Herein, we developed nano-sized metabolic precursors (Nano-MPs) for new tumor-targeting strategy to overcome the intrinsic limitations of biological ligands such as the limited number of biological receptors and the heterogeneity in tumor tissues. We conjugated the azide group-containing metabolic precursors, triacetylated N-azidoacetyl-d-mannosamine to generation 4 poly(amidoamine) dendrimer backbone. The nano-sized dendrimer of Nano-MPs could generate azide groups on the surface of tumor cells homogeneously regardless of cell types via metabolic glycoengineering. Importantly, these exogenously generated ‘artificial chemical receptors’ containing azide groups could be used for bioorthogonal click chemistry, regardless of phenotypes of different tumor cells. Furthermore, in tumor-bearing mice models, Nano-MPs could be mainly localized at the target tumor tissues by the enhanced permeation and retention (EPR) effect, and they successfully generated azide groups on tumor cells in vivo after an intravenous injection. Finally, we showed that these azide groups on tumor tissues could be used as ‘artificial chemical receptors’ that were conjugated to bioorthogonal chemical group-containing liposomes via in vivo click chemistry in heterogeneous tumor-bearing mice. Therefore, overall results demonstrated that our nano-sized metabolic precursors could be extensively applied to new alternative tumor-targeting technique for molecular imaging and drug delivery system, regardless of the phenotype of heterogeneous tumor cells.

中文翻译：

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使用体内生物正交点击化学的纳米级代谢前体，用于异质性肿瘤靶向策略

在这里，我们开发了纳米尺寸的代谢前体（Nano-MPs）用于新的肿瘤靶向策略，以克服生物配体的固有局限性，例如有限的生物受体数量和肿瘤组织中的异质性。我们共轭叠氮代谢前体基团的，三乙酰Ñ -azidoacetyl- d-甘露糖胺生成第4代聚（酰胺基胺）树状聚合物骨架。纳米MPs的纳米树枝状大分子可以通过代谢糖工程技术在肿瘤细胞表面均匀地生成叠氮基团，而与细胞类型无关。重要的是，这些包含叠氮化物基团的外源生成的“人工化学受体”可用于生物正交点击化学，而不管不同肿瘤细胞的表型如何。此外，在荷瘤小鼠模型中，纳米MPs可能主要通过增强的渗透和保留（EPR）效应定位在靶肿瘤组织上，并在体内成功地在肿瘤细胞上生成了叠氮基团。静脉注射后。最后，我们证明了这些肿瘤组织上的叠氮化物基团可以用作“人工化学受体”，通过异质性荷瘤小鼠体内的点击化学作用与包含生物正交化学基团的脂质体偶联。因此，总体结果表明，无论异质肿瘤细胞的表型如何，我们的纳米级代谢前体均可广泛应用于分子成像和药物输送系统的新型替代肿瘤靶向技术。