Improvements in the treatment of brain tumors have produced little impact on outcomes over the past three decades. We propose the development of targeted, multifunctional nanoparticles designed to improve the survival of brain tumor patients by increasing surgical efficiency and mediating adjuvant photodynamic therapy. By optically imaging tumor margins, targeted multifunctional nanoparticles will enable maximal surgical resection, while minimizing adjacent tissue damage. In addition, the same nanoparticles will be used intraoperatively to mediate photodynamic therapy, thereby eradicating occult or un-resectable tumor. This combination presents a unique approach towards a highly significant practical outcome, a large quantitative improvement in the survival statistics of patients with malignant brain cancers. For instance, increases in survival on the order of up to 100% are expected for pediatric low/high grade glioma. Specifically we propose the synthesis of dye-labeled nanoparticles that can be administered intravenously and selectively targeted to brain tumors to optimize the ability of neurosurgeons to delineate neoplasm and healthy nervous tissue. Furthermore, it is proposed that photodynamic components inside the same targeted nanoparticles will enable the eradication of residual tumor following surgical resection. The surgical exposure, performed for resection, will provide a corridor for the efficient delivery of visible laser light to unresectable or occult tumor, for photodynamic therapy. The multifunctional nanoparticles will consist of a biodegradable polyacrylamide core containing blue delineation dye and photosensitizer. 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 with tumor-homing F3 peptide. We demonstrated previously the high therapeutic index, non-toxicity and bio-elimination of similar nanoparticles. The ability of targeted multifunctional nanoparticles to enable intraoperative optical delineation and photodynamic therapy (PDT) will be tested in several animal models of glioma. The proposed research was designed and will be carried out by an existing collaborative team of investigators, including experts in applied physics, bio-nanotechnology, chemistry, neurosurgery, neuropathology, neurotoxicology, optical and MRI imaging, and photodynamic therapy.
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