SBIR Phase I: Targeted Small Molecular Taxane Delivery for Triple Negative Breast Cancer Treatment

该SBIR I期项目旨在开发一种新型癌症靶向技术，即通过锚定点击化学（ATTACK）进行主动组织靶向，用于三阴性乳腺癌（TNBC）的靶向治疗。TNBC是乳腺癌的一种亚型，发生在10-20%的诊断乳腺癌中，更有可能影响年轻人，非洲裔美国人，西班牙裔和BRCA 1基因突变的人。目前，TNBC患者主要用化疗药物治疗，并且由于缺乏雌激素受体（ER）、孕酮受体（PR）或激素表皮生长因子受体2（Her 2/neu）而不能从现有的靶向治疗中获益。该项目将开发第一个基于细胞标记的靶向技术（ATTACK）用于TNBC治疗。将开发一种新的非天然糖，用于通过代谢将人工受体插入TNBC上，然后靶向人工受体，通过受体与紫杉烷类药物之间的特异性反应来递送治疗性紫杉烷类药物，从而对TNBC进行癌症特异性标记。该项目涉及化学，生物学，材料工程和制药科学的跨学科知识组合。该项目的成功开发将为未来TNBC患者提供有效的靶向治疗药物，改善患者的生活质量。SBIR I期项目旨在开发一种新型的癌症靶向技术，即通过锚定点击化学的主动组织靶向（ATTACK），用于靶向治疗三阴性乳腺癌（TNBC）。ATTACK可以通过从头设计的非天然糖的癌症特异性人工受体插入和随后的叠氮化物点击反应介导的治疗药物的靶向递送来治疗没有建立细胞表面受体的非靶向癌症。目前，TNBC患者主要用化疗药物治疗，并且由于缺乏雌激素受体（ER）、孕酮受体（PR）或激素表皮生长因子受体2（Her 2/neu）而不能从现有的靶向治疗中获益。该项目将开发第一个基于细胞标记的靶向技术（ATTACK）用于TNBC治疗。非天然唾液酸（一种糖）前体与叠氮化物将首先用于肿瘤特异性标记细胞表面和随后的靶向。将合成多种紫杉烷候选物，并将研究缀合物的初步体外DMPK性质，包括溶解度、血浆稳定性、肝微粒体代谢和细胞毒性MTT测定。还将在小鼠肿瘤模型中研究紫杉烷候选物与非天然糖标记组合的体内生物分布和功效，以验证药物候选物的抗TNBC功效。第一阶段研究的完成将使新型癌症靶向疗法的进一步转化发展成为临床应用。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This SBIR Phase I project proposes to develop a novel cancer targeting technology, Active Tissue Targeting via Anchored ClicK Chemistry (ATTACK), for targeted treatment of triple negative breast cancer (TNBC). TNBC is a subtype of breast cancer that occurs in 10-20% of diagnosed breast cancers and is more likely to affect younger people, African Americans, Hispanics, and those with BRCA1 gene mutation. Currently, TNBC patients are mainly treated with chemotherapeutics and cannot benefit from existing targeting therapeutics due to the lack of Estrogen receptor (ER), progesterone receptor (PR) or hormone epidermal growth factor receptor 2 (Her2/neu). This project will develop the first cell labeling based targeting technology (ATTACK) for TNBC treatment. A novel unnatural sugar will be developed for cancer-specific labeling of TNBC through metabolization to insert an artificial receptor onto TNBC and then target the artificial receptor to deliver therapeutic taxanes through a specific reaction between the receptor and the taxanes-drugs. The project involves interdisciplinary combination of knowledge from chemistry, biology, materials engineering, and pharmaceutical science. The successful development of the project will afford an effective targeted therapeutic drug for TNBC patients with improved quality of life in the future.This SBIR Phase I project proposes to develop a novel cancer targeting technology, Active Tissue Targeting via Anchored ClicK Chemistry (ATTACK), for targeted treatment of triple negative breast cancer (TNBC). ATTACK can treat untargetable cancers that do not have established cell surface receptors through cancer-specific artificial receptor insertion of de novo designed unnatural sugars and subsequent azide-Click reaction mediated targeted delivery of therapeutic drugs. Currently, TNBC patients are mainly treated with chemotherapeutics and cannot benefit from existing targeting therapeutics due to the lack of Estrogen receptor (ER), progesterone receptor (PR) or hormone epidermal growth factor receptor 2 (Her2/neu). This project will develop the first cell labeling based targeting technology (ATTACK) for TNBC treatment. Unnatural sialic acid (a type of sugar) precursors with azide will be first used for tumor-specific labeling on cell surface and subsequent targeting. Multiple taxane candidates will be synthesized and preliminary in vitro DMPK properties of the conjugates will be studied including solubility, plasma stability, liver microsome metabolization, and cytotoxic MTT assay. In vivo biodistribution and efficacy of the taxane candidates in combination with unnatural sugar labeling will also be studied in mice tumor models to validate the anti-TNBC efficacy of the drug candidates. The accomplishment of the Phase I research will enable further translational development of the novel cancer-targeting therapeutics into clinical applications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.