Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, TX, USA.
Section of Immunology, Allergy and Rheumatology, Department of Medicine, Biology of Inflammation Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.
Sci Adv. 2020 Jun 12;6(24):eabb3900. doi: 10.1126/sciadv.abb3900. eCollection 2020 Jun.
Cyclosporine A (CsA) is a powerful immunosuppressant, but it is an ineffective stand-alone treatment for systemic lupus erythematosus (SLE) due to poor target tissue distribution and renal toxicity. We hypothesized that CD71 (transferrin receptor 1)-directed delivery of CsA to the lymphatic system would improve SLE outcomes in a murine model. We synthesized biodegradable, ligand-conjugated nanoparticles [P2Ns-gambogic acid (GA)] targeting CD71. GA conjugation substantially increased nanoparticle association with CD3 or CD20 lymphocytes and with intestinal lymphoid tissues. In orally dosed MRL- mice, P2Ns-GA-encapsulated CsA increased lymphatic drug delivery 4- to 18-fold over the ligand-free formulation and a commercial CsA capsule, respectively. Improved lymphatic bioavailability of CsA was paralleled by normalization of anti-double-stranded DNA immunoglobulin G titer, plasma cytokines, and glomerulonephritis. Thus, this study demonstrates the translational potential of nanoparticles that enhance the targeting of lymphatic tissues, transforming CsA into a potent single therapeutic for SLE.
环孢素 A（CsA）是一种强效的免疫抑制剂，但由于其在靶组织中分布不良和肾毒性，CsA 单独使用对于治疗系统性红斑狼疮（SLE）效果不佳。我们假设将 CsA 通过 CD71（转铁蛋白受体 1）靶向递送至淋巴系统，将改善 SLE 小鼠模型的预后。我们合成了靶向 CD71 的生物可降解配体偶联纳米颗粒[P2Ns-藤黄酸（GA）]。GA 偶联显著增加了纳米颗粒与 CD3 或 CD20 淋巴细胞以及肠道淋巴组织的结合。在口服给予 MRL-/-小鼠后，P2Ns-GA 包封的 CsA 分别比无配体制剂和商业 CsA 胶囊使淋巴系统药物递送增加了 4-18 倍。CsA 的淋巴生物利用度提高与抗双链 DNA 免疫球蛋白 G 滴度、血浆细胞因子和肾小球肾炎的正常化平行。因此，本研究证明了增强靶向淋巴组织的纳米颗粒具有转化潜力，可将 CsA 转化为治疗 SLE 的强效单一药物。
