Improvements in the treatment of brain tumors have produced little impact on outcomes over the past three decades. Still, survival for both pediatric and adult brain tumors is known to be maximized by radiographically complete surgical resection. Unfortunately, even with the best microsurgical technique, resection may leave behind residual, MRI-demonstrable tumor. We propose the development of intravenously-administered, dye-labeled nanoparticles selectively targeted to brain tumors that will optimize the ability of neurosurgeons to delineate neoplasm from healthy nervous tissue. By maximizing surgical resection and minimizing adjacent tissue damage, targeted nanoparticles will ultimately improve the treatment of brain tumor patients. The proposed nanoparticles will consist of a biodegradable polyacrylamide core containing an optical dye. The nanoparticle size (30-70 nm) has been designed to allow extravasation across areas of blood brain barrier breakdown characteristic of tumors, while minimizing passage across an intact blood-brain barrier. The localization of nanoparticles at tumor sites will be optimized by coating nanoparticles tumor-homing F3 peptide. We have previously demonstrated the high therapeutic index, nontoxicity and bioelimination of similar nanoparticles. The ability of multifunctional nanoparticles to enable intraoperative optical delineation will be tested in several animal models of glioma. Qualitative evaluation of targeted nanoparticle-mediated delineation will be carried out in the rat cranial window model because it allows real-time, in vivo visualization of superficial experimental gliomas. These experiments will allow us to accurately characterize the nature of the contrast that the nanoparticles will provide with respect to surrounding viable brain tissue. Quantitave evaluation will utilize computer-based image analysis techniques to compare targeted nanoparticle-based estimates tumor volume with clinically-relevant, MRI-based estimates of tumor volume. In summary, this proposal introduces a novel approach to enhancing brain tumor surgery, via biophotonic nanodevices previously developed in our laboratories. The proposed nanodevices are expected to dramatically improve the treatment of brain tumors by developing novel methods for intraoperative visual imaging. The ultimate goal is to reduce morbidity and mortality in brain tumor patients by maximizing surgical precision. ? ? ? ?
| Orringer, Daniel A; Chen, Thomas; Huang, Dah-Luen et al. (2011) A technical description of the brain tumor window model: an in vivo model for the evaluation of intraoperative contrast agents. Acta Neurochir Suppl 109:259-63 |
| Orringer, Daniel A; Chen, Thomas; Huang, Dah-Luen et al. (2010) The brain tumor window model: a combined cranial window and implanted glioma model for evaluating intraoperative contrast agents. Neurosurgery 66:736-43 |
| Orringer, Daniel A; Koo, Yong-Eun L; Chen, Thomas et al. (2009) In vitro characterization of a targeted, dye-loaded nanodevice for intraoperative tumor delineation. Neurosurgery 64:965-71; discussion 971-2 |
| Orringer, D A; Koo, Y E; Chen, T et al. (2009) Small solutions for big problems: the application of nanoparticles to brain tumor diagnosis and therapy. Clin Pharmacol Ther 85:531-4 |
