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Targeting apoptotic cells to enhance radiotherapy

靶向凋亡细胞以增强放射治疗

基本信息

批准号：
10538071
负责人：
Jianghong Rao
金额：
$ 57.42万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538071
关键词：
Address Advanced Malignant Neoplasm Apoptosis Apoptotic Biochemical Brachytherapy CASP3 gene Cancer Etiology Cancer Patient Cardiovascular Diseases Cells Cessation of life Clinical Combined Modality Therapy Deposition Development Disease Disease-Free Survival Distant Metastasis Dose Drug Kinetics Early treatment Elements Epithelial Cells External Beam Radiation Therapy Failure Feedback Fluorescence Follow-Up Studies Functional disorder Goals Heterogeneity Hydrolysis Iatrogenesis Image Imaging Techniques Impaired cognition In Vitro Intensity-Modulated Radiotherapy Investigation Low Dose Radiation Lymph Node Dissections Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Medical center Mental Depression Nanotechnology Organ Patients Pelvic lymph node group Penetration Permeability Pharmaceutical Preparations Phase I Clinical Trials Population Positron-Emission Tomography Prodrugs Property Prostate Prostate Cancer therapy Prostatic Neoplasms Quality of life Radiation Radiation Dose Unit Radiation Toxicity Radiation therapy Radiation-Sensitizing Agents Radical Prostatectomy Radio Radiosensitization Reactive Oxygen Species Recurrence Recurrent tumor Reporting Research Resistance development S-nitro-N-acetylpenicillamine Scheme Sexual Health Specificity Technology Testing Therapeutic Time Tissues Toxic effect Treatment Failure Treatment Protocols Treatment outcome United States affective disturbance androgen deprivation therapy base cancer care cancer cell cancer radiation therapy cancer therapy chemotherapy clinical application design diabetes risk drug release profile empowered health related quality of life high risk image guided image guided radiation therapy imaging facilities imaging probe improved in vivo in vivo evaluation irradiation men mouse model nanoassembly nanoparticle nanoparticle delivery neoplastic cell novel optimal treatments overtreatment partial response personalized intervention prostate cancer cell prostate cancer model radiation effect radiation response self assembly side effect small molecule systemic toxicity targeted treatment therapeutic evaluation treatment effect treatment response treatment strategy tumor tumor heterogeneity tumor xenograft

项目摘要

ABSTRACT Radiation therapy is a potent element of standard cancer care, used in the treatment of over half of all cancer patients. While the clinical benefits of radiotherapy are well documented, the dose to adjacent and intermeshed normal organs and subsequent toxicity remains the biggest obstacle to continued escalation of radiation doses to tumors in order to obtain cancer cures with RT. Significant number of patients will develop locally persistent/recurrent tumors after radiotherapy. Therefore, radiosensitizing compounds, radiosensitizers, have been developed to enhance tumor killing effects without escalation of radiation doses. However, their clinical applications are limited due to invasive or insufficient tumor delivery and lack of specificity or systemic toxicity. The goal of this project is to develop a prodrug-based therapeutic strategy empowered by a nanotechnology pioneered by us —in cellulo nanoassembly—to amplify and enhance radiotherapeutic efficacy for treating prostate cancer. Unlike common nanoparticle-based delivery approach, this delivery strategy does not rely on the tumor enhanced permeability and retention effect. We propose to take advantage of the intrinsic heterogeneous response to radiation therapy by targeting this initial population of apoptotic cells for depositing radiosensitizers and enhancing radiotherapeutic effects. The project will develop and characterize the new prodrug radiosensitizers for targeting apoptosis (Aim 1); investigate the pharmacokinetics, toxicity and validate the in vivo treatment mechanism (Aim 2); and develop an image-guided treatment strategy, followed by a comprehensive evaluation of the therapeutic benefit in orthotopic prostate cancer mouse models (Aim 3).

摘要放射治疗是标准癌症护理的一个有效元素，用于治疗超过一半的癌症。癌症患者。虽然放射治疗的临床益处已被充分证明，但邻近和邻近组织的剂量相互交织的正常器官和随后的毒性仍然是继续升级的最大障碍，放射剂量的肿瘤，以获得癌症治愈与RT。显着数量的患者将发展放疗后局部持续/复发肿瘤。因此，放射增敏化合物，放射增敏剂，已经被开发用于增强肿瘤杀伤效果而不增加辐射剂量。但他们的由于侵入性的或不充分的肿瘤递送以及缺乏特异性或全身性的毒性该项目的目标是开发一种基于前药的治疗策略，我们率先采用纳米技术--在细胞内进行纳米组装--以放大和增强辐射功效用于治疗前列腺癌。与常见的基于纳米颗粒的递送方法不同，这种递送策略确实不依赖于肿瘤的增强渗透和滞留作用。我们建议利用内在的通过靶向该凋亡细胞的初始群体以沉积对放射疗法的异质性反应，放射增敏剂和增强放射性效果。该项目将开发和表征新的靶向细胞凋亡的前体放射增敏剂（目的1）;研究其药代动力学、毒性和验证体内治疗机制（目标2）;并制定图像引导治疗策略，然后进行在原位前列腺癌小鼠模型中的治疗益处的综合评价（目的3）。