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

描述（由申请人提供）：该提案“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用于治疗非霍奇金淋巴瘤的新型治疗和诊断药物输送技术。非侵入性成像技术（如MRI）和使用PLGA纳米颗粒靶向给药的结合是Carigent Therapeutics的主要重点，我们相信这种技术可以获得显著的临床效益。可生物降解的PLGA纳米颗粒对化疗药物的控制、持续释放已被证明在提高药物疗效方面是有效的，因为它能够更好地在细胞内和延长时间内递送药物。Carigent Therapeutics开发了一种表面修饰PLGA纳米颗粒的方法，不仅可以添加高密度的表面PEG基团以防止被身体清除，而且还可以靶向部分，如抗体，以提高针对特定细胞的特异性和效力。此外，我们已经证明，我们可以系住图像造影剂，包括钆，以实现颗粒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的最先进分期技术相比，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，该提案分为3个具体目标：(1)具有新颖和专有表面修饰的PLGA纳米颗粒的配方和表征；(2)纳米颗粒表面组成的体外优化；(3)在体内评价纳米颗粒在小鼠模型中的药代动力学和分布，以及在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；包括纳米颗粒在模拟生理环境中的活性和药物释放。我们相信前两个特定目标的完成将导致阿霉素负载的、MR敏感的纳米颗粒能够循环更长时间，允许b细胞定位、附着和内化。在具体目标3中，将在淋巴瘤小鼠模型中测试该优化制剂，以建立药物疗效和诊断潜力的临床前数据。公共卫生相关性：题为“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、负载多柔比星的聚合物纳米颗粒的发展，旨在提高多柔比星的安全性和有效性，同时实现肿瘤的非侵入性成像和药物递送的跟踪。这项技术不仅将提高淋巴瘤治疗中广泛使用的化疗药物的安全性和有效性，而且还将改进基于图像的分期技术和药物传递的跟踪。

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.