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A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
An 211At-labeled alpha-melanocyte stimulating hormone peptide analog for targeted alpha therapy of metastatic
Hiroyuki Suzuki1, Saki Yamashita2, Shoko Tanaka2
1Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan. h.suzuki@chiba-u.jp.
Purpose:
Patients who develop metastatic melanoma have a very poor prognosis, and new treatments are needed to improve the response rates. Melanocortin-1 receptor (MC1R) is a promising target for radionuclide therapy of metastatic melanoma, and alpha-melanocyte stimulating hormone (α-MSH) peptide analogs show high affinities to MC1Rs. Because targeted alpha therapy (TAT) can be a desirable treatment for metastatic melanoma, this study aimed to develop an 211At-labeled α-MSH peptide analog for TAT of metastatic melanoma.
Methods:
We designed an α-MSH analog labeled with 211At using a neopentyl glycol scaffold via a hydrophilic linker. Preliminary studies using 125I-labeled α-MSH analogs were performed to identify suitable hydrophilic linkers. Then, [211At]NpG-GGN4c was prepared using a procedure similar to that of the 125I-labeled counterpart, [125I]NpG-GGN4b. The biodistribution profile of [211At]NpG-GGN4c in B16F10 tumor-bearing mice was compared with that of [125I]NpG-GGN4b. B16F10 tumor-bearing mice were treated with a single dose of vehicle or [211At]NpG-GGN4c (1 or 0.4 MBq).
Results:
The D-Glu-D-Arg linker was identified as the optimal hydrophilic linker because of its high affinity for MC1R and good biodistribution profile, especially with low accumulation in the liver and intestine. [211At]NpG-GGN4c showed tumor accumulation comparable to that of [125I]NpG-GGN4b and maintained the tumor radioactivity retention from 1 to 3 h postinjection. [211At]NpG-GGN4c exhibited a dose-dependent inhibitory effect on B16F10 xenograft growth without apparent body weight loss.
Conclusion:
[211At]NpG-GGN4c showed dose-dependent efficacy against B16F10 xenografts, suggesting that [211At]NpG-GGN4c is a promising TAT agent for treating metastatic melanoma.
Insights
This study developed a novel alpha-melanocyte stimulating hormone (α-MSH) peptide analog labeled with Astatine-211 ([211At]) for targeted alpha therapy (TAT). The new agent, [211At]NpG-GGN4c, effectively inhibited metastatic melanoma growth in mice.
Area of Science:
- Nuclear Medicine
- Radiopharmaceutical Chemistry
- Oncology
Background:
- Metastatic melanoma presents a poor prognosis, necessitating advanced therapeutic strategies.
- Melanocortin-1 receptor (MC1R) is a validated target for metastatic melanoma treatment.
- Alpha-melanocyte stimulating hormone (α-MSH) peptide analogs exhibit high affinity for MC1Rs.
Purpose of the Study:
- To develop an Astatine-211 ([211At])-labeled α-MSH peptide analog for targeted alpha therapy (TAT).
- To evaluate the efficacy of the novel radiopharmaceutical in preclinical models of metastatic melanoma.
Main Methods:
- Design of an α-MSH analog ([211At]NpG-GGN4c) utilizing a neopentyl glycol scaffold and a hydrophilic linker.
- Optimization of the hydrophilic linker using Iodine-125 ([125I])-labeled α-MSH analogs.
- Assessment of biodistribution and therapeutic efficacy in B16F10 tumor-bearing mice.
Main Results:
- The D-Glu-D-Arg linker was identified as optimal, showing high MC1R affinity and favorable biodistribution.
- [211At]NpG-GGN4c demonstrated comparable tumor accumulation and retention to [125I]NpG-GGN4b.
- Astatine-211 ([211At]) labeled NpG-GGN4c exhibited dose-dependent inhibition of B16F10 xenograft growth without significant toxicity.
Conclusions:
- The developed [211At]-labeled α-MSH analog, [211At]NpG-GGN4c, shows significant therapeutic potential.
- This agent demonstrates promising efficacy for targeted alpha therapy in metastatic melanoma.
- Further investigation of [211At]NpG-GGN4c as a TAT agent for metastatic melanoma is warranted.
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