Intracellular Self-Assembly of Theranostic Nanoparticles for Enhanced Imaging and Tumor Therapy

用于增强成像和肿瘤治疗的治疗诊断纳米颗粒的细胞内自组装

基本信息

批准号：
10400220
负责人：
Jeff W. Bulte
金额：
$ 52.69万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2020-07-10 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10400220
关键词：
Affect Anti-Inflammatory Agents Antineoplastic Agents Arginine Aspirin Biodistribution Blood Caspase Cell division Cell membrane Cells Cellular Membrane Chemical Agents Chemicals Colon Carcinoma Contrast Media DNA Methylation DNA Methylation Inhibition DU145 Data Detection Drug Efflux Drug Exposure Enzymes FDA approved Failure Formulation Glutathione Goals Hour Human Hydroxyl Radical Image Image Enhancement In Vitro Injectable Intravenous Kidney LNCaP Label Length Liver MRI Scans Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Mediating Membrane Proteins Modeling Modification Multi-Drug Resistance Mus Nanostructures Near-infrared optical imaging Optics Organ Penetration Peptides Permeability Pharmaceutical Preparations Pharmacology Physical condensation Prediction of Response to Therapy Property Proprotein Convertases Prostate Prostate Cancer therapy Protons Reaction Salicylic Acids Signal Transduction Spleen Testing Therapeutic Time Toxic effect Transgenic Mice Treatment Efficacy Validation Xenograft Model asparaginylendopeptidase base biomaterial compatibility cancer cell cancer imaging chemical reaction clinical translation clinically relevant contrast enhanced efflux pump imaging biomarker imaging platform in vivo inhibitor mouse model nanoparticle nanotheranostics near infrared dye neoplastic cell novel novel anticancer drug overexpression prognostic prostate cancer cell prostate cancer cell line prostate cancer model protein aminoacid sequence self assembly single molecule small molecule subcutaneous success theranostics transgenic adenocarcinoma of mouse prostate treatment response tumor tumor growth uptake

项目摘要

Our overall aim is to develop a precision-based nanotheranostic platform where the imaging signal may serve as an early predictive imaging biomarker for intracellular nanoparticle accumulation and therapeutic response. New anti-cancer agents continue to be developed, but many fail due to the tumor developing (multi-) drug resistance. Cellular membrane proteins acting as a drug efflux pump have been identified, and while some promising agents enter tumor cells, they cannot always be retained long enough to be effective. We aim to exploit the enzyme legumain (an asparaginyl endopeptidase) that is overexpressed in prostate cancer cells for specific cleavage of an olsalazine (Olsa)-conjugated peptide substrate, following which the substrate self- assembles into intracellular nanoparticles. This enzyme-driven self-assembly serves several purposes: 1) intracellular entrapment with minimal drug efflux; 2) prolonged tumor drug exposure; and 3) minimal toxicity to normal organs due to rapid blood clearance of non-assembled single molecules. We have preliminary data demonstrating this concept to be feasible in vivo. Since it does not only serve as an anti-cancer drug through inhibition of DNA methylation, but also as a non-metallic, label-free contrast agent for chemical exchange saturation transfer magnetic resonance imaging (CEST MRI), olsalazine is a unique theranostic agent. The drug can be visualized without modification, allowing direct imaging without pharmacological alterations that may affect self-assembly and/or biodistribution. Following in vitro selection of an optimal Olsa-CBT-800CW-Rn- AAN substrate with maximum tumor cell penetration and retention in legumain-overexpressing DU145 cells (Aim 1), we will test this compound for its in vivo nanotheranostic properties in an orthotopic mouse prostate tumor model (Aim 2) and a transgenic mouse model (TRAMP mouse) where normal prostate cells undergo a malignant transformation over time (Aim 3). If successful, this approach may be extended to other enzyme- targeted CEST MRI-detectable theranostic platforms for imaging tumor aggressiveness, drug accumulation, and predicting therapeutic response.

我们的总体目的是开发一个基于精确的纳米骨抑制平台，其中成像信号可能用作早期预测成像生物标志物，用于细胞内纳米颗粒积累和治疗回复。新的抗癌剂继续开发，但是由于肿瘤发展（多）而失败耐药性。已经鉴定出充当药物外泵的细胞膜蛋白，而一些有前途的药物进入肿瘤细胞，不能总是保留足够长的时间以至于有效。我们的目标利用在前列腺癌细胞中过表达的酶（一种天冬酰胺内肽酶）为了特异性裂解（OLSA）（OLSA）偶联的肽底物，然后底物自我自我组装成细胞内纳米颗粒。这种酶驱动的自组装有几个目的：1）细胞内捕集，最少的药物外排； 2）长时间的肿瘤药物暴露； 3）最小的毒性由于非组装单分子的快速血液清除而引起的正常器官。我们有初步数据证明这个概念在体内是可行的。由于它不仅可以通过抑制DNA甲基化，但也是非金属的无标签对比剂的化学交换药物饱和转移磁共振成像（CEST MRI），Olsalazine是一种独特的疗法剂。这可以在没有修改的情况下可视化药物，从而可以直接成像，而无需进行药理学改变可能会影响自组装和/或生物分布。在体外选择最佳OLSA-CBT-800CW-RN- AAN底物具有最大肿瘤细胞渗透和在过表达的DU145细胞中的保留率（AIM 1），我们将在原位小鼠前列腺中测试该化合物的体内纳米固醇特性肿瘤模型（AIM 2）和转基因小鼠模型（流浪小鼠）在正常的前列腺中经历A 随着时间的推移，恶性转变（AIM 3）。如果成功，则可以将这种方法扩展到其他酶 - 有针对性的CEST MRI可检测疗法平台，用于成像肿瘤侵袭性，药物积累，并预测治疗反应。