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: 10307535
• 负责人: Zhaoqianqi Feng
• 金额: $ 9.29万
• 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/10307535
• 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/文摘