Nanoparticles' enhanced permeation and retention (EPR) variations due to tumor heterogeneity in naturally occurring brain tumors are commonly neglected in preclinical nanomedicine studies. Recent pathological studies have shown striking similarities between brain tumors in humans and dogs, indicating that canine brain tumors may be a valuable model to evaluate nanoparticles' EPR in this context. We recruited canine clinical cases with spontaneous brain tumors to investigate nanoparticles' EPR in different brain tumor pathologies using surface-enhanced Raman spectroscopy (SERS). We used gold nanoparticles due to their surface plasmon effect that enables their sensitive and microscopic resolution detection using the SERS technique. Raman microscopy of the resected tumors showed heterogeneous EPR of nanoparticles into oligodendrogliomas and meningiomas of different grades, without any detectable traces in necrotic parts of the tumors or normal brain. Raman observations were confirmed by scanning electron microscopy (SEM) and X-ray elemental analyses, which enabled localization of individual nanoparticles embedded in tumor tissues. Our results demonstrate nanoparticles' EPR and its variations in clinically relevant, spontaneous brain tumors. Such heterogeneities should be considered alongside routine preoperative imaging and histopathological analyses in order to accelerate clinical management of brain tumors using nanomedicine approaches.

Introduction

To report the potential value of pre-operative ¹⁸F-FDOPA PET and anatomic MRI in diagnosis and prognosis of glioma patients.

Methods

Forty-five patients with a pathological diagnosis of glioma with pre-operative ¹⁸F-FDOPA PET and anatomic MRI were retrospectively examined. The volume of contrast enhancement and T2 hyperintensity on MRI images along with the ratio of maximum ¹⁸F-FDOPA SUV in tumor to normal tissue (T/N SUV_max) were measured and used to predict tumor grade, molecular status, and overall survival (OS).

Results

A significant correlation was observed between WHO grade and: the volume of contrast enhancement (r = 0.67), volume of T2 hyperintensity (r = 0.42), and ¹⁸F-FDOPA uptake (r = 0.60) (P < 0.01 for each correlation). The volume of contrast enhancement and ¹⁸F-FDOPA T/N SUV_max were significantly higher in glioblastoma (WHO IV) compared with lower grade gliomas (WHO I-III), as well as for high-grade gliomas (WHO III-IV) compared with low-grade gliomas (WHO I-II). Receiver-operator characteristic (ROC) analyses confirmed the volume of contrast enhancement and ¹⁸F-FDOPA T/N SUV_max could each differentiate patient groups. No significant differences in ¹⁸F-FDOPA uptake were observed by IDH or MGMT status. Multivariable Cox regression suggested age (HR 1.16, P = 0.0001) and continuous measures of ¹⁸F-FDOPA PET T/N SUV_max (HR 4.43, P = 0.016) were significant prognostic factors for OS in WHO I-IV gliomas.

Conclusions

Current findings suggest a potential role for the use of pre-operative ¹⁸F-FDOPA PET in suspected glioma. Increased ¹⁸F-FDOPA uptake may not only predict higher glioma grade, but also worse OS.