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PEGylation modulation of peptides promotes PET detection of cancers
https://repo.qst.go.jp/records/82859
https://repo.qst.go.jp/records/82859ed694607-3e26-4403-b7ab-40fcc5499e1f
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2021-05-19 | |||||
| タイトル | ||||||
| タイトル | PEGylation modulation of peptides promotes PET detection of cancers | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Kuan, Hu
× Kuan, Hu× Lin, Xie× Zhang, Yiding× Masayuki, Hanyu× Zhang, Ming-Rong× Kuan, Hu× Lin, Xie× Zhang, Yiding× Masayuki, Hanyu× Zhang, Ming-Rong |
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| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Objectives: Peptides are a class of important drug molecules for positron emission tomography (PET) tracers. However, native peptides are prone to enzymatic degradation. Polyethylene glycol modification (PEGylation) is an FDA approved strategy for improving peptide stability. PEGylation can prolong the blood circulation and enhance the cellular uptake and tissue retention of peptides, thus promoting the bioavailability and target accessibility. Despite these benefits, PEGylation is likely to damage the binding ability of peptides to their targets and cause severe allergic reactions in the living body, if the PEG is improperly anchored to peptides. Besides, body excretion of PEGylated peptides is usually slowed compare to unpegylated peptides. However, these issues thus far are poorly understood. In this light, a systematic investigation of how does the PEGylation (including PEG size, PEGylation position, and topology of PEG) affect the pharmacological properties and in vivo fate of peptides is exceptionally significant. In this study, we reported the PEGylation of a PD-L1 binding peptide with different PEG moieties, and studied the in vivo behavior of these PEGylated peptides in animal models. Methods: We synthesized a PD-L1 (immune checkpoint) binding peptide (NOTA-SGQYASYHCWCWKNPGRSGGSK, NOTA-TPP-1), which has two cysteine residues. Three kinds of PEG molecules, namely linear PEG (PEG, M.W.=5000), 4 arm PEG (4PEG, M.W.=5000), and 8 arm PEG (8PEG, M.W.=10000), were used to modify the NOTA-TPP-1. The PEGylation occurred between the cysteine of TPP-1 and the maleimide of PEG. Specifically, the NOTA-TPP-1 was firstly incubated with 64Cu for 10 min at 80℃ to generate [64Cu]NOTA-TPP-1. Then PEG molecules were mixed with [64Cu]NOTA-TPP-1 with molar ratios of 1.2:1, 1:4.5, 1: 8.5 for PEG, 4PEG, and 8PEG, respectively. The reactions were monitored by radio HPLC to check the modification efficiency. For PET imaging, C57/BL6J mice bearing MC38 tumors were injected with different tracers (0.5 mCi per mouse) intravenously. The mice were imaged at designated time points to monitor the pharmacokinetics and dynamics of the tracers. Results: [64Cu]NOTA-TPP-1 was obtained with a radiochemical yield of up to 99%. The PEGylation with linear PEG achieved an efficiency of 98% after 6 hours of incubation, while that was 78% for 4PEG and 8PEG accordingly. We also found that more branches of PEG caused an increase of the retention time in radio HPLC, resulting in the retention times with an order of [ 64Cu]NOTA-TPP-1-8PEG>[64Cu]NOTA-TPP-1-4PEG >[64Cu]NOTA-TPP-1-PEG>[64Cu]NOTA-TPP-1. The non-PEGylated [64Cu]NOTA-TPP-1 was rapidly eliminated by the kidney and bladder, and the tumor uptake of this tracer was weak. For PEGylated peptides, the tumor uptake and retention were significantly enhanced, and the branch number correlates well with the tumor uptake of the tracers. In particular, 8PEG modification leads to the highest tumor uptake and longest retention, followed by 4PEG modification. However, the PEGylation remarkably influenced the renal clearance of the tracers, and larger PEG delayed kidney elimination. Conclusions: Our results indicate that PEGylation modulation of peptides is a viable way to improve the PET imaging capacity of peptides. |
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| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | eSRS | |||||
| 発表年月日 | ||||||
| 日付 | 2021-05-17 | |||||
| 日付タイプ | Issued | |||||
