scholarly journals HGG-17. FOCUSED ULTRASOUND-ENHANCED DELIVERY OF RADIOLABELED AGENTS TO DIFFUSE INTRINSIC PONTINE GLIOMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i20-i21
Author(s):  
Dezhuang Ye ◽  
Xiaohui Zhang ◽  
Lihua Yang ◽  
Yimei Yue ◽  
Yuan-chuan Tai ◽  
...  
Keyword(s):  
Half Life ◽  
Focused Ultrasound ◽  
Temporal Distribution ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Genetically Engineered ◽  
Pontine Glioma ◽  
Delivery Outcome ◽  
Efficient Delivery ◽  
Genetically Engineered Mouse Model ◽  
Tumor Virus

Abstract Diffuse intrinsic pontine glioma (DIPG) arising in the brainstem is the deadliest pediatric brain cancer with nearly 100% fatality and a median survival of <1 year. The critical location in the brainstem and the often intact blood-brain barrier (BBB) pose significant challenges in the treatment of DIPG. The objective of this study was to demonstrate the potential for focused ultrasound-induced BBB disruption (FUS-BBBD) to improve DIPG treatment by enhancing the safe and efficient delivery of drugs. A genetically engineered mouse model of DIPG was generated using the RCAS (replication-competent avian sarcoma-leucosis virus long-terminal repeat with splice acceptor)/tumor virus A modeling system. A magnetic resonance-guided FUS (MRgFUS) system was used to induce BBB disruption in these mice with the FUS targeted at the center of the tumor. Two radiolabeled agents with different sizes were used to evaluate the delivery efficiency of the FUS-BBBD technique in DIPG mice: a small-molecular radiotracer, 68Ga-DOTA-ECL1i, and a radiolabeled nanoparticle, 64Cu-labeled copper nanoparticles (64Cu-CuNCs, ~ 5 nm in diameter). 68Ga-DOTA-ECL1i (half-life ~ 1 h) and 64Cu-CuNCs (half-life ~13 h) were intravenously injected into the mice after FUS sonication, and microPET/CT imaging was performed at 1 h and 24 h, respectively, to evaluate the spatial-temporal distribution of these two agents in the brain and quantify the delivery outcome. FUS treatment increased the uptake of 68Ga-DOTA-ECL1i and 64Cu-CuNCs to the DIPG tumor by 3.25 folds and 4.07 folds on average, respectively. These findings demonstrated, for the first time, that FUS can increase BBB permeability in a murine model of DIPG and significantly enhance the delivery of agents of different sizes into the DIPG tumor.

scholarly journals DDEL-05. BLOOD-BRAIN BARRIER DISRUPTION AND ENHANCED RADIOSENSITIZERS EXTRAVASATION UPON FOCUSED ULTRASOUND FOR TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii284-iii284
Author(s):  
Elvin ‘t Hart ◽  
Marc Derieppe ◽  
Maaike Bruin ◽  
Helena Besse ◽  
Rianne Haumann ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Focused Ultrasound ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Brain Barrier ◽  
Local Drug Delivery ◽  
Parp Inhibition ◽  
Mechanical Index ◽  
Pontine Glioma ◽  
Blood Brain ◽  
Drug Concentrations

Abstract Poor prognosis of diffuse midline glioma, including diffuse intrinsic pontine glioma (DIPG), reflects the low efficacy of current treatment strategies, mainly due to (1) a largely intact blood-brain barrier (BBB) and (2) the proficiency of tumour tissues to upregulate multiple DNA repair genes, resulting into radio-resistance. In vitro studies showed therapeutic benefit by combining radiotherapy and radiosensitizers, while pre-clinical and clinical studies evidenced safe and transient opening of the BBB using microbubble mediated focused ultrasound (FUS). Previously, we demonstrated the enhanced extravasation of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor in the mouse pons. Local drug delivery was applied using an in-house built X-ray image-guided FUS system with a 1 MHz mono-element transducer delivering a tone-burst pulse with a mechanical index of 0.4. Tissue/blood drug concentrations were analysed by LC-MS/MS, 30 minutes after intraperitoneal injection of 10 mg/kg olaparib. The FUS system allowed for precise treatment of the pons, proven by local extravasation of Evans Blue-conjugated albumin. A significant 5.1 fold median increase was observed in absolute concentrations in the pons after FUS intervention compared to the control and a 4.9 fold increase of the median tissue-blood ratio (*p<0.05). No significant differences were detected in brain regions outside the ultrasound focus and other organs, confirming the local intervention. With this, the 299 nM equivalent olaparib concentration found in the pons will facilitate PARP inhibition in future murine patient-derived xenograft tumour models, thus leading to a greater therapeutic effect when in combination with radiotherapy treatment of DIPG.

scholarly journals HGG-11. LEPTOMENINGEAL DISEASE AND TUMOR DISSEMINATION ALONG CSF PATHWAYS IN A MURINE DIPG MODEL: IMPLICATIONS FOR STUDY OF THE TUMOR-CSF-EPENDYMAL MICROENVIRONMENT

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i19-i19
Author(s):  
Shelei Pan ◽  
Dezhuang Ye ◽  
Yimei Yue ◽  
Lihua Yang ◽  
Christopher Pacia ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Genetic Alterations ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Genetically Engineered ◽  
Leptomeningeal Disease ◽  
Tumor Spread ◽  
Csf Dissemination ◽  
Tumor Dissemination ◽  
Genetically Engineered Mouse Model ◽  
Ventricle Volume

Abstract Background Leptomeningeal disease and hydrocephalus are present in up to 30% of patients with diffuse intrinsic pontine glioma (DIPG), however there are no animal models of cerebrospinal fluid (CSF) dissemination. As the tumor-CSF-ependymal microenvironment may play an important role in tumor pathogenesis, we identified characteristics of the Nestin-tumor virus A (Nestin-Tva) genetically engineered mouse model (GEMM) that make it ideal to study the interaction of tumor cells with the CSF and its associated pathways with implications for the development of treatment approaches to address CSF dissemination in DIPG. Methods A Nestin-TVa model of DIPG utilizing the three most common DIPG genetic alterations (H3.3K27M, PDGF-B, p53) was used for this study. All animals underwent MR imaging and a subset underwent histopathologic analysis with H&E and beta-IV tubulin. Results Tumor dissemination within the CSF pathways (ventricles, leptomeninges) was present in 76% (25/33) of animals, with invasion of the choroid plexus, disruption of the ciliated ependyma and regional subependymal fluid accumulation. Ventricular enlargement consistent with hydrocephalus was present in 94% (31/33). Ventricle volume correlated with region specific transependymal CSF flow (periventricular T2 signal), localized anterior to the lateral ventricles. Subependymal tumor cells were also present subjacent to the 4th ventricle in a post-mortem human specimen. Conclusions This is the first study to report CSF pathway tumor dissemination an animal model of DIPG and is representative of CSF dissemination seen clinically. Understanding the CSF-tumor-ependymal microenvironment has significant implications for treatment of DIPG through targeting mechanisms of tumor spread within the CSF pathways.

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