Environmentally-adaptive nanoparticles with focal irradiation for cancer therapy

描述（由申请人提供）：纳米颗粒（NPs）作为一种有前途的工具被广泛追求，以增加抗癌治疗药物在肿瘤中的生物分布，从而减少化疗的一般暴露。人们普遍认为，肿瘤周围有缺陷的脉管系统和淋巴系统为NPs在肿瘤中积累提供了选择性的机会。然而，以这种方式输送到肿瘤的量仅占给药NPs总量的一小部分（~5%）。这一挑战可以通过使用肿瘤特异性配体修饰NPs表面来解决，但由于肿瘤的异质性和遗传不稳定性，其益处往往有限。由于高组织刚度和间质液压力，NPs进入肿瘤的渗透有限，这加剧了使用NPs给药的挑战。要彻底改变目前基于np的药物递送现状，需要一种新的策略来增加输送到肿瘤并被肿瘤保留的np的数量，超过目前基于所谓的增强渗透和保留（EPR）效应或其他靶向策略的被动递送可能达到的水平。我们的长期目标是开发一种新的药物输送策略，在更大程度上提高纳米药物对实体肿瘤的输送。该应用的目的是通过协同应用环境适应性NPs （ENPs）和图像引导辐射诱导通透性（IGRIP）来增强抗癌药物在实体肿瘤中的积累、保留和渗透。我们的中心假设是，与传统的非适应性NPs相比，在肿瘤中形成阳离子表面或缩小尺寸的NPs将更好地保留和/或穿透肿瘤，并且这种NPs的肿瘤积聚将通过靶向照射而积极增加，从而导致局部微血管通透性增加。该项目的基本原理是，它的成功完成将使更多的抗癌治疗药物能够用于实体瘤，而不是目前现有的技术，从而提高癌症治疗的有效性。我们将通过以下三个具体目标来实现我们的目标，其中我们将优化ENPs的合成和模型抗癌药物紫杉醇（PTX）的包封（目标1），验证IGRIP在前列腺癌（Pica）小鼠模型中的作用，并优化NP递送的照射方案（目标2）。基于优化的ENPs和照射方案，我们将在异食异食小鼠中关联PTX递送的药代动力学和生物分布与抗肿瘤作用，以测试与Abraxane相比，ENPs在PTX递送肿瘤中的有效性以及IGRIP对ENP递送的增强（目的3）。通过这项研究的完成，我们希望证实我们的方法是一种有效的方法，可以增加纳米药物在实体肿瘤中的生物分布，提高治疗潜力。

DESCRIPTION (provided by applicant): Nanoparticles (NPs) have been widely pursued as a promising tool to increase the biodistribution of anti-cancer therapeutics in tumors, thereby reducing the general exposure to chemotherapy. It is generally acknowledged that defective vasculature and lymphatic systems surrounding tumors offer a selective opportunity for NPs to accumulate in tumors. However, the amount delivered to tumors this way is only a small fraction (~5%) of the total administered NPs. This challenge may be addressed by decorating the surface of NPs using a tumor-specific ligand, but the benefit is often limited due to the heterogeneity and genetic instability of tumors. Challenges in drug delivery using NPs are aggravated by the limited penetration of NPs into tumors, due to high tissue stiffness and interstitial fluid pressure. Substantive departure from the status quo NP-based drug delivery requires a new strategy to increase the amount of NPs delivered to and retained by tumors beyond the level currently possible based on passive delivery via the so-called enhanced permeability and retention (EPR) effect or other targeting strategies. Our long term goal is to develop a new drug delivery strategy that enhances delivery of nanomedicine into solid tumors to a greater extent than currently achieved. The objective of this application is to enhance the accumulation, retention, and penetration of anti-cancer drugs into solid tumors, via synergistic application of environmentally-adaptive NPs (ENPs) and image-guided radiation-induced permeability (IGRIP). Our central hypothesis is that NPs developing cationic surface or reduced size specifically in tumors will be better retained and/or penetrated in tumors than conventional non-adaptive NPs, and tumor accumulation of such NPs will be actively increased by targeted irradiation that results in local increase of microvascular permeability. The rationale for this project is that its successful completion will enable the delivery of a greater amount of anti- cancer therapeutics to solid tumors than currently achieved with existing technology, thereby enhancing the effectiveness of cancer therapy. We will achieve our objective by pursuing the following three specific aims, where we will optimize the synthesis of ENPs and encapsulation of a model anti-cancer drug, paclitaxel (PTX) (Aim 1) and validate the IGRIP effect in a mouse model of prostate cancer (Pica) and optimize the irradiation regimen for NP delivery (Aim 2). Based on the optimized ENPs and irradiation regimen, we will correlate the pharmacokinetics and biodistribution of PTX delivery and anti-tumor effects in mice with Pica, to test the effectiveness of ENPs in PTX delivery to tumors as compared to Abraxane and the IGRIP enhancement of ENP delivery (Aim 3). By the completion of this study, we expect to have confirmed our approach as a valid methodology to increase biodistribution of nanomedicine into solid tumors and enhance therapeutic potential.