Environmentally-adaptive nanoparticles with focal irradiation for cancer therapy

摘要 纳米颗粒（NPs）作为一种有前途的工具，已被广泛追求，以增加生物分布的一个， 在肿瘤中的抗癌疗法，从而减少对化疗的一般暴露。一般 承认肿瘤周围有缺陷的脉管系统和淋巴系统提供了选择性的机会， NPs在肿瘤中积累的可能性。然而，以这种方式递送到肿瘤的量仅是一小部分- 占总给药NP的约5%。这一挑战可以通过修饰纳米颗粒的表面来解决 使用肿瘤特异性配体，但由于肿瘤特异性配体的异质性和遗传不稳定性， 肿瘤的使用NP的药物递送的挑战由于NP进入肿瘤的有限渗透而加剧， 这是由于高组织硬度和间质流体压力。实质性地改变现状 药物递送需要一种新的策略来增加递送到肿瘤并被肿瘤保留的NPs的量 超过了目前基于通过所谓的增强渗透性的被动递送的可能水平， 保留（EPR）效应或其他靶向策略。 我们的长期目标是开发一种新的药物输送策略，提高纳米药物的输送 在更大程度上转化为实体瘤。此应用程序的目的是提高 通过协同应用抗癌药物， 环境适应性纳米粒子（ENPs）和图像引导辐射诱导渗透性（IGRIP）。我们的中央 假设是，在肿瘤中形成阳离子表面或尺寸缩小的纳米颗粒将被更好地保留 和/或渗透到肿瘤中，并且这种NP的肿瘤积累将被抑制。 通过靶向照射积极增加，导致局部微血管通透性增加。那个... 该项目的成功完成将使更多的抗- 与目前用现有技术实现的相比， 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， 在那里，我们将优化ENPs的合成和抗癌药物紫杉醇（PTX）模型的封装 (Aim 1）验证IGRIP在前列腺癌（PCa）小鼠模型中的作用并优化照射 NP给药方案（目标2）。基于优化的ENPs和照射方案，我们将关联 PTX递送的药代动力学和生物分布以及在具有PCa的小鼠中的抗肿瘤作用，以测试PTX递送的效果。 与Abraxane相比，ENP在PTX递送至肿瘤中的有效性以及ENP的IGRIP增强 交付（目标3）。通过这项研究的完成，我们希望已经证实我们的方法是一个有效的方法- 纳米药物在实体瘤中的生物分布，并增强治疗潜力。

ABSTRACT Nanoparticles (NPs) have been widely pursued as a promising tool to increase the biodistribution of an- ti-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 oppor- tunity for NPs to accumulate in tumors. However, the amount delivered to tumors this way is only a small frac- tion (~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 ra- tionale 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 (PCa) 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 PCa, to test the effec- tiveness 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 meth- odology to increase biodistribution of nanomedicine into solid tumors and enhance therapeutic potential.