Pterygium is a degenerative disease that characterized by excessive fibrovascular proliferation. To reduce the recurrence rate, surgery is the main strategy, in combination with adjacent procedures or adjunctive therapy. One of the most common adjunctive agents, mitomycin C (MMC), is known as an alkylating agent that inhibits fibroblast proliferation but is limitedly applied in pterygium due to various complications. A previous study demonstrated that activated pterygium subconjunctival fibroblasts overexpressed low-density lipoprotein (LDL) receptors. In this study, we designed and synthesized MMC-loaded mesoporous silica nanoparticles conjugated with LDL (MMC@MSNs-LDL) to deliver MMC into activated pterygium fibroblasts in a targeted manner. The MMC loading efficiency was approximately 6%. The cell viability test (CCK-8 assay) revealed no cytotoxicity for the empty carrier MSNs at a concentration of ≤1 mg/ml after administration for 48 h in subconjunctival fibroblasts. Primary pterygium and normal human subconjunctival fibroblasts with or without stimulation by vascular endothelial growth factor (VEGF) were treated as follows: 1) 10 μg/ml MMC@MSNs-LDL for 24 h (MMC concentration: 0.6 μg/ml); 2) 0.2 mg/ml MMC for 5 min then cultured for 24 h after MMC removal; and 3) normal culture without any drug treatment. At 24 h, the anti-proliferative effect of MMC@MSNs-LDL in activated pterygium fibroblasts was similar to that of MMC (cell viability: 46.2 ± 5.5% vs 40.5 ± 1.1%, respectively, P = 0.349). Furthermore, the cytotoxicity of MMC@MSNs-LDL to normal fibroblasts with or without VEGF stimulation was significantly lower than that of traditional MMC (cell viability: 75.6 ± 4.4% vs 36.0 ± 1.5%, respectively, P < 0.001; 84.7 ± 5.5% vs 35.7 ± 1.3%, P < 0.001). The binding of fluorescently labeled MMC@MSNs-LDL in fibroblasts was assessed using confocal fluorescence microscopy. The uptake of targeted nanoparticles in fibroblasts was time dependent and saturated at 6 h. VEGF-activated pterygium fibroblasts showed more uptake of MMC@MSNs-LDL than normal fibroblasts with or without VEGF activation (both P < 0.001). Our data strongly suggest that MMC@MSNs-LDL had an effective antiproliferative role in activated pterygium fibroblasts, with reduced toxicity to normal fibroblasts compared to traditional application of MMC. LDL-mediated drug delivery might have great potential in the management of pterygium recurrence.

翼状is肉是一种退行性疾病，其特征是过度的血管扩张。为了降低复发率，手术是主要策略，并与邻近的手术或辅助治疗相结合。最常见的辅助剂之一是丝裂霉素C（MMC），它是一种抑制成纤维细胞增殖的烷基化剂，但由于各种并发症，其在翼状ery肉中的应用受到限制。先前的研究表明，激活的结膜下翼状ery肉成纤维细胞过度表达了低密度脂蛋白（LDL）受体。在这项研究中，我们设计并合成了与LDL（MMC @ MSNs-LDL）偶联的MMC负载的介孔二氧化硅纳米颗粒，以靶向方式将MMC输送到活化的翼状fi肉成纤维细胞中。MMC的加载效率约为6％。细胞活力测试（CCK-8分析）显示，结膜下成纤维细胞中给药48小时后，≤1mg / ml的空载体MSNs没有细胞毒性。对有或没有血管内皮生长因子（VEGF）刺激的原发性翼状and肉和正常人结膜下成纤维细胞进行如下处理：1）10μg/ ml MMC @ MSNs-LDL持续24 h（MMC浓度：0.6μg/ ml）；2）MMC 0.2 mg / ml 5分钟，去除MMC后培养24 h；3）未经任何药物治疗的正常培养。在24小时时，MMC @ MSNs-LDL在活化的翼状pt肉成纤维细胞中的抗增殖作用与MMC相似（细胞活力分别为46.2±5.5％和40.5±1.1％，P = 0.349）。此外，MMC @ MSNs-LDL对有或无VEGF刺激的正常成纤维细胞的细胞毒性显着低于传统MMC（细胞活力分别为75.6±4.4％vs 36.0±1.5％，P <0.001; 84.7±5.5％vs 35.7 ±1.3％，P <0.001）。使用共聚焦荧光显微镜评估成纤维细胞中荧光标记的MMC @ MSNs-LDL的结合。成纤维细胞中靶向纳米颗粒的吸收是时间依赖性的，并在6 h达到饱和。VEGF激活的翼状fi肉成纤维细胞比具有或不具有VEGF激活的正常成纤维细胞显示更多的MMC @ MSNs-LDL吸收（均P <0.001）。我们的数据强烈表明，MMC @ MSNs-LDL在活化的翼状肉成纤维细胞中具有有效的抗增殖作用，与传统的MMC应用相比，对正常成纤维细胞的毒性降低。