Interactions of Microbicide Nanoparticles with a Simulated Vaginal Fluid Jose ́ das Neves,* ,†,‡ Cristina M. R. Rocha, § Maria Pilar Gonc ̧ alves, § Rebecca L. Carrier, ∥ Mansoor Amiji, ⊥ Maria Fernanda Bahia, † and Bruno Sarmento †,‡,# † Laboratory of Pharmaceutical Technology, LTF/CICF, Faculty of Pharmacy, University of Porto, Porto, Portugal ‡ CICS−Centro de Investigaç ã o em Ciê ncias da Saú de, Department of Pharmaceutical Sciences, Instituto Superior de Ciê ncias da Saú de-Norte, CESPU, Gandra, Portugal § REQUIMTE, Department of Chemical Engineering, Faculty of Engineering, University of Porto, Porto, Portugal ∥ Department of Chemical Engineering, Northeastern University, Boston, Massachusetts 02115, United States ⊥ Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts 02115, United States # INEB−Instituto de Engenharia Biome ́ dica, Biomaterials Division, NEWTherapies Group, Porto, Portugal * S Supporting Information 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. KEYWORDS: mucin, mucoadhesion, mucosal drug delivery, microbicides, rheology, particle tracking 1. INTRODUCTION The development of vaginal microbicides has attracted a great deal of attention in recent years. 1,2 These products are intended to be applied in the vaginal canal around the time of intercourse in order to prevent the sexual transmission of HIV and/or potentially other pathogens. Among different strategies and drug delivery systems, 3 the development of nanotechnology-based carriers has been recently proposed as a valuable approach in order to deliver active microbicide drugs. 4 As in the case of other mucosal routes, the interaction of drug nanocarriers with the cervicovaginal mucus is of paramount importance. For instance, Received: July 26, 2012 Revised: September 20, 2012 Accepted: September 24, 2012 Published: September 24, 2012 Article pubs.acs.org/molecularpharmaceutics © 2012 American Chemical Society 3347 dx.doi.org/10.1021/mp300408m | Mol. Pharmaceutics 2012, 9, 3347−3356