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.

项目概要 目前，很少有合成系统能够实现对微观或时间的鲁棒、按需空间和时间控制。 生物环境中的纳米囊泡透化。我们建议以原理验证为基础 实验建立了这种膜透化系统的可行性并应用该系统 技术目标：1）触发肿瘤中的药物释放，2）通过捕获肿瘤微血管内容物 远程加载和检索方法。外部刺激驱动货物释放的几种方法 已被提议；而据我们所知，远程捕获和检索微血管的概念 尚未探索使用纳米囊泡中触发渗透性的内容。到目前为止，基本上所有 用于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释放其内容物的系统 通过直接或间接加热来调节体温。然而，此类机制不适合触发方 释放调节和狭窄的热操作窗口妨碍了载体在生理条件下的稳定性 温度。此外，生理条件缺乏稳定性阻碍了更高的要求 这些材料的应用，例如稍后时间点的触发释放以及远程加载和 恢复。在这里，我们提出了一种基于卟啉的全新控释系统 磷脂掺杂 (PoPD) 脂质体直接通过近红外 (NIR) 光瞬时透化， 临床上适用的刺激，在“关闭状态”下的驱动可以忽略不计，并且干扰最小 生物组织。以精确的空间和时间打开和关闭体内纳米囊泡的能力 控制可能会带来治疗和理解癌症的全新方法。我们综合了一部小说 由临床批准的成分酯化的吸光单体，产生高度稳定的 卟啉双层。值得注意的是，短暂暴露于温和的近红外光下会诱导快速且完全的货物释放 辐照使用最佳卟啉-磷脂（但不是游离卟啉）掺杂。与之前描述的不同 系统中，释放是在没有本体溶液光热加热或化学反应的情况下发生的。在 在体外生理条件下，近红外辐射导致释放速率增加 25,000 倍 主动加载的阿霉素，比之前描述的触发释放大几个数量级 方法。诱导渗透率可用于卸载和装载货物，并且可以调节 通过改变卟啉掺杂、辐照强度和辐照持续时间，可实现高度可调的操作 透化。该项目有三个具体目标。目标 1：开发可打开和释放的微米和纳米囊泡 响应近红外光按需关闭；目标 2：使用近红外光向癌症患者提供癌症治疗 肿瘤；目标 3：使用捕获和检索策略对肿瘤微血管内容物进行采样。