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征的性质的药物新的作用机制。通过“远程装载”方法（L-DXR）将多柔比星封装在长循环脂质体中代表了一类新的抗癌剂中的第一种，并且最近被FDA批准。然而，其全部作用和机制仍有待确定。以前，我们证明了大幅度延长寿命的大鼠轴承原位植入耐药脑肿瘤时，给予L-DXR，但不自由DXR。我们最近观察到，重复剂量的L-DXR（但不是等效剂量的游离DXR）增加肿瘤血管通透性，介导血管屏障破坏。正常的脉管系统似乎不受影响。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损害血管渗透性的性质的机制基础，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破坏来增强治疗的潜力，不仅优化肿瘤沉积和L-DXR本身的治疗效果，而且还促进其他药物的治疗效果。选择性肿瘤血管屏障破坏可以改善基因载体系统的渗透和作用，并可以增加肿瘤对具有互补作用机制的药物（如抗血管生成剂）的敏感性。将使用一系列渗透性探针和免疫组织学方法研究重复L-DXR治疗引起的血管渗透性变化。游离DXR将用作对照。功能性磁共振（fMR）成像将能够动态观察肿瘤灌注和血管通透性的变化。将使用TNP-470和紫杉醇研究血管通透性妥协对潜在互补剂活性的影响;前者是一种充分表征的抗血管生成剂，而后者是一种具有一些抗血管生成特性的活性化疗剂。将使用携带模型基因的病毒载体探测血管通透性变化对其他大分子载体递送的影响。

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.