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Peptide-radionuclide conjugates, in common contexts, are often categorized under PRRT (Peptide Receptor Radionuclide Therapy) or radiopharmaceutical conjugates. Its core concept can be summed up in one sentence: the peptide is responsible for "targeting the site", while the radionuclide takes charge of "killing tumor cells".

This type of drug usually consists of several parts: a peptide that can recognize tumor-associated receptors, a linker/chelation structure, and a radionuclide for diagnosis or therapy. The peptide segment binds to specific receptors highly expressed on the surface of tumor cells, such as the somatostatin receptors commonly seen in neuroendocrine tumors. After binding, the receptor-peptide complex can be internalized by the cell, and the radionuclide subsequently releases radiation near or inside the tumor cell, causing DNA damage to inhibit or kill the tumor cell. PRRT precisely uses radiolabeled peptides to selectively target tumor cells that express the corresponding receptors, delivering therapeutic radiation to the tumor site ^[PMC]^.

The difference between it and traditional radiotherapy is that conventional external beam radiotherapy irradiates the tumor area from outside the body, while peptide-radionuclide conjugate drugs enter the body through blood circulation, relying on the recognition between peptides and receptors to bring the radionuclide close to the tumor tissue. The goal of this approach is not "systemic average distribution", but to make the radiation dose more concentrated in the lesion sites that express the target. Relevant reviews also mention that the advantage of PRRT lies in achieving highly sensitive and specific molecular-level therapy through in vivo receptor targeting ^[PubMed]^.

From the perspective of drug design, peptides have several advantages in this class of drugs. Peptide molecules are usually small, with relatively fast tissue penetration and in vivo clearance rates. Compared with large-molecule antibodies, the background signal drops faster during imaging or therapy. Peptides are also relatively easy to modify through sequence engineering, cyclization, and optimization of linkers and chelating agents to adjust affinity, stability and pharmacokinetic properties. A review has summarized that peptide ligands feature low immunogenicity, favorable pharmacokinetics, and relatively simple production ^[MDPI]^.

Another important advantage is that it enables "theranostic integration". The same type of targeting peptide can be conjugated with diagnostic radionuclides and therapeutic radionuclides respectively: when used for PET/SPECT imaging, it can first determine whether the tumor expresses the corresponding target and whether the drug can accumulate in the lesion. After confirming eligibility, therapeutic radionuclides can be used for treatment. PRRT has become a relatively mature theranostic pathway in neuroendocrine tumors, especially for somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors ^[PMC]^.

Different radionuclides also bring different therapeutic characteristics. For example, ^177Lu, ^90Y, ^225Ac can be used in therapeutic scenarios, while ^68Ga and others are suitable for PET imaging. Chelating agents such as DOTA can help peptides bind to different radiometal nuclides. The particle type, range and energy of different nuclides vary, which will affect the applicable tumor size, lesion distribution and toxicity management ^[SNM Journals]^.

Of course, this type of drug is not without limitations. It requires sufficient target receptor expression in the tumor, otherwise the drug cannot effectively accumulate. Normal tissues such as the kidneys and bone marrow may also be exposed to certain levels of radiation. Nephrotoxicity is a key concern in PRRT, but clinically, measures such as amino acid infusion can be used to reduce the radiation dose to the kidneys.