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.

Nanotechnology in reproductive medicine: Opportunities for clinical translation

“…The developed formulation exhibited a remarkable improvement (roughly five-fold) in the sustained delivery of the drug in comparison to the non-adhesive alternative formulation. The results of the research highlighted the potential of the adhesive PLA-HPG nano-formulation for intravaginal therapeutics to treat and prevent STIs [65]. Aside from STIs associated with HSV, Wagner et al [66] developed a nanoparticle-based targeted approach that comprised microbicidal drugs encapsulated in mucous-penetrating PLGA-PEG nanoparticles for intravaginal inoculation against STIs.…”

Intravaginal poly-(D, L-lactic-co-glycolic acid)-(polyethylene glycol) drug-delivery nanoparticles induce pro-inflammatory responses with Candida albicans infection in a mouse model

“…Vulvovaginal candidiasis is an opportunistic fungal infection predominantly caused by overgrowth of Candida albicans that colonizes the vagina. The infection induces a strong inflammatory response in localized vaginal and vulvar epithelial tissues [ 1 ]. It remains the most prevalent organism in both mucosal and systemic yeast infections.…”

“…We recently showed that vaginal epithelial cells (VEC) in vitro contribute to inflammatory recruitment by secreting inflammatory cytokines after recognizing C . albicans through Nod-like receptors and a pyroptosis mechanism [ 1 ]. Though the innate immune response is required for clearance of C .…”

Synthesis of Polyphosphate‐Loaded Nanoparticles Using Inverse Miniemulsion Polymerization for Sustained Delivery to the Gastrointestinal Tract

“…Our group has focused on the production of nanoparticles composed of a polyethylene glycol diacrylate (PEGDA)–n‐vinyl pyrrolidone (NVP) crosslinked hydrogel matrix encapsulated with phosphate salts and synthesized using an inverse miniemulsion polymerization process . Polyethylene glycol (PEG)‐coated nanoparticles, or PEGylated nanoparticles have demonstrated significant promise in drug delivery research as their surface does not promote non‐specific tissue binding while allowing for deeper penetration and longer circulation times especially in mucosal tissues . However, it must be noted that in these prior studies the nanoparticles investigated were composed of different material structures (linear polymers or crystalline materials ) and subsequently surface‐coated with PEG.…”

“…Polyethylene glycol (PEG)‐coated nanoparticles, or PEGylated nanoparticles have demonstrated significant promise in drug delivery research as their surface does not promote non‐specific tissue binding while allowing for deeper penetration and longer circulation times especially in mucosal tissues . However, it must be noted that in these prior studies the nanoparticles investigated were composed of different material structures (linear polymers or crystalline materials ) and subsequently surface‐coated with PEG. The development of crosslinked hydrogel PEG nanoparticles for drug delivery applications is rare.…”