Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
Int J Biol Sci. 2023 Jan 1;19(1):156-166. doi: 10.7150/ijbs.76148. eCollection 2023.
: The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many tumors and involved in the activation of the latency associated peptide (LAP)/TGFβ complex, represent potential targets for tumor imaging and therapy. We investigated the tumor-homing properties of a chromogranin A-derived peptide containing an RGDL motif followed by a chemically stapled alpha-helix (called "), which selectively recognizes the LAP/TGFβ complex-binding site of αvβ6 and αvβ8. Peptide was labeled with IRDye 800CW (a near-infrared fluorescent dye) or with F-NOTA (a label for positron emission tomography (PET)); the integrin-binding properties of free peptide and conjugates were then investigated using purified αvβ6/αvβ8 integrins and various αvβ6/αvβ8 single - or double-positive cancer cells; tumor-homing, biodistribution and imaging properties of the conjugates were investigated in subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, and in mice bearing subcutaneous αvβ8-positive prostate tumors. studies showed that can bind both integrins with high affinity and inhibits cell-mediated TGFβ activation. The IRDye and -NOTA conjugates could bind purified αvβ6/αvβ8 integrins with no loss of affinity compared to free peptide, and selectively recognized various αvβ6/αvβ8 single- or double-positive cancer cells, including cells from pancreatic carcinoma, melanoma, oral mucosa, bladder and prostate cancer. static and dynamic optical near-infrared and PET/CT imaging and biodistribution studies, performed in mice with subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, showed high target-specific uptake of fluorescence- and radio-labeled peptide by tumors and low non-specific uptake in other organs and tissues, except for excretory organs. Significant target-specific uptake of fluorescence-labeled peptide was also observed in mice bearing αvβ8-positive prostate tumors. The results indicate that can home to αvβ6- and/or αvβ8-positive tumors, suggesting that this peptide can be exploited as a ligand for delivering imaging or anticancer agents to αvβ6/αvβ8 single- or double-positive tumors, or as a tumor-homing inhibitor of these TGFβ activators.
: αvβ6- 和 αvβ8-整联蛋白是两种细胞黏附受体，在许多肿瘤中上调，并参与潜伏相关肽 (LAP)/TGFβ 复合物的激活，它们是肿瘤成像和治疗的潜在靶点。我们研究了含有 RGDL 基序的嗜铬粒蛋白 A 衍生肽（后面跟着化学订书钉 α-螺旋，称为 "）的肿瘤归巢特性，该肽选择性识别 αvβ6 和 αvβ8 的 LAP/TGFβ 复合物结合位点。肽 用近红外荧光染料 IRDye 800CW（一种近红外荧光染料）或 F-NOTA（一种正电子发射断层扫描（PET）的标记物）标记；然后使用纯化的 αvβ6/αvβ8 整联蛋白和各种 αvβ6/αvβ8 单阳性或双阳性癌细胞研究游离肽和缀合物的整合素结合特性；在皮下和原位 αvβ6 阳性胰腺癌以及携带皮下 αvβ8 阳性前列腺肿瘤的小鼠中研究了缀合物的肿瘤归巢、生物分布和成像特性。研究表明， 可以与两种整联蛋白高亲和力结合，并抑制细胞介导的 TGFβ 激活。与游离肽相比，IRDye 和 -NOTA 缀合物与纯化的 αvβ6/αvβ8 整联蛋白结合时没有亲和力损失，并且可以选择性地识别各种 αvβ6/αvβ8 单阳性或双阳性癌细胞，包括胰腺癌、黑色素瘤、口腔黏膜、膀胱癌和前列腺癌的细胞。在具有皮下和原位 αvβ6 阳性胰腺癌的小鼠中进行的静态和动态光学近红外和 PET/CT 成像和生物分布研究表明，荧光和放射性标记肽通过肿瘤的高靶特异性摄取和其他器官和组织的低非特异性摄取，除了排泄器官。在携带 αvβ8 阳性前列腺肿瘤的小鼠中也观察到荧光标记肽的显著靶特异性摄取。结果表明， 可以归巢到 αvβ6-和/或 αvβ8-阳性肿瘤，这表明该肽可以作为将成像或抗癌剂递送至 αvβ6/αvβ8 单阳性或双阳性肿瘤的配体，或作为这些 TGFβ 激活剂的肿瘤归巢抑制剂。
