Nanodelivery to enhance the imaging and therapy of breast cancer

描述(申请人提供)：目前的癌症靶向显像剂和治疗方法需要进入实体肿瘤以达到其目标并最有效。然而，体内的内皮细胞和其他生物屏障限制了肿瘤的被动进入，导致肿瘤内浓度非常有限，疗效较差。纳米粒(NP)可以部分通过减缓肾脏排泄来改善小分子药物的药代动力学和药效学；然而，有限的穿透EC屏障和网状内皮系统(RES)的快速摄取阻碍了NP向肿瘤的传递。迫切需要设计新的探针和系统来研究限制体内传递的关键生物界面，以及如何克服和利用它们来执行图像引导药物传递(IGDD)，最终提高乳腺癌的治疗效果。我们研究计划的总体目标是探索使用一种新发现的、活跃的跨内皮细胞转运途径，即小凹，以提供一种有效的解决方案来靶向和输送NP及其治疗货物。小窝泵送系统能够实现组织特异性靶向和穿透，以克服目前药物输送范例的局限性，并提高治疗效果。为了实现这一目标，我们将利用活体显微镜(IVM)直接在体内研究肿瘤EC屏障的功能，并确定小凹可以在多大程度上靶向将NP泵入肿瘤。我们的中心假设是，将小凹靶向抗体与NP携带者联系起来，将增加抗体将放射性核素等小药物输送到肿瘤中的能力，从而极大地提高治疗效果。这一假说是在我们以前的工作和新的初步数据的基础上提出的。它将通过追求两个特定的目标进行测试：1)表征带有小凹特异性抗体的树枝状大分子的体内递送和免疫靶向特性；2)研究将树枝状大分子靶向肿瘤内皮细胞小窝以提高放射治疗和疗效的作用。我们将制备和表征不同大小的免疫偶联树枝状大分子，并使用先进的多模式成像技术和新的乳腺肿瘤IVM模型系统来评估和优化体内靶向、递送和疗效。这项工作将提供第一个针对小窝的乳腺癌纳米疗法的原型。这一贡献意义重大，因为跨越体内屏障并逃脱RES的能力可以创造一种范式转变，从被动的经血管输送转向使用主动的泵送途径，将药物活性物质快速且特定地输送到乳腺肿瘤，从而极大地提高治疗效果。这些发现预计将通过推进癌症研究和肿瘤学产生立即的积极影响，所获得的信息可能将为IGDD提供一种新的小窝介导的药物输送系统，以帮助治疗乳腺癌并改善乳腺癌患者的生活质量。

DESCRIPTION (provided by applicant): Current cancer-targeted imaging agents and therapies require entry inside solid tumors to reach their targets and be most effective. However, endothelial cells (EC) and other biological barriers in vivo restrict passive entry into tumors, leading to very limited intratumoral concentrations and poor efficacy. Nanoparticles (NP) can potentially improve pharmacokinetics and pharmacodynamics of small drugs in part by slowing renal excretion; however, limited penetration across EC barriers and rapid uptake by the reticuloendothelial system (RES) impede NP delivery into tumors. There is an urgent need to devise new probes and systems to study key biological interfaces that restrict delivery in vivo and how they can be overcome and exploited to perform image guided drug delivery (IGDD) that ultimately enhances therapeutic impact for breast cancer. The overall goal of our research program is to explore the use of a newly discovered, active transendothelial transport pathway, the caveolae, to provide an effective solution to target and deliver NP and their therapeutic cargo. The caveolae pumping system enables tissue-specific targeting and penetration to overcome the limitations of current drug delivery paradigms and to improve therapeutic efficacy. Towards this goal, we will study tumor EC barrier function directly in vivo using intravital microscopy (IVM) and determine the degree to which caveolae can be targeted to pump NP into tumors. Our central hypothesis is that linking caveolae-targeting antibodies to NP carriers will increase the capacity of antibodies to deliver small drugs such as radionuclides into tumors and thereby greatly improve therapeutic impact. This hypothesis is formulated on the basis of our prior work and new preliminary data. It will be tested by pursuing two specific aims: 1) To characterize in vivo delivery and immunotargeting properties of dendrimers functionalized with caveolae-specific antibodies; 2) To investigate the utility of targeting dendrimers to tumor endothelial caveolae to enhance radiotherapy and efficacy. We will prepare and characterize immunoconjugated dendrimers of different sizes and use advanced multimodality imaging technologies and novel mammary tumor IVM model systems to evaluate and optimize in vivo targeting, delivery and efficacy. This work will provide the first prototype of caveolae-targeted breast cancer nanotherapies. This contribution is significant because the ability to pump NP across in vivo barriers and escape the RES could create a paradigm shift away from passive transvascular delivery towards using an active pumping pathway to deliver pharmaceutically active agents rapidly and specifically into breast tumors and thereby greatly enhance therapeutic impact. Such findings are expected to have an immediate positive impact through advancing cancer research and oncology with the likelihood that the gained information will provide a novel caveolae-mediated drug delivery system for IGDD to help treat breast cancer and to improve the quality of life of those patients suffering from breast cancer.