results indicate that EV glycan nodes do not substantially differ among a small set of healthy donors. These results lay the framework for the further evaluation of all EV glycan classes as diagnostic markers, therapeutic targets, and biologically active components in health and disease.
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http://dx.doi.org/10.3390/cells9091946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563425PMC
August 2020

Lipoprotein-based drug delivery.

Adv Drug Deliv Rev 2020 11;159:377-390. Epub 2020 Aug 11.

Department of Biochemistry and Molecular Biology, Department of Physiology and Biomedical Engineering, Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Biology, University of North Florida, Jacksonville, FL 32224, USA; Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address:

Lipoproteins (LPs) are circulating heterogeneous nanoparticles produced by the liver and intestines. LPs play a major role in the transport of dietary and endogenous lipids to target cells through cell membrane receptors or cell surface-bound lipoprotein lipase. The stability, biocompatibility, and selective transport of LPs make them promising delivery vehicles for various therapeutic and imaging agents. This review discusses isolation, manufacturing, and drug loading techniques used for LP-based drug delivery, as well as recent applications for diagnosis and treatment of cancer, atherosclerosis, and other life-threatening diseases.
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http://dx.doi.org/10.1016/j.addr.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747060PMC
August 2021

Extracellular vesicles for treatment of solid organ ischemia-reperfusion injury.

Am J Transplant 2020 12 28;20(12):3294-3307. Epub 2020 Jul 28.

Department of Cardiothoracic Surgery, Mayo Clinic, Jacksonville, Florida, USA.

As the incidence of ischemia-reperfusion (I-R) injury has substantially increased, there is a pressing need to develop effective strategies to treat this global health issue. I-R injury can affect all organs and is associated with high morbidity and mortality rates. Pathological settings such as myocardial infarction, stroke, hemorrhagic shock, and solid organ transplant are particularly prone to cause I-R injury. Ischemia (hypoxia) and/or reperfusion (reoxygenation) induces various forms of cellular and structural damage. A major cause of damage is local inflammatory responses, which may spread to produce more advanced systemic inflammation. Management of I-R injury relies primarily on supportive measures, as specific treatment strategies are lacking. Extracellular vesicles (EVs) are cell-secreted nano-scale structures containing various biomolecules involved in cell communication and multiple physiological processes. EVs derived from certain cell types have been shown to exhibit anti-inflammatory, antioxidant, and angiogenic properties. This review provides an overview of EV-based therapeutics for I-R injury in kidneys, liver, heart, lungs, and brain. Additionally, the mechanisms by which EVs protect against I-R injury are discussed. Promising preclinical findings highlight the potential clinical use of EVs for I-R injury.
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http://dx.doi.org/10.1111/ajt.16164DOI Listing
December 2020

Insights from nanomedicine into chloroquine efficacy against COVID-19.

Nat Nanotechnol 2020 04;15(4):247-249

Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL, USA.

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http://dx.doi.org/10.1038/s41565-020-0674-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094976PMC
April 2020

The solid progress of nanomedicine.

Drug Deliv Transl Res 2020 06;10(3):726-729

Drug Research Program, Division of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, FI-00014, Helsinki, Finland.

This commentary article conveys the views of the board of the Nanomedicine and Nanoscale Delivery Focus Group of the Controlled Release Society regarding the decision of the United States National Cancer Institute (NCI) in halting funding for the Centers of Cancer Nanotechnology Excellence (CCNEs), and the subsequent editorial articles that broadened this discussion. Graphical abstract.
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http://dx.doi.org/10.1007/s13346-020-00743-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228908PMC
June 2020

Adipose-Derived Biogenic Nanoparticles for Suppression of Inflammation.

Small 2020 03 18;16(10):e1904064. Epub 2020 Feb 18.

Department of Biochemistry and Molecular Biology, Department of Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL, 32224, USA.

