Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery

Glioblastoma multiforme (GBM) is one of the most intractable of human cancers, principally because of the highly infiltrative nature of these neoplasms. Tracking and eradicating infiltrating GBM cells and tumor microsatellites is of utmost importance for the treatment of this devastating disease, yet effective strategies remain elusive. Here we report polymeric nanoparticle-engineered human adipose-derived stem cells (hADSCs) overexpressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as drug-delivery vehicles for targeting and eradicating GBM cells in vivo. Our results showed that polymeric nanoparticle-mediated transfection led to robust up-regulation of TRAIL in hADSCs, and that TRAIL-expressing hADSCs induced tumor-specific apoptosis. When transplanted in a mouse intracranial xenograft model of patient-derived glioblastoma cells, hADSCs exhibited long-range directional migration and infiltration toward GBM tumor. Importantly, TRAIL-overexpressing hADSCs inhibited GBM growth, extended survival, and reduced the occurrence of microsatellites. Repetitive injection of TRAIL-overexpressing hADSCs significantly prolonged animal survival compared with single injection of these cells. Taken together, our data suggest that nanoparticle-engineered TRAIL-expressing hADSCs exhibit the therapeutically relevant behavior of “seek-and-destroy” tumortropic migration and could be a promising therapeutic approach to improve the treatment outcomes of patients with malignant brain tumors.

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Novel Phospholipid-Based Labrasol Nanomicelles Loaded Flavonoids for Oral Delivery with Enhanced Penetration and Anti-Brain Tumor Efficiency

Current Drug Delivery ◽

10.2174/1567201817666200210120950 ◽

2020 ◽

Vol 17 (3) ◽

pp. 229-245

Author(s):

Gang Wang ◽

Junjie Wang ◽

Rui Guan

Keyword(s):

Drug Delivery ◽

Brain Tumor ◽

Oral Delivery ◽

Safe Delivery ◽

Drug Delivery Vehicles ◽

Therapeutic Benefits ◽

Delivery Vehicles ◽

The Brain

Background: Owing to the rich anticancer properties of flavonoids, there is a need for their incorporation into drug delivery vehicles like nanomicelles for safe delivery of the drug into the brain tumor microenvironment. Objective: This study, therefore, aimed to prepare the phospholipid-based Labrasol/Pluronic F68 modified nano micelles loaded with flavonoids (Nano-flavonoids) for the delivery of the drug to the target brain tumor. Methods: Myricetin, quercetin and fisetin were selected as the initial drugs to evaluate the biodistribution and acute toxicity of the drug delivery vehicles in rats with implanted C6 glioma tumors after oral administration, while the uptake, retention, release in human intestinal Caco-2 cells and the effect on the brain endothelial barrier were investigated in Human Brain Microvascular Endothelial Cells (HBMECs). Results: The results demonstrated that nano-flavonoids loaded with myricetin showed more evenly distributed targeting tissues and enhanced anti-tumor efficiency in vivo without significant cytotoxicity to Caco-2 cells and alteration in the Trans Epithelial Electric Resistance (TEER). There was no pathological evidence of renal, hepatic or other organs dysfunction after the administration of nanoflavonoids, which showed no significant influence on cytotoxicity to Caco-2 cells. Conclusion: In conclusion, Labrasol/F68-NMs loaded with MYR and quercetin could enhance antiglioma effect in vitro and in vivo, which may be better tools for medical therapy, while the pharmacokinetics and pharmacodynamics of nano-flavonoids may ensure optimal therapeutic benefits.

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Delivery Efficacy Differences of Intravenous and Intraperitoneal Injection of Exosomes: Perspectives from Tracking Dye Labeled and MiRNA Encapsulated Exosomes

Current Drug Delivery ◽

10.2174/1567201817666200122163251 ◽

2020 ◽

Vol 17 (3) ◽

pp. 186-194 ◽

Cited By ~ 2

Author(s):

Xueying Zhou ◽

Zhelong Li ◽

Wenqi Sun ◽

Guodong Yang ◽

Changyang Xing ◽

...

