Singlet Oxygen Degradable Materials to Harness the Near-Infrared Biological Transparency Window Efficiently

 产品说明：使用光来触发药物的高度局部释放是有希望的，但是除了可以直接用光照射的组织的治疗之外，光触发的药物释放受到在“近红外窗口”之外的波长（在大约650 - 1300 nm之间）通过组织的极其有限的透射的阻碍。在该窗口中有效吸收光的光不稳定部分几乎不存在，并且进入该窗口用于触发递送的现有技术方法，例如纳米颗粒的光热加热或光可裂解接头的双光子吸收，低效地使用光，因此即使使用强大的光源也具有高度有限的有效穿透深度。我们的长期目标是开发可用于药物按需释放的光不稳定触发释放材料平台。本申请的目的是开发一种新的材料方法来光触发的客人交付，使用组织穿透光释放被困客人。基于我们实验室的先前工作和文献先例，我们的中心假设是具有基于烷氧基并苯的交联剂的水凝胶将在波长大于650 nm的单线态氧（1 O2）光敏化时分解，并且这些材料的纳米颗粒将使得能够有效地光诱导释放客体。该项目的基本原理是，这种材料将利用一种高效的红光驱动的光物理过程，该过程已经被FDA批准-1 O2光敏化-以引起治疗剂的光诱导释放。Samuel托马斯教授是该应用交叉的两个领域的公认专家-i）光不稳定聚合物材料和ii）光生1 O2与并苯的反应，而Qiaobing Xu教授是纳米医学和药物递送方面的专家。我们将测试我们的中心假设，并通过追求以下具体目标来实现我们的目标：1。降解宏观水凝胶与交联剂含有烷氧基化并苯诱导1 O2光生波长≥ 650 nm; 2.从1 O2不稳定的纳米凝胶中释放药物阿霉素。该应用是创新的，因为它避免了当前访问生物NIR窗口的方法所固有的低效率。我们期望我们的方法将产生以下结果：i）在1 O2的光生作用下按需分解的新材料平台，ii）一系列基于并苯的部分，其在1 O2诱导的键断裂中跨越广泛的反应性范围，以及iii）在用组织渗透性红光或近红外光照射时将货物释放到游离溶液中的纳米颗粒。 本研究，沿着后续长期研究，将通过增加光诱导治疗递送的功效产生重要的积极影响，这将通过空间和时间控制减轻递送药物的脱靶效应以及照射本身的副作用。这项研究意义重大，因为它将使空间选择性 引发药物释放到组织中比目前可实现的更深。

 DESCRIPTION: The use of light to trigger a highly localized release of drugs is promising but with the exception of treatment of tissues that can be irradiated with light directly, photo-triggered drug release is hindered by the extremely limited transmission through tissues of wavelengths outside of the "near-infrared window", between approximately 650 - 1300 nm. Photolabile moieties that absorb light efficiently in this window are nearly non-existent, and state-of-the-art approaches to access this window for triggered delivery, such as photothermal heating of nanoparticles or two-photon absorption of photocleavable linkers, use light inefficiently and therefore have highly limited effective penetration depths, even with powerful light sources. Our long-term goal is to develop photolabile triggered-release material platforms that are useful for the on- demand release of drugs. The objective of this application is to develop a new materials approach to phototriggered guest delivery that uses tissue-penetrant light to release trapped guests. Our central hypothesis, based on both previous works in our laboratory and literature precedent, is that hydrogels with alkoxyacene-based cross linkers will decompose upon photosensitization of singlet oxygen (1O2) with wavelengths greater than 650 nm, and that nanoparticles of these materials will enable efficient light- induced release of guests. The rationale of this project is that such materials will harness an efficient, red light-driven photophysical process that is already FDA-approved-1O2 photosensitization-to cause photoinduced release of therapeutics. Prof. Samuel Thomas is a recognized expert in the two areas where this application intersect-i) photolabile polymeric materials and ii) the reactions of photogenerated 1O2 with acenes, while Prof. Qiaobing Xu is an expert in nanomedicine and drug delivery. We will test our central hypothesis and accomplish our objective by pursuing the following Specific Aims: 1. Degrade macroscopic hydrogels with cross linkers containing alkoxylated acenes induced by 1O2 photogenerated with wavelengths ≥ 650 nm; 2. Release the drug doxorubicin from 1O2-labile nanogels. This application is innovative, as it is circumvents the inefficiencies inherent to current approaches to accessing the biological NIR window. We expect that our approach will yield the following outcomes: i) new material platforms that decompose on demand upon photogeneration of 1O2, ii) a series of acene-based moieties that span a broad range of reactivity in 1O2-induced bond cleavage, and iii) nanoparticles that release cargo into free solution upon irradiation with tissue-penetrant red or near-infrared light. This study, along with subsequent long-term studies, will have an important positive impact by increasing the efficacy of photo-induced therapeutic delivery, which will mitigate both off-target effects of the delivered drugs through spatial and temporal control, as well as side effects of irradiation itself. The proposed research is significant because it will enable spatially-selective triggered drug release deeper into tissues than is currently achievable.