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      siRNA-based breast cancer therapy by suppressing 17β-hydroxysteroid dehydrogenase type 1 in an optimized xenograft cell and molecular biology model in vivo

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          Abstract

          Purpose

          Hormone-dependent breast cancer is the most common form of breast cancer, and inhibiting 17β-HSD1 can play an attractive role in decreasing estrogen and cancer cell proliferation. However, the majority of existing inhibitors have been developed from estrogens and inevitably possess residual estrogenicity. siRNA knockdown provides a highly specific way to block a targeted enzyme, being especially useful to avoid estrogenicity. Application of 17β-HSD1-siRNA in vivo is limited by the establishment of an animal model, as well as the potential nuclease activity in vivo. We tried to reveal the in vivo potential of 17β-HSD1-siRNA-based breast cancer therapy.

          Materials and methods

          To establish a competent animal model, daily subcutaneous injection of an estrone micellar aqueous solution was adopted to provide the substrate for estradiol biosynthesis. The effects of three different doses of estrone (0.1, 0.5, and 2.5 µg/kg/day) on tumor growth in T47D-17β-HSD1-inoculated group were investigated and compared with the animals inoculated with wild type T47D cells. To solve in vivo delivery problem of siRNA, “17β-HSD1-siRNA/LPD”, a PEGylated and modified liposome–polycation–DNA nanoparticle containing 17β-HSD1-siRNA was prepared by the thin film hydration method and postinsertion technology. Finally, “17β-HSD1-siRNA/LPD” was tested in the optimized model. Tumor growth and 17β-HSD1 expression were assessed.

          Results

          Comparison with the untreated group revealed significant suppression of tumor growth in “17β-HSD1-siRNA/LPD”-treated group when HSD17B1 gene expression was knocked down.

          Conclusion

          These findings showed promising in vivo assessments of 17β-HSD1-siRNA candidates. This is the first report of an in vivo application of siRNA for steroid-converting enzymes in a nude mouse model.

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          Most cited references 39

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          Exploring the Role of RGD-Recognizing Integrins in Cancer

          Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine.
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            17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development.

            17β-Hydroxysteroid dehydrogenases (17β-HSDs) are oxidoreductases, which play a key role in estrogen and androgen steroid metabolism by catalyzing final steps of the steroid biosynthesis. Up to now, 14 different subtypes have been identified in mammals, which catalyze NAD(P)H or NAD(P)(+) dependent reductions/oxidations at the 17-position of the steroid. Depending on their reductive or oxidative activities, they modulate the intracellular concentration of inactive and active steroids. As the genomic mechanism of steroid action involves binding to a steroid nuclear receptor, 17β-HSDs act like pre-receptor molecular switches. 17β-HSDs are thus key enzymes implicated in the different functions of the reproductive tissues in both males and females. The crucial role of estrogens and androgens in the genesis and development of hormone dependent diseases is well recognized. Considering the pivotal role of 17β-HSDs in steroid hormone modulation and their substrate specificity, these proteins are promising therapeutic targets for diseases like breast cancer, endometriosis, osteoporosis, and prostate cancer. The selective inhibition of the concerned enzymes might provide an effective treatment and a good alternative to the existing endocrine therapies. Herein, we give an overview of functional and structural aspects for the different 17β-HSDs. We focus on steroidal and non-steroidal inhibitors recently published for each subtype and report on existing animal models for the different 17β-HSDs and the respective diseases. Article from the Special issue on Targeted Inhibitors. Copyright © 2011 Elsevier Ltd. All rights reserved.
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              Characterization of cationic lipid-protamine-DNA (LPD) complexes for intravenous gene delivery.

              A previous study has shown an efficient, systemic transgene expression in mice via intravenous administration of a LPD formulation composed of DOTAP liposomes, protamine sulfate and plasmid DNA. In this study, factors affecting the in vivo performance of this formulation were further evaluated. A protocol in which liposomes were mixed with protamine before the addition of plasmid DNA was shown to produce small condensed particles with a diameter of about 135 nm. These particles were stable over time and gave a high level of gene expression in all tissues examined including lung, heart, spleen, liver and kidney with the highest level of expression in the lung. Inclusion of dioleoylphosphatidylethanolamine (DOPE) as a helper lipid significantly decreased the in vivo activity of LPD. In contrast, inclusion of cholesterol as a helper lipid increased the in vivo transfection efficiency of LPD and more importantly, decrease the amount of cationic lipid required for the maximal level of gene expression. Studies on the interaction between mouse serum and LPD showed that LPD became negatively charged after exposure to serum, and LPDs containing different helper lipids varied in the amount of associated serum proteins. LPD containing DOPE was more enriched in a protein corresponding to albumin in molecular weight. These results suggest that the mechanism of LPD-mediated intravenous gene delivery might be different from that of in vitro lipofection and that serum protein association might be a major factor limiting the in vivo transfection by LPD.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2019
                22 February 2019
                : 13
                : 757-766
                Affiliations
                [1 ]NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, and Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai 200032, China, fenglinglinxin@ 123456163.com
                [2 ]Axe Molecular Endocrinology and Nephrology, CHU Research Center and Department of Molecular Medicine, Laval University, Québec, G1V 4G2, QC, Canada, sxlin@ 123456crchul.ulaval.ca
                Author notes
                Correspondence: ShengXiang Lin, Axe Molecular Endocrinology and Nephrology, CHU Research Center and Department of Molecular Medicine, Laval University, T 455c, 2705 Boulevard Laurier, Québec, G1V 4G2, QC, Canada, Tel +1 418 654 2296, Fax +1 418 654 2761, Email sxlin@ 123456crchul.ulaval.ca
                LingLin Feng, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Fudan University, and Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Room 904, No 1 Research Building, 2140 Xietu Road, Shanghai 200032, China, Tel +86 64 438 657, Fax +86 216 417 1047, Email fenglinglinxin@ 123456163.com
                [*]

                These authors contributed equally to this work

                Article
                dddt-13-757
                10.2147/DDDT.S180836
                6391152
                © 2019 Li et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                gene silencing, animal model, estrogen, breast cancer, hsd17b1

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