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）：个性化治疗需要评估药物输送的成像方法。在临床上，脂质体剂，例如脂质体doxil，在乳腺癌或卵巢癌中有效，但目前缺乏预测可能反应的方法的方法。对于选择可能从药物中受益的患者以及避免反应不良的患者毒性的毒性，需要这种方法。响应取决于交付和成像输送，应有助于响应预测以及能够开发技术以提高输送/治疗功效的技术，即使在最初是非反应者的患者中也是如此。对于成像，MR提供了出色的软组织对比度，但由于缺乏临床上可用的代理，用于预测具有足够信号和低背景以及适当的架构以模仿治疗剂的临床可用试剂，因此尚未获得全面资本来评估输送。临床使用的药物通常会提供一个gadolinium Ion/螯合物。需要扩增方案来提供每个纳米颗粒的多个成像部分，但是，由于过量的gadolinium（GD）浓度会导致信号损失，因此需要仔细进行这项工作。我们最近证明，脂质体可以在表面和脂质体内部和脂质体（双GD）上产生脂质体，并且它们的每纳米颗粒的松弛度比传统的GD芝麻酸盐高约10,000倍。对于纳米粒子疗法，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脂质体的成像可以通过评估递送来预测脂质体治疗的反应，并且对脉管系统的操纵可以改善反应。为了评估递送，将产生与脂质体Doxil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渗透性和保留效应（EPR）传播并陷入肿瘤脉管系统。脉管系统的功能特征可以由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理学剂操纵；我们假设可以利用这些方法来改善纳米颗粒治疗剂向肿瘤的递送。 SA1。检验以下假设：双GD脂质体的大小与治疗脂质体相同的大小可以预测乳腺癌和卵巢癌模型中对治疗脂质体的反应。 SA2。检验以下假设：使用快速作用剂血管操作可以改善对治疗性脂质体的反应，而快速起作用剂主要影响正常血管以影响血管参数，例如血管收缩，血管降低和/或渗透性，并可以通过使用双 - GD脂质体。 SA3。检验以下假设：使用主要影响肿瘤血管（例如抗血管生成剂）来改变血管功能的药物的血管操作可以改善对治疗性脂质体的反应，以改变血管功能，并且可以通过使用Dual-GD脂质体进行成像来预测这种反应。