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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：
10207626
负责人：
Jeff W. Bulte
金额：
$ 51.64万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207626
关键词：
Affect Anti-Inflammatory Agents Antineoplastic Agents Arginine Aspirin Biodistribution Blood Caspase Cell division Cell membrane Cells Cellular Membrane Chemical Agents Chemicals Cleaved cell 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/antagonist 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.

我们的总体目标是开发一个基于精密的纳米治疗平台，其中成像信号可以作为细胞内纳米颗粒积累和治疗的早期预测成像生物标志物回复。新的抗癌药物不断被开发，但许多都因肿瘤的发展而失败（多）耐药性。已鉴定出充当药物流出泵的细胞膜蛋白，同时一些有前途的药物进入肿瘤细胞，但它们不能总是保留足够长的时间以发挥作用。我们的目标利用在前列腺癌细胞中过度表达的 Legumain 酶（一种天冬酰胺酰内肽酶）用于奥沙拉嗪 (Olsa) 缀合肽底物的特异性裂解，随后底物自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) 细胞内包埋，药物流出最少； 2）肿瘤药物暴露时间延长； 3) 毒性最小由于非组装单分子的快速血液清除而导致正常器官。我们有初步数据证明这个概念在体内是可行的。因为它不仅可以作为抗癌药物抑制 DNA 甲基化，还可作为非金属、无标记造影剂进行化学交换饱和转移磁共振成像（CEST MRI），奥沙拉嗪是一种独特的治疗诊断剂。这药物无需修改即可可视化，无需药理学改变即可直接成像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- 后 AAN 底物在过表达 legumain 的 DU145 细胞中具有最大的肿瘤细胞渗透和保留能力（目标 1），我们将在原位小鼠前列腺中测试该化合物的体内纳米治疗特性肿瘤模型（目标 2）和转基因小鼠模型（TRAMP 小鼠），其中正常前列腺细胞经历随着时间的推移发生恶性转变（目标 3）。如果成功的话，这种方法可能会扩展到其他酶靶向 CEST MRI 可检测治疗诊断平台，用于对肿瘤侵袭性、药物积累、并预测治疗反应。