Approach to improve therapeutic efficacy, difficulties, and outlook for radionuclide therapy

Radionuclide therapy (RNT) is an emerging branch of nuclear medicine employing small molecules, aptamers, peptides, and antibodies are used as payloads to deliver a lethal dosage of beta/alpha radiation to the target areas. With the promising therapeutic results of Bexxar®, Zevalin®, PSMA, DOTA-TATE, and many bone metastasis radiopharmaceuticals, it has become imperative for nuclear physicians must now delve deeply for the ultimate benefit of their patients. There are various therapeutic agents whose clinical response varies from few to 60%, and during the course of a few cycles of administration, tumors develop resistance. To enhance cell killing, rituximab and other molecules were tagged with beta-emitting radionuclides, and the magnitude of apoptosis and lurking mechanisms of cell death were studied in combination with chemotherapeutic drugs. Apoptotic cell death was highest in combination with chemotherapeutic agents compared to unlabeled or labeled drugs alone. It has found G1 as well as G2 cell cycle arrest with different radiopharmaceuticals in combination with chemotherapeutic agents. In most of the cases, downregulation of bclxl and cleavage of PARP and activation of p38 MAPK were prominent pathways. In addition to this, SOD1 and ceramide activation are also reported. Despite being the least toxic, in clinics, their lack of popularity can be attributed to the difficulty of delivering them and the growing availability of innovative medicines. Even after twenty years of first FDA approved radioimmunotherapeutic (RIT) agents, the FDA has not yet approved any RIT agent despite encouraging early results. The conjugated molecules are more vulnerable to destruction by high-energy radionuclides that emit alpha or beta particles, which could lead to poor stability in radiopharmaceuticals. Despite these challenges, the advantages of radionuclide therapeutic agents extend beyond the radiation 's particulate form, aside from their ability to eradicate radioresistant hypoxic cells. Such RNT agents have the potential to be an effective agent that can be successfully targeted and treat tumor metastases. (author)