A randomized, controlled comparison of a stannous-containing dentifrice for reducing gingival bleeding and balancing the oral microbiome relative to a positive control.

PURPOSE: To evaluate the effect of a stannous-containing fluoride dentifrice on gingival health and on the composition of the oral microbiome versus a positive control dentifrice over 2 weeks, in a population of healthy adults with self-reported sub-optimal oral health at baseline. METHODS: This was a randomized, controlled, double-blind clinical study. 87 subjects with self-reported sub-optimal oral health at enrollment were randomized to brush twice daily with either an experimental dentifrice (n= 43) or a marketed positive control dentifrice (n= 43), both containing stannous chloride and 0.321% sodium fluoride. All subjects used a soft, manual toothbrush that was provided. The Mazza modification of gingival papillary bleeding Index (Mazza GI) was used to assess gingivitis at baseline and at Week 2. Supragingival plaque was collected for microbiome composition analyses at baseline, Week 1, and Week 2. RESULTS: 83 subjects completed the study. Baseline means were balanced between the treatment groups (P> 0.34). At Week 2, the positive control dentifrice demonstrated a 63.8% statistically significant (P< 0.0001) reduction relative to baseline for Mazza number of gingival bleeding sites. The experimental stannous containing dentifrice provided a comparable 63.5% gingival bleeding reduction versus baseline. There was no significant (P= 0.96) difference between the two dentifrices for either Mazza GI score or number of bleeding sites measured. The microbiome composition analysis at Week 1 found that 28 gingivitis-associated bacterial genera, including Porphyromonas, Tannerella, and Fusobacterium, were significantly inhibited in both dentifrice groups when compared to baseline, while the relative abundance of genera associated with oral health, such as Rothia, Streptococcus, Haemophilus, and Lautropia, was significantly elevated after treatment. These improvements in the oral ecosystem were sustained at Week 2. CLINICAL SIGNIFICANCE: An experimental stannous-containing sodium fluoride dentifrice significantly reduced gingival bleeding comparable to a positive control, and both dentifrices promoted a shift in the oral microbiome towards those genera associated with oral health in a subject population with self-reported sub-optimal oral health at baseline.

Interactions and effects of a stannous-containing sodium fluoride dentifrice on oral pathogens and the oral microbiome.

Numerous studies have investigated the effects of stannous ions on specific microbes and their efficacy in reducing dental plaque. Nonetheless, our understanding of their impact on the oral microbiome is still a subject of ongoing exploration. Therefore, this study sought to evaluate the effects of a stannous-containing sodium fluoride dentifrice in comparison to a zinc-containing sodium fluoride dentifrice and a control group on intact, healthy oral biofilms. Utilizing the novel 2bRAD-M approach for species-resolved metagenomics, and FISH/CLSM with probes targeting periodontal and caries associated species alongside Sn2+ and Zn2+ ions, we collected and analyzed in situ biofilms from 15 generally healthy individuals with measurable dental plaque and treated the biofilms with dentifrices to elucidate variations in microbial distribution. Although significant shifts in the microbiome upon treatment were not observed, the use of a stannous-containing sodium fluoride dentifrice primarily led to an increase in health-associated commensal species and decrease in pathogenic species. Notably, FISH/CLSM analysis highlighted a marked reduction in representative species associated with periodontitis and caries following treatment with the use of a stannous-containing sodium fluoride dentifrice, as opposed to a zinc-containing sodium fluoride dentifrice and the control group. Additionally, Sn2+ specific intracellular imaging reflected the colocalization of Sn2+ ions with P. gingivalis but not with other species. In contrast, Zn2+ ions exhibited non-specific binding, thus suggesting that Sn2+ could exhibit selective binding toward pathogenic species. Altogether, our results demonstrate that stannous ions could help to maintain a healthy oral microbiome by preferentially targeting certain pathogenic bacteria to reverse dysbiosis and underscores the importance of the continual usage of such products as a preventive measure for oral diseases and the maintenance of health.

Longitudinal Multi-omics and Microbiome Meta-analysis Identify an Asymptomatic Gingival State That Links Gingivitis, Periodontitis, and Aging.

Most adults experience episodes of gingivitis, which can progress to the irreversible, chronic state of periodontitis, yet roles of plaque in gingivitis onset and progression to periodontitis remain elusive. Here, we longitudinally profiled the plaque metagenome, the plaque metabolome, and salivary cytokines in 40 adults who transited from naturally occurring gingivitis (NG) to healthy gingivae (baseline) and then to experimental gingivitis (EG). During EG, rapid and consistent alterations in plaque microbiota, metabolites, and salivary cytokines emerged as early as 24 to 72 h after oral-hygiene pause, defining an asymptomatic suboptimal health (SoH) stage of the gingivae. SoH features a swift, full activation of 11 salivary cytokines but a steep synergetic decrease of plaque-derived betaine and Rothia spp., suggesting an anti-gum inflammation mechanism by health-promoting symbionts. Global, cross-cohort meta-analysis revealed, at SoH, a greatly elevated microbiome-based periodontitis index driven by its convergence of both taxonomical and functional profiles toward the periodontitis microbiome. Finally, post-SoH gingivitis development accelerates oral microbiota aging by over 1 year within 28 days, with Rothia spp. depletion and Porphyromonas gingivalis elevation as hallmarks. Thus, the microbiome-defined, transient gum SoH stage is a crucial link among gingivitis, periodontitis, and aging.IMPORTANCE A significant portion of world population still fails to brush teeth daily. As a result, the majority of the global adult population is afflicted with chronic gingivitis, and if it is left untreated, some of them will eventually suffer from periodontitis. Here, we identified periodontitis-like microbiome dysbiosis in an asymptomatic SoH stage as early as 24 to 72 h after oral-hygiene pause. SoH features a swift, full activation of multiple salivary cytokines but a steep synergetic decrease of plaque-derived betaine and Rothia spp. The microbial ecology during early gingivitis is highly similar to that in periodontitis under both taxonomical and functional contexts. Unexpectedly, exposures to gingivitis can accelerate over 10-fold the normal rate of oral microbiota aging. Our findings underscore the importance of intervening at the SoH stage of gingivitis via proper oral-hygiene practices on a daily basis, so as to maintain a periodontitis-preventive plaque and ensure the healthy aging of the oral ecosystem.

