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In situ cancer cell specific synthesis of gold nanoclusters for radiosensitization of pancreatic cancer

原位癌细胞特异性合成金纳米簇用于胰腺癌放射增敏

基本信息

批准号：
10039805
负责人：
Sunil Krishnan
金额：
$ 42.54万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10039805
关键词：
Acids Address Affect Aftercare Biodistribution Biological Buffers Bypass Cancerous Carcinoma in Situ Cell Nucleus Cells Cellular biology Clinical Clinical Data Collagen Complex Data Desmoplastic Development Diffuse Diffusion Dose Drug Delivery Systems Electrons Environment Exhibits Glycosaminoglycans Gold Hafnium Human In Situ In Vitro Incidence Ions Kinetics Literature Malignant Neoplasms Malignant neoplasm of pancreas Mammalian Cell Modeling Modernization Mucous Membrane Mus Natural regeneration Normal Cell Nuclear Organ Pancreas Patients Physiological Probability Proteoglycan Radiation Radiation Dose Unit Radiation Interaction Radiation Tolerance Radiation therapy Radiosensitization Recording of previous events Reporting Salts Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Traction Treatment outcome Unresectable Xenograft procedure advanced pancreatic cancer aqueous base cancer cell cancer radiation therapy clinical implementation clinical practice clinical translation cytotoxic gastrointestinal improved in vivo innovation insight interstitial irradiation mortality mouse model nanoGold nanocluster nanomaterials nanoparticle neoplastic cell novel strategies pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm radiation resistance radioresistant therapy outcome therapy resistant tumor uptake

项目摘要

Abstract. Pancreatic cancer is one of the most aggressive human malignancies, with a yearly incidence that equals its mortality. Radiation therapy (RT) is an integral component of modern therapy for locally advanced unresectable pancreatic cancers. However, its ultimate utility is severely limited by the fact that some cancer cells are resistant to RT. This problem is further amplified by the presence of gastrointestinal mucosa immediately adjacent to the tumor that makes dose escalation difficult and often not readily achievable. A novel approach to enhancing the radiation dose delivered to tumors is by transiently increasing the radiation-interaction probability of the target tissues using high atomic number (Z) nanomaterials. However, pancreatic cancer is characterized by hypovascularity in the setting of a dense stromal component that serves as a formidable physiological barrier to the delivery of drugs and nanoparticles. Therapeutic strategies, which can bypass the desmoplasia `fortress' and apply therapy without significantly affecting healthy cells and tissues would address the critical issues inherently presented by the pancreatic cancer. Here we propose to solve this delivery challenge by a paradigm shift from delivery of pre-made high-Z nanoparticles to an atomic size gold precursors (i.e., gold ions) for tumor radiosensitization thus achieving the ultimate reduction in size of a therapeutic agent – an atomic scale. Our hypothesis is that small gold ions (i) will uniformly distribute throughout the tumor as their diffusion is not likely to be impeded by the stroma, and (ii) will be reduced to gold nanoparticles (GNPs) by cancer cells that (iii) will result in cancer cell radiosensitization to RT. This hypothesis is based on our compelling preliminary data demonstrating efficient synthesis of GNPs from gold ions inside pancreatic cancer cells but not normal cells. Further, the biosynthesized GNPs exhibited a high nuclear localization that is critical for efficient radiosensitization due to a higher dose delivery to nuclei by the secondary Auger electrons. In addition, a number of recent reports demonstrated intracellular synthesis of GNPs from chloroauric acid by mammalian cells with a preferential nuclear localization of the nanoparticles further supporting our hypothesis. Interestingly, this phenomenon has not been previously considered for applications in radiotherapy. We see it as a highly innovative and exciting opportunity to greatly improve radiosensitization efficiency of cancer cells in situ. We envision clinical implementation of our approach as an added boost to significantly increase efficacy of stereotactic body radiotherapy in patients with a pancreatic tumor. Recent clinical data from our group and others shows that radiation dose enhancement increases overall survival of locally advanced pancreatic cancer patients. However, the proximity of gastrointestinal mucosa to the tumor in many instances precludes this dose escalation in clinical practice. We expect that changing the current paradigm from delivery of pre-made GNPs to in situ synthesis of GNPs by cancer cells will overcame delivery barriers in pancreatic tumors and will result in a highly significant sensitization of pancreatic cancer cells to RT that can greatly improve treatment outcomes.

摘要。胰腺癌是最具侵袭性的人类恶性肿瘤之一，年发病率为