Stimuli-responsive crosslinked theranostics against advanced prostate cancer

针对晚期前列腺癌的刺激反应性交联治疗诊断学

基本信息

批准号：
8972768
负责人：
Yuanpei Li
金额：
$ 34.27万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8972768
关键词：
Advanced Development Affinity American Androgens Architecture Autoradiography Biodistribution Blood Blood Circulation Cancer Etiology Cancer Patient Cessation of life Cleaved cell Crosslinker Detection Development Disease Dissociation Disulfides Drug Delivery Systems Drug Efflux Drug Kinetics Drug resistance Encapsulated Energy Transfer Evaluation Exhibits Fluorescence Goals Growth Heat-Shock Proteins 90 Image Imagery Immunohistochemistry Inductively Coupled Plasma Mass Spectrometry Integrins Lead Ligands Magnetic Resonance Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Measures Molecular Molecular Medicine Monitor Multimodal Imaging Nature Neoplasm Metastasis P-Glycoprotein PUVA Photochemotherapy Pathway interactions Patient Care Patients Peptide Hydrolases Permeability Pharmaceutical Preparations Physiological Positron-Emission Tomography Primary Neoplasm Process Property Prostatic Neoplasms Publishing Quality of life Reducing Agents Reporting Research Resistance SCID Mice Scheme Series Signal Transduction Signaling Molecule Site Stimulus System Therapeutic Time Toxic effect Treatment outcome Xenograft Model Xenograft procedure accurate diagnosis base cancer diagnosis castration resistant prostate cancer chemotherapy crosslink deprivation design docetaxel effective therapy fluorescence imaging image guided improved in vivo inhibitor/antagonist innovation male men molecular imaging mortality mouse model nano nanoformulation nanoparticle novel optical imaging premature public health relevance resistance mechanism response spatiotemporal standard care targeted treatment theranostics tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of all cancer-related deaths and the most commonly diagnosed cancer among males in US. Castration-resistant prostate cancer (CRPC) is an incurable and lethal form of the disease. Docetaxel-based chemotherapy is the first-line standard treatment for CRPC. However, the efficacy of systemic chemotherapy is limited by poor efficiency in the delivery, drug resistance and systemic toxicity. The goal of this project is to develop novel stimuli-responsive cross-linked theranostics (SCTs) for image-guided delivery of mechanism-based molecular medicine to circumvent treatment-resistance and systemic toxicity for advanced prostate cancer. SCTs integrate unique stimuli-responsive crosslinking strategies and highly potent avß3 integrin targeting ligand (LXW64) into a novel multifunctional nanoporphyrin system with unique architecture-dependent imaging properties. The goal of Aim 1 is to design and synthesize a series of SCTs with boronate, disulfide and protease-cleavable crosslinkers that are responsive to the intrinsic stimuli at the tumor microenvironment, such as acidic pH, reducing agents and proteases, respectively. SCTs will be decorated with LXW64 to enhance their targeting capability to advanced prostate cancer. In Aim 2, the spatiotemporal distribution of SCTs including pharmacokinetics, biodistribution and intratumoral delivery and drug release, will be quantitatively investigated by multimodal imaging (NIRFI, PET and MRI) in orthotopic prostate cancer xenograft models. The 64Cu signal of SCTs from PET imaging will be measured quantitatively so that the pharmacokinetics and biodistribution of SCTs can be determined. The activation of the MRI and NIRF imaging functions correlates with the level of local stimuli and can be considered as an indication of nanoparticle dissociation and drug release. The imaging results will be validated by inductively coupled plasma mass spectrometry (ICP-MS) for quantitative Gd level, autoradiography and förster resonance energy transfer (FRET) for drug release as well as immunohistochemistry for protease and integrin level. In Aim 3, SCID mice bearing docetaxel-resistance prostate cancer xenograft will be treated with SCTs that are co-loaded with a new heat shock protein 90 inhibitor (ganetespib) and docetaxel. These novel nano-formulations hold promise for circumventing drug efflux through P-glycoprotein and inhibiting alternative growth pathways, two important mechanisms of resistance to docetaxel. Tumor regression associated with response to therapy will be quantified by molecular imaging, and correlated with molecular changes in tumor microenvironment. Successful development of the proposed theranostic agents will significantly improve the imaging sensitivity for monitoring the therapeutic delivery process, and enhance the delivery of mechanism-based drugs to overcome docetaxel resistance. Results from this study will be significant not only in advancing the development of a novel theranostic nano-platform for effective therapy of advanced prostate cancer, but also in providing a new framework of using stimuli-responsive cross-linked theranostics for image-guided drug delivery.

描述（由申请人提供）：前列腺癌是所有癌症相关死亡的第二大原因，也是美国男性中最常诊断出的癌症，去势抵抗性前列腺癌（CRPC）是一种无法治愈且致命的疾病。基于化疗的化疗是 CRPC 的一线标准治疗方法，但全身化疗的疗效因给药效率差、耐药性和全身毒性而受到限制。交联的治疗诊断学 (SCT) 用于图像引导递送基于机制的分子医学，以避免晚期前列腺癌的治疗耐药性和全身毒性。SCT 将独特的刺激响应交联策略和高效的 avß3 整合素靶向配体 (LXW64) 整合到一种新型多功能中。具有独特的结构依赖性成像特性的纳米卟啉系统目标 1 的目标是设计和合成一系列具有硼酸盐、在目标 2 中，分别对肿瘤微环境中的内在刺激（例如酸性 pH 值、还原剂和蛋白酶）进行修饰的二硫键和蛋白酶可裂解交联剂将增强其对晚期前列腺癌的靶向能力。 SCT的时空分布，包括药代动力学、生物分布和瘤内递送和药物释放，将通过多模态成像（NIRFI、PET和原位前列腺癌异种移植模型中的 64Cu 信号将被定量测量，以便确定 MRI 和 NIRF 成像功能的激活与局部刺激和水平的相关性。可以被视为纳米颗粒解离和药物释放的指示，成像结果将通过电感耦合等离子体质谱（ICP-MS）进行定量验证。用于药物释放的 Gd 水平、放射自显影和福斯特共振能量转移 (FRET) 以及用于蛋白酶和整合素水平的免疫组织化学在目标 3 中，将使用与多西紫杉醇抗性前列腺癌异种移植物共同加载的 SCID 小鼠进行治疗。新型热休克蛋白 90 抑制剂 (ganetespib) 和多西紫杉醇这些新型纳米制剂有望规避药物。通过P-糖蛋白流出和抑制替代生长途径，这是多西他赛耐药的两个重要机制，与治疗反应相关的肿瘤消退将通过分子成像进行量化，并与所提出的治疗诊断剂的分子变化相关。显着提高监测治疗递送过程的成像灵敏度，并增强基于机制的药物递送以克服多西紫杉醇耐药性。这项研究的结果不仅对推进新型治疗诊断纳米平台的开发具有重要意义。有效治疗晚期前列腺癌，还提供了使用刺激响应交联治疗诊断学进行图像引导药物输送的新框架。