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Targeting through Selective Cell Labeling

通过选择性细胞标记进行靶向

基本信息

批准号：
9761524
负责人：
Jianjun Cheng
金额：
$ 46.98万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761524
关键词：
Antibody-drug conjugates Antineoplastic Agents Azides Biologic Development Biological Biological Markers Biology Cancer Biology Canis familiaris Cathepsin L Cell surface Cells Chemicals Chemistry Chemotherapy-Oncologic Procedure Cisplatin Clinical Coupled Data Development Dose Doxorubicin Drug Delivery Systems Drug Targeting Engineering Epidermal Growth Factor Receptor Estrogen Receptors Histone Deacetylase Human Immune Immunotherapy In Vitro Label Lead Length Malignant Neoplasms Mannose Mediating Metabolic Metabolism Modeling Mus Nanoimmunotherapy OX40 Paclitaxel Pharmaceutical Preparations Phase Progesterone Receptors Property Safety Sialic Acids Structure Surface Surface Properties System Technology Testing Therapeutic Tissues Transforming Growth Factor alpha Transforming Growth Factor beta Receptors Treatment Efficacy Tumor Markers Work analog base cancer cell cancer immunotherapy cancer therapy chemotherapy clinical translation cyanine dye 5 density design functional group improved in vivo inhibitor/antagonist innovation nano nanomedicine nanoparticle nanoparticle drug nanotherapeutic new technology novel overexpression poly(lactide)polymerization side effect small molecule success sugar targeted agent targeted cancer therapy targeted treatment therapeutic nanoparticles triple-negative invasive breast carcinoma tumor

项目摘要

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.

生物靶向已经成为癌症治疗中的关键概念。尽管一些生物学的临床成功尽管存在着针对性系统，但仍然存在着重大挑战。例如，很少有肿瘤特异性生物标志物，以足够高的水平表达以用于靶向药物递送。许多癌症没有肿瘤特异性这些生物标志物适合于靶向。一个明确的例子是三阴性乳腺癌（TNBC），肿瘤其不过度表达雌激素受体、孕酮受体和人表皮生长因子受体 2.因此，非常需要开发能够广泛用于靶向的新技术，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）- 仅在癌细胞中有代谢活性但在非癌细胞/组织中无代谢活性的甘露糖类似物，并且此类叠氮基-甘露糖类似物的代谢导致癌细胞上N3基团的“过度表达表面作为内源性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癌症提供一种完全基于小分子的靶向技术，建立生物标志物。我们的目标是将这种新的癌症靶向技术应用于纳米医学并开发出一种有效的纳米治疗药物，用于靶向癌症化疗和免疫治疗，跨国公司。本项目要检验的关键假设是（1）在体外和体内癌症中是否有效靶向可以基于叠氮化物（一种合成的化学官能团）的内源性插入来实现，非天然生物标志物，随后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结合纳米医学可用于治疗通常不可靶向的癌症。