{"created":"2023-05-15T14:53:36.927380+00:00","id":73014,"links":{},"metadata":{"_buckets":{"deposit":"026f98e5-fb93-4ada-b80d-eaf4acff70c7"},"_deposit":{"created_by":1,"id":"73014","owners":[1],"pid":{"revision_id":0,"type":"depid","value":"73014"},"status":"published"},"_oai":{"id":"oai:repo.qst.go.jp:00073014","sets":["10:28"]},"author_link":["719550","719549"],"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:\nIn recent years, cancer immunotherapy has been progressing rapidly and shown tremendous promises as a next generation of cancer treatment strategy. Among all cancer immunotherapy modalities, the immune checkpoint blockade of PD-L1 or PD-1 has deemed as the most promising therapeutic modality towards a lot of cancers. Photothermal therapy (PTT) employs the heat generated from the absorbed optical energy by light-absorbing agents accumulated in the tumor to ablate tumor cells. Black phosphorus nanosheets (BPs), a type of newly developed two-dimensional (2D) material, have attracted tremendous research interest owing to their distinctive physical/chemical properties1. BPs provide very high surface-to-volume ratios among various nanomaterials. Significantly, BP has an excellent photothermal effect under near-infrared (NIR) irradiation, which gives a high photothermal conversion efficiency as high as 28%. BPs possess excellent biocompatibility and biodegradability properties under physiological conditions2. Here, we aim to develop a theranostic platform based on the BP and PD-L1 ligand peptides. The antitumor therapy is anticipated to achieve by checkpoint blockade via the peptide loading on the BP nanosheets, while the 64Cu was carried by BP to achieve the real-time positron emission tomography (PET) imaging of therapeutic effects.\n\\nMethods:\nConstrained PD-L1 peptide optimization: A previously reported PD-L1 binding peptide TPP-1 was selected as the lead peptide. Two strategies were applied to stabilize the β-hairpin conformation of the peptides. One strategy is β-turn template; another one is cross-strand Tryptophan-Tryptophan interactions. The generated peptides were measured with SPR assay to determine their binding affinities towards PD-L1. The secondary structure was detected by circular dichroism spectroscopy and two-dimension NMR.\nChelator-free labeling of BP with copper-64 and nanocomplex forming: The 64Cu produced in house was diluted with HEPES buffer and mixed with BP nanosheets. The reaction was conducted at room temperature for 2 hours with constant shaking. The resulting BP@64Cu was easily collected by centrifugation. This nanocomplex was resuspended in buffer and the beta hairpin peptide was added. After incubation, peptide-modified BP@64Cu nanocomplex as a final product was obtained by filtration. \nIn vitro cellular uptake and in vivo PET imaging: The cellular uptake mechanism was investigated by fluorescent imaging and radioactivity experiment. The blocking assay was also performed. The release kinetics of 64Cu and peptide from the nanocomplex was studied at different pH values. The in vitro cell viability and T-cell activation efficiency were also examined. PET imaging was performed in MDA-MB-231 bearing Balb/c nude mice. Ex vivo biodistribution in the major organs of tumor mice was also performed. Finally, the anti-cancer therapy by photothermal effect and immune checkpoint blockade was conducted. \n\\nResults:\n64Cu ions bound tightly to the BP nanosheets. A constrained β-hairpin peptide showed 25-folds higher binding affinity to PD-L1 than the precursor peptide, which displayed well-defined hairpin conformation and can be adhered to the BP nanosheets thus forming a sandwich structure. The nanocomplex BP@64Cu@TPP showed effective internalization by the cancer cells and can be blocked by the excess of free TPP peptide. PET imaging results indicated that the 64Cu-nanocomplex can be efficiently accumulated in the tumor site. Moreover, this nanocomplex showed significant tumor growth inhibition in the mice model. Strikingly, the BP showed little unwanted residue in the major organs and all cleared from the body until the end of PET scan (48 h). \n\\nConclusions:\nThe BP@64Cu@TPP nanocomplex is a potential theranostic platform for both tumor expressed PD-L1 detection and imaging-guided immunotherapy in combination with photothermal therapy. Further preclinical biosafety study of the nanoparticles will be carefully studied in due course. \n\\nAcknowledgements: We thank Dr. Lu Wang from Jinan University and Dr. Weizhi Wang from China NCNST for their help in research materials and SPR experiment, respectively. We also thank Dr. Steven Liang from MGH for his help on material characterization and discussion. Thank the grant aid from the QST Diversity promotion collaboration program. \nReferences:\n[1] Hu K. et al. (2018) Small, 14, 1801701. [2] Hu K. et al. (2018) J Mater Chem B, 5, 5433-5440. [3] Hu K. et al. under preparation.","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":"719549","nameIdentifierScheme":"WEKO"}]},{"creatorNames":[{"creatorName":"Hu Kuan","creatorNameLang":"en"}],"nameIdentifiers":[{"nameIdentifier":"719550","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":"Constrained β-hairpin peptide-stabilized BP nanosheets for theranostics in PD-L1(+) tumors","item_titles":{"attribute_name":"タイトル","attribute_value_mlt":[{"subitem_title":"Constrained β-hairpin peptide-stabilized BP nanosheets for theranostics in PD-L1(+) tumors"}]},"item_type_id":"10005","owner":"1","path":["28"],"pubdate":{"attribute_name":"公開日","attribute_value":"2018-11-14"},"publish_date":"2018-11-14","publish_status":"0","recid":"73014","relation_version_is_last":true,"title":["Constrained β-hairpin peptide-stabilized BP nanosheets for theranostics in PD-L1(+) tumors"],"weko_creator_id":"1","weko_shared_id":-1},"updated":"2023-05-15T19:33:41.755712+00:00"}