A Potent Blood–Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model

The poor permeability of theranostic agents across the blood-brain-barrier (BBB) significantly hampers the development of new treatment modalities for neurological diseases. We have discovered a new biomimetic nanocarrier using heparin (HP) that effectively passes the BBB and targets glioblastoma. Specifically, we designed HP coated gold nanoparticles (HP-AuNPs) that were labeled with three different imaging modalities namely, fluorescein (FITC-HP-AuNP), radioisotope 68Gallium (68Ga-HP-AuNPs), and MRI active gadolinium (Gd-HP-AuNPs). The systemic infusion of FITC-HP-AuNPs in three different mouse strains (C57BL/6JRj, FVB, and NMRI-nude) displayed excellent penetration and revealed uniform distribution of fluorescent particles in the brain parenchyma (69-86%) with some accumulation in neurons (8-18%) and microglia (4-10%). Tail-vein administration of radiolabeled 68Ga-HP-AuNPs in healthy rats also showed 68Ga-HP-AuNP inside the brain parenchyma and in areas containing cerebrospinal fluid, such as the lateral ventricles, the cerebellum, and brain stem. Finally, tail-vein administration of Gd-HP-AuNPs (that display ~3 fold higher relaxivity than that of commercial Gd-DTPA) in an orthotopic glioblastoma (U87MG xenograft) model in nude mice demonstrated enrichment of T1-contrast at the intracranial tumor with a gradual increase in the contrast in the tumor region between 1h-3h. We believe, our finding offers the untapped potential of HP-derived-NPs to deliver cargo molecules for treating neurological disorders.

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A predictive microfluidic model of human glioblastoma to assess trafficking of blood-brain barrier penetrant nanoparticles

10.1101/2021.12.07.471663 ◽

2021 ◽

Author(s):

Joelle P. Straehla ◽

Cynthia Hajal ◽

Hannah C. Safford ◽

Giovanni Offeddu ◽

Natalie Boehnke ◽

...

Keyword(s):

Brain Tumor ◽

Blood Brain Barrier ◽

Therapeutic Potential ◽

Xenograft Model ◽

Tumor Vasculature ◽

Brain Barrier ◽

Human Glioblastoma ◽

Blood Brain

The blood-brain barrier represents a significant challenge for the treatment of high-grade gliomas, and our understanding of drug transport across this critical biointerface remains limited. To advance preclinical therapeutic development for gliomas, there is an urgent need for predictive in vitro models with realistic blood-brain barrier vasculature. Here, we report a vascularized human glioblastoma (GBM) model in a microfluidic device that accurately recapitulates brain tumor vasculature with self-assembled endothelial cells, astrocytes, and pericytes to investigate the transport of targeted nanotherapeutics across the blood-brain barrier and into GBM cells. Using modular layer-by-layer assembly, we functionalized the surface of nanoparticles with GBM-targeting motifs to improve trafficking to tumors. We directly compared nanoparticle transport in our in vitro platform with transport across mouse brain capillaries using intravital imaging, validating the ability of the platform to model in vivo blood-brain barrier transport. We investigated the therapeutic potential of functionalized nanoparticles by encapsulating cisplatin and showed improved efficacy of these GBM-targeted nanoparticles both in vitro and in an in vivo orthotopic xenograft model. Our vascularized GBM model represents a significant biomaterials advance, enabling in-depth investigation of brain tumor vasculature and accelerating the development of targeted nanotherapeutics.

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Function of the Blood-Brain Barrier and Restriction of Drug Delivery to Invasive Glioma Cells: Findings in an Orthotopic Rat Xenograft Model of Glioma

Drug Metabolism and Disposition ◽

10.1124/dmd.112.048322 ◽

2012 ◽

Vol 41 (1) ◽

pp. 33-39 ◽

Cited By ~ 105

Author(s):

Sagar Agarwal ◽

Pooja Manchanda ◽

Michael A. Vogelbaum ◽

John R. Ohlfest ◽

William F. Elmquist

Keyword(s):

Drug Delivery ◽

Blood Brain Barrier ◽

Xenograft Model ◽

Glioma Cells ◽

Brain Barrier ◽

Blood Brain

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Patient derived orthotopic xenograft models of Medulloblastoma lack a functional blood brain barrier

Neuro-Oncology ◽

10.1093/neuonc/noaa266 ◽

2020 ◽

Author(s):

Laura A Genovesi ◽

Simon Puttick ◽

Amanda Millar ◽

Marija Kojic ◽

Pengxiang Ji ◽

...

