A Vaginal Nanoformulation of a SphK Inhibitor Attenuates lipopolysaccharide-induced Preterm Birth in Mice

Abstract

Aim: Previously, we have shown that inhibition of SphK by the SphK inhibitor-II (SKI II) prevents lipopolysaccharide-induced preterm birth in mice. The aim of this study was to develop a vaginal self-nanoemulsifying drug-delivery system (SNEDDS) for SKI II. Materials & methods: A SKI II-loaded SNEDDS was characterized and tested in a murine preterm birth model. Results: The SNEDDS immediately formed a gel and then slowly emulsified to nanoglobules with over 500-fold enhancement of SKI II solubility at vaginal pH. Intravaginal administration of the SKI II SNEDDS significantly decreased lipopolysaccharide-induced preterm birth in mice. Conclusion: A vaginal nanoformulation of SKI II represents a novel, noninvasive approach to prevent preterm birth.

Graphical abstract

A SphK inhibitor-II-loaded self-nanoemulsifying drug-delivery system for the prevention of preterm birth. Schematic diagram representing a SKI II-loaded nanoparticle composed of dimethylacetamide, medium chain triglycerides and Kolliphor HS 15, which significantly enhances aqueous solubility and maintains supersaturation. The dense PEG layer is helpful in facilitating mucus penetration and rapid transport to the uterus. Vaginal retention is increased due to in situ gelling, and efficacy is increased by targeted drug-delivery and uterine first pass effect. The SKI II self-nanoemulsifying drug-delivery system rescues a significant number of pups from spontaneous abortion and represents a novel, noninvasive approach to prevent preterm birth.

Keywords:

• inflammation
• lipopolysaccharide
• nanoformulation
• preterm birth
• SKI II
• SNEDDS
• sphingosine kinase inhibitor
• vaginal administration

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Financial & competing interests disclosure

SE Reznik received funding from a Nassau Health Care Corporation Grant (FY2016-2019) and a St John's University Seed Grant (FY2015-16). SE Reznik and CR Ashby have submitted a patent application on the use of SphK inhibitor II for preterm birth. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. All experimental protocols were approved by the St John's University Institutional Animal Care and Use Committee. In addition, all of the experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. In accordance with the St John's University Animal Care and Use Committee, mice were sacrificed 24 h after intraperitoneal administration of lipopolysaccharide administration. In accordance with the St John's University Animal Care and Use Committee, the pups and dams were sacrificed at the end of the experiment.