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Liposomal 2-Methoxyestradiol Nanoparticles for Treatment of Uterine Leiomyoma in a Patient-Derived Xenograft Mouse Model.
Reprod Sci. 2020 Jul 06 [Online ahead of print]RS

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.

Authors+Show Affiliations

Department of Gynecology & Obstetrics, Johns Hopkins University, 4940 Eastern Ave, Baltimore, MD, 21224-2780, USA. mboraha1@jhmi.edu.Department of Obstetrics and Gynecology, and Biomedical Engineering Center, University of Texas Medical Branch, Galveston, TX, USA.Biomedical Engineering Center, University of Texas Medical Branch, Galveston, TX, USA.Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. bozpolat@mdanderson.org.Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32632769

Citation

Borahay, Mostafa A., et al. "Liposomal 2-Methoxyestradiol Nanoparticles for Treatment of Uterine Leiomyoma in a Patient-Derived Xenograft Mouse Model." Reproductive Sciences (Thousand Oaks, Calif.), 2020.
Borahay MA, Vincent KL, Motamedi M, et al. Liposomal 2-Methoxyestradiol Nanoparticles for Treatment of Uterine Leiomyoma in a Patient-Derived Xenograft Mouse Model. Reprod Sci. 2020.
Borahay, M. A., Vincent, K. L., Motamedi, M., Tekedereli, I., Salama, S. A., Ozpolat, B., & Kilic, G. S. (2020). Liposomal 2-Methoxyestradiol Nanoparticles for Treatment of Uterine Leiomyoma in a Patient-Derived Xenograft Mouse Model. Reproductive Sciences (Thousand Oaks, Calif.). https://doi.org/10.1007/s43032-020-00248-w
Borahay MA, et al. Liposomal 2-Methoxyestradiol Nanoparticles for Treatment of Uterine Leiomyoma in a Patient-Derived Xenograft Mouse Model. Reprod Sci. 2020 Jul 6; PubMed PMID: 32632769.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Liposomal 2-Methoxyestradiol Nanoparticles for Treatment of Uterine Leiomyoma in a Patient-Derived Xenograft Mouse Model. AU - Borahay,Mostafa A, AU - Vincent,Kathleen L, AU - Motamedi,Massoud, AU - Tekedereli,Ibrahim, AU - Salama,Salama A, AU - Ozpolat,Bulent, AU - Kilic,Gokhan S, Y1 - 2020/07/06/ PY - 2020/03/25/received PY - 2020/06/30/accepted PY - 2020/06/23/revised PY - 2020/7/8/pubmed PY - 2020/7/8/medline PY - 2020/7/8/entrez KW - 2-ME KW - 2-methoxyestradiol KW - 2ME KW - Fibroid KW - Leiomyoma KW - Liposomes KW - Nanoparticles KW - Treatment JF - Reproductive sciences (Thousand Oaks, Calif.) JO - Reprod Sci N2 - 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. SN - 1933-7205 UR - https://www.unboundmedicine.com/medline/citation/32632769/Liposomal_2-Methoxyestradiol_Nanoparticles_for_Treatment_of_Uterine_Leiomyoma_in_a_Patient-Derived_Xenograft_Mouse_Model L2 - https://journals.sagepub.com/doi/10.1007/s43032-020-00248-w?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -
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