Recyclable cell-surface chemical tags for repetitive cancer targeting
Recyclable cell-surface chemical tags for repetitive cancer targeting
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DOI：
10.1016/j.jconrel.2022.05.007
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发表时间：
2022-05-11
影响因子：
10.8
通讯作者：
Wang，Hua
中科院分区：
文献类型：
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作者：
Bhatta，Rimsha;Han，Joonsu;Wang，Hua
代谢聚糖标记提供了一种简单而强大的工具，通过非天然糖的代谢糖工程过程将化学标签安装到细胞膜上。然后，这些细胞表面化学标签可以通过有效的化学作用介导治疗剂的靶向缀合，这已经被广泛探索用于癌症靶向治疗。然而，常用的体内化学物质如叠氮化物-环辛炔和四嗪-环辛烯化学物质仅允许一次性使用细胞表面化学标签，这对长期、连续的细胞靶向提出了挑战。在这里，我们表明，细胞表面的酮基团可以回收到细胞膜后，与酰肼轴承分子共价结合，使重复靶向酰肼轴承剂。在通过pH响应性腙连接与酮标记的癌细胞缀合后，Alexa Fluor 488-酰肼变得内化并进入内体/溶酶体，其中酮-糖可以释放和再循环。然后，再循环的酮基团可以介导Alexa Fluor 647-酰肼的靶向缀合。我们还表明，阿霉素酰肼可以靶向酮标记的癌细胞，以增强癌细胞杀伤力。这项研究验证了细胞表面化学标签的可回收性，用于使用可逆化学重复靶向癌细胞，这将极大地促进基于代谢聚糖标记的有效癌症靶向治疗的未来发展。
Metabolic glycan labeling provides a facile yet powerful tool to install chemical tags to the cell membrane via metabolic glycoengineering processes of unnatural sugars. These cell-surface chemical tags can then mediate targeted conjugation of therapeutic agents via efficient chemistries, which has been extensively explored for cancer-targeted treatment. However, the commonly used in vivo chemistries such as azide-cyclooctyne and tetrazine-cyclooctene chemistries only allow for one-time use of cell-surface chemical tags, posing a challenge for long-term, continuous cell targeting. Here we show that cell-surface ketone groups can be recycled back to the cell membrane after covalent conjugation with hydrazide-bearing molecules, enabling repetitive targeting of hydrazide-bearing agents. Upon conjugation to ketone-labeled cancer cells via a pH-responsive hydrazone linkage, Alexa Fluor 488-hydrazide became internalized and entered endosomes/lysosomes where ketone-sugars can be released and recycled. The recycled ketone groups could then mediate targeted conjugation of Alexa Fluor 647-hydrazide. We also showed that doxorubicin-hydrazide can be targeted to ketone-labeled cancer cells for enhanced cancer cell killing. This study validates the recyclability of cell-surface chemical tags for repetitive targeting of cancer cells with the use of a reversible chemistry, which will greatly facilitate future development of potent cancer-targeted therapies based on metabolic glycan labeling.