Personalizing Nanoparticle Therapy

个性化纳米粒子治疗

• 批准号: 8265915
• 负责人: VIKAS KUNDRA
• 金额: $ 32.44万
• 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/8265915
• 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.

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，脂质体制剂，如脂质体多西平，对小部分患者有效，例如乳腺癌或卵巢癌，但目前缺乏预测那些可能有反应的患者的方法。为了有效地选择可能从药物中受益的患者，以及避免对没有反应的患者产生重大毒性，这些方法都是必要的。反应依赖于给药，成像给药应该有助于反应预测，并使改进给药/治疗效果的技术发展成为可能，即使在最初无应答的患者中也是如此。在成像方面，MR提供了极好的软组织对比度，但由于缺乏临床上可用的预测递送的试剂，这些试剂具有足够的信号和低背景，以及适当的结构来模拟治疗剂，因此尚未完全用于评估递送。临床使用的试剂通常提供一种Gd离子/螯合物。每个纳米颗粒需要放大方案来提供多个成像部分，然而，这需要谨慎地完成，因为过量的Gd(Gd)浓度可能导致信号损失。我们最近证明，可以在脂质体表面和内部使用Gd-螯合物(双Gd)创建脂质体，并且每纳米颗粒的弛豫度比传统的Gd-螯合物高约10,000倍。对于纳米颗粒疗法，传递是一个影响疗效的因素，并且依赖于血管系统。我们假设，使用双Gd脂质体的成像可以通过评估递送来预测脂质体治疗的反应，并且血管系统的操作可以改善反应。为了评估释放情况，将生产与脂质体多西环素相同大小的成像脂质体。这种大小(~100-200 nm)的脂质体倾向于通过增强的通透性和滞留效应(EPR)进入肿瘤血管并被包裹。血管系统的功能特征可以通过影响正常血管系统或影响异常血管生成肿瘤血管系统的药理学药物来操纵；我们假设这些可能被用来改善纳米颗粒治疗药物对肿瘤的输送。SA1.在乳腺癌和卵巢癌模型中，验证双Gd脂质体与治疗性脂质体大小相同的假设可以预测治疗性脂质体的反应。SA2.测试这样一种假设，即通过使用主要影响正常血管以影响血管收缩、血管扩张和/或通透性等血管参数的快速作用剂，可以通过血管操纵来改善对治疗性脂质体的反应，并且可以通过使用双Gd脂质体进行成像来预测反应。SA3.验证这样一种假设，即通过使用主要影响肿瘤血管的药物(如抗血管生成剂)来改变血管功能，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Gd脂质体进行成像来预测反应。