{"created":"2023-05-15T15:01:04.797846+00:00","id":82859,"links":{},"metadata":{"_buckets":{"deposit":"075b5fcd-2172-4080-9e23-1baad3bc37aa"},"_deposit":{"created_by":1,"id":"82859","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"82859"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00082859","sets":["10:29"]},"author_link":["950429","950430","950426","950427","950432","950431","950428","950424","950425","950433"],"item_10005_date_7":{"attribute_name":"発表年月日","attribute_value_mlt":[{"subitem_date_issued_datetime":"2021-05-17","subitem_date_issued_type":"Issued"}]},"item_10005_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Objectives: Peptides are a class of important drug molecules for positron emission tomography\n(PET) tracers. However, native peptides are prone to enzymatic degradation. Polyethylene glycol\nmodification (PEGylation) is an FDA approved strategy for improving peptide stability. PEGylation\ncan prolong the blood circulation and enhance the cellular uptake and tissue retention of peptides,\nthus promoting the bioavailability and target accessibility. Despite these benefits, PEGylation is\nlikely to damage the binding ability of peptides to their targets and cause severe allergic reactions\nin the living body, if the PEG is improperly anchored to peptides. Besides, body excretion of\nPEGylated peptides is usually slowed compare to unpegylated peptides. However, these issues\nthus far are poorly understood. In this light, a systematic investigation of how does the PEGylation\n(including PEG size, PEGylation position, and topology of PEG) affect the pharmacological\nproperties and in vivo fate of peptides is exceptionally significant. In this study, we reported the\nPEGylation of a PD-L1 binding peptide with different PEG moieties, and studied the in vivo\nbehavior of these PEGylated peptides in animal models.\nMethods: We synthesized a PD-L1 (immune checkpoint) binding peptide\n(NOTA-SGQYASYHCWCWKNPGRSGGSK, NOTA-TPP-1), which has two cysteine residues.\nThree kinds of PEG molecules, namely linear PEG (PEG, M.W.=5000), 4 arm PEG (4PEG,\nM.W.=5000), and 8 arm PEG (8PEG, M.W.=10000), were used to modify the NOTA-TPP-1. The\nPEGylation occurred between the cysteine of TPP-1 and the maleimide of PEG. Specifically, the\nNOTA-TPP-1 was firstly incubated with 64Cu for 10 min at 80℃ to generate\n[64Cu]NOTA-TPP-1. Then PEG molecules were mixed with [64Cu]NOTA-TPP-1 with\nmolar ratios of 1.2:1, 1:4.5, 1: 8.5 for PEG, 4PEG, and 8PEG, respectively. The reactions\nwere monitored by radio HPLC to check the modification efficiency. For PET imaging,\nC57/BL6J mice bearing MC38 tumors were injected with different tracers (0.5 mCi per\nmouse) intravenously. The mice were imaged at designated time points to monitor the\npharmacokinetics and dynamics of the tracers.\nResults: [64Cu]NOTA-TPP-1 was obtained with a radiochemical yield of up to 99%. The\nPEGylation with linear PEG achieved an efficiency of 98% after 6 hours of incubation, while that\nwas 78% for 4PEG and 8PEG accordingly. We also found that more branches of PEG caused an\nincrease of the retention time in radio HPLC, resulting in the retention times with an order of\n[ 64Cu]NOTA-TPP-1-8PEG>[64Cu]NOTA-TPP-1-4PEG\n>[64Cu]NOTA-TPP-1-PEG>[64Cu]NOTA-TPP-1. The non-PEGylated [64Cu]NOTA-TPP-1 was\nrapidly eliminated by the kidney and bladder, and the tumor uptake of this tracer was weak. For\nPEGylated peptides, the tumor uptake and retention were significantly enhanced, and the branch\nnumber correlates well with the tumor uptake of the tracers. In particular, 8PEG modification leads\nto the highest tumor uptake and longest retention, followed by 4PEG modification. However, the\nPEGylation remarkably influenced the renal clearance of the tracers, and larger PEG delayed\nkidney elimination.\nConclusions: Our results indicate that PEGylation modulation of peptides is a viable way to\nimprove the PET imaging capacity of peptides.","subitem_description_type":"Abstract"}]},"item_10005_description_6":{"attribute_name":"会議概要（会議名, 開催地, 会期, 主催者等）","attribute_value_mlt":[{"subitem_description":"eSRS","subitem_description_type":"Other"}]},"item_access_right":{"attribute_name":"アクセス権","attribute_value_mlt":[{"subitem_access_right":"metadata only access","subitem_access_right_uri":"http://purl.org/coar/access_right/c_14cb"}]},"item_creator":{"attribute_name":"著者","attribute_type":"creator","attribute_value_mlt":[{"creatorNames":[{"creatorName":"Kuan, Hu"}],"nameIdentifiers":[{"nameIdentifier":"950424","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Lin, Xie"}],"nameIdentifiers":[{"nameIdentifier":"950425","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Yiding"}],"nameIdentifiers":[{"nameIdentifier":"950426","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Masayuki, Hanyu"}],"nameIdentifiers":[{"nameIdentifier":"950427","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong"}],"nameIdentifiers":[{"nameIdentifier":"950428","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Kuan, Hu","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"950429","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Lin, Xie","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"950430","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Yiding","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"950431","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Masayuki, Hanyu","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"950432","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Zhang, Ming-Rong","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"950433","nameIdentifierScheme":"WEKO"}]}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"eng"}]},"item_resource_type":{"attribute_name":"資源タイプ","attribute_value_mlt":[{"resourcetype":"conference object","resourceuri":"http://purl.org/coar/resource_type/c_c94f"}]},"item_title":"PEGylation modulation of peptides promotes PET detection of cancers","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"PEGylation modulation of peptides promotes PET detection of cancers"}]},"item_type_id":"10005","owner":"1","path":["29"],"pubdate":{"attribute_name":"公開日","attribute_value":"2021-05-19"},"publish_date":"2021-05-19","publish_status":"0","recid":"82859","relation_version_is_last":true,"title":["PEGylation modulation of peptides promotes PET detection of cancers"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T20:09:12.315535+00:00"}