Extracellular vesicles secreted from adipose-derived mesenchymal stem cells (ADSCs) have therapeutic effects in inflammatory diseases. However, production of extracellular vesicles (EVs) from ADSCs is costly, inefficient, and time consuming. The anti-inflammatory properties of adipose tissue-derived EVs and other biogenic nanoparticles have not been explored. In this study, biogenic nanoparticles are obtained directly from lipoaspirate, an easily accessible and abundant source of biological material. Compared to ADSC-EVs, lipoaspirate nanoparticles (Lipo-NPs) take less time to process (hours compared to months) and cost less to produce (clinical-grade cell culture facilities are not required). The physicochemical characteristics and anti-inflammatory properties of Lipo-NPs are evaluated and compared to those of patient-matched ADSC-EVs. Moreover, guanabenz loading in Lipo-NPs is evaluated for enhanced anti-inflammatory effects. Apolipoprotein E and glycerolipids are enriched in Lipo-NPs compared to ADSC-EVs. Additionally, the uptake of Lipo-NPs in hepatocytes and macrophages is higher. Lipo-NPs and ADSC-EVs have comparable protective and anti-inflammatory effects. Specifically, Lipo-NPs reduce toll-like receptor 4-induced secretion of inflammatory cytokines in macrophages. Guanabenz-loaded Lipo-NPs further suppress inflammatory pathways, suggesting that this combination therapy can have promising applications for inflammatory diseases.
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http://dx.doi.org/10.1002/smll.201904064DOI Listing
March 2020

Extracellular vesicle-based drug delivery systems for cancer treatment.

Theranostics 2019 17;9(26):8001-8017. Epub 2019 Oct 17.

Department of Transplantation/Department of Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL, 32224, USA.

Extracellular vesicles (EVs) are naturally occurring cell-secreted nanoparticles that play important roles in many physiological and pathological processes. EVs enable intercellular communication by serving as delivery vehicles for a wide range of endogenous cargo molecules, such as RNAs, proteins, carbohydrates, and lipids. EVs have also been found to display tissue tropism mediated by surface molecules, such as integrins and glycans, making them promising for drug delivery applications. Various methods can be used to load therapeutic agents into EVs, and additional modification strategies have been employed to prolong circulation and improve targeting. This review gives an overview of EV-based drug delivery strategies in cancer therapy.
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http://dx.doi.org/10.7150/thno.37097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857056PMC
September 2020

Systematic comparison of methods for determining the in vivo biodistribution of porous nanostructured injectable inorganic particles.

Acta Biomater 2019 10 3;97:501-512. Epub 2019 Aug 3.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address:

With a wide variety of biodistribution measurement techniques reported in the literature, it is important to perform side-by-side comparisons of results obtained with different methods on the same particle platform, to determine differences across methods, highlight advantages and disadvantages, and inform methods selection according to specific applications. Inorganic nanostructured particles (INPs) have gained a central role in the development of injectable delivery vectors thanks to their controllable design, biocompatibility, and favorable degradation kinetic. Thus, accurate determination of in vivo biodistribution of INPs is a key aspect of developing and optimizing this class of delivery vectors. In this study, a systematic comparison of spectroscopy (inductively coupled plasma optical emission spectroscopy), fluorescence (in vivo imaging system, confocal microscopy, and plate reader), and radiolabeling (gamma counter)-based techniques is performed to assess the accuracy and sensitivity of biodistribution measurements in mice. Each method is evaluated on porous silicon particles, an established and versatile injectable delivery platform. Biodistribution is evaluated in all major organs and compared in terms of absolute results (%ID/g and %ID/organ when possible) and sensitivity (σ). Finally, we discuss how these results can be extended to inform method selection for other platforms and specific applications, with an outlook to potential benefit for pre-clinical and clinical studies. Overall, this study presents a new practical guide for selection of in vivo biodistribution methods that yield quantitative results. STATEMENT OF SIGNIFICANCE: The significance of this work lies in the use of a single platform to test performances of different biodistribution methods in vivo, with a strict quantitative metric. These results, united with the qualitative comparison of advantages and disadvantages of each technique, are aimed at supporting the rational choice of each different method according to the specific application, to improve the quantitative description of biodistribution results that will be published by others in the future.
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http://dx.doi.org/10.1016/j.actbio.2019.08.002DOI Listing
October 2019

Clinical Cancer Nanomedicine.

Nano Today 2019 Apr 6;25:85-98. Epub 2019 Mar 6.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, USA.

