Carbosilane dendrimer nanotechnology outlines of the broad HIV blocker profile L. Chonco a, b , M. Pion a, b , E. Vacas a, b , B. Rasines b, c , M. Maly d, e , M.J. Serramía a, b , L. López-Fernández a, b , J. De la Mata b, c , S. Alvarez a, b , R. Gómez b, c , M.A. Muñoz-Fernández a, b, ⁎ a Laboratorio de InmunoBiología Molecular y Plataforma de Laboratorio, Hospital General Universitario Gregorio Marañón, Madrid, Spain b Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain c Dpto. de Química Inorgánica, Universidad de Alcalá, Campus Universitario, 28871 Alcalá de Henares, Madrid, Spain, Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain d Faculty of Science, J. E. Purkinje University, Ceske mladeze 8, 400 96 Usti n. L., Czech Republic e University of Applied Science of Southern Switzerland, Lab Appl Math & Phys LAMFI, CH-6928 Manno, Switzerland abstract article info Article history: Received 31 March 2012 Accepted 26 April 2012 Available online 28 May 2012 Keywords: Dendrimer Microbicide Anti-HIV activity Biocompatibility Molecular modeling Researchers have been working hard for more than 20 years to develop safe and effective microbicides to em- power women to better control their own sexual life and to protect themselves against HIV and other sexually transmitted infections (STIs). Microbicide classes include moderately specific macromolecular anionic polymers that block HIV and other STIs, and HIV specific drugs that inhibit viral entry and reverse transcription. Based on innovative nanotechnology design, we showed a novel water-soluble anionic carbosilane dendrimer (2G-S16) as a propitious molecule against HIV-infection. A state-of-the-art research was accomplished that focused on bio- medical cutting-edge techniques such as in vitro and in vivo cytotoxicity assays performed on female rabbit gen- ital tracts, simulate in vitro model of vaginal epithelium in order to evaluate HIV transmission blockade through the monolayer, complete gene expression profiling experiment to study deregulated genes after 2G-S16 exposi- tion, molecular dynamics simulation of 2G-S16 molecule against principal proteins of HIV particles and pro- and anti-inflammatory cytokine profile study. Therefore, a high-throughput study and detailed analysis of the results were achieved in this article. We provided promising outcomes to encourage 2G-S16 as a hopeful microbicide. © 2012 Elsevier B.V. All rights reserved. 1. Introduction About 33.3 million adults were living with HIV/AIDS at the end of 2009, the majority of them in developing countries. More than 50% adults living with HIV/AIDS are women and more than 90% of all adoles- cent and adult HIV infections have resulted from heterosexual inter- course (UNAIDS, http://www.unaids.org/data/epi2010/). Women and girls are especially vulnerable and account for slightly more than half of all people living with HIV worldwide, notably in Sub-Saharan Africa. Effective HIV prevention options for women are clearly needed in this setting. While vaccines hold promise [1] and that the use of highly active antiretroviral therapy in HIV-infected patient could have a pre- ventive effect on HIV transmission [2], approaches to completely avoid HIV transmission remain elusive. Pre-exposure prophylaxis with orally administered antiretroviral drugs may prove to be effective, but there are substantial concerns for toxicities associated with long-term exposure, the risk for selecting resistant viral variants and the side effects of treatment could lead to a low adherence to this type of treatment [3]. Microbicides could be an alternative way to build preven- tative approaches to battle HIV transmission [4–7]. Topical drugs at different stage of development emerge as poten- tial efficient prophylaxis candidates, notably the CAPRISA 004 study (http://www.caprisa.org) that is based on 1% tenofovir vaginal gel al- beit recent announcements of CAPRISA group of work mentioned that efficiency needs to be put in perspective regarding the last results re- lated to tenofovir gel [8–10]. Inside the field, several nanoparticles have been tested as topical microbicide by themselves due to their chemical characteristics [7,10,11]. Candidate microbicides derived from nano-device until now have showed no significant protection against HIV, with higher rates of infection in the treatment compared to the placebo arms in clinical trials [12–14]. Two clinical trials with the naphthalene sulfonate polymer PRO 2000 gel were published. No protection in HIV or HSV-2 acquisition was observed among women randomized to coitally dependent intravaginal application of PRO 2000 [5,15]. A phase I randomized placebo controlled clinical trial of the safety of SPL7013 dendrimer-based polyanions (VivaGel®) in healthy women showed no toxicity [16,17] and potent antiviral ac- tivity was observed against HIV-1 and HSV-2 immediately following vaginal administration [18]. But some limitations were still detected such as lack of large spectrum microbicide against HIV-1 strains using CCR5 as co-receptor or against other viral types. Because of this high amount of new synthesized or natural molecules, a complete Journal of Controlled Release 161 (2012) 949–958 ⁎ Corresponding author at: Laboratorio Inmunobiología Molecular, Hospital General Universitario Gregorio Marañón, C/Dr. Esquerdo 46, 28007, Madrid, Spain. Tel.: + 34 91 5868565; fax: +34 91 5868018. E-mail address: mmunoz.hgugm@salud.madrid.org (MA. Muñoz-Fernández). 0168-3659/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2012.04.050 Contents lists available at SciVerse ScienceDirect Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel NANOMEDICINE