Predicting and optimizing the territory of blood–brain barrier opening by superselective intra-arterial cerebral infusion under dynamic susceptibility contrast MRI guidance

Janowski, Mirosław; Walczak, Piotr; Pearl, Monica S.

doi:10.1177/0271678x15615875

Cited by 40 publications

(42 citation statements)

References 13 publications

(12 reference statements)

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“…5,14,15 We have recently shown that MRI guidance is excellent for improving precision of IA infusion-based opening of the blood-brain barrier and chemotherapeutic drug delivery, while X-ray fluoroscopy lacks sufficient sensitivity. 16,17 Here, we show that this method is pivotal for imaging of stem cell infusion in real-time, which, in turn, enables outstanding precision of IA cell transplantation. In this study, we used therapeutic stem cells of different sizes-small glial restricted precursors (GRPs), and large mesenchymal stem cells (MSCs)-to emphasize the value and benefits of realtime image-guidance.…”

Section: Introductionmentioning

confidence: 88%

Real-time MRI for precise and predictable intra-arterial stem cell delivery to the central nervous system

Walczak

Wojtkiewicz

Nowakowski

et al. 2016

J Cereb Blood Flow Metab

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Stem cell therapy for neurological disorders reached a pivotal point when the efficacy of several cell types was demonstrated in small animal models. Translation of stem cell therapy is contingent upon overcoming the challenge of effective cell delivery to the human brain, which has a volume ∼1000 times larger than that of the mouse. Intra-arterial injection can achieve a broad, global, but also on-demand spatially targeted biodistribution; however, its utility has been limited by unpredictable cell destination and homing as dictated by the vascular territory, as well as by safety concerns. We show here that high-speed MRI can be used to visualize the intravascular distribution of a superparamagnetic iron oxide contrast agent and can thus be used to accurately predict the distribution of intra-arterial administered stem cells. Moreover, high-speed MRI enables the real-time visualization of cell homing, providing the opportunity for immediate intervention in the case of undesired biodistribution.

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Section: Introductionmentioning

confidence: 88%

Real-time MRI for precise and predictable intra-arterial stem cell delivery to the central nervous system

Walczak

Wojtkiewicz

Nowakowski

et al. 2016

J Cereb Blood Flow Metab

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“…Rabbits,are relatively large with a vasculature size and anatomy suitable for navigation of intra-arterial catheters as far as the posterior circulation of the brain[5]. The difficulty with using rabbits for modeling brain tumors is the lack of immunodeficient models.…”

Section: Discussionmentioning

confidence: 99%

“…Our work demonstrated that predictable, precise, and highly selective opening of the BBB can be achieved in a rabbit model utilizing MRI in conjunction with conventional angiographic procedures [5]. In addition, the intra-arterial approach enables the immediate delivery of local, targeted chemotherapy after confirmation of BBB opening as well as monitoring the biodistribution in a label-free fashion by chemical exchange saturation transfer (CEST) MRI[6–8].…”

Section: Introductionmentioning

confidence: 99%

Rabbit Model of Human Gliomas: Implications for Intra-Arterial Drug Delivery

et al. 2017

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The prognosis for malignant brain tumors remains poor despite a combination of surgery, radiotherapy, and chemotherapy. This is partly due to the blood-brain barrier, a major obstacle that prevents therapeutic agents from effectively reaching the tumor. We have recently developed a method for precise and predictable opening of the blood-brain barrier via the intra-arterial administration of mannitol, a hyperosmolar agent, in a rabbit model, whose vascular anatomy facilitates the use of standard interventional neuroradiology techniques and devices. To date, however, no protocols are available that enable human glioma modeling in rabbits. In this article, we report on the xenotransplantation of a human glioblastoma (GBM-1) in adult New Zealand rabbits. We induced multi-drug immunosuppression (Mycophenolate Mofetil, Dexamethasone, Tacrolimus) and stereotactically implanted GBM-1 tumor cells into rabbit brains. The rabbits were followed for 42 days, monitored by MRI and body weight measurements, and underwent postmortem histopathological analysis. On MRI, brain tumors were identified on T2-weighted scans. On histopathology, tumors were detected with hematoxylin/eosin and their human origin was confirmed with immunohistochemistry against human-specific antigens. Our method for human glioma modeling in rabbits provides the foundation to test novel treatment strategies, including intra-arterial therapeutic agent delivery.

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“…It has been already shown that intra-arterial infusion of GPs at a proper velocity is safe (Janowski et al 2013). In addition, the recently introduced IA injection under high-speed, real-time MRI guidance adds to the predictability and precision of the procedure of GP delivery (Janowski et al 2016). The same method can be used for blood brain barrier opening, which can additionally facilitate homing of stem cells (Janowski et al 2016).…”

Section: Cell Delivery Routes Optimal For Wide Distribution Of Gpsmentioning

confidence: 99%

“…In addition, the recently introduced IA injection under high-speed, real-time MRI guidance adds to the predictability and precision of the procedure of GP delivery (Janowski et al 2016). The same method can be used for blood brain barrier opening, which can additionally facilitate homing of stem cells (Janowski et al 2016). However, safe and precise delivery is insufficient, as the injected cells still need to traverse the vessel wall.…”

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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Predicting and optimizing the territory of blood–brain barrier opening by superselective intra-arterial cerebral infusion under dynamic susceptibility contrast MRI guidance

Cited by 40 publications

References 13 publications

Real-time MRI for precise and predictable intra-arterial stem cell delivery to the central nervous system

Real-time MRI for precise and predictable intra-arterial stem cell delivery to the central nervous system

Rabbit Model of Human Gliomas: Implications for Intra-Arterial Drug Delivery

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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