Environmentally-adaptive nanoparticles with focal irradiation for cancer therapy

描述（由申请人提供）：纳米颗粒（NP）已被广泛用作增加抗癌治疗剂在肿瘤中的生物分布的有前途的工具，从而减少对化疗的一般暴露。一般认为，肿瘤周围的血管和淋巴系统缺陷为NP在肿瘤中积累提供了选择性机会。然而，以这种方式递送到肿瘤的量仅占总施用纳米颗粒的一小部分（~5%）。这一挑战可以通过使用肿瘤特异性配体装饰纳米颗粒的表面来解决，但由于肿瘤的异质性和遗传不稳定性，这种益处往往有限。由于高组织硬度和间质流体压力，使用NP的药物递送的挑战由于NP向肿瘤中的有限渗透而加剧。从基于NP的药物递送的现状的实质性偏离需要一种新的策略，以增加递送到肿瘤并被肿瘤保留的NP的量，超过目前基于被动递送通过所谓的增强的渗透性和保留（EPR）效应或其他靶向策略的可能水平。 我们的长期目标是开发一种新的药物递送策略，该策略能够在比目前更大的程度上增强纳米药物向实体瘤中的递送。本申请的目的是通过协同应用环境适应性纳米颗粒（ENPs）和图像引导辐射诱导渗透性（IGRIP），增强抗癌药物在实体瘤中的积累、保留和渗透。我们的中心假设是，与传统的非适应性NP相比，在肿瘤中特异性地形成阳离子表面或减小尺寸的NP将更好地保留和/或渗透在肿瘤中，并且这种NP的肿瘤积累将通过靶向照射而主动增加，从而导致微血管通透性的局部增加。该项目的基本原理是，它的成功完成将使实体瘤的抗癌治疗比现有技术更有效，从而提高癌症治疗的有效性。我们将通过追求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）的封装（目标1），并在前列腺癌小鼠模型（Pica）中验证IGRIP效应，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，我们将用Pica将PTX递送的药代动力学和生物分布与小鼠中的抗肿瘤作用相关联，以测试ENPs与Abraxane相比在PTX递送至肿瘤中的有效性和ENP递送的IGRIP增强（目的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种有效的方法，可以增加纳米药物在实体瘤中的生物分布，并增强治疗潜力。

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.