Targeting through Selective Cell Labeling

生物靶向一直是癌症治疗中的一个关键概念。尽管一些生物学的临床上取得了成功 在瞄准系统方面，仍然存在重大挑战。例如，很少有肿瘤特异性生物标记物 以足够高的水平表达，可用于靶向药物输送。许多癌症没有肿瘤特异性 可用于靶向的生物标记物。一个明确的例子是三阴性乳腺癌(TNBCs)，即肿瘤 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，迫切需要开发能够广泛应用于靶标的新技术 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部分(N3)- 仅在癌细胞中代谢活跃但在非癌细胞/组织中不活跃的甘露糖类似物， 这些叠氮甘露糖类似物的代谢导致N3基团在癌细胞上的过度表达 作为体内和体外点击化学介导靶向的内源性插入肿瘤生物标记物的表面。 我们的工作将为许多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应用到纳米医学中 并开发一种有效的纳米疗法，用于靶向癌症化疗和免疫治疗 TNBCS。在这个项目中要检验的关键假设是(1)在体外和体内癌症是否有效 可以基于合成化学官能团叠氮化物的内源插入来实现靶向，例如 非天然生物标志物，其次是体外和体内共价点击化学和(2)这一新的 靶向技术与纳米药物相结合，可以用于治疗通常非靶向的癌症。

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.