Engineered Near-infrared Light Sensitive Nanovesicles for Precise Image-Guided Thermally Triggered Cancer Therapy

纳米载体在控制附带损伤和改善多种化疗药物的生物分布方面显示出巨大的潜力。实现这一性能改进的一个关键现象是，由于其血管系统的高渗透性，纳米载体优先积累到癌症组织中。然而，肿瘤的异质性分布和纳米载体的药物释放是一个问题，我们的目标是解决这个问题，工程多功能纳米载体结合实时成像和触发释放是实现精确和高效治疗的迫切需要。温度敏感型囊泡最近引起了越来越多的关注，这些囊泡系统已经进入临床(其中ThermoDox是最先进的形式)。然而，用于触发药物释放的加热技术都是基于对肿瘤块的整体加热，具有加热不均匀和亚热的局限性。因此，为了克服上述缺点，我们提出了一种一体化的图像引导和热响应纳米囊泡，将抗癌药物包裹在其内部并标记光敏的临床批准的吲哚青绿(ICG)染料。ICG的近红外(NIR)吸光度对于肿瘤的深度穿透和最小化光散射是必不可少的。我们之前已经证明，ICG标记的非温度敏感囊泡的外部激活允许非侵入性的动态成像分布到肿瘤中。在这个项目中，我们假设在热触发的囊泡的外膜中掺入ICG不仅可以跟踪肿瘤块中的非侵袭性分布，而且还可以将染料分子吸收的光辐射转化为局部热。在温度敏感型囊泡的外膜上产生纳米级的光热加热有望与更有效的热触发药物释放相关，并减少不必要的热损害。

Nanocarriers have demonstrated great potential to control collateral damage and improve biodistribution of a variety of chemotherapeutic agents. A phenomenon that is key to enable this performance improvement is the preferential accumulation of nanocarriers into a cancerous tissue due the hyperpermeability of its vasculature. However, the heterogeneous tumour distribution and drug release from nanocarriers is an issue.Our aim is to solve the problem engineering multifunctional nanocarriers to combine real-time imaging and triggered release is highly required to achieve precise and efficient therapy. Temperature-responsive vesicles has been attracting increasing attention lately and these vesicular systems have found their way into the clinic (with Thermodox being the most advanced form). However, the heating technologies used to trigger drug release are all based on bulk heating of the tumour mass which has the limitation of uneven and sub-thermal heating.Therefore, to overcome the shortcomings listed above, we propose the engineering of all-in-one image-guided and thermal responsive nano-vesicles that encapsulate anti-cancer drugs in their interior and labelled with light sensitive-clinically approved-indocyanine green (ICG) dye. The ICG near-infrared (NIR) absorbance is essential to allow deep tumour penetration and minimise light scattering. We have shown previously that external activation of ICG-labelled non-temperature sensitive vesicles allows non-invasive dynamic imaging of the distribution into the tumour.In this project we hypothesize that the incorporation of ICG in the outer membrane of thermally triggered vesicles will not only allow the tracking the non-invasive distribution in the tumour mass, but also to transduce the absorbed light radiation by the dye molecules into local heat. The generation of photothermal heating at the nanoscale level in the outer membrane of temperature-sensitive vesicles is expected to be associated with more efficient thermally triggered drug release with less unwanted thermal damage.