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: 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
• 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

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。

项目成果

In Vivo MRI Tracking of Tumor Vaccination and Antigen Presentation by Dendritic Cells.

肿瘤疫苗接种和树突状细胞抗原呈递的体内 MRI 跟踪。

• 发表时间: 2022-04
• 影响因子: 3.1
• 作者: Bulte, Jeff W M;Shakeri
• 通讯作者: Shakeri

In Vivo Cellular Magnetic Imaging: Labeled vs. Unlabeled Cells.

体内细胞磁成像：标记细胞与未标记细胞。

• 发表时间: 2022-12-09
• 影响因子: 19
• 作者: Bulte, Jeff W M;Wang, Chao;Shakeri
• 通讯作者: Shakeri

Cell-Penetrating and Enzyme-Responsive Peptides for Targeted Cancer Therapy: Role of Arginine Residue Length on Cell Penetration and In Vivo Systemic Toxicity.

用于靶向癌症治疗的细胞穿透和酶响应肽：精氨酸残基长度对细胞穿透和体内全身毒性的作用。

• DOI: 10.1021/acsami.3c14908
• 发表时间: 2024-02-22
• 期刊: ACS applied materials & interfaces
• 影响因子: 9.5
• 作者: Behnaz Ghaemi;Swati Tanwar;Aruna Singh;D. R. Arifin;Michael T McMahon;Ishan Barman;Jeff W M Bulte
• 通讯作者: Jeff W M Bulte

Tumor-tropic Trojan horses: Using mesenchymal stem cells as cellular nanotheranostics.

肿瘤特洛伊木马：使用间充质干细胞作为细胞纳米治疗。

• 发表时间: 2024
• 影响因子: 12.4
• 作者: Rosu, Ana;Ghaemi, Behnaz;Bulte, Jeff W M;Shakeri
• 通讯作者: Shakeri

Enzyme-mediated intratumoral self-assembly of nanotheranostics for enhanced imaging and tumor therapy.

酶介导的纳米治疗瘤内自组装用于增强成像和肿瘤治疗。

• DOI: 10.1002/wnan.1786
• 发表时间: 2022-07
• 期刊: Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology
• 作者: Yue Yuan;J. Bulte
• 通讯作者: J. Bulte