225Ac-DOTA-Substance P as a potential radiopharmaceutical for targeted alpha therapy of glioblastoma multiforme

Gliomas, particularly WHO grade IV glioblastoma multiforme (GBM) are one of the most common and aggressive primary types of the cancer of the central nervous system and are composed of morphologically diverse population of cells in the tumour mass. Despite all current forms of treatment such as advanced surgery techniques, radiation therapy and chemotherapy, the life expectancy of patients diagnosed with GBM is 12 to 15 months displaying the worst median overall survival among all human neoplasms. Targeted alpha therapy has been shown to overcome chemo- and radioresistance in vitro and thus presents a promising new approach for therapy of GBM. The findings that high affinity Substance P receptor NK1 is high consistently expressed in primary malignant gliomas and in the intratumoral and peritumoral vasculature makes this receptor a very attractive target for glioma cancer therapy.JRC.G.I.5-Advanced Nuclear Knowledg

In vitro evaluation of 225Ac-DOTA-Substance P for targeted alpha therapy of glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most malignant form of brain tumors with dismal prognosis despite treatment by surgery combined with radiotherapy and chemotherapy. The neuropeptide Substance P (SP) is the physiological ligand of the neurokinin‐1 receptor, which is highly expressed in glioblastoma cells. Thus, SP represents a potential ligand for targeted alpha therapy. In this study, a protocol for the synthesis of SP labeled with the alpha emitter 225Ac was developed and binding affinity properties were determined. The effects of 225Ac‐DOTA‐SP were investigated on human glioblastoma cell lines (T98G, U87MG, U138MG) as well as GBM stem cells. A significant dose‐dependent reduction in cell viability was detected up to 6 days after treatment. Also, colony‐forming capacity was inhibited at the lower doses tested. In comparison, treatment with the conventional agent temozolomide showed higher cell viability and colony‐forming capacity. 225Ac‐DOTA‐SP treatment caused induction of late apoptosis pathways. Cells were arrested to G2/M‐phase upon treatment. Increasing doses and treatment time caused additional S‐phase arrest. Similar results were obtained using human glioblastoma stem cells, known to show radioresistance. Our data suggest that 225Ac‐DOTA‐SP is a promising compound for treatment of GBM.JRC.G.I.5-Advanced Nuclear Knowledg