In spite of huge clinical efforts, and a wealth of data on tumor biology, survival from glioma has not significantly changed in the last 25 years. Extent of resection remains the most important determinant of survival for gliomas of all grades. However, the ability to achieve total resection is limited due to the infiltrative nature of gliomas, making it difficult for surgeons to distinguish between tumor and normal brain tissue. Thus, it is important to develop new imaging and drug delivery technologies to specifically image cancer cells during surgical resection, while providing means to focally treat residual tumor deposits interspaced in normal brain. Several strategies have been developed to improve the extent of tumor resection while limiting damage to surrounding brain, including intraoperative MRI and fluorescence imaging. However, these methods suffer from one or several shortcomings, such as lack of light for deep tissue penetration, not actively crossing blood-brain barrier (BBB) and membranes of tumor cells, lack of precise overlap of white light and fluorescence images, and/or time delayed imaging of tumor delineations. A promising recent method is based on Chlorotoxin- Indocyanine Green (ICG) conjugate (BLZ-100, ?tumor paint?, presently in phase 1 clinical trial) for improved Targeted NIR Fluorescence Guided Resection (TFGR). However, resection alone will not be sufficient for complete removal of infiltrating glioma cells without sacrificing healthy brain tissue. We hypothesize that our novel glioma targetable imaging and treatment nanoconjugates are able to cross the BBB for guided surgery. We also hypothesize that similar nanoconjugates can effectively eradicate postsurgical remnant glioma cells inhibiting in a dual-pronged fashion the major glioblastoma markers, protein kinase CK2 and epidermal growth factor receptor (EGFR and EGFRvIII mutant).
Specific Aim 1. Synthesis and characterization of novel glioma targetable near infrared (NIR) fluorescent imaging agents. Nanoimaging agents PMLA/CTX/ICG and PMLA/CTX/anti-TfRmAb/ICG will be synthesized and studied for producing intensive NIR fluorescence, suitable physico-chemical properties, synthetic reproducibility and stability. Tumor visualization with an optimized device for clinical intra-operative NIR fluorescence imaging will be performed to determine lead nanoconjugate for brain tumor imaging.
Specific Aim 2. Synthesis and characterization of nanoconjugates for glioblastoma multiforme treatment. Precise glioma treatment depends on tumor-specific molecular subtype/heterogeneity verified by different molecular markers (CK2 introduced as a novel biomarker, and EGFR/EGFRvIII highly expressed in glioma).
Specific Aim 3. Toxicity study of nanoconjugates for brain tumor imaging and treatment. To ensure translation of the results to the clinical trial, the selected lead nanodrugs from in vitro and in vivo efficacy studies must be examined in preparation for IND approval by FDA.
In spite of huge scientific and clinical effort, and a wealth of new data on glioma biology, the patients? survival did not significantly change in the last 25 years. Resection of the tumor bulk has been the major clinically successful course in the treatment of glioblastoma, however, gliomas are not completely separable from the normal brain due to deep infiltration of tumor cells into normal brain parenchyma thus, it is important to develop new imaging and drug delivery technologies for effective glioma targeting to specifically image cancer cells and effectively treat after. Our proposal focusing on this unmet clinical need fully fits the NIH FOA PAR-13-185 ?The innovating research in image-guided drug delivery (IGDD) for cancer and other diseases?.
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