International Journal of Nanomedicine (Mar 2019)
In vitro comparison of liposomal drug delivery systems targeting the oxytocin receptor: a potential novel treatment for obstetric complications
Abstract
Susan Hua,1,2 Benjamin Vaughan3 1Therapeutic Targeting Research Group, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia; 2Hunter Medical Research Institute, New Lambton Heights, NSW, Australia; 3Centre for Organic Electronics, University of Newcastle, Callaghan, NSW, Australia Introduction: Targeted intervention to the uterus has great potential for the treatment of obstetric complications (eg, preterm birth, dysfunctional labor, and postpartum hemorrhage) by improving the effectiveness and safety of therapeutic compounds. In particular, targeting the oxytocin receptor (OTR) is a novel approach for drug delivery to the uterus. The aim of this study was to report the complete data set for the pharmaceutical synthesis and in vitro characterization of PEGylated liposomes conjugated with anti-OTR monoclonal antibodies (OTR-Lipo) or atosiban (ATO-Lipo, OTR antagonist). Methods: OTR-targeted liposomal platforms composed of 1,2-distearoyl-sn-glycero-2-phosphocholine and cholesterol were prepared according to the method of dried lipid film hydration. Ligands were conjugated with the surface of liposomes using optimized methods to maximize conjugation efficiency. The liposomes were characterized for particle size, ligand conjugation, drug encapsulation, liposome stability, specificity of binding, cellular internalization, mechanistic pathway of cellular uptake, and cellular toxicity. Results: Both OTR-Lipo and ATO-Lipo showed significant and specific binding to OTRs in a concentration-dependent manner compared to all control groups. There was no significant difference in binding values between OTR-Lipo and ATO-Lipo across all concentrations evaluated. In addition, OTR-Lipo (81.61%±7.84%) and ATO-Lipo (85.59%±8.28%) demonstrated significantly increased cellular internalization in comparison with rabbit IgG immunoliposomes (9.14%±1.71%) and conventional liposomes (4.09%±0.78%) at 2.02 mM phospholipid concentration. Cellular association following liposome incubation at 4.05 mM resulted in similar findings. Evaluation of the mechanistic pathway of cellular uptake indicated that they undergo internalization through both clathrin- and caveolin-mediated mechanisms. Furthermore, cellular toxicity studies have shown no significant effect of both liposomal platforms on cell viability. Conclusion: This study further supports OTRs as a novel pharmaceutical target for drug delivery. OTR-targeted liposomal platforms may provide an effective way to deliver existing therapies directly to myometrial tissue and avoid adverse effects by circumventing non-target tissues. Keywords: liposomes, nanoparticles, targeted drug delivery, oxytocin receptor, uterus, obstetric complications
