Wagner R Doug, Johnson Shemedia J, Danielsen Zhixia Yan, Lim Jin-Hee, Mudalige Thilak, Linder Sean
Microbiology Division, National Center for Toxicological Research, Jefferson, Arkansas, United States of America.
Division of Clinical Pharmacology IV, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, White Oak, Maryland, United States of America.
PLoS One. 2017 Apr 3;12(4):e0175250. doi: 10.1371/journal.pone.0175250. eCollection 2017.
Mucous-penetrating nanoparticles consisting of poly lactic acid-co-glycolic acid (PLGA)-polyethylene glycol (PEG) could improve targeting of microbicidal drugs for sexually transmitted diseases by intravaginal inoculation. Nanoparticles can induce inflammatory responses, which may exacerbate the inflammation that occurs in the vaginal tracts of women with yeast infections. This study evaluated the effects of these drug-delivery nanoparticles on VK2(E6/E7) vaginal epithelial cell proinflammatory responses to Candida albicans yeast infections. Vaginal epithelial cell monolayers were infected with C. albicans and exposed to 100 μg/ml 49.5 nm PLGA-PEG nanospheres or 20 μg/ml 1.1 x 500 nm PEG-functionalized graphene oxide (GO-PEG) sheets. The cells were assessed for changes in mRNA and protein expression of inflammation-related genes by RT-qPCR and physiological markers of cell stress using high content analysis and flow cytometry. C. albicans exposure suppressed apoptotic gene expression, but induced oxidative stress in the cells. The nanomaterials induced cytotoxicity and programmed cell death responses alone and with C. albicans. PLGA-PEG nanoparticles induced mRNA expression of apoptosis-related genes and induced poly (ADP-ribose) polymerase (PARP) cleavage, increased BAX/BCL2 ratios, and chromatin condensation indicative of apoptosis. They also induced autophagy, endoplasmic reticulum stress, and DNA damage. They caused the cells to excrete inflammatory recruitment molecules chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-1α (IL1A), interleukin-1β (IL1B), calprotectin (S100A8), and tumor necrosis factor α (TNF). GO-PEG nanoparticles induced expression of necrosis-related genes and cytotoxicity. They reduced autophagy and endoplasmic reticulum stress, and apoptotic gene expression responses. The results show that stealth nanoparticle drug-delivery vehicles may cause intracellular damage to vaginal epithelial cells by several mechanisms and that their use for intravaginal drug delivery may exacerbate inflammation in active yeast infections by increased inflammatory recruitment.
由聚乳酸-乙醇酸共聚物（PLGA）-聚乙二醇（PEG）组成的黏液穿透性纳米颗粒可通过阴道接种改善用于性传播疾病的杀菌药物的靶向性。纳米颗粒可诱导炎症反应，这可能会加剧酵母菌感染女性阴道中发生的炎症。本研究评估了这些药物递送纳米颗粒对VK2（E6/E7）阴道上皮细胞对白色念珠菌酵母菌感染的促炎反应的影响。阴道上皮细胞单层感染白色念珠菌，并暴露于100μg/ml的49.5nm PLGA-PEG纳米球或20μg/ml的1.1×500nm聚乙二醇功能化氧化石墨烯（GO-PEG）片。通过逆转录定量聚合酶链反应（RT-qPCR）评估细胞炎症相关基因的mRNA和蛋白质表达变化，并使用高内涵分析和流式细胞术评估细胞应激的生理标志物。白色念珠菌暴露抑制了凋亡基因表达，但诱导了细胞内的氧化应激。纳米材料单独以及与白色念珠菌共同作用时均诱导了细胞毒性和程序性细胞死亡反应。PLGA-PEG纳米颗粒诱导了凋亡相关基因的mRNA表达，并诱导了聚（ADP-核糖）聚合酶（PARP）裂解，增加了BAX/BCL2比值以及表明凋亡的染色质凝聚。它们还诱导了自噬、内质网应激和DNA损伤。它们导致细胞分泌炎症募集分子趋化因子（C-X-C基序）配体1（CXCL1）、白细胞介素-1α（IL1A）、白细胞介素-1β（IL1B）、钙卫蛋白（S100A8）和肿瘤坏死因子α（TNF）。GO-PEG纳米颗粒诱导了坏死相关基因的表达和细胞毒性。它们减少了自噬和内质网应激以及凋亡基因表达反应。结果表明，隐形纳米颗粒药物递送载体可能通过多种机制对阴道上皮细胞造成细胞内损伤，并且它们用于阴道药物递送可能会通过增加炎症募集而加剧活动性酵母菌感染中的炎症。
