Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model

Yu, Dou; Li, Gina; Lesniak, Maciej S.; Balyasnikova, Irina V.

doi:10.3791/55845

Cited by 7 publications

(7 citation statements)

References 15 publications

(42 reference statements)

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“…On the other hand, a strong fluorescent A 488 signal was detected exclusively in the brains of the RVG9R-inoculated group. In addition, we compared this mouse placement position to the supine position method that has been used previously 17 , as well as to the awake method, for efficacy. We inoculated a fixed amount of RVG9R-A 488 (100 µg) and assayed biodistribution at 48 h postinoculation.…”

Section: Representative Resultsmentioning

confidence: 99%

A Positioning Device for the Placement of Mice During Intranasal siRNA Delivery to the Central Nervous System

Ullah

Chung

Beloor

et al. 2019

JoVE

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Intranasal (IN) drug delivery to the brain has emerged as a promising method to bypass the blood-brain barrier (BBB) for the delivery of drugs into the central nervous system (CNS). Recent studies demonstrate the use of a peptide, RVG9R, incorporating the minimal receptor-binding domain of the Rabies virus glycoprotein, in eliciting the delivery of siRNA into neurons in the brain. In this protocol, the peptide-siRNA formulation is delivered intranasally with a pipette in the dominant hand, while the anesthetized mouse is restrained by the scruff with the nondominant hand in a "head down-and-forward position" to avoid drainage into the lung and stomach upon inhalation. This precise gripping of mice can be learned but is not easy and requires practice and skill to result in effective CNS uptake. Furthermore, the process is long-drawn, requiring about 45 min for the administration of a total volume of ~20-30 µL of solution in 1-2 µL droplet volumes per inhalation, with 3-4 min rest periods between each inhalation. The objective of this study is to disclose a mouse positioning device that enables the appropriate placement of mice for efficient IN administration of the peptide-siRNA formulation. Multiple features are incorporated into the design of the device, such as four or eight positioning chairs with adjustable height and tilt to restrain anesthetized mice in the head down-and-forward position, enabling easy visualization of the mice's nares and a built-in heating pad to maintain the mice's body temperatures during the procedure. Importantly, the ability to treat four or eight mice simultaneously with RVG9R-siRNA complexes in this manner enables studies on a much quicker time scale, for the testing of an IN therapeutic siRNA approach. In conclusion, this device allows for appropriate and controlled mouse head positioning for IN application of RVG9R-siRNA and other therapeutic molecules, such as nanoparticles or antibodies, for CNS delivery.

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Section: Representative Resultsmentioning

confidence: 99%

A Positioning Device for the Placement of Mice During Intranasal siRNA Delivery to the Central Nervous System

Ullah

Chung

Beloor

et al. 2019

JoVE

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“…99 This method of delivery is non-invasive, rapid, and offers BBB bypass. 100 Cells showed improved targeting and less accumulation in peripheral organs, compared to systemic dosage. 101 Additionally, intranasal delivery allows for repeated dosages, [102][103][104][105] making it more practical than other methods.…”

Section: Intranasal Deliverymentioning

confidence: 99%

“…Of note, a hypoxic-ischemic brain injury neonatal primate model demonstrated migration of intranasally delivered MSCs to the site of injury, suggesting a feasible translation. 96 Overall (Table 1), 42,45,51,77,78,81,82,84,90,91,100,[102][103][104][105]110 IV, intracerebral, and IA routes have been the most utilized and investigated for stem cell administration in preclinical and clinical studies. IV administration facilitates widespread implementation and avoids invasive procedures, but reduces brain tissue penetration due to cell diffusion and risks accumulation in other organs such as the liver, spleen, and lungs.…”

Section: Intranasal Deliverymentioning

confidence: 99%

“…Intranasallydelivered cells collect beneath the nasal mucosa, close to the turbinate bones, and travel through the cribriform plate [ 99 ]. This method of delivery is non-invasive, rapid, and offers BBB bypass [ 100 ]. Cells showed improved targeting and less accumulation in peripheral organs, compared to systemic dosage [ 101 ].…”

