Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, No. 174 Shazheng Road, Chongqing 400044, China.
Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Tykistökatu 6A, Turku 20520, Finland.
Acta Biomater. 2019 Mar 1;86:416-428. doi: 10.1016/j.actbio.2019.01.002. Epub 2019 Jan 3.
Combined photothermal and gene therapy provides a promising modality toward cancer treatment, yet facile integration and controlled codelivery of gene payloads and photothermal conversion agents (PTCAs) remains a great challenge. Inspired by the robust wet adhesion of marine mussels, we present a rationally designed nanosystem constructed by using hybrid mesoporous polydopamine nanoparticles (MPDA) with sub-100 nm sizes and a high photothermal conversion efficiency of 37%. The surface of the particles were modified with tertiary amines by the facile Michael addition/Schiff base reactions of PDA to realize high siRNA loading capacity (10 wt%). Moreover, a successful calcium phosphate (CaP) coating via biomineralization was constructed on the cationic nanoparticle to prohibit premature release of siRNA. The CaP coating underwent biodegradation in weakly-acidic subcellular conditions (lysosomes). The synergistic integration of tertiary amines and catechol moieties on the subsequently exposed surfaces was demonstrated to feature the destabilization/disruption ability toward model cellular membranes via the greatly enhanced interfacial adhesion and interactions. Consequently, sufficient permeability of lysosomal membranes, and in turn, a high lysosomal escape efficiency, was realized, which then resulted in high gene silencing efficiencies via sufficient cytosolic delivery of siRNA. When an efficient knocking down (65%) of survivin (an inhibitor of apoptosis proteins) was combined with a subsequent photothermal ablation, remarkably higher therapeutic efficiencies were observed both in vitro and in vivo, as compared with monotherapy. The system may help to pave a new avenue on the utilization of bio-adhesive surfaces for handling the obstacles of combined photothermal and gene therapy. STATEMENT OF SIGNIFICANCE: Polydopamine (PDA) based porous photothermal-conversion agent (PTCA) with sufficiently high conversion efficiency was employed to deliver photothermal/gene therapy modalities towards cancer treatment. CaP coating via PDA-induced biomineralization was constructed to prohibit premature release of siRNA loaded in the pore space of the nanocarriers. Responsive degradation of CaP also led to the exposure of membrane-lytic surfaces built through the synergistic integration of tertiary amines and catechol moieties, and in turn the significantly enhanced lysosomal escape and cytosol siRNA delivery. Therapeutic targeting of survivin was successfully applied for activation of apoptosis and programmed cell death. Combined photothermal and gene therapy improved therapeutic effectiveness.
联合光热和基因治疗为癌症治疗提供了一种很有前途的方法，但简便地整合和控制基因有效载荷和光热转换剂（PTCAs）的共递仍然是一个巨大的挑战。受海洋贻贝强大的湿黏附启发，我们提出了一种合理设计的纳米系统，该系统由具有亚 100nm 尺寸和 37%高光热转换效率的混合介孔聚多巴胺纳米粒子（MPDA）构建。通过 PDA 的简单迈克尔加成/席夫碱反应，将粒子表面修饰上叔胺，实现了高 siRNA 载量（10wt%）。此外，通过生物矿化在阳离子纳米颗粒上成功构建了钙磷（CaP）涂层，以阻止 siRNA 的过早释放。在弱酸性细胞内条件（溶酶体）下，CaP 涂层经历了生物降解。随后暴露表面上的叔胺和儿茶酚部分的协同整合，通过界面粘附和相互作用的大大增强，显示出对模型细胞膜的破坏能力。因此，溶酶体膜的通透性得到了充分提高，从而实现了高溶酶体逃逸效率，进而通过 siRNA 的充分胞质递送实现了高基因沉默效率。当与随后的光热消融相结合，有效地敲低（65%）凋亡抑制蛋白 survivin 时，与单一疗法相比，在体外和体内都观察到了更高的治疗效率。该系统可能有助于为利用生物黏附表面来处理联合光热和基因治疗的障碍开辟新途径。
