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

• 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
• 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

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种基于精确的纳米治疗诊断平台，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性成像生物标志物 反应新的抗癌药物继续开发，但许多失败，由于肿瘤的发展（多） 耐药性细胞膜蛋白作为药物外排泵已被确定，而 一些有希望的药剂进入肿瘤细胞后，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豆荚蛋白酶（一种天冬酰胺酰内肽酶） 用于特异性切割奥沙拉嗪（Olsa）缀合的肽底物，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： 具有最小药物流出的细胞内包埋; 2）延长的肿瘤药物暴露;和3）对 由于非组装单分子的快速血液清除，正常器官。我们有初步数据 证明了该概念在体内是可行的。由于它不仅通过以下途径作为抗癌药物 抑制DNA甲基化，也可作为非金属、无标记的化学交换造影剂 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。的 药物可以可视化而无需修改，允许直接成像而无需药理学改变， 可能影响自组装和/或生物分布。在体外选择最佳的Olsa-CBT-800 CW-Rn-1后， AAN底物在豆类蛋白过表达的DU 145细胞中具有最大的肿瘤细胞渗透和保留 (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治疗诊断特性 肿瘤模型（Aim 2）和转基因小鼠模型（TRAMP小鼠），其中正常前列腺细胞经历了 随着时间的推移发生恶性转化（目标3）。如果成功，这种方法可以扩展到其他酶- 靶向CEST MRI可检测的治疗诊断平台，用于成像肿瘤侵袭性，药物积聚， 和预测治疗反应。