Laboratory of Future Nanomedicines and Theoretical Chronopharmaceutics, Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City , 2464 Charlotte, Kansas City, Missouri 64108, United States.
Department of Chemistry, University of Missouri-Kansas City , 5100 Rockhill Road, Kansas City, Missouri 64110, United States.
Mol Pharm. 2017 Oct 2;14(10):3512-3527. doi: 10.1021/acs.molpharmaceut.7b00555. Epub 2017 Sep 13.
The purpose of this study was to engineer a model anti-HIV microbicide (tenofovir) drug delivery system targeting HIV-1 envelope glycoprotein gp120 (HIV-1 g120) for the prevention of HIV sexual transmission. HIV-1 g120 and mannose responsive particles (MRP) were prepared through the layer-by-layer coating of calcium carbonate (CaCO) with concanavalin A (Con A) and glycogen. MRP average particle size ranged from 881.7 ± 15.45 nm to 1130 ± 15.72 nm, depending on the number of Con A layers. Tenofovir encapsulation efficiency in CaCO was 74.4% with drug loading of 16.3% (w/w). MRP was non-cytotoxic to Lactobacillus crispatus, human vaginal keratinocytes (VK2), and murine macrophage RAW 264.7 cells and did not induce any significant proinflammatory nitric oxide release. Overall, compared to control, no statistically significant increase in proinflammatory cytokine IL-1α, IL-1β, IL-6, MKC, IL-7, and interferon-γ-inducible protein 10 (IP10) levels was observed. Drug release profiles in the presence of methyl α-d-mannopyranoside and recombinant HIV-1 envelope glycoprotein gp120 followed Hixson-Crowell and Hopfenberg kinetic models, indicative of a surface-eroding system. The one Con A layer containing system was found to be the most sensitive (∼2-fold increase in drug release vs control SFS:VFS) at the lowest HIV gp120 concentration tested (25 μg/mL). Percent mucoadhesion, tested ex vivo on porcine vaginal tissue, ranged from 10% to 21%, depending on the number of Con A layers in the formulation. Collectively, these data suggested that the proposed HIV-1 g120 targeting, using MRP, potentially represent a safe and effective template for vaginal microbicide drug delivery, if future preclinical studies are conclusive.
本研究旨在构建一种靶向 HIV-1 包膜糖蛋白 gp120（HIV-1 g120）的抗 HIV 微生态制剂（替诺福韦）药物递送系统，用于预防 HIV 性传播。通过碳酸钙（CaCO）与伴刀豆球蛋白 A（Con A）和糖原的层层包裹，制备了 HIV-1 g120 和甘露糖响应颗粒（MRP）。MRP 的平均粒径范围为 881.7±15.45nm 至 1130±15.72nm，取决于 Con A 层数。CaCO 中替诺福韦的包封效率为 74.4%，载药量为 16.3%（w/w）。MRP 对乳酸乳球菌、人阴道角质形成细胞（VK2）和鼠巨噬细胞 RAW 264.7 细胞均无细胞毒性，且不会诱导任何明显的促炎型一氧化氮释放。总体而言，与对照组相比，促炎细胞因子白细胞介素-1α、白细胞介素-1β、白细胞介素-6、MKC、白细胞介素-7 和干扰素-γ诱导蛋白 10（IP10）水平未见统计学显著升高。在甲基-α-D-甘露吡喃糖苷和重组 HIV-1 包膜糖蛋白 gp120 的存在下，药物释放曲线符合 Hixson-Crowell 和 Hopfenberg 动力学模型，表明这是一种表面侵蚀系统。在测试的最低 HIV gp120 浓度（25μg/mL）下，发现含有 1 层 Con A 的系统最敏感（与对照 SFS:VFS 相比，药物释放增加约 2 倍）。在猪阴道组织上进行的离体黏膜黏附率测试结果显示，黏附率范围为 10%至 21%，具体取决于制剂中 Con A 层数。总之，如果未来的临床前研究结论一致，这些数据表明，使用 MRP 靶向 HIV-1 g120 可能为阴道微生态制剂药物递送提供一种安全有效的模板。
