Environmentally-adaptive nanoparticles with focal irradiation for cancer therapy

用于癌症治疗的局部照射的环境适应性纳米粒子

• 批准号: 9241253
• 负责人: Yoon Yeo
• 金额: $ 34.92万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241253
• 关键词: Abraxane; Acidity; Address; Adverse effects; Antineoplastic Agents; Biodistribution; Cancer Model; Cancer Patient; Cations; Chemotherapy-Oncologic Procedure; Deposition; Development; Dose; Drug Delivery Systems; Drug Kinetics; Effectiveness; Exposure to; Extracellular Matrix; Extravasation; Genetic; Goals; Heterogeneity; Intercellular Fluid; Ligands; Lymphatic System; Malignant Neoplasms; Malignant neoplasm of prostate; Matrix Metalloproteinases; Methodology; Microvascular Permeability; Mission; Modeling; Mus; Outcomes Research; Paclitaxel; Particle Size; Patients; Penetration; Peptide Hydrolases; Permeability; Pharmacodynamics; Pica Disease; Public Health; Quality of life; Radiation; Radiobiology; Regimen; Research; Research Personnel; Resources; Solid Neoplasm; Surface; Surface Properties; Technology; Testing; Therapeutic; Time; Tissues; Translating; Tumor Tissue; United States National Institutes of Health; anti-cancer therapeutic; antitumor effect; base; cancer therapy; chemotherapy; clinical practice; human disease; image guided; improved; irradiation; mouse model; nanomedicine; nanoparticle; neoplastic cell; novel therapeutics; pressure; prevent; prostate cancer model; public health relevance; tool; tumor; tumor growth; tumor microenvironment

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.

描述（由申请人提供）：纳米颗粒（NP）作为一种有前景的工具而被广泛追求，以增加肿瘤中抗癌治疗的生物分布，从而减少化疗的总体暴露。人们普遍认为，肿瘤周围有缺陷的脉管系统和淋巴系统为纳米粒子在肿瘤中积累提供了选择性的机会。然而，以这种方式递送至肿瘤的量仅占所施用纳米颗粒总量的一小部分（~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，其益处往往受到限制。由于高组织硬度和间质液压力，纳米颗粒对肿瘤的渗透有限，加剧了使用纳米颗粒进行药物输送的挑战。与基于纳米粒子的药物递送现状的实质性背离需要一种新的策略，以增加递送到肿瘤并被肿瘤保留的纳米粒子的数量，使其超过目前基于通过所谓的增强渗透性和保留（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递送策略，比目前实现的更大程度地增强纳米药物向实体瘤的递送。该应用的目的是通过环境适应性纳米粒子（ENP）和图像引导辐射诱导渗透性（IGRIP）的协同应用，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，与传统的非适应性纳米颗粒相比，在肿瘤中形成阳离子表面或减小尺寸的纳米颗粒将在肿瘤中更好地保​​留和/或渗透，并且通过靶向照射，导致局部微血管通透性增加，将主动增加此类纳米颗粒的肿瘤积累。该项目的基本原理是，其成功完成将能够向实体瘤提供比目前现有技术更多的抗癌治疗药物，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 ENP 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 (Pica) 小鼠模型中验证 IGRIP 效果，并优化 NP 递送的照射方案（目标 2）。基于优化的 ENP 和照射方案，我们将在 Pica 小鼠中将 PTX 递送的药代动力学和生物分布与抗肿瘤作用相关联，以测试 ENP 与 Abraxane 相比在 PTX 递送至肿瘤中的有效性以及 ENP 递送的 IGRIP 增强（目标 3）。通过完成这项研究，我们希望确认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。