Polymeric Micelles for Targeted Delivery of Contrast Agents Through the Nose-to-Brain Route in Image-Guided Brain Cancer Surgery - Surgery has a key role in the management of many types of brain cancers. In fact, the completion of surgical resection is a key prognostic factor in brain cancer treatment. This requires surgeons to identify residual tumors as well as to margin the proximity of the tumor to adjacent normal tissue. Subjective assessments, such as palpation or visual observations, are commonly used by oncology surgeons during resection to differentiate cancer lesions from normal tissue, which could potentially result in either an incomplete tumor resection, or accidental removal of normal tissue. Moreover, malignant brain tumors are even more difficult to distinguish from normal brain tissue, and resecting noncancerous tissue may create neurological defects after surgery. Therefore, utilizing an intraoperative, real-time guidance technique in the operating room is essential to quickly optimize the resection margin in brain tumors ultimately improving surgical outcomes. In this proposed study, first, we aspire to develop and characterize tumor-targeting polymeric micelles that carry a self-quenched near- infrared (NIR) imaging agent (Aim 1). These will be a micelles-based on/off fluorescence switch system where the whole-body fluorescence remains low (“off”) until those are released from the micelles as monomers, emitting strong fluorescence (“on”) on the tumor tissues. Secondly, we will evaluate the practicality of this system when administered intranasally for providing optical image guidance during brain cancer surgery. In vivo whole-body optical imaging on glioma-bearing xenograft mice will be obtained upon intranasal delivery of the tumor-targeting polymeric micelles carrying an NIR imaging agent in self-quenched state (Aim 2A). We will then test this system in the “simulated” operating room where intranasally delivered system provides intraoperative image guidance to support complete tumor excision and superior surgical outcome on glioma- bearing xenograft mice (Aim 2B). We believe that intranasally administered polymeric micelles developed for this proposed work will help overcome some fundamental challenges that fluorescence imaging faces by avoiding the BBB and delivering a contrast agent effectively and selectively to brain tumors. We expect that the results we obtain from this proposed work will open the possibility of employing intranasally administered optical imaging agent for visualizing brain tumors that minimizes incomplete tumor resection or accidental removal of surrounding normal tissues during surgery. Tumor removal surgery supported by intraoperative image guidance will highly likely demonstrate high surgical accuracy and precision and can significantly improve surgical outcomes and patient survival, potentially adding decades of quality life.