Keyword(s):

Intraperitoneal Injection ◽

Drug Delivery Vehicles ◽

C Elegans ◽

Administration Routes ◽

In Vivo Distribution ◽

Obesity Therapy ◽

Delivery Vehicles ◽

Visceral Adipose ◽

Mirna Abundance

Background: Exosomes are cell-derived nanovesicles that play vital roles in intercellular communication. Recently, exosomes are recognized as promising drug delivery vehicles. Up till now, how the in vivo distribution of exosomes is affected by different administration routes has not been fully understood. Methods: In the present study, in vivo distribution of exosomes following intravenous and intraperitoneal injection approaches was systemically analyzed by tracking the fluorescence-labeled exosomes and qPCR analysis of C. elegans specific miRNA abundance delivered by exosomes in different organs. Results: The results showed that exosomes administered through tail vein were mostly taken up by the liver, spleen and lungs while exosomes injected intraperitoneally were more dispersedly distributed. Besides the liver, spleen, and lungs, intraperitoneal injection effectively delivered exosomes into the visceral adipose tissue, making it a promising strategy for obesity therapy. Moreover, the results from fluorescence tracking and qPCR were slightly different, which could be explained by systemic errors. Conclusion: Together, our study reveals that different administration routes cause a significant differential in vivo distribution of exosomes, suggesting that optimization of the delivery route is prerequisite to obtain rational delivery efficiency in detailed organs.

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Biodistribution and Pharmacokinectics of Liposomes and Exosomes in a Mouse Model of Sepsis

Pharmaceutics ◽

10.3390/pharmaceutics13030427 ◽

2021 ◽

Vol 13 (3) ◽

pp. 427

Author(s):

Amin Mirzaaghasi ◽

Yunho Han ◽

So-Hee Ahn ◽

Chulhee Choi ◽

Ji-Ho Park

Keyword(s):

Drug Delivery ◽

Therapeutic Potential ◽

Hek293t Cell ◽

Biological Properties ◽

Context Analysis ◽

Drug Delivery Vehicles ◽

Delivery Vehicles ◽

Diseased State ◽

Sepsis And Septic Shock

Exosomes have attracted considerable attention as drug delivery vehicles because their biological properties can be utilized for selective delivery of therapeutic cargoes to disease sites. In this context, analysis of the in vivo behaviors of exosomes in a diseased state is required to maximize their therapeutic potential as drug delivery vehicles. In this study, we investigated biodistribution and pharmacokinetics of HEK293T cell-derived exosomes and PEGylated liposomes, their synthetic counterparts, into healthy and sepsis mice. We found that biodistribution and pharmacokinetics of exosomes were significantly affected by pathophysiological conditions of sepsis compared to those of liposomes. In the sepsis mice, a substantial number of exosomes were found in the lung after intravenous injection, and their prolonged blood residence was observed due to the liver dysfunction. However, liposomes did not show such sepsis-specific effects significantly. These results demonstrate that exosome-based therapeutics can be developed to manage sepsis and septic shock by virtue of their sepsis-specific in vivo behaviors.

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Stamina-Enhancing Effects of Human Adipose-Derived Stem Cells

Cell Transplantation ◽

10.1177/09636897211035409 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110354

Author(s):

Eun-Jung Yoon ◽

Hye Rim Seong ◽

Jangbeen Kyung ◽

Dajeong Kim ◽

Sangryong Park ◽

...

Keyword(s):

Physical Activity ◽

Stem Cells ◽

Locomotor Activity ◽

Tissue Injury ◽

Male Rats ◽

Adipose Derived Stem Cells ◽

Sprague Dawley ◽

Serum Triglycerides

Stamina-enhancing effects of human adipose derived stem cells (hADSCs) were investigated in young Sprague-Dawley rats. Ten-day-old male rats were transplanted intravenously (IV) or intracerebroventricularly (ICV) with hADSCs (1 × 106 cells/rat), and physical activity was measured by locomotor activity and rota-rod performance at post-natal day (PND) 14, 20, 30, and 40, as well as a forced swimming test at PND 41. hADSCs injection increased the moving time in locomotor activity, the latency in rota-rod performance, and the maximum swimming time. For the improvement of physical activity, ICV transplantation was superior to IV injection. In biochemical analyses, ICV transplantation of hADSCs markedly reduced serum creatine phosphokinase, lactate dehydrogenase, alanine transaminase, and muscular lipid peroxidation, the markers for muscular and hepatic injuries, despite the reduction in muscular glycogen and serum triglycerides as energy sources. Notably, hADSCs secreted brain-derived neurotrophic factor (BDNF) and nerve growth factor in vitro, and increased the level of BDNF in the brain and muscles in vivo. The results indicate that hADSCs enhance physical activity including stamina not only by attenuating tissue injury, but also by strengthening the muscles via production of BDNF.

