Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland; School of Pharmacy, RCSI, Dublin, Ireland.
Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland; Trinity Centre for Bioengineering, Trinity College Dublin (TCD), Dublin, Ireland; Advanced Materials and Bioengineering Research (AMBER) Centre, RCSI & TCD, Dublin, Ireland.
Acta Biomater. 2017 Jan 15;48:110-119. doi: 10.1016/j.actbio.2016.10.001. Epub 2016 Oct 20.
Lysolipid-based thermosensitive liposomes (LTSL) embedded in a chitosan-based thermoresponsive hydrogel matrix (denoted Lipogel) represents a novel approach for the spatiotemporal release of therapeutic agents. The entrapment of drug-loaded liposomes in an injectable hydrogel permits local liposome retention, thus providing a prolonged release in target tissues. Moreover, release can be controlled through the use of a minimally invasive external hyperthermic stimulus. Temporal control of release is particularly important for complex multi-step physiological processes, such as angiogenesis, in which different signals are required at different times in order to produce a robust vasculature. In the present work, we demonstrate the ability of Lipogel to provide a flexible, easily modifiable release platform. It is possible to tune the release kinetics of different drugs providing a passive release of one therapeutic agent loaded within the gel and activating the release of a second LTSL encapsulated agent via a hyperthermic stimulus. In addition, it was possible to modify the drug dosage within Lipogel by varying the duration of hyperthermia. This can allow for adaption of drug dosing in real time. As an in vitro proof of concept with this system, we investigated Lipogels ability to recruit stem cells and then elevate their production of vascular endothelial growth factor (VEGF) by controlling the release of a pro-angiogenic drug, desferroxamine (DFO) with an external hyperthermic stimulus. Initial cell recruitment was accomplished by the passive release of hepatocyte growth factor (HGF) from the hydrogel, inducing a migratory response in cells, followed by the delayed release of DFO from thermosensitive liposomes, resulting in a significant increase in VEGF expression. This delayed release could be controlled up to 14days. Moreover, by changing the duration of the hyperthermic pulse, a fine control over the amount of DFO released was achieved. The ability to trigger the release of therapeutic agents at a specific timepoint and control dosing level through changes in duration of hyperthermia enables sequential multi-dose profiles.
This paper details the development of a heat responsive liposome loaded hydrogel for the controlled release of pro-angiogenic therapeutics. Lysolipid-based thermosensitive liposomes (LTSLs) embedded in a chitosan-based thermoresponsive hydrogel matrix represents a novel approach for the spatiotemporal release of therapeutic agents. This hydrogel platform demonstrates remarkable flexibility in terms of drug scheduling and sequencing, enabling the release of multiple agents and the ability to control drug dosing in a minimally invasive fashion. The possibility to tune the release kinetics of different drugs independently represents an innovative platform to utilise for a variety of treatments. This approach allows a significant degree of flexibility in achieving a desired release profile via a minimally invasive stimulus, enabling treatments to be tuned in response to changing symptoms and complications.
基于溶血磷脂的温敏脂质体（LTSL）嵌入壳聚糖基温敏水凝胶基质（表示为 Lipogel）代表了一种用于治疗剂时空释放的新方法。将载药脂质体包封在可注射水凝胶中可以使局部脂质体保留，从而在靶组织中提供延长的释放。此外，可以通过使用微创外部热刺激来控制释放。释放的时间控制对于复杂的多步骤生理过程尤为重要，例如血管生成，其中为了产生强健的脉管系统，需要在不同时间使用不同的信号。在本工作中，我们证明了 Lipogel 提供灵活，易于修改的释放平台的能力。可以调整不同药物的释放动力学，为凝胶内装载的一种治疗剂提供被动释放，并通过热刺激激活第二种包裹的 LTSL 封装剂的释放。此外，可以通过改变热疗的持续时间来改变 Lipogel 中的药物剂量。这可以允许实时适应药物剂量。作为该系统的体外概念验证，我们研究了 Lipogel 通过控制外部热刺激下促血管生成药物去铁胺（DFO）的释放来募集干细胞并提高其血管内皮生长因子（VEGF）产生的能力。初始细胞募集是通过水凝胶中肝细胞生长因子（HGF）的被动释放来完成的，诱导细胞的迁移反应，然后从热敏脂质体中延迟释放 DFO，导致 VEGF 表达显著增加。这种延迟释放可以控制长达 14 天。此外，通过改变热疗脉冲的持续时间，可以实现对 DFO 释放量的精细控制。通过改变热疗持续时间在特定时间点触发治疗剂释放并控制剂量水平的能力实现了顺序多剂量曲线。
本文详细介绍了一种用于控制释放促血管生成治疗剂的热响应脂质体负载水凝胶的开发。基于溶血磷脂的温敏脂质体（LTSL）嵌入壳聚糖基温敏水凝胶基质代表了一种用于治疗剂时空释放的新方法。这种水凝胶平台在药物调度和排序方面表现出显著的灵活性，能够释放多种试剂，并能够以微创方式控制药物剂量。独立调整不同药物释放动力学的可能性代表了一种创新的平台，可用于各种治疗方法。这种方法通过微创刺激实现所需释放曲线的程度的灵活性，使治疗能够根据症状和并发症的变化进行调整。
