Alexandros Bouras

Magnetic nanoparticles: an emerging technology for malignant brain tumor imaging and therapy

Magnetic nanoparticles (MNPs) represent a promising nanomaterial for the targeted therapy and imaging of malignant brain tumors. Conjugation of peptides or antibodies to the surface of MNPs allows direct targeting of the tumor cell surface and potential disruption of active signaling pathways present in tumor cells. Delivery of nanoparticles to malignant brain tumors represents a formidable challenge due to the presence of the blood–brain barrier and infiltrating cancer cells in the normal brain. Newer strategies permit better delivery of MNPs systemically and by direct convection-enhanced delivery to the brain. Completion of a human clinical trial involving direct injection of MNPs into recurrent malignant brain tumors for thermotherapy has established their feasibility, safety and efficacy in patients. Future translational studies are in progress to understand the promising impact of MNPs in the treatment of malignant brain tumors.

Nanotechnology Applications for Glioblastoma

Glioblastoma remains one of the most difficult cancers to treat and represents the most common primary malignancy of the brain. Although conventional treatments have found modest success in reducing the initial tumor burden, infiltrating cancer cells beyond the main mass are responsible for tumor recurrence and ultimate patient demise. Targeting residual infiltrating cancer cells requires the development of new treatment strategies. The emerging field of cancer nanotechnology holds promise in the use of multifunctional nanoparticles for imaging and targeted therapy of glioblastoma. This article examines the current state of nanotechnology in the treatment of glioblastoma and directions of further study.

Intraoperative Spectroscopy with Ultrahigh Sensitivity for Image-Guided Surgery of Malignant Brain Tumors

Intraoperative cancer imaging and fluorescence-guided surgery have attracted considerable interest because fluorescence signals can provide real-time guidance to assist a surgeon in differentiating cancerous and normal tissues. Recent advances have led to the clinical use of a natural fluorophore called protoporphyrin IX (PpIX) for image-guided surgical resection of high-grade brain tumors (glioblastomas). However, traditional fluorescence imaging methods have only limited detection sensitivity and identification accuracy and are unable to detect low-grade or diffuse infiltrating gliomas (DIGs). Here we report a low-cost hand-held spectroscopic device that is capable of ultrasensitive detection of protoporphyrin IX fluorescence in vivo, together with intraoperative spectroscopic data obtained from both animal xenografts and human brain tumor specimens. The results indicate that intraoperative spectroscopy is at least 3 orders of magnitude more sensitive than the current surgical microscopes, allowing ultrasensitive detection of as few as 1000 tumor cells. For detection specificity, intraoperative spectroscopy allows the differentiation of brain tumor cells from normal brain cells with a contrast signal ratio over 100. In vivo animal studies reveal that protoporphyrin IX fluorescence is strongly correlated with both MRI and histological staining, confirming that the fluorescence signals are highly specific to tumor cells. Furthermore, ex vivo spectroscopic studies of excised brain tissues demonstrate that the hand-held spectroscopic device is capable of detecting diffuse tumor margins with low fluorescence contrast that are not detectable with current systems in the operating room. These results open new opportunities for intraoperative detection and fluorescence-guided resection of microscopic and low-grade glioma brain tumors with invasive or diffusive margins.

5-Aminolevulinic Acid Guided Sampling of Glioblastoma Microenvironments Identifies Pro-Survival Signaling at Infiltrative Margins

Glioblastoma (GBM) contains diverse microenvironments with uneven distributions of oncogenic alterations and signaling networks. The diffusely infiltrative properties of GBM result in residual tumor at neurosurgical resection margins, representing the source of relapse in nearly all cases and suggesting that therapeutic efforts should be focused there. To identify signaling networks and potential druggable targets across tumor microenvironments (TMEs), we utilized 5-ALA fluorescence-guided neurosurgical resection and sampling, followed by proteomic analysis of specific TMEs. Reverse phase protein array (RPPA) was performed on 205 proteins isolated from the tumor margin, tumor bulk, and perinecrotic regions of 13 previously untreated, clinically-annotated and genetically-defined high grade gliomas. Differential protein and pathway signatures were established and then validated using western blotting, immunohistochemistry, and comparable TCGA RPPA datasets. We identified 37 proteins differentially expressed across high-grade glioma TMEs. We demonstrate that tumor margins were characterized by pro-survival and anti-apoptotic proteins, whereas perinecrotic regions were enriched for pro-coagulant and DNA damage response proteins. In both our patient cohort and TCGA cases, the data suggest that TMEs possess distinct protein expression profiles that are biologically and therapeutically relevant.