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Elimination of Reperfusion-Induced Microcirculatory Alterations In Vivo by Adipose-Derived Stem Cell Supernatant without Adipose-Derived Stem Cells

Plastic & Reconstructive Surgery ◽

10.1097/prs.0000000000001097 ◽

2015 ◽

Vol 135 (4) ◽

pp. 1056-1064 ◽

Cited By ~ 7

Author(s):

Wei Z. Wang ◽

Xin-Hua Fang ◽

Shelley J. Williams ◽

Linda L. Stephenson ◽

Richard C. Baynosa ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Adipose Derived Stem Cells ◽

Adipose Derived Stem Cell ◽

Cell Supernatant

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High glucose induces early senescence in adipose-derived stem cells by accelerating p16 and mTOR

Biomedical Research and Therapy ◽

10.15419/bmrat.v6i6.548 ◽

2019 ◽

Vol 6 (6) ◽

pp. 3213-3221

Author(s):

Hieu Liem Pham ◽

Phuc Van Pham

Keyword(s):

Stem Cells ◽

High Glucose ◽

Glucose Concentration ◽

Culture Medium ◽

Diabetic Patients ◽

Adipose Derived Stem Cells ◽

Differentiation Potential ◽

Normal Glucose

Introduction: The senescence of stem cells is the primary reason that causes aging of stem cell-containing tissues. Some hypotheses have suggested that high glucose concentration in diabetic patients is the main factor that causes senescence of cells in those patients. This study aimed to evaluate the effects of high glucose concentrations on the senescence of adipose-derived stem cells (ADSCs). Methods: ADSCs were isolated and expanded from human adipose tissues. They were characterized and confirmed as mesenchymal stem cells (MSCs) by expression of surface markers, their shape, and in vitro differentiation potential. They were then cultured in 3 different media- that contained 17.5 mM, 35 mM, or 55 mM of D-glucose. The senescent status of ADSCs was recorded by the expression of the enzyme beta-galactosidase, cell proliferation, and doubling time. Real-time RT-PCR was used to evaluate the expression of p16, p21, p53 and mTOR. Results: The results showed that high glucose concentrations (35 mM and 55 mM) in the culture medium induced senescence of human ADSCs. The ADSCs could progress to the senescent status quicker than those cultured in the lower glucose-containing medium (17.5 mM). The senescent state was related to the up-regulation of p16 and mTOR genes. Conclusion: These results suggest that high glucose in culture medium can trigger the expression of p16 and mTOR genes which cause early senescence in ADSCs. Therefore, ADSCs should be cultured in low glucose culture medium, or normal glucose concentration, to extend their life in vitro as well as in vivo.

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hPSC-Derived Enteric Ganglioids Model Human ENS Development and Function

10.1101/2022.01.04.474746 ◽

2022 ◽

Author(s):

Homa Majd ◽

Ryan M Samuel ◽

Jonathan T Ramirez ◽

Ali Kalantari ◽

Kevin Barber ◽

...

Keyword(s):

Ex Vivo ◽

Xenograft Model ◽

Developmental Relationships ◽

Drug Candidates ◽

Effective Strategies ◽

Wide Range ◽

Functional Features ◽

And Function

The enteric nervous system (ENS) plays a central role in gut physiology and mediating the crosstalk between the gastrointestinal (GI) tract and other organs. The human ENS has remained elusive, highlighting the need for an in vitro modeling and mapping blueprint. Here we map out the developmental and functional features of the human ENS, by establishing robust and scalable 2D ENS cultures and 3D enteric ganglioids from human pluripotent stem cells (hPSCs). These models recapitulate the remarkable neuronal and glial diversity found in primary tissue and enable comprehensive molecular analyses that uncover functional and developmental relationships within these lineages. As a salient example of the power of this system, we performed in-depth characterization of enteric nitrergic neurons (NO neurons) which are implicated in a wide range of GI motility disorders. We conducted an unbiased screen and identified drug candidates that modulate the activity of NO neurons and demonstrated their potential in promoting motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define the developmental programs involved in NO neuron specification and discovered that PDGFR inhibition boosts the induction of NO neurons in enteric ganglioids. Transplantation of these ganglioids in the colon of NO neuron-deficient mice results in extensive tissue engraftment, providing a xenograft model for the study of human ENS in vivo and the development of cell-based therapies for neurodegenerative GI disorders. These studies provide a framework for deciphering fundamental features of the human ENS and designing effective strategies to treat enteric neuropathies.

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