Personalizing Nanoparticle Therapy

个性化纳米粒子治疗

• 批准号: 8094004
• 负责人: VIKAS KUNDRA
• 金额: $ 33.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094004
• 关键词: Affect; Anatomy; Angiogenesis Inhibitors; Architecture; Blood Vessels; Cancer Model; Characteristics; Doxorubicin Hydrochloride Liposome; Drug Delivery Systems; Encapsulated; Functional Imaging; Gadolinium; Image; Ions; Liposomes; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Patients; Permeability; Pharmaceutical Preparations; Scheme; Signal Transduction; Surface; Testing; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Travel; Treatment Efficacy; Vasodilation; breast cancer diagnosis; chemotherapy; gadolinium oxide; imaging modality; improved; malignant breast neoplasm; nanoparticle; response; soft tissue; technique development; tumor; vasoconstriction

DESCRIPTION (provided by applicant): Personalized therapy requires imaging methods for assessing drug delivery. Clinically, liposomal agents, such as liposomal doxil, are effective in small subsets of patients, for example, with breast or ovarian cancer, but at present, methods for predicting those that may respond are lacking. Such methods are needed both for efficacy in selecting patients who may benefit from the drug, and avoiding significant toxicity in patients who will not respond. Response is dependent on delivery and imaging delivery should aide response prediction as well as enable development of techniques for improving delivery/therapeutic efficacy even in patients that were initially non-responders. For imaging, MR provides superb soft tissue contrast, but has not been fully capitalized upon for assessing delivery due to a dearth of clinically available agents for predicting delivery that have sufficient signal and low background as well as appropriate architecture to mimic the therapeutic agent. Clinically used agents generally deliver one gadolinium ion/chelate. Amplification schemes are needed to deliver multiple imaging moieties per nanoparticle, however, this need to be done carefully because excess gadolinium (Gd) concentration can result in signal loss. We recently demonstrated that liposomes can be created with Gd-chelates on both the surface and within liposomes (Dual-Gd), and that these have approximately 10,000X greater relaxivity per nanoparticle than traditional Gd-chelates. For nanoparticle therapeutics, delivery is a factor in efficacy and is dependent on the vasculature. We hypothesize that imaging using Dual-Gd liposomes can predict response to liposomal therapy by assessing delivery, and that manipulation of the vasculature can improve response. To assess delivery, imaging liposomes of the same size as liposomal doxil will be produced. Liposomes of such size (~100-200 nm) tend to travel to and get entrapped in tumor vasculature via the enhanced permeability and retention effect (EPR). The functional characteristics of the vasculature can be manipulated by pharmacologic agents that affect normal vasculature or that affect the aberrant angiogenic tumor vasculature; we hypothesize that these may be exploited to improve delivery of nanoparticle therapeutics to the tumor. SA1. Test the hypothesis that Dual-Gd liposomes made the same size as therapeutic-liposomes can predict response to therapeutic-liposomes in breast and ovarian cancer models. SA2. Test the hypothesis that response to therapeutic-liposomes can be improved by vascular manipulation using fast acting agents that affect primarily normal blood vessels to affect vascular parameters such as vasoconstriction, vasodilatation, and/or permeability and that response can be predicted by imaging using Dual-Gd liposomes. SA3. Test the hypothesis that response to therapeutic-liposomes can be improved by vascular manipulation using agents that affect primarily tumor vessels, such as the anti-angiogenic agents, to alter vascular function and that response can be predicted by imaging using Dual-Gd liposomes. PUBLIC HEALTH RELEVANCE: The proposal seeks to investigate imaging methods to evaluate delivery of nanoparticle chemotherapy to predict response and to create methods to improve such delivery and therefore improve survival in patients with cancer.

描述（由申请人提供）：个性化治疗需要成像方法来评估药物输送。临床上，脂质体药物，例如脂质体doxil，对一小部分患者有效，例如乳腺癌或卵巢癌患者，但目前缺乏预测可能有反应的患者的方法。需要这样的方法，既可以有效地选择可能从该药物中受益的患者，又可以避免对无反应的患者产生显着的毒性。反应取决于递送，成像递送应有助于反应预测，并能够开发改善递送/治疗效果的技术，即使对于最初无反应的患者也是如此。对于成像，MR 提供了极好的软组织对比度，但由于缺乏临床上可用的具有足够信号和低背景以及适当架构来模拟治疗剂的用于预测递送的试剂，因此尚未充分利用来评估递送。临床使用的试剂通常递送一种钆离子/螯合物。需要放大方案来为每个纳米粒子提供多个成像部分，但是，这需要小心地进行，因为过量的钆 (Gd) 浓度会导致信号丢失。我们最近证明，脂质体可以在表面和脂质体内部使用 Gd 螯合物（双 Gd）来创建，并且每个纳米颗粒的弛豫度比传统的 Gd 螯合物高约 10,000 倍。对于纳米颗粒治疗，递送是功效的一个因素，并且取决于脉管系统。我们假设使用双 Gd 脂质体成像可以通过评估递送来预测对脂质体治疗的反应，并且脉管系统的操纵可以改善反应。为了评估递送，将生产与脂质体 doxil 大小相同的成像脂质体。这种尺寸（~100-200 nm）的脂质体往往会通过增强的渗透性和保留效应（EPR）进入肿瘤血管系统并被捕获。脉管系统的功能特征可以通过影响正常脉管系统或影响异常血管生成肿瘤脉管系统的药物来操纵；我们假设这些可用于改善纳米颗粒治疗剂向肿瘤的递送。 SA1。测试以下假设：双 Gd 脂质体与治疗性脂质体大小相同，可以预测乳腺癌和卵巢癌模型中对治疗性脂质体的反应。 SA2。测试这样的假设：使用快速作用剂主要影响正常血管以影响血管参数（例如血管收缩、血管舒张和/或渗透性），可以通过血管操作来改善对治疗性脂质体的反应，并且可以通过使用双成像技术来预测反应钆脂质体。 SA3。检验以下假设：使用主要影响肿瘤血管的药物（例如抗血管生成剂）通过血管操作来改变血管功能，可以改善对治疗性脂质体的反应，并且可以通过使用双 Gd 脂质体成像来预测反应。 公共健康相关性：该提案旨在研究成像方法来评估纳米颗粒化疗的递送，以预测反应，并创建改进此类递送的方法，从而提高癌症患者的生存率。