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

• 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
• 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

 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见的诊断癌症。去势抵抗性前列腺癌（CRPC）是一种无法治愈的致命疾病。多西他赛为基础的化疗是CRPC的一线标准治疗。然而，全身化疗的疗效受到给药效率低、耐药性和全身毒性的限制。本项目的目标是开发新型刺激响应交联 治疗诊断学（SCT）用于基于机制的分子药物的图像引导递送，以规避晚期前列腺癌的治疗抗性和全身毒性。SCT将独特的刺激响应性交联策略和高效的α v β 3整联蛋白靶向配体（LXW 64）整合到具有独特的结构依赖性成像特性的新型多功能纳米卟啉系统中。目的1的目标是设计和合成一系列具有硼酸盐、二硫化物和蛋白酶可切割交联剂的SCT，这些交联剂分别对肿瘤微环境的内在刺激（例如酸性pH、还原剂和蛋白酶）有反应。SCT将用LXW 64装饰，以增强其对晚期前列腺癌的靶向能力。在目标2中，SCT的时空分布，包括药代动力学，生物分布和肿瘤内递送和药物释放，将通过多模式成像（NIRFI，PET和MRI）在原位前列腺癌异种移植模型中进行定量研究。将定量测量PET成像中SCT的64 Cu信号，以便确定SCT的药代动力学和生物分布。MRI和NIRF成像功能的激活与局部刺激的水平相关，并且可以被认为是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法（ICP-MS）进行验证，用于定量Gd水平，放射自显影和福斯特共振能量转移（FRET）用于药物释放，以及免疫组织化学用于蛋白酶和整联蛋白水平。在目标3中，携带紫杉醇耐药性前列腺癌异种移植物的SCID小鼠将用共负载有新的热休克蛋白90抑制剂（ganetespib）和多西他赛的SCT治疗。这些新型纳米制剂有望通过P-糖蛋白和抑制替代生长途径（多西他赛耐药的两个重要机制）规避药物外排。将通过分子成像定量与治疗反应相关的肿瘤消退，并与肿瘤微环境中的分子变化相关。所提出的治疗诊断剂的成功开发将显著提高用于监测治疗递送过程的成像灵敏度，并增强基于机制的药物的递送以克服多西他赛耐药性。这项研究的结果将不仅在推进一种新的治疗诊断纳米平台的发展，有效治疗晚期前列腺癌，但也提供了一个新的框架，使用刺激响应交联治疗诊断图像引导的药物输送。