Abstract
Recently the vaginal route consider as an ideal route for drug delivery systems (DDS) administration. This is because, it is suitable for lower drug dosage, higher drug concentration in the genital tract tissues and lower drug concentration in pregnant women blood circulation. However, the vaginal route administration faces many challenges due to the physiology as well as the complexity of vaginal tissue histology. Here in this study, during diestrus stage (optimal condition for foreign substance internalization), single or dual size of fluorescent thiol-organosilica nanoparticles (tOS-NPs) were administrated intravaginally. The biodistribution and reactivity of tOS-NPs in different tissues of the female genital tract were investigated under the fluorescence microscope. Furthermore, using immunohistochemical staining, the expression of F4/80 protein and the role of macrophages in transport and re-location of tOS-NPs from vaginal lumen into different genital tissues or other organs were investigated. This study showed that, tOS-NPs size and type of tissue are important in biodistribution and uptake of tOS-NPs in the genital tract. Small size (100 nm) of tOS-NPs was highly accumulated in the genital tract tissues especially endometrial epithelium compared with large tOS-NPs (1000 nm). Contradictory, the large size induced the expression of F4/80 protein and the number of vaginal macrophages compared with small size. However, both small and large sizes of tOS-NPs were found co-localized with F4/80+ macrophages, located in the vaginal, endometrial and ovarian tissues. The tOS-NPs intravaginally administrated were found in the splenic tissues, indicating its ability to enter the blood circulation from the vaginal lumen. Additionally, the high accumulation of tOS-NPs in the endometrial epithelium indicated the endometrial first pass effect of tOS-NPs. As a result, high concentration of tOS-NPs in the endometrial epithelium may reduce the concentration of tOS-NPs-based DDS in the blood circulation and their side effects. Furthermore, during vaginal tissue optimal condition (diestrus stage), understanding the fate and biodistribution of tOS-NPs will introduce important data about the development of save and effective DDS for the pregnant women.
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References
Ajayi AF, Akhigbe RE (2020) Staging of the estrous cycle and induction of estrus in experimental rodents: an update. Fertil Res Pract 6:5. https://doi.org/10.1186/s40738-020-00074-3
Alipour M, Halwani M, Omri A, Suntres ZE (2008) Antimicrobial effectiveness of liposomal polymyxin B against resistant Gram-negative bacterial strains. Int J Pharm 355:293–298. https://doi.org/10.1016/j.ijpharm.2007.11.035
Anderson DJ, Marathe J, Pudney J (2014) The structure of the human vaginal stratum corneum and its role in immune defense. Am J Reprod Immunol 71:618–623. https://doi.org/10.1111/aji.12230
Awaad A (2015) Histopathological and immunological changes induced by magnetite nanoparticles in the spleen, liver and genital tract of mice following intravaginal instillation. JOBAZ 71C:32–47. https://doi.org/10.1016/j.jobaz.2015.03.003
Awaad A, Nakamura M, Ishimura K (2012a) Histochemical and biochemical analysis of the size-dependent nanoimmunoresponse in mouse Peyer’s patches using fluorescent organosilica particles. Int J Nanomedicine 7:1423–1439. https://doi.org/10.2147/IJN.S28675
Awaad A, Nakamura M, Ishimura K (2012b) Imaging of size-dependent uptake and identification of novel pathways in mouse Peyer’s patches using fluorescent organosilica particles. Nanomedicine 8:627–636. https://doi.org/10.1016/j.nano.2011.08.009
Awaad A, Adly MA, Hosny D (2018) Spleen immunotoxicities induced by intratesticular injection of magnetic nanoparticles and the role of Echinacea purpurea extract: a histological and immunohistochemical study. J Histotechnol 41:94–110. https://doi.org/10.1080/01478885.2018.1472857
Ballou B, Lagerholm BC, Ernst LA, Bruchez MP, Waggoner AS (2004) Noninvasive imaging of quantum dots in mice. Bioconjug Chem 15:79–86. https://doi.org/10.1021/bc034153y
