Biodistribution Of Exosomes Research Articles

Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury.

Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a promising approach. In this study, we investigate the effects of intranasally administered exosomes in an animal model. Exosomes were isolated from the cell supernatants using the ultracentrifugation method. Brain injury was induced in Sprague-Dawley rats through a transient four-vessel occlusion model. Intranasal administration was conducted with 3 × 108 exosome particles in 20 µL of PBS or PBS alone, administered daily for 7 days post-injury. Long-term cognitive behavioral assessments, biodistribution of exosomes, and histological evaluations of apoptosis and neuroinflammation were conducted. Exosomes were primarily detected in the olfactory bulb one hour after intranasal administration, subsequently distributing to the striatum and midbrain. Rats treated with exosomes exhibited substantial improvement in cognitive function up to 28 days after the insult, and demonstrated significantly fewer apoptotic cells along with higher neuronal cell survival in the hippocampus. Exosomes were found to be taken up by microglia, leading to a decrease in the expression of cytotoxic inflammatory markers.

Intravenous Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Spinal Cord Injury by Regulating Neutrophil Extracellular Trap Formation through Exosomal miR-125a-3p.

Spinal cord injury (SCI) leads to devastating sequelae, demanding effective treatments. Recent advancements have unveiled the role of neutrophil extracellular traps (NETs) produced by infiltrated neutrophils in exacerbating secondary inflammation after SCI, making it a potential target for treatment intervention. Previous research has established that intravenous administration of stem cell-derived exosomes can mitigate injuries. While stem cell-derived exosomes have demonstrated the ability to modulate microglial reactions and enhance blood-brain barrier integrity, their impact on neutrophil deactivation, especially in the context of NETs, remains poorly understood. This study aims to investigate the effects of intravenous administration of MSC-derived exosomes, with a specific focus on NET formation, and to elucidate the associated molecular mechanisms. Exosomes were isolated from the cell supernatants of amnion-derived mesenchymal stem cells using the ultracentrifugation method. Spinal cord injuries were induced in Sprague-Dawley rats (9 weeks old) using a clip injury model, and 100 μg of exosomes in 1 mL of PBS or PBS alone were intravenously administered 24 h post-injury. Motor function was assessed serially for up to 28 days following the injury. On Day 3 and Day 28, spinal cord specimens were analyzed to evaluate the extent of injury and the formation of NETs. Flow cytometry was employed to examine the formation of circulating neutrophil NETs. Exogenous miRNA was electroporated into neutrophil to evaluate the effect of inflammatory NET formation. Finally, the biodistribution of exosomes was assessed using 64Cu-labeled exosomes in animal positron emission tomography (PET). Rats treated with exosomes exhibited a substantial improvement in motor function recovery and a reduction in injury size. Notably, there was a significant decrease in neutrophil infiltration and NET formation within the spinal cord, as well as a reduction in neutrophils forming NETs in the circulation. In vitro investigations indicated that exosomes accumulated in the vicinity of the nuclei of activated neutrophils, and neutrophils electroporated with the miR-125a-3p mimic exhibited a significantly diminished NET formation, while miR-125a-3p inhibitor reversed the effect. PET studies revealed that, although the majority of the transplanted exosomes were sequestered in the liver and spleen, a notably high quantity of exosomes was detected in the damaged spinal cord when compared to normal rats. MSC-derived exosomes play a pivotal role in alleviating spinal cord injury, in part through the deactivation of NET formation via miR-125a-3p.

