Role of Radioiodine in Cancer Therapy: A Review of the Design and Challenges in Selecting Radioligands from Natural Sources

The use of radioactive isotopes in cancer treatment has marked a pivotal shift in modern medicine, where precise diagnosis and targeted therapy now blend to offer patients more effective care with minimized side effects. Despite significant advancements, the exploration of iodine-labeled radioligands from natural sources remains underdeveloped, and comprehensive evaluations of their design, pharmacokinetics, and clinical relevance are still lacking. This gap has created a pressing need for systematic studies that bridge natural product chemistry with radiopharmaceutical applications. Since the initial application of iodine-131 in thyroid treatments, radioisotopes such as iodine-125 and iodine-131 have gained prominence in oncology due to their dual functionality: they enable accurate imaging while delivering therapeutic radiation directly to tumor cells, reducing harm to surrounding healthy tissues. Recent advancements in radiopharmaceuticals, particularly iodine-labeled compounds, aim to further improve this balance by enhancing cancer treatment efficacy and safety. This review synthesizes findings from clinical and experimental studies that explore a range of iodine-labeled compounds, including natural agents like hypericin, curcumin, and piperine, as well as various synthetic analogs. Key methodologies for incorporating iodine, such as the Iodogen method and other stable-labeling techniques, are evaluated for their impact on the compounds� pharmacokinetics, stability, and therapeutic performance. Furthermore, in silico methods are highlighted for their contribution to optimize the molecular structures, binding affinities, and specificity, streamlining the selection of high-potential candidates for radiopharmaceutical applications. Findings reveal that iodine-labeled compounds effectively concentrate in tumor cells, enhancing selectivity and reducing radiation exposure to non-cancerous tissues. Notably, these compounds demonstrate stability in biological environments, making them viable options for integrated diagnostic and therapeutic purposes. Moving forward, the ongoing refinement of compound stability and targeted biodistribution is crucial in ensuring these therapies can meet the demands of precision oncology and improve clinical outcomes across various cancer types. © 2025 Fakih et al.