Targeted radiotherapy of pigmented melanoma with ¹³¹I-5-IPN

There has been no satisfactory treatment for advanced melanoma until now. Targeted radionuclide therapy (TRNT) may be a promising option for this heretofore lethal disease. Our goal in this study was to synthesize ¹³¹I-N-(2-(diethylamino)ethyl)-5-(iodo-131I)picolinamide (¹³¹I-5-IPN) and evaluate its therapeutic ability and toxicity as a radioiodinated melanin-targeting therapeutic agent.

The trimethylstannyl precursor was synthesized and labeled with ¹³¹I to obtain ¹³¹I-5-IPN. The pharmacokinetics of ¹³¹I-5-IPN was evaluated through SPECT imaging, and its biodistribution was assessed in B16F10 tumor models and in A375 human-to-mouse xenografts. For TRNT, B16F10 melanoma-bearing mice were randomly allocated to receive one of five treatments (n = 10 per group): group A (the control group) received 0.1 mL saline; group B was treated with an equimolar dose of unlabeled precursor; group C received 18.5 MBq of [¹³¹I]NaI; group D and E received one or two dose of 18.5 MBq ¹³¹I-5-IPN, respectively. TRNT efficacy was evaluated through tumor volume measurement and biology study. The toxic effects of ¹³¹I-5-IPN on vital organs were assessed with laboratory tests and histopathological examination. The radiation absorbed dose to vital organs was estimated based on biodistribution data.

¹³¹I-5-IPN was successfully prepared with a good radiochemistry yield (55% ± 5%, n = 5), and it exhibited a high uptake ratio in melanin-positive B16F10 cells which indicating high specificity. SPECT imaging and biodistribution of ¹³¹I-5-IPN showed lasting high tumor uptake in pigmented B16F10 models for 72 h. TRNT with ¹³¹I-5-IPN led to a significant anti-tumor effect and Groups D and E displayed an extended median survival compared to groups A, B, and C. The highest absorbed dose to a vital organ was 0.25 mSv/MBq to the liver; no obvious injury to the liver or kidneys was observed during treatment. ¹³¹I-5-IPN treatment was associated with reduction of expression of proliferating cell nuclear antigen (PCNA) and Ki67 and cell cycle blockage in G2/M phase in tumor tissues. Decreased vascular endothelial growth factor and CD31 expression, implying reduced tumor growth, was noted after TRNT.

We successfully synthesized ¹³¹I-5-IPN, which presents long-time retention in melanotic melanoma. TRNT with ¹³¹I-5-IPN has the potential to be a safe and effective strategy for management of pigmented melanoma.