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Abstract：
Trabeculectomy is the mainstay of surgical glaucoma treatment, while the success rate was unsatisfying due to postoperative scarring of the filtering blebs. Clinical countermeasures for scar prevention are intraoperative intervention or repeated subconjunctival injections. Herein, we designed a co-delivery system capable of transporting fluorouracil and anti-TGF-β2 oligonucleotide to synergistically inhibit fibroblast proliferation via topical instillation. This co-delivery system was built based on a cationic dendrimer core (PAMAM), which encapsulated fluorouracil within hydrophobic cavity and condensed oligonucleotide with surface amino groups, and was further modified with hyaluronic acid and cell-penetrating peptide penetratin. The co-delivery system was self-assembled into nanoscale complexes with increased cellular uptake and enabled efficient inhibition on proliferation of fibroblast cells. In vivo studies on rabbit trabeculectomy models further confirmed the anti-fibrosis efficiency of the complexes, which prolonged survival time of filtering blebs and maintained their height and extent during wound healing process, exhibiting an equivalent effect on scar prevention compared to intraoperative infiltration with fluorouracil. Qualitative observation by immunohistochemistry staining and quantitative analysis by Western blotting both suggested that TGF-β2 expression was inhibited by the co-delivery complexes. Our study provided a potential approach promising to guarantee success rate of trabeculectomy and prolong survival time of filtering blebs.
摘要：
小梁切除术是青光眼外科治疗的主要手段,而由于术后滤过泡的疤痕，成功率并不令人满意。预防瘢痕的临床对策是术中干预或重复结膜下注射。在这里，我们设计了一种能够转运氟尿嘧啶和抗TGF-β2寡核苷酸的共递送系统,通过局部滴注协同抑制成纤维细胞增殖.这种共递送系统是基于阳离子树枝状聚合物核心（PAMAM）构建的，将氟尿嘧啶包裹在疏水腔内，并与表面氨基缩合寡核苷酸，并进一步用透明质酸和细胞穿透肽进行修饰。共递送系统自组装成纳米级复合物,具有增加的细胞摄取,并且能够有效抑制成纤维细胞的增殖。兔小梁切除术模型的体内研究进一步证实了复合物的抗纤维化功效，延长了过滤泡的存活时间，并在伤口愈合过程中保持了其高度和程度，与术中使用氟尿嘧啶浸润相比，对瘢痕预防具有同等效果。通过免疫组织化学染色的定性观察和通过Western印迹的定量分析都表明TGF-β2表达被共递送复合物抑制。我们的研究提供了一种潜在的方法，有望保证小梁切除术的成功率并延长滤过泡的存活时间。
