Photoresponsive self-assembled structures

光响应自组装结构

• 批准号: RGPIN-2019-07142
• 负责人: Murphy, Robert
• 金额: $ 1.75万
• 依托单位: University of Regina
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739329
• 关键词: Photoresponsive; self; assembled; structures

We are developing amphiphilic organic molecules that respond to light by changing their structure and properties. These light-driven molecular switches (i.e., photoswitches) will be integrated with lipid vesicles to form photoresponsive self-assembled structures. These biocompatible self-assemblies will have potential application in `on-demand' drug delivery and theranostics (i.e., therapy and diagnostics). Nanoparticle delivery vehicles offer many advantages over conventional drug formulations. They increase drug solubility, minimize drug degradation, reduce clearance from the body, and enhance therapeutic efficacy. In addition, a delivery vehicle with light-triggered release provides a high level of spatial and temporal control. As a result, a higher local concentration of therapeutics can be dispensed, reducing the overall injected dose and systemic toxicity. Further, photoresponsive delivery vehicles with reversible photoswitches allow for repeated `on-demand' dosing from a single administration. Currently, the main challenge facing photoresponsive lipid vesicles as drug delivery systems is the lack of control over the release of hydrophobic therapeutic molecules from the lipid bilayer or hydrophilic molecules from the aqueous core. In addition, most photoswitches rely on high-energy UV light for activity. This dependence hinders the use of photoswitches in biomedical applications because UV light can be damaging to endogenous molecules and has relatively poor tissue penetration, which limits its use to organs that can be directly reached by endoscopic techniques. Consequently, the proposed research program will address these issues. First, we will prepare reversible, amphiphilic photoswitches that undergo a large change in hydrophobicity (i.e., a change in solubility) when irradiated with visible or near infrared (NIR) light. Second, we will examine the effect of photoswitch inclusion and isomerization (i.e., activity) on lipid bilayer mechanics. Namely, we will identify lipid vesicle formulations that undergo large changes in membrane fluidity and thickness upon irradiation with visible or NIR light. Significant photoinduced changes in lipid bilayer mechanics should trigger the formation of pores and enhance membrane permeability. Third, we will perform permeation assays to evaluate the effect of photoswitch activity on the delivery of therapeutics from these vesicle formulations. Overall, we will produce photoresponsive, biocompatible self-assemblies with application in drug delivery and theranostics. These objectives represent a systematic approach for achieving photocontrol in lipid-based self-assembled structures. This approach will lead to patentable technologies and benefit public health.

我们正在开发两亲有机分子，通过改变它们的结构和性质来对光做出反应。这些光驱动的分子开关(即光开关)将与脂泡集成，形成光响应的自组装结构。这些生物相容的自组装将在“按需”给药和治疗(即治疗和诊断)方面有潜在的应用。与传统药物相比，纳米颗粒输送载体具有许多优势。它们增加了药物的溶解度，最大限度地减少了药物的降解，减少了从体内的清除，并提高了治疗效果。此外，具有光触发释放的送货车辆提供了高水平的空间和时间控制。因此，可以分配更高的局部浓度的治疗药物，减少总体注射剂量和全身毒性。此外，具有可逆光开关的光响应型递送车辆允许从一次给药中重复“按需”给药。目前，光响应性脂泡作为药物递送系统面临的主要挑战是缺乏对脂双层中疏水性治疗分子或亲水性分子从水核中释放的控制。此外，大多数光开关的活动依赖于高能紫外光。这种依赖性阻碍了光开关在生物医学应用中的使用，因为紫外线可以损害内源性分子，而且组织穿透性相对较差，这将其使用限制在可以通过内窥镜技术直接到达的器官。因此，拟议的研究计划将解决这些问题。首先，我们将制备可逆的两亲性光开关，当受到可见光或近红外(NIR)光照射时，这种光开关的疏水性(即溶解度)会发生很大变化。其次，我们将研究光开关包涵体和异构化(即活性)对脂质双层机制的影响。也就是说，我们将确定在可见光或近红外光照射下，膜流动性和厚度发生重大变化的脂囊制剂。光诱导的脂质双层机制的显著变化应该会触发孔洞的形成，并增强膜的通透性。第三，我们将进行渗透测试，以评估光开关活性对这些囊泡制剂的治疗药物输送的影响。总体而言，我们将生产具有光响应性、生物相容性的自组装材料，并将其应用于药物输送和治疗。这些目标代表了在基于脂质的自组装结构中实现光控制的系统方法。这种方法将带来可申请专利的技术，并使公众健康受益。