Radiolabeled Peptides in Oncology

There has been an exponential growth in the development of radiolabeled peptides for diagnostic and therapeutic applications in the last decade. The automated means of synthesizing these compounds in large quantities and the simplified methods of purifying, characterizing, and optimizing them have kindled attention to peptides as carrier molecules. These new techniques have accelerated the commercial development of radiolabelled peptides, which has provided additional radiopharmaceuticals for the nuclear medicine community.

Peptides have many key properties including fast clearance, rapid tissue penetration, and low antigenicity, and can be produced easily and inexpensively. However, there may be problems with in vivo catabolism, unwanted physiologic effects, and chelate attachment. Radiolabeled peptides have made their greatest impact in the management of relatively rare neuroendocrine malignancies. Indeed, Indium-111 (¹¹¹In)-pentetreotide (¹¹¹In-DTPA-octreotide, Octreoscan®), which binds to somatostatin receptors (SSTRs), has become the diagnostic ‘gold standard’ in these diseases. However, ¹¹¹In-pentetreotide has been less successful in the diagnosis of other more prevalent diseases in which SSTRs are upregulated. Technetium-99m (^99mTc)-depreotide (NeoTect™), a ^99mTc-labeled SSTR-analog, could have wider impact since it has high sensitivity and specificity for lung cancer lesion detection. However, this impact may be minimized by the increased availability of positron emission tomography imaging with Fluorine-18 (¹⁸F)-flourodeoxyglucose, which has similar sensitivity and specificity for lesion identification in this disease, and is currently more widely used. The receptors for bombesin, α-melanocyte-stimulating hormone, neurotensin, and the integrin α_vβ₃, are under active investigation as targets for radiolabelled peptides, but are still in the pre-clinical stage. Compounds directed at the cholecystokinin-B/gastrin receptor have shown promising results in clinical trials in humans.

Radiolabelled peptide therapy is usually indicated for patients with widespread disease that is not amenable to focused radiation therapy or is refractory to chemotherapy. Phase I/II studies using various radiolabelled peptides (including ¹¹¹In-pentetreotide, Yttrium-90 [⁹⁰Y]-DOTA-Phe¹-Tyr³-octreotide, ⁹⁰Y-DOTA-lanreotide, and Lutetium-177 [¹⁷⁷Lu]-DOTA-octreotate) for the treatment of patients with neuroendocrine malignancy are in progress. Over 400 patients have been treated, and the response rate has ranged from 60% to 75%, although few patients have had a complete response. Patients have been given individual doses ranging from 2 to 11 GBq with a slow infusion every 4–8 weeks (up to 12 times). The kidney is the dose-limiting organ and most patients experience a transient decline in blood cell counts. A concomitant infusion of an amino acid mixture can reduce kidney toxicity and increase the effective tumor dose. Other peptides currently under investigation, some of which have shown promising results, include Rhenium-188 (¹⁸⁸Re)-P2045 and ⁹⁰Y-α_vβ₃ antagonist.