Interactions of Microbicide Nanoparticles with a Simulated Vaginal Fluid

Abstract

The interaction with cervicovaginal mucus presents the potential to impact the performance of drug nanocarriers. These systems must migrate through this biological fluid in order to deliver their drug payload to the underlying mucosal surface. We studied the ability of dapivirine-loaded polycaprolactone (PCL)-based nanoparticles (NPs) to interact with a simulated vaginal fluid (SVF) incorporating mucin. Different surface modifiers were used to produce NPs with either negative (poloxamer 338 NF and sodium lauryl sulfate) or positive (cetyltrimethylammonium bromide) surface charge. Studies were performed using the mucin particle method, rheological measurements, and real-time multiple particle tracking. Results showed that SVF presented rheological properties similar to those of human cervicovaginal mucus. Analysis of NP transport indicated mild interactions with mucin and low adhesive potential. In general, negatively charged NPs underwent subdiffusive transport in SVF, i.e., hindered as compared to their diffusion in water, but faster than for positively charged NPs. These differences were increased when the pH of SVF was changed from 4.2 to 7.0. Diffusivity was 50- and 172-fold lower in SVF at pH 4.2 than in water for negatively charged and positively charged NPs, respectively. At pH 7.0, this decrease was around 20- and 385-fold, respectively. The estimated times required to cross a layer of SVF were equal to or lower than 1.7 h for negatively charged NPs, while for positively charged NPs these values were equal to or higher than 7 h. Overall, our results suggest that negatively charged PCL NPs may be suitable to be used as carriers in order to deliver dapivirine and potentially other antiretroviral drugs to the cervicovaginal mucosal lining. Also, they further reinforce the importance in characterizing the interactions of nanosystems with mucus fluids or surrogates when considering mucosal drug delivery.

The role of mucus in cell-based models used to screen mucosal drug delivery

“…The aqueous fluid was modified from Owen & Katz [103] and contained 1.5% (w/v) pig gastric mucin type II, 0.5% (w/v) glucose, 0.351% (w/v) sodium chloride, 0.2% (w/v) lactic acid, 0.14% (w/v) potassium hydroxide, 0.1% (w/v) acetic acid, 0.04% (w/v) urea, 0.0222% (w/v) calcium hydroxide, 0.016% (w/v) glycerol and enough amount hydrochloride acid for pH 4.2. The artificial fluid did not change TEER up to at least 4 h and previous experiments demonstrated similar rheological behavior to native mucus [119]. Experiments using the described models showed that the presence of mucins had considerable impact in both the permeability and cell monolayer accumulation of dapivirine, either in suspension or associated to 170 nm PLGA nanoparticles (Fig.…”

“…First, as previously reviewed by Griessinger et al, multiple techniques have been developed to study the mucus permeation or the mucus diffusion of DDS [117]. Transwell diffusion system (without cell seeding) [118] and multiple particle tracking [119] are mainly used. The second strategy is to add native or simulated vaginal fluid above the reconstructed multiplayer epithelium.…”

“…Thus, mucus-like fluids are mostly considered for such purpose. Different recipes have been proposed in the literature and those containing or modified with commercially available mucins may be of particular interest [103,119,[123][124][125][126][127].…”

Precise engineering of dapivirine-loaded nanoparticles for the development of anti-HIV vaginal microbicides

“…This in turn may potential- 78 ly increase protection against infection while allowing obtaining 79 coitally-independent microbicides. [8], respond to physiological changes occurring upon sexual inter-85 course (e.g., pH changes) [9], enhance drug targeting [10], promote 86 drug penetration and accumulation at genital tissues [11], increase 87 intracellular drug delivery [12], and improve drug activity [13]. 88 Further, drug-loaded polymeric nanoparticles (NPs) may benefi-89 cially affect local genital pharmacokinetics (PK) and, therefore, 90 potentially enhance the ability of antiretroviral compounds to pro-91 tect against infection in a coitally-independent fashion [14].…”

Profiles and technological requirements of urogenital probiotics

“…Referred to the resistance to the environmental conditions, if the strains are going to be administered locally at the urogenital tract, they must be assayed in their resistance to vaginal fluid and/or urine [218,219]. If they will be applied as oral capsule or foods, their survival must be studied in intestinal fluid or into their components, either in one phase assays, or in continuous models resembling the different areas of the intestinal tract [220][221][222][223][224][225][226]..…”