Nanotechnology offers new solutions for the development of cancer therapeutics that display improved efficacy and safety. Although several nanotherapeutics have received clinical approval, the most promising nanotechnology applications for patients still lie ahead. Nanoparticles display unique transport, biological, optical, magnetic, electronic, and thermal properties that are not apparent on the molecular or macroscale, and can be utilized for therapeutic purposes. These characteristics arise because nanoparticles are in the same size range as the wavelength of light and display large surface area to volume ratios. The large size of nanoparticles compared to conventional chemotherapeutic agents or biological macromolecule drugs also enables incorporation of several supportive components in addition to active pharmaceutical ingredients. These components can facilitate solubilization, protection from degradation, sustained release, immunoevasion, tissue penetration, imaging, targeting, and triggered activation. Nanoparticles are also processed differently in the body compared to conventional drugs. Specifically, nanoparticles display unique hemodynamic properties and biodistribution profiles. Notably, the interactions that occur at the bio-nano interface can be exploited for improved drug delivery. This review discusses successful clinically approved cancer nanodrugs as well as promising candidates in the pipeline. These nanotherapeutics are categorized according to whether they predominantly exploit multifunctionality, unique electromagnetic properties, or distinct transport characteristics in the body. Moreover, future directions in nanomedicine such as companion diagnostics, strategies for modifying the microenvironment, spatiotemporal nanoparticle transitions, and the use of extracellular vesicles for drug delivery are also explored.
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http://dx.doi.org/10.1016/j.nantod.2019.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662733PMC
April 2019

Adipose-derived cellular and cell-derived regenerative therapies in dermatology and aesthetic rejuvenation.

Ageing Res Rev 2019 09 24;54:100933. Epub 2019 Jun 24.

Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, 32224, United States; Department of Orthopedic Surgery, Mayo Clinic, Jacksonville, FL, 32224, United States. Electronic address:

Cellular and cell-derived components of adipose-derived tissue for the purposes of dermatologic and aesthetic rejuvenation applications have become increasingly studied and integrated into clinical practice. These components include micro-fragmented fat (nanofat), the stromal vascular fraction (SVF), adipose-derived mesenchymal stem cells (ASC), and extracellular vesicles (EVs), which have all shown capability to repair, regenerate, and rejuvenate surrounding tissue. Various aesthetic applications including hair growth, scar reduction, skin ischemia-reperfusion recovery, and facial rejuvenation are reviewed. In particular, results from preclinical and clinical studies are discussed, with a focus on clarification of nomenclature.
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http://dx.doi.org/10.1016/j.arr.2019.100933DOI Listing
September 2019

Organotropic drug delivery: Synthetic nanoparticles and extracellular vesicles.

Biomed Microdevices 2019 04 15;21(2):46. Epub 2019 Apr 15.

Department of Transplantation Medicine, Mayo Clinic, Jacksonville, Florida, 32224, USA.

Most clinically approved drugs (primarily small molecules or antibodies) are rapidly cleared from circulation and distribute throughout the body. As a consequence, only a small portion of the dose accumulates at the target site, leading to low efficacy and adverse side effects. Therefore, new delivery strategies are necessary to increase organ and tissue-specific delivery of therapeutic agents. Nanoparticles provide a promising approach for prolonging the circulation time and improving the biodistribution of drugs. However, nanoparticles display several limitations, such as clearance by the immune systems and impaired diffusion in the tissue microenvironment. To overcome common nanoparticle limitations various functionalization and targeting strategies have been proposed. This review will discuss synthetic nanoparticle and extracellular vesicle delivery strategies that exploit organ-specific features to enhance drug accumulation at the target site.
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http://dx.doi.org/10.1007/s10544-019-0396-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686136PMC
April 2019

Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.

J Extracell Vesicles 2018 23;7(1):1535750. Epub 2018 Nov 23.

Institute of Biomedicine and Molecular Immunology (IBIM), National Research Council (CNR) of Italy, Palermo, Italy.

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.
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http://dx.doi.org/10.1080/20013078.2018.1535750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322352PMC
November 2018

Tangential Flow Filtration for Highly Efficient Concentration of Extracellular Vesicles from Large Volumes of Fluid.

Cells 2018 Dec 16;7(12). Epub 2018 Dec 16.

Department of Transplantation Medicine; Department of Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL 32224, USA.