Ballou B, Andreko SK, Osuna-Highley E et al (2012) Nanoparticle transport from mouse vagina to adjacent lymph nodes. PLoS ONE 7:e51995. https://doi.org/10.1371/journal.pone.0051995
Byers SL, Wiles MV, Dunn SL, Taft RA (2012) Mouse estrous cycle identification tool and images. PLoS ONE 7:e35538. https://doi.org/10.1371/journal.pone.0035538
Caligioni CS (2009) Assessing reproductive status/stages in mice. Curr Protoc Neurosci Appendix 4:Appendix-4I. https://doi.org/10.1002/0471142301.nsa04is48
Chaowanachan T, Krogstad E, Ball C, Woodrow KA (2013) Drug synergy of tenofovir and nanoparticle-based antiretrovirals for HIV prophylaxis. PLoS ONE 8:e61416. https://doi.org/10.1371/journal.pone.0061416
Chikauraa H, Nakashimaa Y, Fujiwarab Y et al (2016) Effect of particle size on biological response by human monocyte-derived macrophages. Biosurf Biotribol 2:18–2519. https://doi.org/10.1016/j.bsbt.2016.02.003
Cooke PS, Spencer TE, Bartol FF, Hayashi K (2013) Uterine glands: development, function and experimental model systems. Mol Hum Reprod 19:547–558. https://doi.org/10.1093/molehr/gat031
Cu Y, Booth CJ, Saltzman WM (2011) In vivo distribution of surface-modified PLGA nanoparticles following intravaginal delivery. J Control Release 156:258–264. https://doi.org/10.1016/j.jconrel.2011.06.036
Das Neves J, Araújo F, Andrade F et al (2014) Biodistribution and pharmacokinetics of dapivirine-loaded nanoparticles after vaginal delivery in mice. Pharm Res 31:1834–1845. https://doi.org/10.1007/s11095-013-1287-x
Ensign LM, Tang BC, Wang YY et al (2012) Mucus-penetrating nanoparticles for vaginal drug delivery protect against herpes simplex virus. Sci Transl Med 4:138ra79. https://doi.org/10.1126/scitranslmed.3003453
Freitas RA Jr (2005) Nanotechnology, nanomedicine and nanosurgery. Int J Surg 3:243–246. https://doi.org/10.1016/j.ijsu.2005.10.007
Illum L, Jacobsen LO, Müller RH et al (1987) Surface characteristics and the interaction of colloidal particles with mouse peritoneal macrophages. Biomaterials 8:113–117. https://doi.org/10.1016/0142-9612(87)90099-8
Jain TK, Reddy MK, Morales MA et al (2008) Biodistribution, clearance, and biocompatibility of iron oxide magnetic nanoparticles in rats. Mol Pharm 5:316–327. https://doi.org/10.1021/mp7001285
Lacey CJ, Woodhall S, Qi Z et al (2010) Unacceptable side-effects associated with a hyperosmolar vaginal microbicide in a phase 1 trial. Int J STD AIDS 21:714–717. https://doi.org/10.1258/ijsa.2010.010215
Lai SK, Hida K, Shukair S et al (2009) Human immunodeficiency virus type 1 is trapped by acidic but not by neutralized human cervicovaginal mucus. J Virol 83:11196–11200. https://doi.org/10.1128/JVI.01899-08
Lai SK, Wang YY, Hida K et al (2010) Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses. Proc Natl Acad Sci U S A 107(2):598–603. https://doi.org/10.1073/pnas.0911748107
Mallipeddi R, Rohan LC (2010) Nanoparticle-based vaginal drug delivery systems for HIV prevention. Expert Opin Drug Deliv 7:37–48. https://doi.org/10.1517/17425240903338055
McLean AC, Valenzuela N, Fai S, Bennett SA (2012) Performing vaginal lavage, crystal violet staining, and vaginal cytological evaluation for mouse estrous cycle staging identification. J Vis Exp 67:e4389. https://doi.org/10.3791/4389
Merkwitz C, Blaschuk O, Eplinius F et al (2016) A simple method for inducing estrous cycle stage-specific morphological changes in the vaginal epithelium of immature female mice. Lab Anim 50:344–353. https://doi.org/10.1177/0023677215617387
Nakamura M, Ishimura K (2007) Synthesis and characterization of organosilica nanoparticles prepared from 3-mercaptopropyltrimethoxysilane as the single silica source. J Phys Chem C 111:18892–18898. https://doi.org/10.1021/jp075798o
Nakamura M, Ozaki S, Abe M et al (2010) Size-controlled synthesis, surface functionalization, and biological applications of thiol-organosilica particles. Colloids Surf B Biointerfaces 79:19–26. https://doi.org/10.1016/j.colsurfb.2010.03.008
