Decellularized amnion membrane-based thermosensitive vaginal hydrogel enhances ritodrine efficacy and reduces systemic side effects in preterm birth treatment

Preterm birth remains a major cause of maternal and neonatal mortality, primarily due to the lack of effective clinical interventions. Ritodrine, a typical β₂-adrenoceptor agonist with low cost and proven clinical efficacy, faces restrictions in many developed countries because of its systemic side effects. To overcome the clinical limitations of ritodrine, this study developed a decellularized amnion membrane (dAM)-derived thermosensitive hydrogel for vaginal delivery of ritodrine (dAM@Rit). The resulting dAM@Rit exhibited favorable temperature sensitivity, optimal rheological properties, sustained drug release, low cytotoxicity, and high biocompatibility. In vivo fluorescence analyses confirmed the uterine-specific distribution of the drugs through the vaginal delivery of dAM@Rit, facilitated by the uterine first-pass effect. Pharmacodynamic evaluation revealed that dAM@Rit maintenance therapy reduced the preterm birth rate due to the anti-inflammatory properties of dAM and the β₂-adrenoceptor antagonizing effect of ritodrine. Notably, the dAM@Rit formulation also substantially mitigated ritodrine-induced adverse reactions, such as pulmonary edema and rhabdomyolysis. In conclusion, our findings offered a promising strategy to optimize the clinical application of ritodrine for managing preterm birth while minimizing its systemic side effects. STATEMENT OF SIGNIFICANCE: 1. This study designed a thermosensitive hydrogel for the vaginal delivery of ritodrine, achieving targeted uterine drug delivery through the uterine first-pass effect. 2. The hydrogel utilizes decellularized amnion membrane (dAM) as its matrix, which not only exhibits high biocompatibility but also enhances the therapeutic efficacy of ritodrine through its anti-inflammatory properties, synergistically treating premature labor. 3. Compared with intravenous or oral administration, the dAM-based vaginal hydrogel significantly reduces the adverse effects of ritodrine on both mothers and fetuses, offering a safer alternative for the management of preterm birth. 4. This work demonstrates the application of human amniotic membrane-derived biomaterial for pregnancy-related diseases, highlighting the importance of balancing efficacy and safety in clinical applications.