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Liposomal 2-Methoxyestradiol Nanoparticles for Treatment of Uterine Leiomyoma in a Patient-Derived Xenograft Mouse Model

  • General Gynecology: Original Article
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Abstract

Uterine leiomyomas represent a challenging problem with limited medical treatment options. The anti-tumor agent 2-methoxyestradiol (2-ME) shows promising results but its efficacy is limited by inadequate pharmacokinetics. We previously demonstrated that 2-ME nanoparticles can be successfully formulated and that they show improved in vitro anti-leiomyoma cell activity. Here, we examined the effects of the in vivo delivery of 2-ME nanoparticles in a patient-derived xenograft (PDX) leiomyoma mouse model. Patient-derived leiomyoma tumor tissues were xenografted subcutaneously in estrogen/progesterone pretreated immunodeficient NOG mice. Animals (n = 12) were treated with liposomal 2-ME nanoparticles by intra-peritoneal (IP) injection (50 mg/kg/dose, three times weekly) or control for 28 days. Tumor volume was measured weekly by calipers and prior to sacrifice by ultrasound. In addition, the expression of the cell proliferation marker Ki67 and the apoptosis marker cleaved caspase-3 in tumor tissues after treatment were measured by immunohistochemistry. Liposomal 2-ME treatment was associated with a significant tumor growth inhibition (30.5% less than controls as early as 2 weeks, p = 0.025). In addition, injections of liposomal 2-ME inhibited the expression of the proliferation marker Ki67 (55.8% reduction, p < 0.001). Furthermore, liposomal 2-ME treatment was associated with a 67.5% increase of cleaved caspase-3 expression of increase (p = 0.048). Our findings suggest that liposomal nanoparticle formulation can successfully deliver 2-ME and can be a promising therapeutic strategy for uterine leiomyoma. Further characterization of the liposomal-2ME, including pharmacokinetics, maximal tolerated dose, and safety, is needed in preclinical models prior to clinical trials.

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Funding

This work was supported, in part, by the NIH grant 1R01HD094380-01 to Mostafa A. Borahay and the Alliance for NanoHealth (ANH) grant for Gokhan S Kilic, Salama A. Salama, and Bulent Ozpolat.

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Authors and Affiliations

  1. Department of Gynecology & Obstetrics, Johns Hopkins University, 4940 Eastern Ave, Baltimore, MD, 21224-2780, USA

    Mostafa A. Borahay

  2. Department of Obstetrics and Gynecology, and Biomedical Engineering Center, University of Texas Medical Branch, Galveston, TX, USA

    Kathleen L. Vincent

  3. Biomedical Engineering Center, University of Texas Medical Branch, Galveston, TX, USA

    Massoud Motamedi

  4. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Ibrahim Tekedereli & Bulent Ozpolat

  5. Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

    Salama A. Salama

  6. Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, USA

    Gokhan S. Kilic

Authors
  1. Mostafa A. Borahay
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  2. Kathleen L. Vincent
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  3. Massoud Motamedi
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  4. Ibrahim Tekedereli
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  5. Salama A. Salama
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  7. Gokhan S. Kilic
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All authors substantially contributed to this project and reviewed and approved the final manuscript.

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Correspondence to Mostafa A. Borahay or Bulent Ozpolat.

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The study was approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Texas Medical Branch at Galveston.

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Borahay, M.A., Vincent, K.L., Motamedi, M. et al. Liposomal 2-Methoxyestradiol Nanoparticles for Treatment of Uterine Leiomyoma in a Patient-Derived Xenograft Mouse Model. Reprod. Sci. 28, 271–277 (2021). https://doi.org/10.1007/s43032-020-00248-w

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  • DOI: https://doi.org/10.1007/s43032-020-00248-w

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