Nakamura M, Awaad A, Hayashi K et al (2012) Thiol-organosilica particles internally functionalized with propidium iodide as a multicolor fluorescence and x-ray computed tomography probe and application for non-invasive functional gastrointestinal tract imaging. Chem Mater 24:3772–3779. https://doi.org/10.1021/cm3023677
Nakamura M, Miyamoto K, Hayashi K, Awaad A et al (2013) Time-lapse fluorescence imaging and quantitative single cell and endosomal analysis of peritoneal macrophages using fluorescent organosilica nanoparticles. Nanomedicine 9:274–283. https://doi.org/10.1016/j.nano.2012.05.018
Ouellette M, Masse F, Lefebvre-Demers M et al (2018) Insights into gold nanoparticles as a mucoadhesive system. Sci Rep 8:14357. https://doi.org/10.1038/s41598-018-32699-2
Pacheco P, White D, Sulchek T (2013) Effects of microparticle size and Fc density on macrophage phagocytosis. PLoS ONE 8(4):e60989. https://doi.org/10.1371/journal.pone.0060989
Prodan AM, Iconaru SL, Ciobanu CS et al (2013) Iron oxide magnetic nanoparticles: characterization and toxicity evaluation by in vitro and in vivo assays. J Nanomater 2013:1. https://doi.org/10.1155/2013/587021
Saltzman WM, Radomsky ML, Whaley KJ et al (1994) Antibody diffusion in human cervical mucus. Biophys J 66:508–515. https://doi.org/10.1016/S0006-3495(94)80802-1
Shen R, Richter HE, Clements RH et al (2009) Macrophages in vaginal but not intestinal mucosa are monocyte-like and permissive to human immunodeficiency virus type 1 infection. J Virol 83:3258–3267. https://doi.org/10.1128/JVI.01796-08
Sherwood JK, Zeitlin L, Chen X et al (1996) Residence half-life of IgG administered topically to the mouse vagina. Biol Reprod 54:264–269. https://doi.org/10.1095/biolreprod54.1.264
Suarez SS, Pacey AA (2006) Sperm transport in the female reproductive tract. Hum Reprod Update 12:23–37. https://doi.org/10.1093/humupd/dmi047
Tang BC, Dawson M, Lai SK et al (2009) Biodegradable polymer nanoparticles that rapidly penetrate the human mucus barrier. Proc Natl Acad Sci U S A 106:19268–19273. https://doi.org/10.1073/pnas.0905998106
Wira CR, Fahey JV, Ghosh M et al (2010) Sex hormone regulation of innate immunity in the female reproductive tract: the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens. Am J Reprod Immunol 63:544–565. https://doi.org/10.1111/j.1600-0897.2010.00842.x
Woodrow KA, Cu Y, Booth CJ et al (2009) Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA. Nat Mater 8:526–533. https://doi.org/10.1038/nmat2444
Yao M, He L, McClements DJ, Xiao H (2015) Uptake of gold nanoparticles by intestinal epithelial cells: impact of particle size on their absorption, accumulation, and toxicity. J Agric Food Chem 63:8044–8049. https://doi.org/10.1021/acs.jafc.5b03242
Zaman M, Skwarczynski M, Malcolm JM et al (2011) Self-adjuvanting polyacrylic nanoparticulate delivery system for group A streptococcus (GAS) vaccine. Nanomedicine 7:168–173. https://doi.org/10.1016/j.nano.2010.10.002
Zhang L, Pornpattananangku D, Hu CM, Huang CM (2010) Development of nanoparticles for antimicrobial drug delivery. Curr Med Chem 17:585–594. https://doi.org/10.2174/092986710790416290
Zhang XD, Wu D, Shen X et al (2011) Size-dependent in vivo toxicity of PEG-coated gold nanoparticles. Int J Nanomedicine 6:2071–2081. https://doi.org/10.2147/IJN.S21657
Zhao X, Deak E, Soderberg K et al (2003) Vaginal submucosal dendritic cells, but not Langerhans cells, induce protective Th1 responses to herpes simplex virus-2. J Exp Med 197:153–162. https://doi.org/10.1084/jem.20021109
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Aziz Awaad and Michihiro Nakamura. The first draft of the manuscript was written by Aziz Awaad and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Awaad, A., Nakamura, M. Size-dependent biodistribution of thiol-organosilica nanoparticles and F4/80 protein expression in the genital tract of female mice after intravaginal administration. Histochem Cell Biol 155, 683–698 (2021). https://doi.org/10.1007/s00418-021-01974-1
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DOI: https://doi.org/10.1007/s00418-021-01974-1