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: 9135540
• 负责人: Jonathan F Lovell
• 金额: $ 38.78万
• 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/9135540
• 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; Health; 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; 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; research study; response; seal; tumor; unilamellar vesicle

DESCRIPTION (provided by applicant): 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 actuatin 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.

描述（由申请人提供）：目前，很少有合成系统能够实现生物环境中微米或纳米囊泡透化的稳健、按需的空间和时间控制。我们建议以原理验证实验为基础，建立这种膜透化系统的可行性，并将该技术应用于：1）触发肿瘤中的药物释放，2）通过远程加载和检索方法捕获肿瘤微血管内容物。已经提出了几种由外部刺激驱动的货物释放方法；然而据我们所知，尚未探索利用纳米囊泡触发渗透性远程捕获和检索微血管内容物的概念。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都包含当周围温度通过直接或间接加热升高到体温以上几度时释放其内容物的系统。然而，此类机制不适合触发侧释放调节，并且狭窄的热操作窗口妨碍了载体在生理温度下的稳定性。此外，生理条件下缺乏稳定性阻碍了这些材料的更苛刻的应用，例如稍后时间点的触发释放以及远程加载和恢复。在这里，我们提出了一种全新的控释系统，其基于近红外（NIR）光直接瞬时透化的卟啉磷脂掺杂（PoPD）脂质体，这是一种临床适用的刺激，在“关闭状态”下具有可忽略不计的致动蛋白，并且对生物组织的干扰最小。通过精确的空间和时间控制打开和关闭体内纳米囊泡的能力可能会带来治疗和理解癌症的全新方法。我们合成了一种新型吸光单体，由临床批准的成分酯化，产生高度稳定的卟啉双层。值得注意的是，使用最佳的卟啉-磷脂（但不是游离卟啉）掺杂，短暂暴露于温和的近红外辐射后，可以诱导快速且完全的货物释放。与之前描述的系统不同，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。在体外生理条件下，近红外辐射诱导活性负载阿霉素的释放速率增加 25,000 倍，比之前描述的触发释放方法高出几个数量级。诱导渗透性可用于卸载和装载货物，并且可以通过改变卟啉掺杂、辐照强度和辐照持续时间来调节，以实现高度可调的操作 透化。该项目有三个具体目标。目标 1：开发可响应近红外光按需打开和关闭的微米和纳米囊泡；目标2：利用近红外光向肿瘤提供癌症治疗药物；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。