Multimodal Diagnostic and Therapeutic Nanoparticles for Non-Hodgkin's Lymphoma

非霍奇金淋巴瘤的多模式诊断和治疗纳米颗粒

• 批准号: 7481893
• 负责人: Malgorzata Cartiera
• 金额: $ 20.43万
• 依托单位: CARIGENT THERAPEUTICS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481893
• 关键词: Acute; Affect; Animal Model; Animals; Antibodies; Arts; Avidin; B-Lymphocytes; Basic Science; Behavior; Biodistribution; Blood; Blood Circulation; Bone Marrow; Caliber; Cancer Diagnostics; Cells; Cessation of life; Characteristics; Chemotherapy-Oncologic Procedure; Clinical; Contrast Media; Data; Development; Diagnostic; Disease; Disease Progression; Dose; Doxorubicin; Doxorubicin Hydrochloride Liposome; Drug Controls; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Effectiveness; Elements; Encapsulated; Environment; Ethylene Glycols; Evaluation; Fibrosis; Gadolinium; Gadolinium DTPA; Gadopentetate Dimeglumine; Glycolic-Lactic Acid Polyester; Goals; Hour; Image; Imagery; Imaging Techniques; In Vitro; Incubated; Injection of therapeutic agent; Intracellular Transport; Invasive; Lead; Libraries; Ligands; Liver; Localized; Location; Lymphocyte; Lymphoma; Magnetic Resonance Imaging; Malignant Neoplasms; Marketing; Measures; Medicine; Methodology; Methods; Modality; Modeling; Modification; Monitor; Mus; Necrosis; Neoplasm Metastasis; Non-Hodgkin' s Lymphoma; Numbers; Particle Size; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiological; Positron-Emission Tomography; Preparation; Property; Protocols documentation; Public Health; Purpose; Radiation; Reagent; Relapse; Relaxation; Resistance; Risk; Safety; Schedule; Simulate; Specificity; Staging; Standards of Weights and Measures; Structure; Surface; Surface Properties; System; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Treatment Protocols; Tumor Tissue; Vascularization; base; biodegradable polymer; cancer imaging; cellular targeting; chemotherapy; controlled release; day; density; design; desire; drug distribution; drug efficacy; ethylene glycol; improved; in vivo; lymph nodes; mouse model; nanoparticle; nanoparticulate; novel; novel therapeutics; particle; polylactic acid-polyglycolic acid copolymer; pre-clinical; prevent; response; size; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): The long-term clinical objective of this proposal "Multimodal Diagnostic and Therapeutic Nanoparticles for Non-Hodgkin's Lymphoma" is the development of a novel therapeutic and diagnostic drug delivery technology for specific use in the treatment of non-Hodgkin's lymphoma. The combination of non-invasive imaging techniques such as MRI and targeted drug delivery using PLGA nanoparticles is a primary focus of Carigent Therapeutics, and we believe that there are significant clinical benefits to be gained from such a technology. The controlled, sustained release of chemotherapeutics from biodegradable PLGA nanoparticles has been shown to be effective in increasing drug efficacy due to the ability to better deliver drug intracellularly and for extended periods of time. Carigent Therapeutics has developed a methodology for surface-modifying PLGA nanoparticles, enabling not only the addition of high densities of surface PEG groups to prevent clearance by the body, but also targeting moieties such as antibodies to improve the specificity and potency against specific cells. Additionally, we have shown that we can tether image contrast agents, including gadolinium, to enable non-invasive imaging techniques of particle biodistribution and drug delivery; this may lead to improved tumor identification and an overall reduction in exposure of patients compared to state of the art staging techniques relying on CT or PET. Towards this goal, the proposal is structured into 3 specific aims: (1) the formulation and characterization of PLGA nanoparticles with novel and proprietary surface modifications; (2) the in vitro optimization of nanoparticle surface composition; and (3) the in vivo evaluation of nanoparticle pharmacokinetics and distribution in a mouse model, and diagnostic potential and drug efficacy in a murine lymphoma model. The early portions (specific aims 1 and 2) of the project involve the in vitro characterization and optimization of the nanoparticle system; including activity and release of drug from nanoparticles in a simulated physiologic environment. We believe that completion of these first two specific aims will lead to a doxorubicin-loaded, MR- sensitive nanoparticle capable of circulating for extended times, allowing localization to, attachment, and internalization by B-cells. In specific aim 3, this optimized formulation will be tested in a mouse model of lymphoma to establish preclinical data on drug efficacy and diagnostic potential. PUBLIC HEALTH RELEVANCE: The proposal titled "Multimodal Diagnostic and Therapeutic Nanoparticles for Non-Hodgkin's Lymphoma" outlines the development of a tumor-targeting, MR-sensitive, doxorubicin-loaded polymeric nanoparticle designed to improve the safety and efficacy of doxorubicin while simultaneously enabling non- invasive imaging of tumors and tracking of drug delivery. This technology will not only improve the safety and efficacy of a widely-used chemotherapeutic in the treatment of lymphoma, but also improve image-based staging techniques and tracking of drug delivery.

描述（由申请人提供）：本提案“用于非霍奇金淋巴瘤的多模式诊断和治疗纳米颗粒”的长期临床目标是开发一种新型治疗和诊断药物递送技术，用于非霍奇金淋巴瘤的治疗。非侵入性成像技术（如MRI）和使用PLGA纳米颗粒的靶向药物递送的组合是Carigent Therapeutics的主要重点，我们相信从这种技术中可以获得显着的临床益处。化学治疗剂从可生物降解的PLGA纳米颗粒的受控、持续释放已被证明在增加药物功效方面是有效的，这是由于能够更好地在细胞内和延长的时间段内递送药物。Carigent Therapeutics开发了一种表面改性PLGA纳米颗粒的方法，不仅可以添加高密度的表面PEG基团以防止身体清除，还可以靶向抗体等部分，以提高对特定细胞的特异性和效力。此外，我们已经证明，我们可以拴系图像造影剂，包括钆，以实现粒子生物分布和药物输送的非侵入性成像技术;与依赖于CT或PET的最新分期技术相比，这可能导致肿瘤识别的改善和患者暴露的总体减少。为了实现这一目标，该提案被构建为3个具体目标：（1）具有新型和专有表面修饰的PLGA纳米颗粒的配制和表征;（2）纳米颗粒表面组成的体外优化;以及（3）小鼠模型中纳米颗粒药代动力学和分布的体内评价，以及小鼠淋巴瘤模型中的诊断潜力和药物疗效。该项目的早期部分（具体目标1和2）涉及纳米颗粒系统的体外表征和优化;包括在模拟生理环境中纳米颗粒的活性和药物释放。我们相信，完成这前两个具体目标将导致负载阿霉素的MR敏感性纳米颗粒能够循环延长的时间，允许定位于B细胞、附着并被B细胞内化。在具体目标3中，将在淋巴瘤小鼠模型中测试这种优化的制剂，以建立关于药物功效和诊断潜力的临床前数据。公共卫生关系：这项名为“非霍奇金淋巴瘤的多模式诊断和治疗纳米颗粒”的提案概述了肿瘤靶向、MR敏感、装载阿霉素的聚合物纳米颗粒的开发，该纳米颗粒旨在提高阿霉素的安全性和有效性，同时实现肿瘤的非侵入性成像和药物递送的跟踪。该技术不仅将提高广泛使用的化疗药物治疗淋巴瘤的安全性和有效性，而且还将改善基于图像的分期技术和药物递送的跟踪。