NIR调控的“集束炸弹”式光疗体系用于肿瘤的深层渗透及联合治疗

Emerging therapies for tumor treatment such as photodynamic therapy (PDT) and photothermal therapy (PTT) possess varieties of advantages including high controllability, admirable curative effect and slight side effects. However, the conventional photosensitizers in PDT and PTT are generally hard to reach deep region of tumor ascribe to the disorganized vasculature and high interstitial pressure in tumor tissues. In addition, the hypoxic microenvironment in deep region of tumor restricts therapeutic efficiency of PDT which heavily depends on oxygen concentration. In that case, we designed and synthesized a procedurally controlled "cluster bombs" nano-system for synergistic tumor therapy. The pony-size photothermal photosensitizer, quantum dot (QD), was decorated with penetrating peptides and further linked to photo-to-heat nanoheaters gold nanostar (GNS) by temperature-sensitive initiator. Thereafter, dimethylmaleic anhydride (DA) was modified on the surface of above system to screen charge for extending systemic circulation time. While the "cluster bombs" nano-system arrived in tumor, the first-stage near infrared (NIR) light irradiation could accelerate initiator broking by solar thermal conversion, and the generated alkyl free radical achieved efficient PDT dispense with oxygen. Meantime, the dissociative QD could permeate into deep region of tumor benefits from the penetrating peptides and their subsize, and realize the deep-seated PTT. Upon our design, the broad-spectrum elimination for different types and different depth of tumor cells was achieved by programmed stimulating responses including charge reversal, dimensional change as well as the synergy between PDT and PTT, also provided a new strategy for synergistic tumor therapy in the future.

基于近红外光的光动力学治疗（PDT）与光热治疗（PTT）由于具有可控性强、治疗效率高和副作用小等优点而广泛应用于肿瘤治疗中。然而，由于肿瘤组织通常具有紊乱的脉管系统与较高肿瘤间质压，导致传统光敏剂的肿瘤间质传递受限，难以抵达肿瘤组织深层。此外，肿瘤组织的乏氧特性极大地限制了氧依赖PDT的治疗效果。针对上述问题，拟用温敏引发剂将肿瘤渗透肽修饰的光热量子点键接于光热材料金纳米星表面，并以酸酐对体系进行修饰，设计程序化“集束炸弹”式治疗体系用于肿瘤治疗。近红外光照下体系产热，致使引发剂断裂产生烷基自由基用于非氧依赖的PDT；同时，小尺寸、渗透性强的量子点从体系脱除，二次光照下实现肿瘤深层的PTT。该体系有望通过电势翻转和尺寸变化实现高效的间质传递和深层渗透，利用PDT与PTT的高效协同实现对肿瘤细胞的彻底清除。该体系的设计为程序响应型肿瘤深层治疗体系的开发提供新策略。

由于肿瘤组织通常具有紊乱的脉管系统与较高的肿瘤间质压，治疗剂的肿瘤间质传递受限。而有限的间质传递和不佳的治疗效果，都将导致肿瘤的复发和转移。研究和开发用于肿瘤深层递送的联合治疗体系是增强肿瘤治疗效率的重要途径，并对肿瘤的个性化治疗和彻底清除也大有裨益，具有重要的研究意义与应用价值。本项目设计和制备了具有肿瘤酸响应、酶触发及NIR调控的程序化“集束炸弹”式治疗体系，旨在通过外界近红外光照及肿瘤微环境的刺激响应性实现治疗剂的尺寸变化，增强其渗透性，最终实现治疗剂的深层递送和肿瘤的精准治疗。其中，肿瘤靶向自递送体系KDH在透明质酸保护作用和肿瘤靶向作用下有效定位至肿瘤部位并被其内吞，在肿瘤组织透明质酸酶作用下保护层降解，同时肿瘤组织的酸性环境刺激胶束结构解体，释放细胞凋亡肽和DOX，有效清除了肿瘤组织。多功能递送系统EINP@DOX，将治疗、成像和抗转移功能集于一身，循环至肿瘤组织后，在肿瘤酸性环境下递送体系解体并释放DOX和EGCG，在实现程序性肿瘤治疗的同时，有效抑制了肿瘤细胞的转移；同时还能通过MRI成像实时监测肿瘤治疗情况。多功能的纳米平台GNS-P，结合了siRNA运载能力、肿瘤靶向能力和细胞内化功能，将siRNA利用修饰有穿膜肽的金纳米星载体递送到肿瘤部位并被其内吞，展现了高效的基因递送能力；同时，GNS-P优异的光热转换能力和光声/光热成像能力可进一步用于肿瘤诊疗一体化。NIR调控的光热纳米平台GNS@CuS在NIR刺激下能实现从大到小的转变，有效渗透到肿瘤深层消融肿瘤细胞，并能通过光声/光热成像实现肿瘤诊疗一体化。本项目开发了一系列具有尺寸转换能力的肿瘤联合治疗体系，还赋予了体系肿瘤抗转移的能力和诊断功能，实现不同种类肿瘤细胞的广谱性清除，有效降低了肿瘤细胞的转移，亦能通过多种成像手段对治疗效果进行实时监测，为程序响应型诊疗一体化的肿瘤深层治疗体系提供了一定的研究基础。