Evaluation of a CD206-Targeted Peptide for PET Imaging of Macrophages in Syngeneic Mouse Models of Cancer.
Evaluation of a CD206-Targeted Peptide for PET Imaging of Macrophages in Syngeneic Mouse Models of Cancer.
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DOI：
10.1021/acs.molpharmaceut.2c00977
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发表时间：
2023-04
影响因子：
4.9
通讯作者：
Candace C Parker;Ahmad Bin Salam;Patrick N. Song;Carlos A. Gallegos;Addison Hunt;Clayton C. Yates
中科院分区：
文献类型：
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作者：
Candace C Parker;Ahmad Bin Salam;Patrick N. Song;Carlos A. Gallegos;Addison Hunt;Clayton C. Yates
肿瘤相关巨噬细胞(TAMs)是一种大型吞噬细胞，在肿瘤生物学中扮演着多种角色，是免疫系统反应与肿瘤进展关系的重要组成部分。该多肽RP832c针对M2样巨噬细胞上表达的甘露糖受体(CD206)，并与人和鼠的CD206发生交叉反应。此外，它通过将TAM的数量从M2样(亲肿瘤)转变为M1样表型(抗肿瘤)而显示出治疗特性，并在PD-L1反应不敏感的黑色素瘤小鼠模型中显示出抑制肿瘤耐药性的前景。1，2我们的工作旨在开发一种新型的基于RP832c(Kd=5.64μM)的CD206正电子发射断层扫描成像探针，作为一种直接、非侵入性的方法来评估小鼠癌症模型中的TAMS。我们修改了RP832c，加入了螯合剂DOTA，以允许用PET同位素68Ga进行放射性标记(T1/2=68min；？+=89%)。采用蛋白平板结合试验和表面等离子体共振(SPR)技术测定[68Ga]RP832c与CD206的体外结合特性。在同基因肿瘤模型中进行了PET成像和生物分布研究。在小鼠血清中的稳定性研究表明，68Ga在3h内仍保持络合状态(游离态68Ga不到1%)。结合亲和力研究表明，[68Ga]RP832c与小鼠CD206蛋白高度结合，当与天然RP832c的封闭溶液孵育时，示踪剂的结合被显著阻断。在同基因肿瘤模型中的PET成像和生物分布研究表明，肿瘤和表达CD206的器官摄取了[68Ga]RP832c。在CT26小鼠肿瘤模型中，用[68Ga]RP832c成像的每个肿瘤中CD206存在的百分比与PET成像平均标准化摄取值之间存在显著相关性。数据显示，[68Ga]RP832c是癌症和其他疾病中巨噬细胞成像的有前途的候选者。
Tumor-associated macrophages (TAMs) are large phagocytic cells that play numerous roles in cancer biology and are an important component of the relationship between immune system response and tumor progression. The peptide, RP832c, targets the Mannose Receptor (CD206) expressed on M2-like macrophages and is cross-reactive to both human and murine CD206. Additionally, it exhibits therapeutic properties through its ability to shift the population of TAMs from an M2-like (protumor) toward an M1-like phenotype (antitumor) and has demonstrated promise in inhibiting tumor resistance in PD-L1 unresponsive melanoma murine models. In addition, it has shown inhibition in bleomycin-induced pulmonary fibrosis through interactions with CD206 macrophages.1,2 Our work aims to develop a novel CD206 positron emission tomography (PET) imaging probe based on RP832c (Kd = 5.64 μM) as a direct, noninvasive method for the assessment of TAMs in mouse models of cancer. We adapted RP832c to incorporate the chelator DOTA to allow for radiolabeling with the PET isotope 68Ga (t1/2 = 68 min; ß+ = 89%). In vitro stability studies were conducted in mouse serum up to 3 h. The in vitro binding characteristics of [68Ga]RP832c to CD206 were determined by a protein plate binding assay and Surface Plasmon Resonance (SPR). PET imaging and biodistribution studies were conducted in syngeneic tumor models. Stability studies in mouse serum demonstrated that 68Ga remained complexed up to 3 h (less than 1% free 68Ga). Binding affinity studies demonstrated high binding of [68Ga]RP832c to mouse CD206 protein and that the binding of the tracer was able to be blocked significantly when incubated with a blocking solution of native RP832c. PET imaging and biodistribution studies in syngeneic tumor models demonstrated uptake in tumor and CD206 expressing organs of [68Ga]RP832c. A significant correlation was found between the percentage of CD206 present in each tumor imaged with [68Ga]RP832c and PET imaging mean standardized uptake values in a CT26 mouse model of cancer. The data shows that [68Ga]RP832c represents a promising candidate for macrophage imaging in cancer and other diseases.