Concentration of extracellular vesicles (EVs) from biological fluids in a scalable and reproducible manner represents a major challenge. This study reports the use of tangential flow filtration (TFF) for the highly efficient isolation of EVs from large volumes of samples. When compared to ultracentrifugation (UC), which is the most widely used method to concentrate EVs, TFF is a more efficient, scalable, and gentler method. Comparative assessment of TFF and UC of conditioned cell culture media revealed that the former concentrates EVs of comparable physicochemical characteristics, but with higher yield, less single macromolecules and aggregates (<15 nm in size), and improved batch-to-batch consistency in half the processing time (1 h). The TFF protocol was then successfully implemented on fluids derived from patient lipoaspirate. EVs from adipose tissue are of high clinical relevance, as they are expected to mirror the regenerative properties of the parent cells.
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http://dx.doi.org/10.3390/cells7120273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315734PMC
December 2018

Chloroquine and nanoparticle drug delivery: A promising combination.

Pharmacol Ther 2018 11 20;191:43-49. Epub 2018 Jun 20.

Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address:

Clinically approved cancer therapies include small molecules, antibodies, and nanoparticles. There has been major progress in the treatment of several cancer types over recent decades. However, many challenges remain for optimal use of conventional and nanoparticle-based therapies in oncology including poor drug delivery, rapid clearance, and drug resistance. The antimalarial agent chloroquine has been found to mitigate some of these challenges by modulating cancer cells and the tissue microenvironment. Particularly, chloroquine was recently found to reduce immunological clearance of nanoparticles by resident macrophages in the liver, leading to increased tumor accumulation of nanodrugs. Additionally, chloroquine has been shown to improve drug delivery and efficacy through normalization of tumor vasculature and suppression of several oncogenic and stress-tolerance pathways, such as autophagy, that protect cancer cells from cytotoxic agents. This review will discuss the use of chloroquine as combination therapy to improve cancer treatment.
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http://dx.doi.org/10.1016/j.pharmthera.2018.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677248PMC
November 2018

Chemotherapy Sensitizes Therapy-Resistant Cells to Mild Hyperthermia by Suppressing Heat Shock Protein 27 Expression in Triple-Negative Breast Cancer.

Clin Cancer Res 2018 10 19;24(19):4900-4912. Epub 2018 Jun 19.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas.

Triple-negative breast cancer (TNBC) is a clinically aggressive disease with poor prognosis. Conventional chemotherapeutics are generally able to shrink the tumor mass, but often fail to completely eradicate cancer stem-like cells (CSCs) that are responsible for high risk of relapse and frequent metastases. In this study, we examined thermal sensibility of CSCs, developed an approach that enabled concurrent elimination of both the bulk of cancer cells and CSCs, and investigated the underlying mechanism. We designed a platform consisting of gold nanoparticle-coated porous silicon microparticle (AuPSM) that was also loaded with docetaxel micelles (mDTXs) to enable concurrent killing of the bulk of cancer cells by released mDTX and CSCs by mild hyperthermia upon stimulation of AuPSM with near infrared. In addition, we examined the role of heat shock proteins in sensitizing CSC killing. Finally, we applied mDTX-loaded AuPSM to treat mice with SUM159 and 4T1 orthotopic tumors and evaluated tumor growth and tumor metastasis. MDA-MB-231 and SUM159 TNBC cells treated with mDTX-loaded AuPSM and mild hyperthermia displayed significantly reduced efficiencies in mammosphere formation than those treated with mDTX alone or mild hyperthermia alone. Combination treatment also completely inhibited SUM159 orthotopic tumor growth and 4T1 tumor metastasis. Mechanistically, DTX treatment suppressed expression of heat shock protein 27 in cancer cells including the CSCs, rendering cells sensitive to mild hyperthermia. Our results indicate that chemotherapy sensitizes CSC to mild hyperthermia. We have developed an effective therapeutic approach to eliminate therapy-resistant cells in TNBC. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168413PMC
October 2018

Extracellular vesicle therapeutics for liver disease.

J Control Release 2018 03 31;273:86-98. Epub 2018 Jan 31.

Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, USA; Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Biology, University of North Florida, Jacksonville, FL 32224, USA; Wenzhou Institute of Biomaterials and Engineering, Ningbo Institute of Industrial Technology, Chinese Academy of Sciences, Wenzhou, China. Electronic address:

Extracellular vesicles (EVs) are endogenous nanoparticles that play important roles in intercellular communication. Unmodified and engineered EVs can be utilized for therapeutic purposes. For instance, mesenchymal stem cell (MSC)-derived EVs have shown promise for tissue repair, while drug-loaded EVs have the potential to be used for cancer treatment. The liver is an ideal target for EV therapy due to the intrinsic regenerative capacity of hepatic tissue and the tropism of systemically injected nanovesicles for this organ. This review will give an overview of the potential of EV therapeutics in liver disease. Specifically, the mechanisms by which MSC-EVs induce liver repair will be covered. Moreover, the use of drug-loaded EVs for the treatment of hepatocellular carcinoma will also be discussed. Although there are several challenges associated with the clinical translation of EVs, these biological nanoparticles represent a promising new therapeutic modality for liver disease.
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http://dx.doi.org/10.1016/j.jconrel.2018.01.022DOI Listing
March 2018

A Novel DNA Aptamer for Dual Targeting of Polymorphonuclear Myeloid-derived Suppressor Cells and Tumor Cells.

