Targeting through Selective Cell Labeling

生物靶向一直是癌症治疗的关键概念。尽管一些生物技术在临床上取得了成功 目标系统方面，仍然存在重大挑战。例如，很少有肿瘤特异性生物标志物 表达水平足够高以用于靶向药物递送。许多癌症没有肿瘤特异性 适合靶向的生物标志物。一个明确的例子是三阴性乳腺癌 (TNBC)、肿瘤 不过度表达雌激素受体、孕激素受体和人表皮生长因子受体 2. 因此，非常需要开发可广泛用于靶向治疗的新技术 癌症，特别是那些没有天然生物标志物的癌症。在这项研究中，我们的目标是开发叠氮基部分 (N3)- 甘露糖类似物仅在癌细胞中具有代谢活性，但在非癌细胞/组织中没有代谢活性， 此类叠氮甘露糖类似物的代谢导致N3基团在癌细胞上“过度表达” 表面作为内源插入的肿瘤生物标志物，用于体外和体内点击化学介导的靶向。 我们的工作将为许多不具备这种能力的癌症提供一种完全基于小分子的靶向技术。 已建立的生物标志物。我们的目标是将这种新的癌症靶向技术纳入纳米医学中 并开发有效的纳米疗法用于靶向癌症化疗和免疫疗法 TNBC。本项目要测试的关键假设是（1）在体外和体内癌症是否有效 可以基于叠氮化物（一种合成化学官能团）的内源插入来实现靶向，如 非天然生物标志物，其次是体外和体内共价点击化学，以及（2）这种新的生物标志物是否 靶向技术与纳米医学相结合可用于治疗通常不可靶向的癌症。

Biological targeting has been a key concept in cancer treatment. Despite the clinical success of some biological targeting systems, significant challenges still remain. For example, there are few tumor-specific biomarkers that are expressed at sufficient high level for targeted drug delivery. Many cancers do not have tumor-specific biomarkers that are amenable for targeting. One sure example is triple-negative breast cancers (TNBCs), tumors that do not overexpress estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2. Therefore, there is great need of developing new technology that can be broadly used in the targeting of cancers, in particular those without natural biomarkers. In this study, we aim to develop azido moiety (N3)- mannose analogues that are metabolically active only in cancer cells but are not in non-cancerous cells/tissues, and the metabolism of such azido-mannose analogues lead to “over-expression” of N3 group on cancer cell surfaces as endogenously inserted tumor biomarkers for in vitro and in vivo Click Chemistry mediated targeting. Our work will provide an entirely small-molecule-based targeting technology for many cancers that do not have established biomarkers. We aim to incorporate the use of this new cancer targeting technology in nanomedicine and develop an effective nanotherapeutics for targeted cancer chemotherapy and immunotherapy against TNBCs. The key hypotheses to be tested in this project are (1) whether effective in vitro and in vivo cancer targeting can be achieved based on endogenous insertion of azide, a synthetic chemical functional group, as the unnatural biomarker, followed by in vitro and in vivo covalent Click Chemistry and (2) whether this new targeting technology coupled with nanomedicine can be used to treat cancers that are typically non-targetable.