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在生物环境中实现微或纳米囊泡渗透的鲁棒性，按需空间和时间控制。我们建议以原理验证实验为基础，建立这种膜渗透系统的可行性，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。提出了几种由外界刺激驱动的货物释放方法；然而，据我们所知，利用纳米囊泡的触发通透性远程捕获和检索微血管内容物的概念尚未被探索。到目前为止，从本质上讲，所有生物相容性的外部触发膜渗透纳米载体的方法都包括当周围温度通过直接或间接加热比体温升高几度时释放其内容物的系统。然而，这种机制不适合触发侧释放调制，并且狭窄的热操作窗口妨碍了载流子在生理温度下的稳定性。此外，在生理条件下缺乏稳定性阻碍了这些材料更苛刻的应用，例如在较晚的时间点触发释放以及远程加载和恢复。在这里，我们提出了一种全新的基于卟啉-磷脂掺杂（PoPD）脂质体的控释系统，该脂质体被近红外（NIR）光直接瞬时渗透，这是一种临床应用的刺激，在“关闭状态”下具有可忽略不计的驱动作用，对生物组织的干扰最小。通过精确的空间和时间控制在体内打开和关闭纳米囊泡的能力可能会为治疗和理解癌症带来全新的方法。我们合成了一种新的光吸收单体，由临床批准的成分酯化，产生高度稳定的卟啉双分子层。值得注意的是，在使用最佳卟啉-磷脂（但不是游离卟啉）掺杂的温和近红外照射下短暂暴露后，诱导快速和完全的货物释放。与先前描述的系统不同，释放发生在没有体溶液、光热加热或化学反应的情况下。在体外生理条件下，近红外照射诱导活性负载阿霉素的释放率增加25,000倍，比先前描述的触发释放方法大几个数量级。诱导磁导率可用于装卸货物，并可通过改变卟啉掺杂、辐照强度和辐照时间进行高度可调操纵

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.