Drug carrier of blood/tumor/brain permeability

描述（由申请人提供）：药物载体可以改变药理学，并赋予具有补充载体特性的药物新的作用机制。阿霉素通过“远程装载”方法（L-DXR）封装在长循环脂质体中，是一类新型抗癌药物中的第一种，最近获得了FDA的批准。然而，其全部行动范围和机制仍有待确定。先前的研究表明，当给予L-DXR而非自由DXR时，原位植入耐药脑肿瘤的大鼠寿命显著延长。我们最近观察到，重复剂量的L-DXR（而不是等量剂量的游离DXR）增加肿瘤血管通透性并介导血管屏障的破坏。正常的脉管系统似乎未受影响。这种效应在文献中是前所未有的，具有重要的临床和基础意义。本提案的目的是(a)了解该药物载体系统赋予DXR损害血管通透性特性的机制基础，以及(b)确定该效应的功能后果。特别是，我们将(c)探索通过合理应用肿瘤血管屏障击破来增强治疗的潜力，不仅优化L-DXR本身的肿瘤沉积和治疗效果，而且促进其他药物的治疗效果。选择性肿瘤血管屏障的破坏可以改善基因载体系统的渗透和作用，并且可以增加肿瘤对具有互补作用机制的药物的敏感性，例如抗血管生成药物。重复L-DXR治疗引起的血管通透性变化将使用一系列通透性探针和免疫组织学方法进行研究。免费的DXR将用作控制。功能磁共振成像可以动态观察肿瘤灌注和血管通透性的变化。血管通透性损害对潜在补充剂活性的影响将使用TNP-470和紫杉醇进行研究；前者是一种具有良好特征的抗血管生成药物，而后者是一种具有一定抗血管生成特性的活性化疗药物。血管通透性改变对其他大分子载体递送的影响将通过携带模型基因的病毒载体进行探讨。

DESCRIPTION (provided by applicant): Drug carriers can alter pharmacology and confer novel mechanisms of action upon agents having properties that compliment the characteristics of the carrier. Doxorubicin encapsulated within long-circulating liposomes by means of a "remote loading" method (L-DXR) represents the first in a new class of anticancer agents, and was recently approved by the FDA. However, its full spectrum of action and mechanisms remain to be defined. Previously we demonstrated substantial extension of lifespan for rats bearing an orthotopically-implanted drug-resistant brain tumor when administered L-DXR, but not free DXR. We have recently observed that repetitive doses of L-DXR (but not equivalent doses of free DXR) increase tumor vascular permeability and mediate vascular barrier breakdown. Normal vasculature appears to be unaffected. This effect, unprecedented in the literature, has important clinical and basic implications. The objectives of this proposal are (a) to understand the mechanistic basis by which this drug carrier system confers upon DXR the property of compromising vascular permeability, and (b) to determine the functional consequences of this effect. In particular, we will (c) explore the potential to enhance therapy through rational application of tumor vascular barrier breakdown, not only to optimize tumor deposition and therapeutic effect of L-DXR itself, but also to promote the therapeutic effects of other agents. Selective tumor vascular barrier breakdown could improve the penetration and effects of gene-carrier systems, and could increase the sensitivity of tumors to drugs having complimentary mechanisms of action, such as antiangiogenic agents. Vascular permeability changes resulting from repetitive L-DXR treatment will be investigated using a series of permeability probes and immunohistological approaches. Free DXR will be used as a control. Functional Magnetic Resonance (fMR) imaging will enable dynamic observation of tumor perfusion and vascular permeability changes. Effects of the vascular permeability compromise on the activity of potentially complementary agents will be investigated using TNP-470 and paclitaxel; the former is a well-characterized antiangiogenic agent, while the latter is an active chemotherapeutic agent having some antiangiogenic properties. The effect of vascular permeability changes on delivery by other macromolecular carriers will be probed using viral vectors carrying model genes.