Section: Stem Cell Administration Routesmentioning

confidence: 99%

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Optimizing Stem Cell Therapy after Ischemic Brain Injury

et al. 2020

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Stem cells have been used for regenerative and therapeutic purposes in a variety of diseases. In ischemic brain injury, preclinical studies have been promising, but have failed to translate results to clinical trials. We aimed to explore the application of stem cells after ischemic brain injury by focusing on topics such as delivery routes, regeneration efficacy, adverse effects, and <i>in vivo</i> potential optimization. PUBMED and Web of Science were searched for the latest studies examining stem cell therapy applications in ischemic brain injury, particularly after stroke or cardiac arrest, with a focus on studies addressing delivery optimization, stem cell type comparison, or translational aspects. Other studies providing further understanding or potential contributions to ischemic brain injury treatment were also included. Multiple stem cell types have been investigated in ischemic brain injury treatment, with a strong literature base in the treatment of stroke. Studies have suggested that stem cell administration after ischemic brain injury exerts paracrine effects via growth factor release, blood-brain barrier integrity protection, and allows for exosome release for ischemic injury mitigation. To date, limited studies have investigated these therapeutic mechanisms in the setting of cardiac arrest or therapeutic hypothermia. Several delivery modalities are available, each with limitations regarding invasiveness and safety outcomes. Intranasal delivery presents a potentially improved mechanism, and hypoxic conditioning offers a potential stem cell therapy optimization strategy for ischemic brain injury. The use of stem cells to treat ischemic brain injury in clinical trials is in its early phase; however, increasing preclinical evidence suggests that stem cells can contribute to the down-regulation of inflammatory phenotypes and regeneration following injury. The safety and the tolerability profile of stem cells have been confirmed, and their potent therapeutic effects make them powerful therapeutic agents for ischemic brain injury patients.

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“…The intranasal route has been recently considered as an effective route for stem cell delivery to the mouse brain (Yu et al 2017). The growing popularity of this route is attributable to the non-invasive nature of administration, excellent safety, as well as its selectivity reducing cell distribution in peripheral organs (Li et al 2015; Reitz M 2012).…”

Section: Cell Delivery Routes Optimal For Wide Distribution Of Gpsmentioning

confidence: 99%

Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men

Srivastava

Bulte

Walczak

et al. 2017

Glia

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Neurological disorders are a major threat to public health. Stem cell-based regenerative medicine is now a promising experimental paradigm for its treatment, as shown in pre-clinical animal studies. Initial attempts have been on the replacement of neuronal cells only, but glial progenitors (GPs) are now becoming strong alternative cellular therapeutic candidates to replace oligodendrocytes and astrocytes as knowledge accumulates about their important emerging role in various disease processes. There are many examples of successful therapeutic outcomes for transplanted GPs in small animal models, but clinical translation has proved to be challenging due to the 1,000-fold larger volume of the human brain compared to mice. Human GPs transplanted into the mouse brain migrate extensively and can induce global cell replacement, but a similar extent of migration in the human brain would only allow for local rather than global cell replacement. We review here the mechanisms that govern cell migration, which could potentially be exploited to enhance the migratory properties of GPs through cell engineering pre-transplantation. We furthermore discuss the (dis)advantages of the various cell delivery routes that are available, with particular emphasis on intra-arterial injection as the most suitable route for achieving global cell distribution in the larger brain. Now that therapeutic success has proven to be feasible in small animal models, future efforts will need to be directed to enhance global cell delivery and migration to make bench-to-bedside translation a reality.

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Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model

Cited by 7 publications

References 15 publications

A Positioning Device for the Placement of Mice During Intranasal siRNA Delivery to the Central Nervous System

A Positioning Device for the Placement of Mice During Intranasal siRNA Delivery to the Central Nervous System

Optimizing Stem Cell Therapy after Ischemic Brain Injury

Migratory potential of transplanted glial progenitors as critical factor for successful translation of glia replacement therapy: The gap between mice and men

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