Title : Targeted alpha¬ radionuclide therapy with 225Ac/213Bi¬-DOTA-substance P in patients with malignant gliomas
Abstract:
In recent decades, treatment outcomes for glioma patients, particularly those with glioblastoma multiforme (GBM), have seen little progress. This is largely due to the tumor's unique characteristics, including its heterogeneity at macroscopic, microscopic, and genetic levels, its invasive growth pattern, and the challenge posed by the blood-brain barrier, which restricts drug delivery. The standard treatment approach—surgical resection followed by radiotherapy and chemotherapy—often fails to prevent tumor recurrence, which occurs in nearly all GBM patients. Managing recurrent tumors remains a significant clinical challenge, with repeat surgery (to alleviate mass effect) or salvage chemotherapy often serving as last-resort options. There is a critical need for novel therapies. Targeted alpha therapy using intratumorally administered ²¹³Bi-DOTA-Substance P (SP) or ²²?Ac-DOTAGA-Substance P has emerged as a promising strategy for recurrent GBM. Substance P offers key advantages, including the near-universal overexpression of NK-1 receptors in GBM cells—regardless of malignancy grade—and their presence not only on tumor cells but also in the tumor vasculature, enabling dual targeting of cancerous and vascular structures. While beta-emitting radionuclides have been used in brain tumor therapy, alpha emitters show greater potential due to their radiophysical properties. Early-phase clinical trials of ²¹³Bi/²²?Ac-labeled Substance P for malignant gliomas have yielded encouraging results compared to standard treatments, though larger controlled studies are still needed. Future research should focus on optimizing the compound's biological and chemical properties, as well as refining catheter-based delivery systems to enhance intratumoral distribution within both the tumor core and infiltrative zones.
Keywords: GBM, ²¹³Bi/²²?Ac-labeled Substance P, NK-1 receptors
