title: Polyethylene glycol-functionalized poly (Lactic Acid-co-Glycolic Acid) and graphene oxide nanoparticles induce pro-inflammatory and apoptotic responses in Candida albicans-infected vaginal epithelial cells.
abstract: 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.
authors.affiliation: Microbiology Division, National Center for Toxicological Research, Jefferson, Arkansas, United States of America.
authors.forename: R Doug
authors.identifier: http://orcid.org/0000-0002-4738-5097
authors.initials: RD
authors.lastname: Wagner
authors.affiliation: Microbiology Division, National Center for Toxicological Research, Jefferson, Arkansas, United States of America.
authors.forename: Shemedia J
authors.initials: SJ
authors.lastname: Johnson
authors.affiliation: 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.
authors.forename: Zhixia Yan
authors.initials: ZY
authors.lastname: Danielsen
authors.affiliation: NCTR/ORA Nanotechnology Core Facility Jefferson, Arkansas, United States of America.
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Lim
authors.affiliation: NCTR/ORA Nanotechnology Core Facility Jefferson, Arkansas, United States of America.
authors.forename: Thilak
authors.initials: T
authors.lastname: Mudalige
authors.affiliation: NCTR/ORA Nanotechnology Core Facility Jefferson, Arkansas, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Linder
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002176:Candida albicans / Q000187:drug effects*; D002177:Candidiasis / Q000188:drug therapy*; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D016503:Drug Delivery Systems; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects*; D005260:Female; D006108:Graphite / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage* / Q000494:pharmacology*; D039841:Leukocyte L1 Antigen Complex / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000494:pharmacology*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014621:Vagina / Q000166:cytology / Q000382:microbiology; D014623:Vaginal Diseases / Q000188:drug therapy / Q000382:microbiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D039841:Leukocyte L1 Antigen Complex; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D006108:Graphite