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PSMA-targeted AuNPs for MR guided radiotherapy and radiosensitization

用于 MR 引导放疗和放射增敏的 PSMA 靶向 AuNP

基本信息

批准号：
10576915
负责人：
BULENT AYDOGAN
金额：
$ 65.17万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576915
关键词：
Ablation Address Affinity Anatomy Antigen Targeting Biodistribution Biological Calibration Cancer Patient Cancerous Cells Chicago Clinical Complex Conformal Radiotherapy Contrast Media Contrast Sensitivity DNA strand break Dedications Development Devices Diagnosis Diagnostic Imaging Discrimination Disease Dose Dose Limiting Drug Delivery Systems Electrons Excision FOLH1 gene Gadolinium Goals Gold Histologic Implant Impotence In Vitro Incontinence Individual Intensity-Modulated Radiotherapy Investigation Ligands Low Dose Radiation Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Methods Mus Muscle Muscle Cells Muscle Fibers Nerve Nerve Fibers Neurons Normal Cell Normal tissue morphology Nude Mice Operative Surgical Procedures Organ Patient observation Patients Positioning Attribute Prostate Prostate Ablation Prostate Cancer therapy Prostatectomy Prostatic Neoplasms Qualifying Radiation Radiation Dose Unit Radiation therapy Radiation-Sensitizing Agents Radical Prostatectomy Radiosensitization Recurrence Research Screening for Prostate Cancer Serum Solid Neoplasm Structure Surface Technology Testing Tissues Toxic effect Tumor Burden United States Visualization cancer cell cancer diagnosis clinical investigation clinical translation combat contrast enhanced contrast imaging design experience image guided image guided radiation therapy improved in vivo irradiation men mitochondrial dysfunction mortality nano nanoGold nanocluster nanoparticle neoplastic cell neovasculature next generation novel off-target site particle pre-clinical prostate cancer cell prostate cancer cell line prostate cancer model radiation effect response side effect soft tissue success targeted imaging theranostics therapeutic evaluation therapy development therapy outcome tumor tumor growth tumor progression uptake x-ray irradiation

项目摘要

Clinical radiation therapy is a noninvasive means to mitigate cancer progression, which is prescribed for more than 50% of prostate cancer patients. Development of radiation technology, such as utilizing intensity- modulated radiotherapy (IMRT) to deliver highly conformal radiation dose distributions and image-guided radiotherapy (IGRT) to account for daily changes in target anatomy and positioning, allows unprecedented levels of accuracy and therapy outcome. The prostate is surrounded by many nerves and muscle fibers controlling different excretory and erectile functions that are difficult but necessary to avoid, it still remains a challenge to precisely deliver radiation doses to prostate cancer without damaging the normal surrounding tissues even with image guidance. To avoid excessive irradiation doses, radiosensitizers have been developed to amplify the effects of radiation within tumor cells. Prostate cancer targeted radiosensitizers may offer a means for further relative biological dose escalation with sparing of normal tissue. However, there has been limited preclinical and clinical investigation of targeted radiosensitizers for prostate cancer. To address the challenge, we aim to develop a nanoparticle technology that will improve prostate cancer tissue visualization and discrimination by MRI, allowing greater accuracy in MRI-guided radiation therapy, and provide radiosensitization within the cancer cells. Prostate specific membrane antigen (PSMA) is an ideal target to detect prostate cancer due to its abundant expression in most prostate cancers. We have synthesized a novel high-affinity ligand for PSMA targeting, and conjugated both targeting ligand and Gd(III) complex to gold nanoparticles and nanoclusters (AuNP/NCs). We have demonstrated that these PSMA-targeted AuNP/NC-Gd(III) have a much higher relaxivity than free Gd(III) agents and the NP/NCs can be selectively delivered to PSMA-expressing prostate tumor cells, providing MR image-guided radiation therapy. By delivering Gd(III) conjugated AuNP/NCs directly to prostate cancer cells we will 1) concentrate the Gd(III) agent to the nanoparticle surface while simultaneously calibrating the delivery of more Gd(III) agent to target tissues and less of the agent to non-specific or off-target sites; 2) improve r1 relaxivity and MR sensitivity, which potentially can reduce the given doses to patients and potentially toxicity of Gd(III) agents; 3) discriminate among cancerous, normal, neural, and muscle cells and tissues with MRI, enabling precise diagnosis of prostate cancer and precision radiation therapy; 4) combine gold and gadolinium together to enhance the radiosensitizing effect for potential ablation of prostate cancer using a lower radiation dose; and 5) enable MRI-guided radiotherapy using MRI LINAC device to enhance radiation accuracy and avoid collateral damage to normal tissues. We believe that this approach will impact the quality and success of radiotherapy. Further, PSMA is also expressed on the neovasculature of a number of different solid tumors, so this approach is proof-of-principal for radiation therapy and ablation for other cancers as well.

临床放射治疗是一种非侵入性的手段，以减轻癌症的进展，这是处方药