Personalizing Nanoparticle Therapy

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。在临床上，脂质体药物，如脂质体doxil，是有效的患者，例如，乳腺癌或卵巢癌的小子集，但目前，预测那些可能响应的方法是缺乏的。需要这种方法来选择可能从药物中受益的患者，并避免对无反应的患者产生显著毒性。响应取决于递送，并且成像递送应有助于响应预测，并且能够开发用于改善递送/治疗功效的技术，即使在最初为无响应者的患者中也是如此。对于成像，MR提供了极好的软组织对比度，但是由于缺乏临床上可用于预测递送的具有足够信号和低背景以及适当结构以模拟治疗剂的药剂，因此尚未完全利用MR来评估递送。临床使用的试剂通常递送一种钆离子/螯合物。需要扩增方案来递送每个纳米颗粒的多个成像部分，然而，这需要小心地进行，因为过量的钆（Gd）浓度可导致信号损失。我们最近证明，脂质体可以在表面和脂质体内（双Gd）用Gd螯合物产生，并且这些纳米颗粒的弛豫率比传统的Gd螯合物高约10，000倍。对于纳米颗粒治疗剂，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，并且操纵脉管系统可以改善反应。为了评估递送，将产生与脂质体doxil相同大小的成像脂质体。这种尺寸（约100-200 nm）的脂质体倾向于通过增强的渗透性和保留效应（EPR）进入并截留在肿瘤血管系统中。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试剂来操纵;我们假设这些可以用于改善纳米颗粒治疗剂向肿瘤的递送。SA 1.检验双Gd脂质体与治疗性脂质体大小相同的假设，可以预测乳腺癌和卵巢癌模型对治疗性脂质体的反应。SA 2.检验以下假设：使用主要影响正常血管的速效药物进行血管操作可改善对治疗性脂质体的反应，从而影响血管参数，如血管收缩、血管舒张和/或渗透性，并且可通过使用双Gd脂质体进行成像来预测反应。SA 3.检验以下假设：使用主要影响肿瘤血管的药物（如抗血管生成药物）进行血管操作以改变血管功能，可以改善对治疗性脂质体的反应，并且可以通过使用双Gd脂质体进行成像来预测反应。

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.