Advancing brain tumor precision care with nanomedicine

The prognosis of brain tumors is often poor. Enhancing brain tumor treatment is not only a critical clinical need but also a persistent scientific challenge. Radiotherapy plays a vital role in the current standard treatment regimen, with external radiotherapy being the traditional method. However, this approach faces significant hurdles due to its lack of specificity. Brain tumors tend to infiltrate healthy brain tissue, making complete surgical removal impossible. The residual tumor-initiating cells can develop into more aggressive recurrent tumors. Furthermore, brain tumors can release circulating tumor cells into the bloodstream, contributing to recurrence. Consequently, applying external radiotherapy locally to the head is inadequate, and whole-body radiation is not feasible. There is a pressing need for innovative radiotherapy techniques in clinical settings. Our goal is to create radiolabeled nanomedicine for brain tumor precision radiotherapy. Specifically, we aim to develop radioiodine-131-labeled gold nanoparticles (GNP) coated with nanobodies that target Poly(ADP-ribose) polymerase 1 (PARP1), referred to as [131I]GNP-PARP1, for targeted radiotherapy. Iodine-131 is a well-established therapeutic radionuclide, and PARP1 is a target located near DNA in tumor cells. This new radiotherapeutic agent is anticipated to selectively and effectively destroy tumor cells. We will assess [131I]GNP-PARP1 monotherapy and its combination therapy in mice with brain tumors, and investigate the mechanisms underlying the treatment response in different treatment settings. Additionally, we will employ our innovative PET agent alongside MRI to monitor treatment response. To date, no radiopharmaceuticals have been approved for clinical brain tumor radiotherapy. The outcomes of this project will offer a novel approach to brain tumor radiotherapy and provide significant insights into using nanomedicine to address this unmet clinical need.

Over the past two years, we have successfully developed gold nanoparticles (GNPs) to serve as a radionuclide delivery platform for PET imaging and radiotherapy applications. The conjugation methods, which will be employed in the current research, have been established, and animal studies have been conducted. Concurrently, recent studies have indicated that niacin can enhance host immunity and, unexpectedly, it has proven effective in controlling glioblastoma growth in mouse models. In an ongoing clinical trial, niacin is being combined with standard treatment to assess its potential advantages for glioblastoma patients. In our proof-of-concept study, we discovered [18F]FNA (radiolabeled niacin) as a highly promising imaging agent for diagnosing glioblastoma with PET imaging, and a patent application has been filed in 2024 and currently at the international application phase. We conducted [18F]FNA PET imaging on 40 mice with glioblastoma, using different batches of [18F]FNA on various days, and the imaging was performed by different researchers. Glioblastoma was clearly visible in all 40 tested mice, indicating the robustness of [18F]FNA PET imaging. In a comparative study with current clinical radiotracers, the glucose analog [18F]FDG or the amino acid [11C]methionine, and both were found to be inferior to [18F]FNA PET/CT imaging. [18F]FNA remained stable in vivo for at least 90 minutes, which is sufficient for clinical PET applications. Additionally, [18F]FNA PET can detect cancer metastasis in the brain, liver, and lungs. Our novel PET imaging agent [18F]FNA is expected to become available for clinical use within a few years. In summary, over the past two years, we have established a GNP platform for radionuclide delivery for PET imaging and radiotherapy, and developed [18F]FNA PET as an innovative tool for tumor detection and treatment-response monitoring. These findings lay the groundwork
for us to pursue the new research in this project.