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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.

抽象的。胰腺癌是人类最具侵袭性的恶性肿瘤之一，每年的发病率等于它的死亡率。放射治疗(RT)是局部晚期肿瘤现代治疗的重要组成部分无法切除的胰腺癌。然而，它的最终用途受到严重限制，因为一些癌症细胞对RT有抵抗力。胃肠道粘膜的出现会进一步加剧这个问题。与肿瘤相邻，使剂量增加困难，而且往往不容易实现。一种新的方法来增加对肿瘤的辐射剂量是通过瞬时增加辐射相互作用几率来实现的使用高原子序数(Z)纳米材料的靶组织。然而，胰腺癌的特点是由于作为强大的生理屏障的致密间质成分的设置中的血管减少药物和纳米颗粒的输送。治疗策略，可以绕过促结缔组织增生症的“堡垒” 在不显著影响健康细胞和组织的情况下应用治疗将解决关键问题先天表现为胰腺癌。在这里，我们建议通过一个范例来解决这个交付挑战从预制的高Z纳米颗粒向原子尺寸的肿瘤金前驱体(即金离子)的转移放射增敏因此实现了治疗剂尺寸的最终缩小--原子尺度。我们的假设小金离子(I)将均匀地分布在整个肿瘤中，因为它们不太可能扩散。被基质阻碍，以及(Ii)将被癌细胞还原为金纳米颗粒(GNPs)，(Iii)将导致癌细胞对RT的放射增敏。这一假设是基于我们令人信服的初步数据展示了从胰腺癌细胞内的金离子有效地合成GNPs，但不是正常细胞。此外，生物合成的GNPs表现出高度的核定位，这对效率至关重要二次俄歇电子向原子核输送较高剂量所致的放射增敏作用。此外，还有一些数字最近的报道表明，由氯金酸合成GNPs的哺乳动物细胞具有纳米粒子的优先核定位进一步支持了我们的假设。有趣的是，这这一现象以前并未被考虑应用于放射治疗。我们认为这是一个高度的创新和令人兴奋的机会，极大地提高原位癌细胞的放射增敏效率。我们设想我们的方法在临床上的实施将进一步促进显著提高患者的疗效胰腺肿瘤患者的立体定向体部放疗。来自我们小组和其他人的最新临床数据显示放射剂量增强可提高局部晚期胰腺癌的总体存活率病人。然而，在许多情况下，胃肠道粘膜靠近肿瘤，因此不能使用这种剂量。在临床实践中逐步升级。我们预计，改变目前的模式，从交付预制的GNPs到癌细胞原位合成GNPs将克服胰腺肿瘤的传递障碍，并将导致胰腺癌细胞对RT的高度敏感化可以极大地改善治疗结果。