Delivery of paclitaxel using nanoparticles composed of poly(ethylene oxide)-b-poly(butylene oxide) (PEO-PBO).

An amphiphilic block copolymer poly(ethylene oxide)-b-poly(butylene oxide) (PEO-PBO) was evaluated as a carrier for therapeutic delivery of paclitaxel (PTX). PEO-PBO and PTX form nanoparticles (NPs) by self-assembly upon hydration. The size of these NPs was about 92.71nm and the zeta potential was -5.06mV, which met the requirements for passive tumor targeting through the enhanced permeability and retention effect. Compared with a commonly used block copolymer poly(ethylene glycol)-b-poly-D,L-(lactic acid) (PEG-PDLLA), PEO-PBO forms nanoparticles with superior pharmacokinetic, biodistribution, and tumor inhibitory properties. Meanwhile, results of hemolysis study and CMC determination showed that PEO-PBO had better biocompatibility and stability than PEG-PDLLA. These data suggest that PEO-PBO has potential for application in drug delivery and warrant further evaluation.

Comparative effect of a stannous fluoride toothpaste and a sodium fluoride toothpaste on a multispecies biofilm.

OBJECTIVES: This paper aimed to compare the mode of action of a stannous fluoride-containing toothpaste with a conventional sodium fluoride-containing toothpaste on anti-biofilm properties. METHODS: A three-species biofilm model that consists of Streptococcus mutans, Streptococcus sanguinis and Porphyromonas gingivalis was established to compare the anti-biofilm properties of a stannous fluoride-containing toothpaste (CPH), a conventional sodium fluoride-containing toothpaste (CCP) and a negative control (PBS). The 48h biofilms were subjected to two-minute episodes of treatment with test agents twice a day for 5 consecutive days. Crystal violet staining and XTT assays were used to evaluate the biomass and viability of the treated biofilm. Live/dead staining and bacteria/extracellular polysaccharides (EPS) double-staining were used to visualize the biofilm structure and to quantify microbial/extracellular components of the treated biofilms. Species-specific fluorescent in situ hybridization and quantitative polymerase chain reaction (qPCR) were used to analyze microbial composition of the biofilms after treatment. RESULTS: The biomass and viability of the biofilms were significantly reduced after CPH toothpaste treatment. The inhibitory effect was further confirmed by the live/dead staining. The EPS amounts of the three-species biofilm were significantly reduced by CCP and CPH treatments, and CPH toothpaste demonstrated significant inhibition on EPS production. More importantly, CPH toothpaste significantly suppressed S. mutans and P. gingvalis, and enriched S. sanguinis in the three-species biofilm. In all experiments CPH had a significantly greater effect than CCP (p<0.05) and CCP had a greater effect than PBS (p<0.05). CONCLUSIONS: Stannous fluoride-containing toothpaste not only showed better inhibitory effect against oral microbial biofilm, but was also able to modulate microbial composition within multi-species biofilm compared with conventional sodium fluoride-containing toothpaste.

New Generation Nanomedicines Constructed from Self-Assembling Small-Molecule Prodrugs Alleviate Cancer Drug Toxicity.

The therapeutic index for chemotherapeutic drugs is determined in part by systemic toxicity, so strategies for dose intensification to improve efficacy must also address tolerability. In addressing this issue, we have investigated a novel combinatorial strategy of reconstructing a drug molecule and using sequential drug-induced nanoassembly to fabricate supramolecular nanomedicines (SNM). Using cabazitaxel as a target agent, we established that individual synthetic prodrugs tethered with polyunsaturated fatty acids were capable of recapitulating self-assembly behavior independent of exogenous excipients. The resulting SNM could be further refined by PEGylation with amphiphilic copolymers suitable for preclinical studies. Among these cabazitaxel derivatives, docosahexaenoic acid-derived compound 1 retained high antiproliferative activity. SNM assembled with compound 1 displayed an unexpected enhancement of tolerability in animals along with effective therapeutic efficacy in a mouse xenograft model of human cancer, compared with free drug administered in its clinical formulation. Overall, our studies showed how attaching flexible lipid chains to a hydrophobic and highly toxic anticancer drug can convert it to a systemic self-deliverable nanotherapy, preserving its pharmacologic efficacy while improving its safety profile. Cancer Res; 77(24); 6963-74. ©2017 AACR.