{"created":"2023-05-15T14:48:53.569568+00:00","id":66975,"links":{},"metadata":{"_buckets":{"deposit":"bf5cb71e-e90d-4c81-b76f-5e52964f4de0"},"_deposit":{"created_by":1,"id":"66975","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"66975"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00066975","sets":["10:29"]},"author_link":["658320","658319"],"item_10005_date_7":{"attribute_name":"発表年月日","attribute_value_mlt":[{"subitem_date_issued_datetime":"2018-11-03","subitem_date_issued_type":"Issued"}]},"item_10005_description_5":{"attribute_name":"抄録","attribute_value_mlt":[{"subitem_description":"Objective:\nImmune checkpoint blockade has emerged as a promising cancer treatment paradigm. Unfortunately, there are still a large number of patients and malignancies that do not respond to therapy. A major barrier to validating biomarkers for the prediction and monitoring of responders to clinical checkpoint blockade has been the lack of imaging tools to accurately assess dynamic immune checkpoint expression. The programmed cell death ligand 1 (PD-L1) is expressed in many cancers, and is an important contributor to the maintenance of the immunosuppressive tumor microenvironment. PD-L1 is a prominent target for cancer immunotherapy1,2. TPP-1 peptide, sequenced as: SGQYASYHCWCWRDPGRSGGSK, is a recently discovered PD-L1 ligand with high binding affinity (KD≈94 nM)3. Here we examine the feasibility of developing the TPP-1 as a radiotracer for noninvasive detection of PD-L1 expression in tumors by positron emission tomography (PET). \n\\nMethods:\nTPP-1 peptide was conjugated with NOTA as a chelator for radioisotope labelling. The binding affinity of TPP-1-NOTA was evaluated by surface plasmon resonance. The TPP-1 was subjected to radiolabeling with fluorine-18 or copper-64. In order to further improve the pharmacodynamics of the peptide, 4-arm-PEG was utilized as a vehicle for TPP-1 peptide assembly. The radiolabeling conditions for [18F]AlF-PEG-TPP-1 and [64Cu]-PEG-TPP-1 were optimized. The resulting [18F]AlF-TPP-1, [64Cu]TPP-1, [18F]AlF-PEG-TPP-1, and [64Cu]-PEG-TPP-1 were assessed for stability in saline and in serum. The in vitro specificity of the radiolabelled peptides for PD-L1(+) cell line MDA-MB-231 were tested. Next, we performed small animal PET imaging for 120 min with the four radiolabelled peptides which were injected via the tail vein, respectively. The ex vivo biodistribution of [18F]AlF-PEG-TPP-1 in C57BL/6J mice was conducted.  Finally, the PET scans using the radiolabelled peptides for the imaging of PD-L1 expression were performed in Balb/c nude mice bearing MDA-MB-231 cancer cells. \n\\nResults:\nSurface plasmon resonance showed a NOTA-conjugated TPP-1 binding affinity of ≈120 nM. [18F]AlF-TPP-1 was labelled with a radiochemical yield of 53% ± 10.6%, radiochemical purity of 96.7% ± 2.0%, and molar activity of 7.05 ± 1.5 GBq/µmol. [64Cu]-TPP-1 was labelled with a radiochemical yield of 100%, radiochemical purity of 99.9% ± 0.5%, and molar activity of 36.5 ± 0.2 GBq/µmol. The [18F]AlF-PEG-TPP-1 and [64Cu]-PEG-TPP-1 were synthesized via a one-pot methodology. The peglation of TPP-1 peptide revealed improved stability in the serum. PET imaging in normal mice demonstrated rapid uptakes of the four radiotracers into the PD-L1-rich spleen. The four radiotracers showed significantly different dynamics and intensity. They were rapidly eliminated from most organs and blood, with biodistribution showing prominent renal retention and liver uptake. The PET imaging in xenograft mice model suggested the [64Cu]TPP-1 is a potential lead compound for the in vivo visualization of PD-L1; however, its tumor specificity is still needed for improvement in the following study. \n\\nConclusions:\nOur results show that [64Cu]TPP-1 exhibited some ability to targeting tumor PD-L1 in vivo. Future optimization studies for the TPP-1 peptide will be explored to enhance stability in serum, decrease retention of renal radioactivity and further increase tumor uptake.\n\\nAcknowledgements: We thank Dr. Yimin Zhu from China SINANO for her help on result discussion. Thank the grant aid from the QST Diversity promotion collaboration program. \nReferences: [1] Roy L M et al. (2015) Proc Natl Sci USA, 112, E6506-14. [2] Truillet C et al. (2018) Bioconjug Chem, 29, 96-103. [3] Li C L et al. (2017) Cancer Immunol Res, online version. DOI: 10.1158/2326-6066.CIR-17-0035.","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":"The 10th China-Japan-Korea Symposium on Radiopharmaceutical Sciences(CJKSRS 2018)でのポスター発表","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":"658319","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Hu Kuan","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"658320","nameIdentifierScheme":"WEKO"}]}]},"item_language":{"attribute_name":"言語","attribute_value_mlt":[{"subitem_language":"jpn"}]},"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":"Develop a peptide-based PET radiotracer for imaging PD-L1 expression in cancer","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Develop a peptide-based PET radiotracer for imaging PD-L1 expression in cancer"}]},"item_type_id":"10005","owner":"1","path":["29"],"pubdate":{"attribute_name":"公開日","attribute_value":"2018-11-14"},"publish_date":"2018-11-14","publish_status":"0","recid":"66975","relation_version_is_last":true,"title":["Develop a peptide-based PET radiotracer for imaging PD-L1 expression in cancer"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T20:42:52.269141+00:00"}