Targeting Tumors with Resealable Nanovesicles Permeabilized by NIR Light

利用近红外光透化的可重新密封纳米囊泡靶向肿瘤

• 批准号: 8609764
• 负责人: Jonathan F Lovell
• 金额: $ 38.94万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8609764
• 关键词: Antineoplastic Agents; Biocompatible; Biodistribution; Biological; Biological Process; Biotin; Blood Circulation; Blood flow; Body Temperature; Buffaloes; Caliber; Deposition; Doxorubicin; Drug Delivery Systems; Environment; Exposure to; Fiber Optics; Heart; Heating; Human; In Vitro; Ions; Label; Lead; Light; Liposomes; Malignant Neoplasms; Medical; Membrane; Methods; Nude Mice; Penetration; Permeability; Pharmaceutical Preparations; Phospholipids; Physiological; Porphyrins; Procedures; Process; Proteins; Recovery; Retrieval; Sampling; Side; Site; Solid Neoplasm; Solutions; Stimulus; System; Technology; Temperature; Therapeutic; Time; Tissues; Universities; Vesicle; Xenograft procedure; base; chemical reaction; controlled release; irradiation; monomer; nanocarrier; nanoparticle; nanoscale; nanovesicle; novel; novel strategies; pH gradient; prevent; public health relevance; research study; response; seal; tumor; unilamellar vesicle

PROJECT SUMMARY At present, few synthetic systems can achieve robust, on-demand spatial and temporal control of micro or nanovesicle permeabilization in biological environments. We propose to build upon proof-of-principle experiments establishing the feasibility of such a membrane permeabilization system and to apply this technology towards: 1) triggering drug release in tumors and 2) capturing tumor microvasculature contents via a remote loading and retrieval approach. Several methods for cargo release driven by external stimuli driven have been proposed; whereas to our knowledge the concept of remote capture and retrieval of microvessel contents using triggered permeability in nanovesicles has not yet been explored. So far, essentially all biocompatible approaches for externally triggered membrane permeabilization from nanocarriers comprise systems that release their contents when the surrounding temperatures are raised by a few degrees above body temperature via direct or indirect heating. However, such mechanisms are not amenable to trigger-side release modulation and the narrow thermal operating window precludes carrier stability at physiological temperatures. Furthermore, the lack of stability in physiological conditions prevents more demanding applications of these materials such as triggered release at later time points as well as remote loading and recovery. Here, we propose a fundamentally new controlled release system based on porphyrin- phospholipid doped (PoPD) liposomes transiently permeabilized directly by near infrared (NIR) light, a clinically-applicable stimulus that has negligible actuation in the "off state" and minimal interference with biological tissues. The ability to open and close nanovesicles in the body with precise spatial and temporal control could lead to entirely new approaches to treating and understanding cancer. We synthesized a novel light-absorbing monomer esterified from clinically approved components that gave rise to highly stable porphyrin bilayer. Remarkably, rapid and complete cargo release was induced upon brief exposure to mild NIR irradiation using an optimal porphyrin-phospholipid (but not free porphyrin) doping. Unlike previously described systems, release occurred in the absence of bulk solution photothermal heating or chemical reactions. In physiological conditions in vitro, NIR irradiation induced a 25,000 fold increase in the release rate of actively loaded doxorubicin, orders of magnitude greater than previously described triggered release methods. Induced permeability could be used for both unloading and loading cargo, and could be modulated by varying porphyrin doping, irradiation intensity and irradiation duration for highly tunable manipulation of permeabilization. This project has three specific aims. Aim 1: Develop micro and nanovesicles that open and close on demand in response to NIR light;. Aim 2: Use near infrared light to deliver cancer therapeutics to tumors; Aim 3: Sample tumor microvasculature contents using a capture and retrieve strategy.

项目摘要 目前，很少有合成系统能够实现对微或微系统的鲁棒的、按需的空间和时间控制。 生物环境中的纳米囊泡透化。我们建议建立在原理证明的基础上 建立这种膜透化系统的可行性的实验，并将其应用于 该技术旨在：1）触发肿瘤中的药物释放，以及2）通过微血管捕获肿瘤微血管内容物。 远程加载和检索方法。由外界刺激驱动的货物释放的几种方法 已经提出;而据我们所知，远程捕获和检索微血管的概念 还没有探索在纳米囊泡中使用触发渗透性的内容物。到目前为止，基本上所有 用于从纳米载体外部触发膜透化的生物相容性方法包括 当周围温度升高几度时， 通过直接或间接加热的体温。然而，这样的机制不适合于制造商侧。 释放调节和窄的热操作窗口排除了生理温度下的载体稳定性， 温度此外，在生理条件下缺乏稳定性， 这些材料的应用，例如在稍后的时间点触发释放以及远程加载， 复苏在这里，我们提出了一个全新的基于卟啉的控释系统- 通过近红外（NIR）光直接瞬时透化的磷脂掺杂（PoPD）脂质体， 临床适用的刺激，在“关闭状态”下具有可忽略的致动， 生物组织在体内以精确的空间和时间打开和关闭纳米囊泡的能力 控制可能导致治疗和理解癌症的全新方法。我们合成了一本小说 从临床批准的组分酯化的吸光单体， 卟啉双层值得注意的是，短暂暴露于轻度近红外后，会诱导快速而完全的货物释放 使用最佳的卟啉-磷脂（但不是游离卟啉）掺杂进行辐照。与先前描述的不同， 系统，释放发生在本体溶液光热加热或化学反应的情况下。在 在体外生理条件下，NIR照射诱导了25，000倍的释放速率增加， 活性负载的多柔比星，数量级大于先前描述的触发释放 方法.诱导渗透率可用于卸载和装载货物，并可调节 通过改变卟啉掺杂、照射强度和照射持续时间， 透化作用该项目有三个具体目标。目标1：开发微囊泡和纳米囊泡， 响应NIR光按需关闭;。目标2：使用近红外光将癌症治疗剂输送到 肿瘤;目的3：使用捕获和检索策略对肿瘤微血管内容物进行采样。