Revitalizing PI3K Inhibitors for PET/CT Imaging and Radionuclide Therapy of Multiple Cancers

Phosphoinositide 3-kinase (PI3K) dysregulation drives tumorigenesis through regulation of cell cycle progression and survival. Several small molecular inhibitors targeting PI3K have been approved for tumor treatment. However, these inhibitors exposed unexpected severe off-tumor toxicity, leading to poor patient prognosis. Radiopharmaceuticals based on radiolabeled PI3K inhibitors for targeted internal radionuclide therapy offer a revitalized therapeutic approach to reduced pharmacological toxicity. Herein, we rationally designed and synthesized four bifunctional radiolabeled small-molecule chimeras based on the PI3K inhibitor IMM-H012, denoted as [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-P(1-4). Among them, radiolabeled P4 demonstrated superior pharmacodynamic and pharmacokinetic profiles in multiple tumor models. Moreover, [¹⁷⁷Lu]Lu-P4 substantially suppressed subcutaneous melanoma tumor growth with an acceptable safety profile. Additionally, [¹⁷⁷Lu]Lu-P4 combined with IMM-H012 showed synergistic antitumor effects. The mechanistic study suggested a novel radiosensitization mechanism of ¹⁷⁷Lu to PI3K inhibitors by downregulating fatty acid oxidase expression. These findings reposition PI3K as a versatile theranostic target while providing an effective repurposing strategy for PI3K inhibitors.