Overcoming Tumor Resistance with Enzyme-Instructed Nanoscale Assemblies and Immunotherapies

通过酶指导的纳米组装和免疫疗法克服肿瘤耐药性

• 批准号: 10091415
• 负责人: Zhaoqianqi Feng
• 金额: $ 8.85万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091415
• 关键词: Address; Antitumor Response; Biological Assay; Catalysis; Cell Death; Cells; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinic; Combined Modality Therapy; Confocal Microscopy; Down-Regulation; Drug resistance; Endoplasmic Reticulum; Enzymes; Exhibits; Failure; Goals; Immunofluorescence Immunologic; Immunotherapy; Laboratories; Lead; Malignant Neoplasms; Nanotechnology; Normal tissue morphology; Patients; Pharmaceutical Preparations; Phase; Prevention; Proteins; Relapse; Research; Research Project Grants; Resistance; Survival Rate; System; Techniques; Testing; Time; Treatment Failure; Western Blotting; acquired drug resistance; analog; anti-cancer; anticancer research; base; biomaterial compatibility; cancer cell; cancer drug resistance; cancer immunotherapy; chemical property; chemotherapy; design; drug development; endoplasmic reticulum stress; immune checkpoint blockade; improved; innovation; insight; loss of function; molecular targeted therapies; nanomedicine; nanoscale; novel therapeutics; physical property; post-doctoral training; prevent; public health relevance; resistance mechanism; response; self assembly; side effect; simulation; small molecule; spatiotemporal; success; time use; tumor; tumor immunology

Project Summary/Abstract Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The development of drug resistance could lead to chemotherapy failure and tumor relapse, resulting in reduced survival rates. In addition, despite the unprecedented success achieved in cancer immunotherapy over the past decades, the cancer-cell-intrinsic mechanisms of resistance result in low response rates of patients which remains a major challenge. Therefore, it is urgently necessary to develop novel therapy to address these problems. Recently, our laboratory, headed by my sponsor Dr. Bing Xu, developed anticancer nanomedicine based on enzyme-instructed self-assembly (EISA). The EISA is capable of selective inhibition of tumor without harming normal tissues due to its precise spatiotemporal control. Additionally, by targeting multiple targets, EISA hardly induces acquired drug resistance. Most importantly, combination therapy holds great promise for tumor prevention and treatment. The overall goal of this project is to overcome cancer drug resistance through the application of nanotechnology and combination with anticancer immunotherapy. To achieve this goal, we proposed two following specific aims: 1) During the F99 phase, I propose to develop anticancer nanomedicines based on EISA to target loss-of-function (downregulation) and endoplasmic reticulum (ER) in cancer cells for minimizing the drug resistance and side effect. We designed a two enzyme controlled assembly system to target the downregulation via the combination of enzyme-instructed assembly and disassembly and tested its anticancer efficacy and selectivity. We will also study the EISA in targeting ER for cancer inhibition. The ER targeting ability and dynamic distribution of the designed molecules will be tested. Moreover, we will elucidate the mechanisms of cancer cell death induced by ER targeting. 2) For the K00, the direction of my postdoctoral research will focus on improving the anti-tumor response of immunotherapy through the combination with EISA based nanomedicines. The proposed postdoctoral training will provide me with new insight and techniques in cancer immunology.

项目总结/摘要 对化疗和分子靶向治疗的耐药性是面临的主要问题 目前癌症研究。耐药性的发展可能导致化疗失败， 肿瘤复发，导致生存率降低。此外，尽管取得了前所未有的成功， 在过去的几十年里，癌症免疫疗法取得了巨大的进展，癌症细胞的内在机制， 耐药性导致患者应答率低，这仍然是一个主要挑战。因此有 迫切需要开发新的治疗方法来解决这些问题。最近，我们的实验室， 由我的赞助商徐兵博士领导，开发了基于酶指导的抗癌纳米医学。 自组装（EISA）。EISA能够选择性抑制肿瘤而不损害正常 由于其精确的时空控制。此外，通过瞄准多个目标，EISA几乎 诱导获得性耐药性。最重要的是，联合治疗对肿瘤有很大的希望， 预防和治疗。这个项目的总体目标是克服癌症耐药性 通过应用纳米技术并结合抗癌免疫疗法。实现 这一目标，我们提出了以下两个具体目标： 1)在F99阶段，我建议开发基于EISA的抗癌纳米药物， 靶向癌细胞中功能丧失（下调）和内质网（ER）， 耐药性和副作用。我们设计了一个双酶控制的组装系统， 通过酶指导的组装和拆卸的组合下调，并测试其 抗癌功效和选择性。我们还将研究EISA在靶向ER抑制癌症方面的作用。的 将测试所设计的分子的ER靶向能力和动态分布。而且我们 将阐明ER靶向诱导癌细胞死亡的机制。 2)对于K 00，我的博士后研究方向将集中在提高抗肿瘤 通过与基于EISA的纳米药物的组合，免疫治疗的反应。拟议 博士后培训将为我提供癌症免疫学方面的新见解和技术。