Keyword(s):

Contrast Enhancement ◽

Tumor Cells ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Preclinical Model ◽

Dynamic Contrast Enhancement ◽

Orthotopic Xenograft ◽

Cellular Analysis ◽

Blood Brain ◽

Genetically Engineered Mouse Model

Abstract Background Novel targeted therapies for children diagnosed with medulloblastoma (MB), the most common malignant pediatric brain tumor, are urgently required. A major hurdle in the development of effective therapies is the impaired delivery of systemic therapies to tumor cells due to a specialized endothelial blood-brain barrier (BBB). Accordingly, the integrity of the BBB is an essential consideration in any preclinical model used for assessing novel therapeutics. This study sought to assess the functional integrity of the BBB in several preclinical mouse models of MB. Methods Dynamic contrast enhancement (DCE) magnetic resonance imaging (MRI) was used to evaluate blood-brain tumour-barrier (BBTB) permeability in a murine genetically engineered mouse model (GEMM) of SHH MB, patient-derived orthotopic xenograft (PDOX) models of MB (SHH and Gp3) and orthotopic transplantation of GEMM tumor cells, enabling a comparison of the direct effects of transplantation on the integrity of the BBTB. Immunofluorescence analysis was performed to compare the structural and sub-cellular features of tumor-associated vasculature in all models. Results Contrast enhancement was observed in all transplantation models of MB. No contrast enhancement was observed in the GEMM despite significant tumor burden. Cellular analysis of BBTB integrity revealed aberrancies in all transplantation models, correlating to the varying levels of BBTB permeability observed by MRI in these models. Conclusions These results highlight functional differences in the integrity of the BBTB and tumor vessel phenotype between commonly utilised preclinical models of MB, with important implications for the preclinical evaluation of novel therapeutic agents for MB.

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MEK/MELK inhibition and blood–brain barrier deficiencies in atypical teratoid/rhabdoid tumors

Neuro-Oncology ◽

10.1093/neuonc/noz151 ◽

2019 ◽

Vol 22 (1) ◽

pp. 58-69 ◽

Cited By ~ 6

Author(s):

Michaël H Meel ◽

Miriam Guillén Navarro ◽

Mark C de Gooijer ◽

Dennis S Metselaar ◽

Piotr Waranecki ◽

...

Keyword(s):

Blood Brain Barrier ◽

Primary Cultures ◽

Xenograft Model ◽

Mapk Signaling ◽

Antitumor Efficacy ◽

Brain Barrier ◽

Blood Brain ◽

Atypical Teratoid ◽

Atypical Teratoid Rhabdoid Tumors ◽

Rhabdoid Tumors

Abstract Background Atypical teratoid/rhabdoid tumors (AT/RT) are rare, but highly aggressive. These entities are of embryonal origin occurring in the central nervous system (CNS) of young children. Molecularly these tumors are driven by a single hallmark mutation, resulting in inactivation of SMARCB1 or SMARCA4. Additionally, activation of the MAPK signaling axis and preclinical antitumor efficacy of its inhibition have been described in AT/RT. Methods We established and validated a patient-derived neurosphere culture and xenograft model of sonic hedgehog (SHH) subtype AT/RT, at diagnosis and relapse from the same patient. We set out to study the vascular phenotype of these tumors to evaluate the integrity of the blood–brain barrier (BBB) in AT/RT. We also used the model to study combined mitogen-activated protein kinase kinase (MEK) and maternal embryonic leucine zipper kinase (MELK) inhibition as a therapeutic strategy for AT/RT. Results We found MELK to be highly overexpressed in both patient samples of AT/RT and our primary cultures and xenografts. We identified a potent antitumor efficacy of the MELK inhibitor OTSSP167, as well as strong synergy with the MEK inhibitor trametinib, against primary AT/RT neurospheres. Additionally, vascular phenotyping of AT/RT patient material and xenografts revealed significant BBB aberrancies in these tumors. Finally, we show in vivo efficacy of the non-BBB penetrable drugs OTSSP167 and trametinib in AT/RT xenografts, demonstrating the therapeutic implications of the observed BBB deficiencies and validating MEK/MELK inhibition as a potential treatment. Conclusion Altogether, we developed a combination treatment strategy for AT/RT based on MEK/MELK inhibition and identify therapeutically exploitable BBB deficiencies in these tumors.

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