Delivery of Antibodies into the Murine Brain via Convection-enhanced Delivery

Beffinger, Michal; Schellhammer, Linda; Pantelyushin, Stanislav; Berg, Johannes vom

doi:10.3791/59675

Cited by 7 publications

(6 citation statements)

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“…The injection was performed in a volume of 2 µL at 1 µL/min. A total of 20,000 cells in 2 µL PBS were injected at a speed of 1 µL/min intracranially into mice using a neurostar stereotaxic robot as described in Beffinger et al 2019 [27]. After leaving the needle in place for 2 min, it was retracted at 1 mm/min.…”

Section: Surgical Proceduresmentioning

confidence: 99%

Enzymatic Dissociation Induces Transcriptional and Proteotype Bias in Brain Cell Populations

Mattei

Ivanov

Oostrum

et al. 2020

IJMS

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Different cell isolation techniques exist for transcriptomic and proteotype profiling of brain cells. Here, we provide a systematic investigation of the influence of different cell isolation protocols on transcriptional and proteotype profiles in mouse brain tissue by taking into account single-cell transcriptomics of brain cells, proteotypes of microglia and astrocytes, and flow cytometric analysis of microglia. We show that standard enzymatic digestion of brain tissue at 37 °C induces profound and consistent alterations in the transcriptome and proteotype of neuronal and glial cells, as compared to an optimized mechanical dissociation protocol at 4 °C. These findings emphasize the risk of introducing technical biases and biological artifacts when implementing enzymatic digestion-based isolation methods for brain cell analyses.

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Section: Surgical Proceduresmentioning

confidence: 99%

Enzymatic Dissociation Induces Transcriptional and Proteotype Bias in Brain Cell Populations

Mattei

Ivanov

Oostrum

et al. 2020

IJMS

Self Cite

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“…In the future, investigators can verify this optimization method using patient-specific T1W and DWI data and therapyspecific density and viscosity information. Experimental validation using animal models is a critical step in determining the effectiveness of this quantitative tool [31][32][33][34][35][36][37][38][39] .…”

Section: Discussionmentioning

confidence: 99%

Optimization of catheter placement for convection-enhanced delivery to brain tumors

et al. 2021

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Background: Recent trends suggest that physicians will diagnose thousands of children in the United States with a brain or central nervous system tumor in 2020. Malignant brain tumors are difficult to treat, with low life expectancy rates in children and adults. Convection-enhanced delivery (CED) shows promise for the treatment of brain tumors, yet remains in clinical trials despite being developed more than 20 years ago. To advance CED to standard of care status and help improve survival rates, this study group developed a quantitative computer simulation model to determine and optimize therapy distribution in brain tumors based on the catheter infusion locations for CED. Methods: The simulations resulted in the identification of four infusion reference locations, which were used to conduct an optimization study to identify the optimal locations for CED. Patient-specific T1-weighted images and diffusion-weighted images provided information regarding tumor shape and size and the approximate rate at which therapy distributes at spatial locations within the tumor. Using the images, the researchers in this study developed a model which allowed the calculation of therapy distribution within the tumor while considering its permeability, porosity, and interstitial fluid pressure characteristics. We divided the tumor into regions and calculated distribution for four infusion locations per region. Using the location from each region with the highest volume distribution allowed our study group to conduct the response surface optimization. Results: Twelve optimal locations emerged from the optimization with volume percentage distributions ranging from 7.92% to 9.09%, compared to 2.87% to 6.32% coverage for non-optimal locations. This optimization method improved distribution from 27.80% to 45.95%, which may improve therapeutic value. Conclusions: Catheter placement appears to influence volume therapy distribution percentages. The selection of the highest percentages per region may provide optimal therapy for the entire tumor region.

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“…The cannula holder with attached internal cannula was lowered until flush with the mouse skull to reach the desired injection depth of 4 mm (GBM6) or 4.2 mm (PED17 and SU-DIPGXIII). In all study groups, the same ramped CED infusion protocol was performed with a total volume infused of 20 μL and rates of infusion as follows: 3 μL at 0.2 μL/min, 5 μL at 0.5 μL/min, and 12 μL at 0.8 μL/min [ 51 ]. To avoid reflux into the injection tract, the cannula was removed 10 min after completion of infusion.…”

Section: Methodsmentioning

confidence: 99%

IL-13Rα2 Status Predicts GB-13 (IL13.E13K-PE4E) Efficacy in High-Grade Glioma

et al. 2022

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High-grade gliomas (HGG) are devastating diseases in children and adults. In the pediatric population, diffuse midline gliomas (DMG) harboring H3K27 alterations are the most aggressive primary malignant brain tumors. With no effective therapies available, children typically succumb to disease within one year of diagnosis. In adults, glioblastoma (GBM) remains largely intractable, with a median survival of approximately 14 months despite standard clinical care of radiation and temozolomide. Therefore, effective therapies for these tumors remain one of the most urgent and unmet needs in modern medicine. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is a cell-surface transmembrane protein upregulated in many HGGs, including DMG and adult GBM, posing a potentially promising therapeutic target for these tumors. In this study, we investigated the pharmacological effects of GB-13 (also known as IL13.E13K-PE4E), a novel peptide–toxin conjugate that contains a targeting moiety designed to bind IL-13Rα2 with high specificity and a point-mutant cytotoxic domain derived from Pseudomonas exotoxin A. Glioma cell lines demonstrated a spectrum of IL-13Rα2 expression at both the transcript and protein level. Anti-tumor effects of GB-13 strongly correlated with IL-13Rα2 expression and were reflected in apoptosis induction and decreased cell proliferation in vitro. Direct intratumoral administration of GB-13 via convection-enhanced delivery (CED) significantly decreased tumor burden and resulted in prolonged survival in IL-13Rα2-upregulated orthotopic xenograft models of HGG. In summary, administration of GB-13 demonstrated a promising pharmacological response in HGG models both in vitro and in vivo in a manner strongly associated with IL-13Rα2 expression, underscoring the potential of this IL-13Rα2-targeted therapy in a subset of HGG with increased IL-13Rα2 levels.

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Delivery of Antibodies into the Murine Brain via Convection-enhanced Delivery

Cited by 7 publications

References 0 publications

Enzymatic Dissociation Induces Transcriptional and Proteotype Bias in Brain Cell Populations

Enzymatic Dissociation Induces Transcriptional and Proteotype Bias in Brain Cell Populations

Optimization of catheter placement for convection-enhanced delivery to brain tumors

IL-13Rα2 Status Predicts GB-13 (IL13.E13K-PE4E) Efficacy in High-Grade Glioma

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