<p>In vitro comparison of liposomal drug delivery systems targeting the oxytocin receptor: a potential novel treatment for obstetric complications</p>

Abstract

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.

Oxytocin Receptor Signaling in Vascular Function and Stroke

“…These analogs were able to induce behavioral changes out to 24 h indicating longer halflives, though the ability to induce intracellular calcium uncaging through the OXTR was much less than the endogenous peptide (Cherepanov et al, 2017). With respect to receptor antagonism, OXTR antibodies bound to the surface of liposomes have been tested, but only in targeting myometrium at this point (Hua, 2019;Hua and Vaughan, 2019). In summary, the complex nature of OXTR biology, with diverse, context-dependent cellular processing, homology with the vasopressin receptors, and ubiquitous expression peripherally and centrally, present challenges to the implementation of promising treatments.…”

“…These analogs were able to induce behavioral changes out to 24 h indicating longer half-lives, though the ability to induce intracellular calcium uncaging through the OXTR was much less than the endogenous peptide ( Cherepanov et al, 2017 ). With respect to receptor antagonism, OXTR antibodies bound to the surface of liposomes have been tested, but only in targeting myometrium at this point ( Hua, 2019 ; Hua and Vaughan, 2019 ).…”

Biomedical applications of dendritic fibrous nanosilica (DFNS): recent progress and challenges

“…82 Nanocarriers such as liposomes, micelles, polymeric nanocarriers, dendrimers, hydrogels, metallic nanocarriers, QDs, carbon-based nanocarriers, exosomes, and viruses have been extensively studied for the design of drug delivery systems. 80,[83][84][85][86][87][88][89][90][91][92][93] The design of nanocarriers for drug delivery offers several advantages, including the improvement of hydrophobic drug stability, thereby making them plausible for administration, the enhancement of biodistribution, and pharmacokinetics. This results in improved efficacy, improvement of the EPR effect, increased selective targeting, reduced adverse effects as a consequence of favored accumulation at target sites, and decreased toxicity by using biocompatible nanomaterials.…”

The challenge of using nanotherapy during pregnancy: Technological aspects and biomedical implications

“…NP are also able to cross the placenta and treat the fetus, as in hypoxia situations [ 50 ], and through the transport of macromolecules such as immunoglobulin G to fetal circulation [ 51 ]. In the studies ( in vitro ) of Hua and Vaughan [ 52 ] and Hua [ 53 ] was demonstrated the potential of NP (liposomes) for drug targeting to myometrial tissue. Moreover, Li et al [ 54 ] ( ex vivo ), tested NP by targeting of placental tissue for preeclampsia-treatment.…”