Abstract 372: Biodistribution and tumor targeting of exosomes using mouse models

Abstract Biodistribution studies are relevant models for understanding the fundamental preclinical information of the distribution of drugs to the potential target organs, which provide insight on which on-target or off-target effects might be expected. One of our research focuses is the study of uptake and distribution of bovine milk- and colostrum-derived exosomes, functionalized exosomes and exosomes in polyethyleneimine (PEI) matrix (EPM) using near-infrared fluorescent dye in rodents. Previously, when DiR dye was loaded onto milk exosomes, biodistribution studies showed that route of administration had a significant influence on the tissue distribution with somewhat uniform biodistribution with oral gavage while predominated liver accumulation with the i.v. route. In this study, we show biodistribution of colostrum exosomes, EPM and tumor targeting by attaching tumor targeting ligand, folic acid (FA). We studied the biodistribution of these formulations using exosomes labeled with Alexa Fluor 750 (AF750) in wild-type mice and subcutaneous lung tumor-bearing mice. In various studies we tested: i) biodistribution of exosomes vs EPM, ii) effect of different administration routes such as intravenous (i.v.), oral (p.o.), subcutaneous (s.c.), intranasal (i.n.) and intramuscular (i.m.) on biodistribution, and iii) tumor targeting using FA-functionalized exosomes and EPM. Uniform tissue distribution was observed upon oral administration of exosomes while predominant hepatic accumulation was observed with i.v. administration. The i.n. route resulted in pre-dominant accumulation in lung, whereas i.m. and s.c. delivery had almost similar distribution as observed with i.v. route. The distribution of exosomes and EPM matrix was largely similar. We observed that the fluorescent signals from AF750-labeled FA-Exo and FA-EPM treatment revealed higher tumor accumulation of exosomes as compared to non-functionalized exosomes and EPM, respectively due to overexpression of folate receptors. Time-dependent distribution showed accumulation of EPM in tumors at later time point. The EPM formulations could be detected at the sites otherwise difficult to target such as brain and lymph nodes after systemic administration, thus indicating suitability of these formulations to cross physiological barriers. To validate the therapeutic potential, FA-EPM was loaded with 15 μg siKRAS and injected intravenously to orthotopic A549 lung tumor-bearing mice. Significant reduction in tumor volume (67%; p <0.001) and tumor weight (76%; p <0.001) was observed which corroborated the significant knockdown of KRAS protein (p <0.01). Thus, this novel approach can be used as a nano ‘platform’ for drug delivery due to its increased circulating half-life, high uptake by target cells, and ability to load a diverse range of pharmaceutical therapeutics including biologics such as siRNA. (Supported from Duggan Endowment and 3P biotechnologies, Inc.) Citation Format: Disha Nagesh Moholkar, Raghuram Kandimalla, Farrukh Aqil, Ramesh Gupta. Biodistribution and tumor targeting of exosomes using mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 372.

The role of tumor-isolated exosomes on suppression of immune reactions and cancer progression: A systematic review.

Background: Exosomes are extracellular cells (EVs) emancipated by various cell types and are involved in cell-to-cell transmission. In cancer diseases, exosomes emerge as local and systemic cells to cell mediators of oncogenic information and play a significant role in the advancement of cancer through the horizontal transfer of various molecules, such as proteins and miRNAs. Methods: In this study, 66 articles from PubMed, MEDLINE, Science Direct, Cochrane, EMBASE, and Scopus were used as English sources. Results: The biological distribution of cancer cell-derived exosomes in tumor tissue is an important factor in detecting their role in tumor increase; on the other hand, a limited number of studies have examined the biodistribution of exosomes in tumor tissues. While exosomes function as cancer biomarkers and support cancer treatment, we have a long way to improve the antitumor treatment of exosomes and develop exosome-based cancer diagnostic and therapeutic strategies. Conclusion: This review describes the science and significance of cancer pathogenesis and exosomes relative to cancer treatment resistance.

RETRACTED: Exosomes promote restoration after an experimental animal model of intracerebral hemorrhage

Exosomes are gaining importance because they show great promise in therapeutic applications for several diseases. Particularly in stroke, exosomes derived from mesenchymal stem cell (MSC) therapy work as paracrine effectors responsible for promoting neurovascular remodeling and functional recovery. Adult male rats were subjected to intracerebral hemorrhage (ICH) by intrastriatal injection of collagenase type IV; 24 h after surgery, MSC-derived exosomes were administered through the tail vein. The rats were euthanized at 7 or 28 days after treatment. Functional evaluation, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers, biodistribution of exosomes and secretome proteomics were analyzed. DiI-labeled exosomes were found in the brains of the ICH-treated group and in the liver, lung and spleen. Animals receiving treatment with exosomes showed significantly better results in terms of functional recovery, lesion size, fiber tract integrity, axonal sprouting and white matter repair markers compared with the control group 28 days after stroke. Proteomics analysis of the exosomes identified more than 2000 proteins that could be implicated in brain repair function. In conclusion, white matter integrity was partly restored by exosome administration mediated by molecular repair factors. Exosomes as a treatment could be a heterogeneous process by nature and presents many factors that can influence brain plasticity in an adaptable and versatile manner.

Pharmacokinetics of Exosomes—An Important Factor for Elucidating the Biological Roles of Exosomes and for the Development of Exosome-Based Therapeutics

Exosomes are small membrane vesicles containing lipids, proteins, and nucleic acids. Recently, researchers have uncovered that exosomes are involved in various biological events, such as tumor growth, metastasis, and the immune response, by delivering their cargos to exosome-receiving cells. Moreover, exosomes are expected to be used in therapeutic treatments, such as tissue regeneration therapy and antitumor immunotherapy, because exosomes are effective delivery vehicles for proteins, nucleic acids, and other bioactive compounds. To elucidate the biological functions of exosomes, and for the development of exosome-based therapeutics, the pharmacokinetics of exosomes is important. In this review, we aim to summarize current knowledge about the pharmacokinetics and biodistribution of exosomes. The pharmacokinetics of exogenously administered exosomes is discussed based on the tissue distribution, types of cells taking up exosomes, and key molecules in the pharmacokinetics of exosomes. In addition, recent progress in the methods to control the pharmacokinetics of exosomes is reviewed.