Far-red light-mediated programmable anti-cancer gene delivery in cooperation with photodynamic therapy
Far-red light-mediated programmable anti-cancer gene delivery in cooperation with photodynamic therapy
复制标题
远红光介导的可编程抗癌基因传递与光动力疗法的配合
DOI：
10.1016/j.biomaterials.2018.04.020
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发表时间：
2018
期刊：
影响因子：
14
通讯作者：
Yin Lichen
中科院分区：
文献类型：
--
作者：
Wang Jinhui;He Hua;Xu Xin;Wang Xiao;Chen Yongbing;Yin Lichen
有效的抗癌治疗受到复杂的细胞外和细胞内屏障的阻碍，因此高度需要能够实现可编程基因递送的智能基因载体。基因递送过程的光操纵具有空间和时间精度，而大多数当前策略利用具有较差组织穿透性的短波长UV/可见光或高功率密度近红外（NIR）光，这将导致不期望的热损伤。在此，设计ROS可降解的聚阳离子并与光敏剂（PS）共递送，从而在低光功率密度（低至5 mW cm-2）下使用远红光（661 nm）实现光可编程基因递送。合成了硫代缩酮交联聚乙烯亚胺（TK-PEI）以使p53基因缩合形成纳米复合物（NCs），并将脱镁叶绿素a（Pha）修饰的透明质酸（HA）涂覆到NCs上以增强其胶体稳定性并使其能够靶向癌细胞。短时间（8分钟）光照射产生非致死量的ROS，以破坏内体膜，并通过降解TK-PEI促进p53基因释放，这共同提高了抗癌基因治疗的p53表达水平。在转染后的状态下长时间（30分钟）光照产生致死量的ROS，其协同杀死癌细胞以加强p53基因治疗。据我们所知，这项研究代表了“一石三鸟”的方法来实现合作抗癌基因治疗的第一个例子，使用低功率密度，长波长的可见光作为单一刺激。
Effective anti-cancer therapy is hurdled by the complicated extracellular and intracellular barriers, and thus a smart gene vector that can enable programmable gene delivery is highly demanded. Photo-manipulation of gene delivery processes features spatial and temporal precision, while majority of current strategies utilizes short-wavelength UV/visible light with poor tissue penetration or high-power-density near-infrared (NIR) light that would cause undesired heat damage. Herein, an ROS-degradable polycation was designed and co-delivered with a photosensitizer (PS), thus realizing photo-programmable gene delivery using far-red light (661 nm) at low optical power density (down to 5 mW cm−2). Thioketal-crosslinked polyethylenimine (TK-PEI) was synthesized to condense p53 gene to form nanocomplexes (NCs), and hyaluronic acid (HA) modified with pheophytin a (Pha) was coated onto NCs to enhance their colloidal stability and enable cancer cell targeting. Short-time (8-min) light irradiation produced non-lethal amount of ROS to disrupt the endosomal membranes and facilitate p53 gene release via degradation of TK-PEI, which collectively enhanced p53 expression levels toward anti-cancer gene therapy. Long-time (30-min) light irradiation at the post-transfection state generated lethal amount of ROS, which cooperatively killed cancer cells to strengthen p53 gene therapy. To the best of our knowledge, this study represents the first example of an “one stone, three birds” approach to realize cooperative anti-cancer gene therapy using low-power-density, long-wavelength visible light as a single stimulus.