172. DEVELOPMENT OF A NON-HORMONAL CONTRACEPTIVE: VAGINAL DELIVERY OF A LIF INHIBITOR: ITS TISSUE DISTRIBUTION AND EFFECT ON IMPLANTATION IN MICE

Abstract

Uterine leukaemia inhibitory factor (LIF) is obligatory for fertility in mice and associated with infertility in women. Intraperitoneal injection (IPI) of a long-acting LIF inhibitor conjugated to polyethylene glycol (PEGLA) blocks endometrial LIF action preventing implantation¹. Thus, PEGLA is a promising non-hormonal contraceptive. In women, vaginally applied (VA) compounds preferentially localize to the uterus suggesting a desirable delivery method for contraceptive purposes; however this has not been examined in mice. We aimed to compare the effects of VA and IPI PEGLA on tissue distribution and implantation in mice. Non-pregnant or mated female mice (Pregnant day [D] 2 [D0: day of plug], n=3/group) were given ¹²⁵I-PEGLA by IPI (3x10⁶cpm) or VA (7x10⁵cpm). ¹²⁵I-PEGLA was measured in blood and tissue at various time points. To block implantation, mated mice (n=4/group) were given PEGLA or control by IPI (500μg/injection) or VA (300μg/injection) at 1200h and 2200h on D2 and 1000h on D3 and the uterus examined for implantation sites on D6. ¹²⁵ I-PEGLA accumulated in blood and uterus following IPI more rapidly (10min cf 30min), reached a higher concentration (10min, 6h and [blood] 24h; p<0.05) and remained longer (24h cf 6h) compared to VA. The percentage of protein-bound ¹²⁵I in blood was higher following IPI (79.4+1.9%) than VA (47.5+6.7%) at 6h (p<0.05). Following IPI, ¹²⁵I-PEGLA accumulated in the liver, gall bladder and stomach (2h) and spleen (24h) compared to control while no specific tissue accumulation was observed following VA. PEGLA prevented implantation following IPI (p<0.05) and reduced the size of implantation sites and decidualization in VA compared to controls. This study demonstrated differences in tissue distribution between VA and IPI PEGLA. It showed that VA PEGLA acted on the uterus in mice albeit to a lesser extent than IPI. It suggests that VA PEGLA is a potential route of delivery for contraceptive purposes.