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Novel membrane-permeable contrast agent for brain tumor detection by MRI.

ABSTRACT: One of the key challenges hindering the clinical intervention against brain cancer is defined by the inability to detect brain tumors at an early enough stage to permit effective therapy. Furthermore, the rapid growth and severe lethality of this form of cancer predicate the vital importance of monitoring the development of the pathology and its outcome after therapeutic intervention. With this in mind, we designed a novel membrane-permeant contrast agent, MN-MPAP-Cy5.5, which consists of a superparamagnetic iron oxide core, for MRI conjugated to myristoylated polyarginine peptides, as a membrane translocation module and labeled with the near-infrared dye Cy5.5 for correlative microscopy. This probe showed a remarkable uptake by U-87 human glioma cells in vitro and localized and delineated stereotactically injected tumor in vivo by MRI. Our findings suggest that the agent mediates its effects by translocation of the magnetic nanoparticles label across the leaky tumor vasculature, followed by enhanced accumulation in tumor cells. The noninvasive detection of brain tumors when they are still small represents a formidable challenge from an imaging standpoint. Our study describes an improved strategy to detect brain lesions by utilizing a contrast agent with membrane translocation properties.

SUBMITTER: Kumar M

PROVIDER: S-EPMC3819103 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Novel membrane-permeable contrast agent for brain tumor detection by MRI.

Kumar Mohanraja M Medarova Zdravka Z Pantazopoulos Pamela P Dai Guangping G Moore Anna A

Magnetic resonance in medicine 20100301 3

One of the key challenges hindering the clinical intervention against brain cancer is defined by the inability to detect brain tumors at an early enough stage to permit effective therapy. Furthermore, the rapid growth and severe lethality of this form of cancer predicate the vital importance of monitoring the development of the pathology and its outcome after therapeutic intervention. With this in mind, we designed a novel membrane-permeant contrast agent, MN-MPAP-Cy5.5, which consists of a supe ...[more]

PMID: 20146231

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Project description:Introduction The standard treatment for glioblastoma (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide (TMZ). Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) and are TMZ-resistant, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) is an obstacle to the delivery of chemotherapeutic agents to GBM, and BBB-permeable agents that are efficacious in TMZ-resistant and refractory patients are needed. The large amino acid transporter 1 (LAT1) is expressed on the BBB and in GBM and is detected at much lower levels in normal brain tissue. A LAT1-selective therapeutic would potentially target brain tumors while avoiding uptake by healthy tissue. Methods We report a novel chemical entity (QBS10072S) that combines a potent cytotoxic chemotherapeutic domain (tertiary N-bis(2-chloroethyl)amine) with the structural features of a selective LAT1 substrate and tested it against GBM models in vitro and in vivo. For in vitro studies, DNA damage was assessed with a gamma H2A.X antibody and cell viability was assessed by WST-1 assay and/or CellTiter-Glo assay. For in vivo studies, QBS10072S (with or without radiation) was tested in orthotopic glioblastoma xenograft models, using overall survival and tumor size (as measured by bioluminescence), as endpoints. Results QBS10072S is 50-fold more selective for LAT1 vs. LAT2 in transport assays and demonstrates significant growth suppression in vitro of LAT1-expressing GBM cell lines. Unlike TMZ, QBS10072S is cytotoxic to cells with both high and low levels of MGMT expression. In orthotopic GBM xenografts, QBS10072S treatment significantly delayed tumorigenesis and prolonged animal survival compared to the vehicle without adverse effects. Conclusion QBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat TMZ-resistant and recurrent GBM as monotherapy or in combination with radiation treatment.

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Novel membrane-permeable contrast agent for brain tumor detection by MRI.

Publications

Novel membrane-permeable contrast agent for brain tumor detection by MRI.

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