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Locally administered nanosuspension increases delivery of estradiol for the treatment of vaginal atrophy in mice

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Abstract

Vaginal atrophy affects up to 57% of post-menopausal women, with symptoms ranging from vaginal burning to dysuria. Estradiol hormone replacement therapy may be prescribed to alleviate these symptoms, though many vaginal products have drawbacks including increased discharge and local tissue toxicity due to their hypertonic nature. Here, we describe the development and characterization of a Pluronic F127-coated estradiol nanosuspension (NS) formulation for improved vaginal estradiol delivery. We compare the pharmacokinetics to the clinical comparator vaginal cream (Estrace) and demonstrate increased delivery of estradiol to the vaginal tissue. We utilized ovariectomized (OVX) mice as a murine model of post-menopausal vaginal atrophy and demonstrated equivalent efficacy in vaginal re-epithelialization when dosed with either the estradiol NS or Estrace cream. Further, we demonstrate compatibility of the estradiol NS with vaginal bacteria in vitro. We demonstrate that a Pluronic F127-coated estradiol NS may be a viable option for the treatment of post-menopausal vaginal atrophy.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the JHMI animal husbandry staff and the JHMI Reference Histology lab for their support. The following reagent was obtained through BEI Resources, NIAID, NIH as part of the Human Microbiome Project: Gardnerella vaginalis, Strain JCP8481B, HM-1118, and Lactobacillus crispatus, Strain EX533959VC06, HM-422.

Funding

The project described was supported by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins [NIH grants P30CA006973 and UL1TR003098, and the Shared Instrument Grant S10RR026824]. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCATS or NIH. This work was supported by NIH grants R01HD103124 and R01HD108905. Rachel Shapiro and Hannah Zierden were supported by an NSF GRFP Fellowship, and Kevin DeLong was supported by a Hartwell Foundation Postdoctoral Fellowship.

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD, 21218, USA

    Rachel L. Shapiro, Titania Bethiana, Eliza Duggan & Laura M. Ensign

  2. The Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Rachel L. Shapiro, Titania Bethiana, Davell M. Carter, Jairo Ortiz, Kevin DeLong, Eliza Duggan & Laura M. Ensign

  3. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Davell M. Carter & Laura M. Ensign

  4. Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Jairo Ortiz, Kevin DeLong & Laura M. Ensign

  5. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Nicole Anders & Laura M. Ensign

  6. Department of Pathology, Sibley Memorial Hospital, Johns Hopkins University School of Medicine, Washington, DC, 20016, USA

    Tricia A. Numan

  7. Department of Chemical and Biomolecular Engineering, University of Maryland College Park, College Park, MD, 20742, USA

    Hannah C. Zierden

  8. Department of Gynecology and Obstetrics, Department of Biomedical Engineering, and Department of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Laura M. Ensign

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  1. Rachel L. Shapiro
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Contributions

All authors contributed to the work described in this paper. Rachel Shapiro, Titania Bethiana, Hannah Zierden, Kevin DeLong, and Laura Ensign contributed to the design of experiments. Hannah Zierden and Rachel Shapiro contributed to the design and development of the NS formulation. Nicole Anders developed the analytical LC-MS/MS method and analyzed samples for estradiol levels. Rachel Shapiro, Titania Bethiana, Hannah Zierden, Davell Carter, Jairo Ortiz, Eliza Duggan, and Kevin DeLong conducted experiments. Tricia Numan analyzed and reported on tissue histology slides. Rachel Shapiro, Titania Bethiana, and Laura Ensign analyzed and interpreted the in vivo mouse and bacteria data. Rachel Shapiro and Laura Ensign wrote the manuscript. Kevin Delong and Laura Ensign provided subject matter expertise and guidance for this project. All authors approve the final version of this manuscript.

Corresponding authors

Correspondence to Hannah C. Zierden or Laura M. Ensign.

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Ethics approval

Johns Hopkins program of Animal care and Use is accredited by AAALAC international. Animal care, and procedures follow the Guide for the Care and Use of Laboratory Animals 8th ed. All experimental protocols involving mice were approved by the Johns Hopkins Animal Care and Use Committee. Unless otherwise specified, CD-1 mice were ordered from Charles River Laboratories at 6–8 weeks and were housed in a satellite housing facility in cages of 5 mice.

Consent to participate

No human materials or subjects were used in this study.

Competing interests

The mucus-penetrating particle technology is licensed and in clinical development for ocular indications by Kala Pharmaceuticals. Under a licensing agreement between Kala Pharmaceuticals and the Johns Hopkins University, Laura M. Ensign and the University are entitled to royalty distributions related to the technology. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. All other authors declare that they have no competing interests.

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Shapiro, R.L., Bethiana, T., Carter, D.M. et al. Locally administered nanosuspension increases delivery of estradiol for the treatment of vaginal atrophy in mice. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01618-6

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