Targeting Tumors with Resealable Nanovesicles Permeabilized by NIR Light

描述（由申请人提供）：目前，很少有合成系统可以实现生物环境中微囊泡或纳米囊泡透化的稳健的、按需的空间和时间控制。我们建议建立在建立这种膜透化系统的可行性的原理验证实验的基础上，并将该技术应用于：1）触发肿瘤中的药物释放和2）通过远程加载和检索方法捕获肿瘤微血管内容物。已经提出了由外部刺激驱动的货物释放的几种方法;而据我们所知，尚未探索使用纳米囊泡中的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，基本上所有用于从纳米载体外部触发膜透化的生物相容性方法都包括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，这样的机制不适合于药物侧释放调节，并且窄的热操作窗口排除了生理温度下的载体稳定性。此外，在生理条件下缺乏稳定性阻碍了这些材料的更高要求的应用，例如在稍后的时间点触发释放以及远程加载和恢复。在这里，我们提出了一个全新的控制释放系统的基础上卟啉-磷脂掺杂（PoPD）脂质体瞬时渗透直接通过近红外（NIR）光，一个临床上适用的刺激，具有可忽略不计的actuatin在“关闭状态”和最小的干扰生物组织。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导致治疗和理解癌症的全新方法。我们合成了一种新型的光吸收单体酯化从临床批准的成分，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，在短暂暴露于温和的NIR照射后诱导快速和完全的货物释放。与先前描述的系统不同，释放发生在不存在本体溶液光热加热或化学反应的情况下。在体外生理条件下，NIR照射诱导活性负载的阿霉素的释放速率增加25，000倍，比先前描述的触发释放方法大几个数量级。诱导渗透性可以用于卸载和装载货物，并且可以通过改变卟啉掺杂、照射强度和照射持续时间来调节，以高度可调地操纵细胞。 透化作用该项目有三个具体目标。目标1：开发响应NIR光按需打开和关闭的微囊泡和纳米囊泡;目标2：使用近红外光将癌症治疗剂递送至肿瘤;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。

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.