Surface-Enhanced Resonance Raman Scattering-Guided Brain Tumor Surgery Showing Prognostic Benefit in Rat Models

Abstract

Glioma is the most frequent form of malignant brain tumors. Surgical debulking is a major strategy for glioma treatment. However, there is a great challenge for the neurosurgeons to intraoperatively identify the true margins of glioma because of its infiltrative nature. Tumor residues or microscopic satellite foci left in the resection bed are the main reasons leading to early recurrence as well as poor prognosis. In this study, a surface-enhanced resonance Raman scattering (SERRS) probe was developed to intraoperatively guide glioma resection. In this probe, molecular reporters with absorptive maxima at the near-infrared wavelength range were covalently functionalized on the surface of gold nanostars. This SERRS probe demonstrated an ultrahigh sensitivity with a detection limit of 5.0 pM in aqueous solution. By the development of glioma xenografts in a mouse dorsal skin window chamber, extravasation of this probe from leaky tumor vasculature as functions of time and distance to tumor boundary was investigated. Importantly, the invasive margin of the tumor xenograft was demarcated by this probe with a high signal-to-background ratio. Preoperative magnetic resonance imaging (MRI) first defined the position of orthotopic glioma xenografts in the brain of rat models, and the craniotomy plan was designed. The brain tumor was then excised intraoperatively step-by-step with the assistance of a handheld Raman scanner till the Raman signals of the probe completely disappeared in the resection bed. Notably, longitudinal MRI showed that SERRS-guided surgery significantly reduced the tumor recurrence rate and improved the overall survival of rat models compared with the white light-guided surgery. Overall, this work demonstrates the prognostic benefit of SERRS-guided glioma surgery in animal models. Because delineation of tumor-invasive margins is a common challenge faced by the surgeons, this SERRS probe with a picomolar detection limit holds the promise in improving the surgical outcome of different types of infiltrated tumors.

Keywords: glioma; gold nanostar; handheld Raman detector; image-guided surgery; longitudinal MRI; surface-enhanced resonance Raman scattering (SERRS).