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: 8719708
• 负责人: Yoon Yeo
• 金额: $ 36.14万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719708
• 关键词: Abraxane; Acidity; Address; Adverse effects; Animals; Antineoplastic Agents; Biodistribution; Cancer Model; Cancer Patient; Deposition; Development; Dose; Drug Delivery Systems; Drug Kinetics; Effectiveness; Exposure to; Extracellular Matrix; Extravasation; Genetic Heterogeneity; Goals; Image; 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; Vascular Permeabilities; Work; anti-cancer therapeutic; base; cancer therapy; chemotherapy; clinical practice; human disease; improved; irradiation; mouse model; nanomedicine; nanoparticle; neoplastic cell; novel therapeutics; pressure; prevent; public health relevance; tool; tumor; tumor growth; tumor microenvironment

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.

摘要 纳米粒子(NPs)作为一种有前途的工具，已被广泛应用于提高硝酸铵的生物分布。 钛癌症治疗在肿瘤中，从而减少一般暴露于化疗。它一般都是 承认肿瘤周围血管和淋巴系统的缺陷提供了一种选择性的机会- 让NPs在肿瘤中积聚的时机。然而，通过这种方式传递给肿瘤的量只是一个很小的裂缝- 占给药总量的5%。这一挑战可以通过装饰NP的表面来解决 使用肿瘤特异性配体，但由于其异质性和遗传不稳定性，其益处往往有限。 肿瘤。纳米粒对肿瘤的渗透性有限，加剧了使用纳米粒给药的挑战， 由于较高的组织硬度和间质流体压力。与以NP为基础的现状有实质性的偏离 药物递送需要一种新的策略来增加递送到肿瘤并由肿瘤保留的NPs的数量 超过目前可能的水平，通过所谓的增强渗透性和被动交付 保留(EPR)效应或其他目标策略。 我们的长期目标是开发一种新的药物输送策略，以增强纳米药物的输送 转化为实体肿瘤的程度比目前所取得的更大。此应用程序的目标是增强 通过协同应用抗癌药物在实体肿瘤中的积累、滞留和渗透 环境适应性NPs(ENPs)和图像引导辐射诱导渗透性(IGRIP)。我们的中央 假说是，在肿瘤中形成阳离子表面或尺寸缩小的NPs将被更好地保留 和/或比传统的非适应性NPs更能渗透到肿瘤中，并且这种NPs在肿瘤中的积聚将 通过靶向照射主动增加，导致局部微血管通透性增加。Ra- 这一项目的可能性是，它的成功完成将使更多的反 与现有技术相比，癌症治疗对实体肿瘤的治疗效果更好，从而增强了 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的合成和模型抗癌药物紫杉醇(PTX)的包裹 (目的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在小鼠体内的药代动力学、生物分布及PCA抗肿瘤作用的研究 ENPs在PTX肿瘤靶向传递中的作用与阿布拉沙星的比较及ENP对IGRIP的增强作用 交付(目标3)。到这项研究完成时，我们预计已确认我们的方法是一种有效的冰毒- 气味学以增加纳米药物在实体肿瘤中的生物分布，并增强治疗潜力。