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：
10708827
负责人：
Jianghong Rao
金额：
$ 55.95万
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/10708827
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 Dose Limiting 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 Scheme Sexual Health Specificity Technology Testing Therapeutic Time Tissues Toxic effect Treatment Failure Treatment Protocols Treatment outcome United States affective disturbance androgen deprivation therapy cancer care cancer cell cancer radiation therapy cancer therapy chemotherapy clinical application design diabetes risk drug release profile empowerment 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 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).

抽象的放射疗法是标准癌症护理的潜在元素，用于治疗超过一半癌症患者。虽然放疗的临床益处有充分的文献证明，但剂量均为相邻的剂量相互融合的正常器官和随后的毒性仍然是继续升级的最大障碍辐射剂量为肿瘤以获得RT的癌症治疗。大量患者会发展放疗后局部持续/复发性肿瘤。因此，放射敏化合物，放射增敏剂，已经开发出来增强肿瘤杀伤作用而不会升级辐射剂量。但是，他们临床应用受到侵入性或不足的肿瘤递送以及缺乏特异性或全身性的限制毒性。该项目的目的是制定一种基于前药的理论策略，由纳米技术由我们（在纤维素纳米组装中）启用，以扩大和增强放射治疗效率治疗前列腺癌。与普通纳米颗粒的交付方法不同，这种交付策略确实不依赖肿瘤增强的渗透性和保留效果。我们建议利用固有的通过靶向凋亡细胞的初始种群来沉积，对放射治疗的异质反应放射敏剂并增强放射治疗效应。该项目将开发并描述新的用于靶向细胞凋亡的前药辐射增敏剂（AIM 1）；研究药代动力学，毒性和验证体内治疗机制（AIM 2）；并制定图像引导的治疗策略，然后对原位前列腺癌小鼠模型中治疗益处的全面评估（AIM 3）。