Abstract
PurposeThere 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.MethodsThe 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.Results131I-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.ConclusionWe 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.
Highlights
An estimated 132,000 new cases of melanoma are diagnosed every year worldwide [1]
Radiochemical purity was analyzed by analytic high-pressure liquid chromatography (HPLC) with a flow count radiation detector (Meinaite, Germany) using a column (Elite Hypersil® ODS/ODS2 C-18 column, Alltech, USA) (4.6 × 250 mm, 5 μm particle size)
The tracer was synthesized with a good radiochemical yield (50–60%), high radiochemical purity (> 98%), and specific activity (5.45–6.55 GBq/μmol)
Summary
An estimated 132,000 new cases of melanoma are diagnosed every year worldwide [1]. Patients with distant metastases still have a poor prognosis, the 5-year survival is only 17% [2]. The common first-line therapy such as dacarbazine with a complete response of approximately 5% is of very limited benefit for advanced melanoma [3]. Our knowledge of the molecular biology and immunoregulatory mechanisms in melanoma has greatly expanded, which has brought about great advances for treatment of this lethal cancer. Several novel targeted therapeutic agents including immunotherapy drugs have been developed and approved for advanced melanoma treatment [2], including BRAF inhibitors (vemurafenib), anti-CTLA-4 agents (ipilimumab), and anti-PD-1 agents (nivolumab and pembrolizumab). More evidence on long-term benefit still needs to be collected. In this context, radiotherapy and targeted radionuclide therapy (TRNT) of melanoma has recently been receiving attention [4, 5]
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