title: 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.
authors.affiliation: Laboratory of Pharmaceutical Technology, LTF/CICF, Faculty of Pharmacy, University of Porto, Porto, Portugal. j.dasneves@gmail.com
authors.forename: José
authors.initials: J
authors.lastname: das Neves
authors.forename: Cristina M R
authors.initials: CM
authors.lastname: Rocha
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Gonçalves
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Carrier
authors.forename: Mansoor
authors.initials: M
authors.lastname: Amiji
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Bahia
authors.forename: Bruno
authors.initials: B
authors.lastname: Sarmento
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D001826:Body Fluids / Q000737:chemistry* / Q000187:drug effects; D000077286:Cetrimonium; D002593:Cetrimonium Compounds / Q000737:chemistry / Q000378:metabolism; D004058:Diffusion; D016503:Drug Delivery Systems; D005260:Female; D054303:HIV Reverse Transcriptase / Q000493:pharmacokinetics; D006801:Humans; D009093:Mucus / Q000187:drug effects / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage*; D010316:Particle Size; D020442:Poloxamer / Q000737:chemistry / Q000378:metabolism; D011091:Polyesters / Q000737:chemistry; D011743:Pyrimidines / Q000493:pharmacokinetics*; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry / Q000378:metabolism; D013499:Surface Properties; D014018:Tissue Distribution; D014621:Vagina / Q000737:chemistry* / Q000187:drug effects; D014867:Water / Q000737:chemistry / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D002593:Cetrimonium Compounds; D011091:Polyesters; D011743:Pyrimidines; D014867:Water; D020442:Poloxamer; C016240:polycaprolactone; D012967:Sodium Dodecyl Sulfate; D054303:HIV Reverse Transcriptase; C481671:Dapivirine; D000077286:Cetrimonium