Theranostics 2018 1;8(1):31-44. Epub 2018 Jan 1.

Department of Nanomedicine, Houston Methodist Hospital Research Institute, Houston, TX 77030, USA.

Aptamers have the potential to be used as targeting ligands for cancer treatment as they form unique spatial structures. In this study, a DNA aptamer (T1) that accumulates in the tumor microenvironment was identified through selection and validation in breast cancer models. The use of T1 as a targeting ligand was evaluated by conjugating the aptamer to liposomal doxorubicin. T1 exhibited a high affinity for both tumor cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Treatment with T1 targeted doxorubicin liposomes triggered apoptosis of breast cancer cells and PMN-MDSCs. Suppression of PMN-MDSCs, which serve an immunosuppressive function, leads to increased intratumoral infiltration of cytotoxic T cells. The cytotoxic and immunomodulatory effects of T1-liposomes resulted in superior therapeutic efficacy compared to treatment with untargeted liposomes, highlighting the promise of T1 as a targeting ligand in cancer therapy.
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http://dx.doi.org/10.7150/thno.21342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743458PMC
November 2018

A chloroquine-induced macrophage-preconditioning strategy for improved nanodelivery.

Sci Rep 2017 10 23;7(1):13738. Epub 2017 Oct 23.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.

Site-specific localization is critical for improving the therapeutic efficacy and safety of drugs. Nanoparticles have emerged as promising tools for localized drug delivery. However, over 90% of systemically injected nanocarriers typically accumulate in the liver and spleen due to resident macrophages that form the mononuclear phagocyte system. In this study, the clinically approved antimalarial agent chloroquine was shown to reduce nanoparticle uptake in macrophages by suppressing endocytosis. Pretreatment of mice with a clinically relevant dose of chloroquine substantially decreased the accumulation of liposomes and silicon particles in the mononuclear phagocyte system and improved tumoritropic and organotropic delivery. The novel use of chloroquine as a macrophage-preconditioning agent presents a straightforward approach for addressing a major barrier in nanomedicine. Moreover, this priming strategy has broad applicability for improving the biodistribution and performance of particulate delivery systems. Ultimately, this study defines a paradigm for the combined use of macrophage-modulating agents with nanotherapeutics for improved site-specific delivery.
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http://dx.doi.org/10.1038/s41598-017-14221-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653759PMC
October 2017

Contribution of Kupffer cells to liposome accumulation in the liver.

Colloids Surf B Biointerfaces 2017 Oct 15;158:356-362. Epub 2017 Jul 15.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address:

The liver is a major barrier for site-specific delivery of systemically injected nanoparticles, as up to 90% of the dose is usually captured by this organ. Kupffer cells are thought to be the main cellular component responsible for nanoparticle accumulation in the liver. These resident macrophages form part of the mononuclear phagocyte system, which recognizes and engulfs foreign bodies in the circulatory system. In this study, we have compared two strategies for reducing nanoparticle accumulation in the liver, in order to investigate the specific contribution of Kupffer cells. Specifically, we have performed a comparison of the capability of pegylation and Kupffer cell depletion to reduce liposome accumulation in the liver. Pegylation reduces nanoparticle interactions with all types of cells and can serve as a control for elucidating the role of specific cell populations in liver accumulation. The results indicate that liposome pegylation is a more effective strategy for avoiding liver uptake compared to depletion of Kupffer cells, suggesting that nanoparticle interactions with other cells in the liver may also play a contributing role. This study highlights the need for a more complete understanding of factors that mediate nanoparticle accumulation in the liver and for the exploration of microenvironmental modulation strategies for reducing nanoparticle-cell interactions in this organ.
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http://dx.doi.org/10.1016/j.colsurfb.2017.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645238PMC
October 2017
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