Targeting Protumoral Tumor-Associated Macrophages with Nanobody-Functionalized Nanogels through Strain Promoted Azide Alkyne Cycloaddition Ligation,Bioconjugate Chemistry

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Targeting Protumoral Tumor-Associated Macrophages with Nanobody-Functionalized Nanogels through Strain Promoted Azide Alkyne Cycloaddition Ligation
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2018-06-11 00:00:00 , DOI: 10.1021/acs.bioconjchem.8b00319
Lutz Nuhn _{1,

2,

3} , Evangelia Bolli _{4,

5} , Sam Massa _{4,

5} , Isabel Vandenberghe ₆ , Kiavash Movahedi _{4,

5} , Bart Devreese ₆ , Jo A. Van Ginderachter _{4,

5} , Bruno G. De Geest _{1,

2}

Affiliation

Tumor-associated macrophages (TAMs) with high expression levels of the Macrophage Mannose Receptor (MMR, CD206) exhibit a strong angiogenic and immune suppressive activity. Thus, they are a highly attractive target in cancer immunotherapy, with the aim to modulate their protumoral behavior. Here, we introduce polymer nanogels as potential drug nanocarriers which were site-specifically decorated with a Nanobody (Nb) specific for the MMR. Using azide-functionalized RAFT chain transfer agents, they provide access to amphiphilic reactive ester block copolymers that self-assemble into micelles and are afterwards core-cross-linked toward fully hydrophilic nanogels with terminal azide groups on their surface. MMR-targeting Nb can site-selectively be functionalized with one single cyclooctyne moiety by maleimide-cysteine chemistry under mildly reducing conditions which enables successful chemoorthogonal conjugation to the nanogels. The resulting Nb-functionalized nanogels were highly efficient in targeting MMR-expressing cells and TAMs both in vitro and in vivo. We believe that these findings pave the road for targeted eradication or modulation of pro-tumoral MMR^high TAMs.

中文翻译：

通过应变促进叠氮化物炔烃环加成连接靶向纳米肿瘤功能化纳米凝胶与肿瘤相关的巨噬细胞。

具有高表达水平的巨噬细胞甘露糖受体（MMR，CD206）的肿瘤相关巨噬细胞（TAMs）表现出很强的血管生成和免疫抑制活性。因此，它们是癌症免疫疗法中极具吸引力的靶标，目的在于调节其肿瘤行为。在这里，我们介绍了高分子纳米凝胶作为潜在的药物纳米载体，这些分子用针对MMR的纳米抗体（Nb）进行了位点修饰。通过使用叠氮化物官能化的RAFT链转移剂，它们可以进入两亲性反应性酯嵌段共聚物，该共聚物自组装成胶束，然后向其表面上带有末端叠氮化物基团的完全亲水的纳米凝胶进行核交联。靶向MMR的Nb可以在温和的还原条件下通过马来酰亚胺-半胱氨酸化学方法通过一个环辛炔基位点选择性地官能化，从而实现成功的化学正交结合至纳米凝胶。所得的Nb-官能化的纳米凝胶在体外和体内均可有效靶向表达MMR的细胞和TAM。我们相信，这些发现为有针对性地根除或调节肿瘤前MMR铺平了道路。^高TAM。

更新日期：2018-06-11

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