Magnetofluorescent nanoplatform for glioblastoma therapy

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ABSTRACT: Glioblastoma multiforme (GBM) is among the most lethal and aggressive cancers. Standard of care starts with surgery, to eliminate most of the tumor mass, followed by a combination of chemotherapy and radiation therapy to eradicate residual tumor tissue. However, the infiltrating nature of these tumors renders it almost impossible to resect all of the tumor mass, while preserving eloquent brain tissue. A major challenge with current chemotherapeutic drugs to treat GBM are their lack of efficient crossing across the brain blood barrier (BBB), preventing enough drug to reach the tumor area, which often results in recurrence of the tumor. Herein, we propose to develop a BBB-crossing, glioma cell targeting magnetofluorescent nanoprobe for the image-guided delivery of drugs across the BBB and into GBM tumors. At the core of our platform technology is Feraheme (FH), an FDA-approved superparamagnetic iron oxide nanoparticle (SPION). To FH, we conjugate hepthamethine cyanine (HMC), a unique near infrared fluorescent ligand that specifically targets the organic anion transporter protein (OATP) overexpressed in various tumors, including GBM microvasculature. HMC’s ability to cross the BBB and internalize into GBM cancer cells is mediated by the OATP subtypes OATP1A2 and OATP2B. Upon conjugation of HMC to FH, the resulting HMC-FH nanoprobe has a unique combination of the following properties: (1) dual magnetic (MRI) and near infrared fluorescent properties, (2) BBB-crossing and specific glioma targeting ability, with no accumulation in heathy brain, and (3) delivery of drugs across BBB with specific accumulation in brain tumors, acting as a glioma-specific image-guided delivery nanodrug. Our preliminary studies show that HMC-FH selectively accumulates in intracranial human GBM tumor xenographs in nude mice, particularly in in infiltrating areas within the brain. In addition, studies show that HMC-FH crosses the BBB in the tumor area and associates with the GBM cells within the tumor, facilitating drug delivery and reducing tumor size in mice when paclitaxel is encapsulated within the HMC-FH. Therefore, we hypothesize that HMC-FH can facilitate the delivery of drugs across the BBB and into glioma tumor cells, causing tumor remission and increasing survival in mice with orthotopic intracranial GBM. In addition, biodistribution and tumor uptake studies will be done in a spontaneous high-grade glioma canine model. To test our hypothesis, the following specific aims will be pursued: 1) Optimization of drug loading into HMC-FH, 2) Study the mechanism of BBB crossing and GBM cancer cell internalization of HMC-FH, 3) Investigate HMC-FH biodistribution, tumor uptake, retention and ability to deliver drugs in an intracranial tumor mouse models using human and canine derived GBM cells, 4) Investigate the biodistribution, tumor uptake and retention of HMC-FH in a canine GBM model