**Abstract**

Tumors like glioblastoma are inaccessible due to blood brain barrier. The permeability of radioisotopes can be improved by conjugating them with nanoparticles. The most common malignant adult brain tumor is glioblastoma, which has very poor patient prognosis. The mean survival for highly proliferative glioblastoma is only 10–14 months despite an aggressive radiotherapy and chemotherapy following debulking surgery. β<sup>−</sup> particle emitters like 131I, 90Y, 186/188Re, and 177Lu have been coupled with nanoparticles and used for treatment of glioblastoma. These radiopharmaceutical compounds have resulted in a stabilization and improvement of the neurological status with minimal side effects. Similarly, α particle emitters like 213Bi, 211At, and 225Ac are an innovative and interesting alternative. Alpha particles deliver a high proportion of their energy inside the targeted cells within a few micrometers from the emission point versus several millimeters for β<sup>−</sup> particles. Thus, α particles are highly efficient in killing tumor cells with minimal irradiation of healthy tissues and permits targeting of isolated tumor cells. This has been confirmed by subsequent clinical trials which showed better therapeutic efficacy and minimal side effects, thus opening a new and promising era for glioblastoma medical care using α therapy.

**Keywords:** radioisotopes, nanoparticles, brain targeting, glioblastoma, blood brain barrier, theranostics

## **1. Introduction**

Nuclear medicine involves use of radioactive atoms for diagnosis and/or therapy. For therapeutic purposes, to obtain specific irradiation of tumor cells, radioactivity is attached to a pharmaceutical molecule that binds to specific molecules expressed on the target tumor cells. This specific radioactive molecule is known as radiopharmaceutical. The pharmacological specific component of a therapeutic radiopharmaceutical can be based on the target protein structure which may include peptides or monoclonal antibodies, or molecular structures like nanoparticles [1]. The radioactive part may consist of massive particle emitters capable of delivering ionizing energy locally as Auger electrons, or β− or α particles. Auger electrons are low-energy electrons that emit localized irradiation, few nanometers around the emission point with high biological effects. Beta-negative particles have a comparatively low linear energy transfer (LET) and emit their energy over a few millimeters in comparison to alpha particles. The choice of the radionuclide is based upon the size of the tumor. For example, yttrium-90 emits a long-range beta emission and could be useful for proliferating tumors of large size, while lutetium-177 having a

short range emission could be used for treatment retreating tumors of small size. Alpha particles deliver a high fraction of their energy inside the targeted cells, leading to highly efficient killing. This makes them suitable for targeting cells of isolated tumor and minimal residual disease [2, 3].

Radioimmunotherapy, radiopeptide therapy and radionanoparticles are three important strategies of nuclear medicine for glioblastoma therapy. The four main prerequisites for successful radionuclide therapy for glioblastoma are selection of an appropriate target (integrin, tenascin, cadherin, EGFR, chemokine receptors or neurokinin receptors), physicochemical properties of the radionuclide, physicochemical properties of the targeting vector and its size [4]. For therapeutic purposes, nuclear medicine practitioners typically use β− particle emitters like 131I, 90Y, 186/188Re, and 177Lu. These radioisotopes have been coupled with nanoparticles, monoclonal antibodies, or peptides for treatment of glioblastoma. These radiopharmaceuticals have resulted in maintenance and/or improvement of the neurological status with only short-term side effects. The evidence for glioblastoma targeted radiotherapy has not only proven for β− particle emitters but also for α particle emitters. 213Bi, 211At, and 225Ac are some of the particle emitters which are recently attracting the interest of the scientific community. They are capable of delivering high amount of their energy within few micrometers close to their emission point in comparison to some few millimeters for β− particles. The α particles have been found highly efficient in killing tumor cells with minimal irradiation of healthy tissues and permits targeting of isolated tumor cells [1, 5].
