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).

抽象的放射治疗是标准癌症治疗的一个重要组成部分，用于治疗一半以上的癌症虽然放射治疗的临床益处已得到充分证明，但对邻近和癌症患者的剂量。正常器官的相互交织和随后的毒性仍然是继续升级的最大障碍为了通过放射疗法治愈癌症而对肿瘤进行放射剂量的治疗将导致大量患者出现这种情况。放射治疗后局部持续/复发的肿瘤因此，放射增敏化合物、放射增敏剂、已开发出增强肿瘤杀伤效果而不增加辐射剂量的方法。由于侵入性或肿瘤递送不足以及缺乏特异性或系统性，临床应用受到限制该项目的目标是开发一种基于前药的治疗策略。我们在纤维素纳米组装中首创纳米技术，以放大和增强放射治疗功效与常见的基于纳米颗粒的递送方法不同，这种递送策略确实有效不依赖肿瘤增强的通透性和滞留效应，我们建议利用其内在的作用。通过靶向凋亡细胞的初始群体进行沉积，对放射治疗产生异质反应该项目将开发和表征新的放射增敏剂和增强放射治疗效果。用于靶向细胞凋亡的前药放射增敏剂（目标 1）；研究药代动力学、毒性并验证体内治疗机制（目标 2）；并制定图像引导治疗策略，然后制定综合评估原位前列腺癌小鼠模型的治疗效果（目标 3）。