5-氨基酮戊酸/金三角双载药纳米醇脂体的制备及其经皮光动力/光热协同治疗增生性瘢痕的实验研究

At present, the therapeutic efficiency of photodynamic therapy (PDT) on hypertrophic scars (HS) are mainly compromised by two factors: poor scar penetration of photosensitizer (PS) and low reactive oxygen species (ROS) production from PS under irradiation. To overcome these limitations of PDT, a synergistic photodynamic/photothermal therapy (PDT/PTT) on HS is developed by using a photosensitizer 5-aminolevulinic acid (ALA) combined with high-performance photothermal agents of Gold nanotriangles (GNTs). Biocompatible ALA and GNTs dual-loaded ethosomal vesicles (ALA/GNTs-ES) is prepared to promote ALA/GNTs penetrating into full thickness scar, homogenously and effectively. Under irradiation of laser, the local surface plasma resonance (LSPR) and photo-thermal conversion efficiency of GNTs can promote ROS generation, as well as generate direct thermal damage to establish PDT/PTT dual mode therapy. In this research, in vitro HS penetration study, in vitro fibroblasts and in vivo rabbit era HS model study will be done to investigate the abilities of ALA/GNTs-ES in HS penetration, fibroblast apoptosis promotion. Furthermore, the synergistic PDT/PTT approach based on ALA/GNTs-ES will be well studied in synergistic mechanism and efficacy for HS treatment. It will establish approach for HS treatment by synergistic PDT/PTT approach with encouraging perspectives.

增生性瘢痕的光动力治疗（PDT）临床疗效不佳，主要受限于光敏剂瘢痕渗透性能差及光敏剂活性氧簇（ROS）产率低。本研究从提高ROS产率、将单一PDT转变为光动力/光热（PDT/PTT）协同治疗出发。首先应用高透皮性能的纳米醇脂体对光敏剂5-氨基酮戊酸（ALA）和金纳米三角（GNTs）进行包载，构建集瘢痕渗透、光动力和光热效应于一体的多功能光敏剂（ALA/GNTs-ES），实现ALA和GNTs在瘢痕组织细胞内同步运输。其次，利用GNTs的表面等离子共振和光热转化效应，通过提高ROS产率和直接热损伤，产生PDT/PTT协同效应增强增生性瘢痕的疗效。本研究将通过离体瘢痕渗透、体外细胞和动物实验研究，阐明ALA/GNTs-ES在瘢痕组织中的渗透性能、CNTs提高ROS产率及PDT/PTT对成纤维细胞凋亡和胶原纤维重塑的影响和作用机制，为最终建立增生性瘢痕全新的PDT/PTT协同治疗模式提供研究基础。

光动力疗法(Photodynamic therapy，PDT)是一种新兴的治疗增生性瘢痕(Hypertrophic scars，HS)的策略，它严重依赖活性氧(reactive oxygen species，ROS)的产生。然而，由于5-氨基酮戊酸(5-aminolevulinic acid，ALA)的传递和激发不理想，导致ROS生成不足，从而限制了PDT治疗增生性瘢痕(HS-PDT)的临床应用。因此，本研究利用超声原位还原法，利用纳米醇质体(Nanoethosomes，ES)同时包载ALA和金纳米三角形(Au nanotriangles，AuNTs)制备了可实现透皮共递送的纳米光敏剂A/A-ES。所制备的A/A-ES可通过局部表面等离子体共振(Localized surface plasmon resonance，LSPR)提高ALA的激发效率，增强瘢痕组织中ROS产率，从而改善HS-PDT治疗效果。A/A-ES可经皮渗透进入瘢痕组织的成纤维细胞中，并在在细胞质中产生足够的原卟啉IX和LSPR效应，有利于ALA的激发和ROS的产生。体外/体内研究表明，A/A-ES通过LSPR可增强ROS生成，显著改善HS-PDT促进HSF凋亡和胶原重塑。因此，本研究提供了一种可行的策略，将透皮给药和LSPR效应结合起来，通过促进ALA的给药和激发来实现和潜在HS-PDT的有益作用。