Enzyme-Activatable Chemokine Conjugates for In Vivo Targeting of Tumor-Associated Macrophages.
Enzyme-Activatable Chemokine Conjugates for In Vivo Targeting of Tumor-Associated Macrophages.
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酶激活趋化因子结合物体内靶向肿瘤相关巨噬细胞。
DOI：
10.1002/anie.202207508
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发表时间：
2022-10-10
影响因子：
16.6
通讯作者：
Vendrell, Marc
中科院分区：
文献类型：
--
作者：
Barth, Nicole D.;Van Dalen, Floris J.;Karmakar, Utsa;Bertolini, Marco;Mendive-Tapia, Lorena;Kitamura, Takanori;Verdoes, Martijn;Vendrell, Marc
肿瘤相关巨噬细胞（TAM）水平升高是大多数癌症预后不良的指标。尽管阻断巨噬细胞向肿瘤募集的抗体和小分子正在作为抗癌疗法进行评估，但这些策略并不是针对巨噬细胞亚群的。在此，我们报告了第一个酶激活趋化因子缀合物，用于有效靶向活肿瘤中确定的巨噬细胞亚群。我们的构建体利用 TAM 中趋化因子受体（例如 CCR2）的高表达和半胱氨酸组织蛋白酶的活性，选择性地针对其他巨噬细胞和免疫细胞（例如中性粒细胞、T 细胞、B 细胞）来靶向这些细胞。此外，我们证明组织蛋白酶激活的趋化因子与荧光和治疗货物兼容，为肿瘤微环境中免疫细胞的靶向治疗诊断探针的设计开辟了新途径。我们描述了第一个酶激活趋化因子缀合物，用于在癌症临床前模型中选择性靶向肿瘤相关巨噬细胞。我们证明这种新的化学设计与荧光和治疗有效负载兼容，为未来制备肿瘤微环境中免疫细胞的治疗诊断探针开辟了途径。
Increased levels of tumor‐associated macrophages (TAMs) are indicators of poor prognosis in most cancers. Although antibodies and small molecules blocking the recruitment of macrophages to tumors are under evaluation as anticancer therapies, these strategies are not specific for macrophage subpopulations. Herein we report the first enzyme‐activatable chemokine conjugates for effective targeting of defined macrophage subsets in live tumors. Our constructs exploit the high expression of chemokine receptors (e.g., CCR2) and the activity of cysteine cathepsins in TAMs to target these cells selectively over other macrophages and immune cells (e.g., neutrophils, T cells, B cells). Furthermore, we demonstrate that cathepsin‐activatable chemokines are compatible with both fluorescent and therapeutic cargos, opening new avenues in the design of targeted theranostic probes for immune cells in the tumor microenvironment. We describe the first enzyme‐activatable chemokine conjugates for selective targeting of tumor‐associated macrophages in preclinical models of cancer. We demonstrate that this new chemical design is compatible with both fluorescent and therapeutic payloads, opening avenues in the preparation of future theranostic probes for immune cells in the tumor microenvironment.
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影响因子：
3.8
作者：
Glass, Evan B.;Hoover, Alyssa A.;Bullock, Kennady K.;Madden, Matthew Z.;Reinfeld, Bradley, I;Harris, Whitney;Parker, Dominique;Hufnagel, Demetra H.;Crispens, Marta A.;Khabele, Dineo;Rathmell, W. Kimryn;Rathmell, Jeffrey C.;Wilson, Andrew J.;Giorgio, Todd D.;Yull, Fiona E.
通讯作者：
Yull, Fiona E.
影响因子：
2.4
作者：
Jeong, Hasong;Hwang, Ilseon;Kwon, Sun Young
通讯作者：
Kwon, Sun Young
影响因子：
64.8
作者：
DE SILVA, AP;GUNARATNE, HQN;MCCOY, CP
通讯作者：
MCCOY, CP
在转移性乳腺癌的小鼠模型中，单核细胞与转移相关巨噬细胞的免疫抑制前体分化。
影响因子：
7.3
作者：
Kitamura T;Doughty-Shenton D;Cassetta L;Fragkogianni S;Brownlie D;Kato Y;Carragher N;Pollard JW
通讯作者：
Pollard JW
影响因子：
5.2
作者：
Cendrowicz E;Sas Z;Bremer E;Rygiel TP
通讯作者：
Rygiel TP