Center for Nanomedicine, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD 21231, USA.
Biomaterials. 2013 Sep;34(28):6922-9. doi: 10.1016/j.biomaterials.2013.05.039. Epub 2013 Jun 13.
Mucosal epithelia use osmotic gradients for fluid absorption and secretion. We hypothesized that administration of hypotonic solutions would induce fluid uptake that could be advantageous for rapidly delivering drugs through mucus to the vaginal epithelium. We found that hypotonic formulations markedly increased the rate at which small molecule drugs and mucoinert nanoparticles (mucus-penetrating particles, or MPP), but not conventional mucoadhesive nanoparticles (CP), reached the vaginal epithelial surface in vivo in mice. Additionally, hypotonic formulations greatly enhanced drug and MPP delivery to the entire epithelial surface, including deep into the vaginal folds (rugae) that drugs or MPP in isotonic formulations failed to reach efficiently. However, hypotonic formulations caused unencapsulated "free" drugs to be drawn through the epithelium, reducing vaginal retention. In contrast, hypotonic formulations caused MPP to accumulate rapidly and uniformly on vaginal surfaces, ideally positioned for localized sustained drug delivery. Using a mouse model of vaginal genital herpes (HSV-2) infection, we found that hypotonic delivery of free drug led to improved immediate protection, but diminished longer-term protection. In contrast, as we previously demonstrated, hypotonic delivery of drug via MPP led to better long-term retention and protection in the vagina. Importantly, we demonstrate that slightly hypotonic formulations provided rapid and uniform delivery of MPP to the entire vaginal surface, thus enabling formulations with minimal risk of epithelial toxicity. Hypotonic formulations for vaginal drug delivery via MPP may significantly improve prevention and treatment of reproductive tract diseases and disorders.
黏膜上皮利用渗透梯度进行液体吸收和分泌。我们假设，给予低渗溶液会诱导液体吸收，这对于通过黏液将药物快速递送至阴道上皮是有利的。我们发现，低渗制剂显著增加了小分子药物和 mucoinert 纳米颗粒（黏液穿透颗粒，或 MPP）到达体内小鼠阴道上皮表面的速度，而不会增加常规黏膜黏附纳米颗粒（CP）的速度。此外，低渗制剂大大增强了药物和 MPP 向整个上皮表面的递送，包括深入到阴道褶皱（皱襞），在等渗制剂中药物或 MPP 无法有效地到达这些部位。然而，低渗制剂会导致未封装的“游离”药物被穿过上皮细胞，从而减少阴道保留。相比之下，低渗制剂会使 MPP 迅速且均匀地积聚在阴道表面，为局部持续药物递送提供了理想的位置。在阴道生殖器疱疹（HSV-2）感染的小鼠模型中，我们发现游离药物的低渗递送导致即时保护得到改善，但长期保护减弱。相比之下，正如我们之前所证明的，通过 MPP 进行低渗药物递送可导致阴道中更好的长期保留和保护。重要的是，我们证明了轻微低渗制剂可迅速且均匀地将 MPP 递送至整个阴道表面，从而使制剂具有最小的上皮毒性风险。通过 MPP 进行阴道药物递送的低渗制剂可能会显著改善生殖道疾病和障碍的预防和治疗。
