Vaginally administered PEGylated LIF Antagonist blocked embryo implantation and eliminated non-target effects on bone in mice

Ellen Menkhorst, Natalie A. Sims, Phillip O. Morgan, Priscilla Soo, Ingrid J. Poulton, Donald Metcalf, Estella Alexandrou, Melissa Gresle, Lois A. Salamonsen, Helmut Butzkueven, Nicos A. Nicola, Evdokia Dimitriadis

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Abstract

Female-controlled contraception/HIV prevention is critical to address health issues associated with gender inequality. Therefore, a contraceptive which can be administered in tandem with a microbicide to inhibit sexually transmitted infections, is desirable. Uterine leukemia inhibitory factor (LIF) is obligatory for blastocyst implantation in mice and associated with infertility in women. We aimed to determine whether a PEGylated LIF inhibitor (PEGLA) was an effective contraceptive following vaginal delivery and to identify non-uterine targets of PEGLA in mice. Vaginally-applied 125I-PEGLA accumulated in blood more slowly (30 min vs 10 min) and showed reduced tissue and blood retention (24 h vs 96 h) compared to intraperitoneal injection in mice. Vaginally-applied PEGLA blocked implantation. PEGLA administered by intraperitoneal injection inhibited bone remodelling whereas vaginally-applied PEGLA had no effect on bone. Further, PEGLA had no effect in an animal model of multiple sclerosis, experimental auto-immune encephalomyelitis, suggesting PEGLA cannot target the central nervous system. Vaginally-administered PEGLA is a promising non-hormonal contraceptive, one which could be delivered alone, or in tandem with a microbicide. Vaginal application reduced the total dose of PEGLA required to block implantation and eliminated the systemic effect on bone, showing the vagina is a promising site of administration for larger drugs which target organs within the reproductive tract.

Original languageEnglish
Article numbere19665
Pages (from-to)1 - 9
Number of pages9
JournalPLoS ONE
Volume6
Issue number5
DOIs
Publication statusPublished - 2011
Externally publishedYes

Cite this

Menkhorst, Ellen ; Sims, Natalie A. ; Morgan, Phillip O. ; Soo, Priscilla ; Poulton, Ingrid J. ; Metcalf, Donald ; Alexandrou, Estella ; Gresle, Melissa ; Salamonsen, Lois A. ; Butzkueven, Helmut ; Nicola, Nicos A. ; Dimitriadis, Evdokia. / Vaginally administered PEGylated LIF Antagonist blocked embryo implantation and eliminated non-target effects on bone in mice. In: PLoS ONE. 2011 ; Vol. 6, No. 5. pp. 1 - 9.
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abstract = "Female-controlled contraception/HIV prevention is critical to address health issues associated with gender inequality. Therefore, a contraceptive which can be administered in tandem with a microbicide to inhibit sexually transmitted infections, is desirable. Uterine leukemia inhibitory factor (LIF) is obligatory for blastocyst implantation in mice and associated with infertility in women. We aimed to determine whether a PEGylated LIF inhibitor (PEGLA) was an effective contraceptive following vaginal delivery and to identify non-uterine targets of PEGLA in mice. Vaginally-applied 125I-PEGLA accumulated in blood more slowly (30 min vs 10 min) and showed reduced tissue and blood retention (24 h vs 96 h) compared to intraperitoneal injection in mice. Vaginally-applied PEGLA blocked implantation. PEGLA administered by intraperitoneal injection inhibited bone remodelling whereas vaginally-applied PEGLA had no effect on bone. Further, PEGLA had no effect in an animal model of multiple sclerosis, experimental auto-immune encephalomyelitis, suggesting PEGLA cannot target the central nervous system. Vaginally-administered PEGLA is a promising non-hormonal contraceptive, one which could be delivered alone, or in tandem with a microbicide. Vaginal application reduced the total dose of PEGLA required to block implantation and eliminated the systemic effect on bone, showing the vagina is a promising site of administration for larger drugs which target organs within the reproductive tract.",
author = "Ellen Menkhorst and Sims, {Natalie A.} and Morgan, {Phillip O.} and Priscilla Soo and Poulton, {Ingrid J.} and Donald Metcalf and Estella Alexandrou and Melissa Gresle and Salamonsen, {Lois A.} and Helmut Butzkueven and Nicola, {Nicos A.} and Evdokia Dimitriadis",
year = "2011",
doi = "10.1371/journal.pone.0019665",
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Menkhorst, E, Sims, NA, Morgan, PO, Soo, P, Poulton, IJ, Metcalf, D, Alexandrou, E, Gresle, M, Salamonsen, LA, Butzkueven, H, Nicola, NA & Dimitriadis, E 2011, 'Vaginally administered PEGylated LIF Antagonist blocked embryo implantation and eliminated non-target effects on bone in mice', PLoS ONE, vol. 6, no. 5, e19665, pp. 1 - 9. https://doi.org/10.1371/journal.pone.0019665

Vaginally administered PEGylated LIF Antagonist blocked embryo implantation and eliminated non-target effects on bone in mice. / Menkhorst, Ellen; Sims, Natalie A.; Morgan, Phillip O.; Soo, Priscilla; Poulton, Ingrid J.; Metcalf, Donald; Alexandrou, Estella; Gresle, Melissa; Salamonsen, Lois A.; Butzkueven, Helmut; Nicola, Nicos A.; Dimitriadis, Evdokia.

In: PLoS ONE, Vol. 6, No. 5, e19665, 2011, p. 1 - 9.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Vaginally administered PEGylated LIF Antagonist blocked embryo implantation and eliminated non-target effects on bone in mice

AU - Menkhorst, Ellen

AU - Sims, Natalie A.

AU - Morgan, Phillip O.

AU - Soo, Priscilla

AU - Poulton, Ingrid J.

AU - Metcalf, Donald

AU - Alexandrou, Estella

AU - Gresle, Melissa

AU - Salamonsen, Lois A.

AU - Butzkueven, Helmut

AU - Nicola, Nicos A.

AU - Dimitriadis, Evdokia

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