Affiliation:
1. Department of Pharmaceutical Sciences College of Pharmacy Oregon State University 2730 S Moody Avenue Portland Oregon 97201 USA
2. Department of Pathology and Laboratory Medicine, and the Center for Developmental Health, School of Medicine Oregon Health & Science University 3181 SW Sam Jackson Park Road Portland OR 97239 USA
3. Department of Obstetrics and Gynecology, School of Medicine Oregon Health & Science University 3181 SW Sam Jackson Park Road Portland OR 97239 USA
Abstract
AbstractThe first‐line treatment for ectopic pregnancy (EP), the chemotherapeutic methotrexate (MTX), has a failure rate of more than 10%, which can lead to severe complications or death. Inadequate accumulation of administered MTX at the ectopic implantation site significantly contributes to therapeutic failure. This study reports the first glutathione‐responsive polymersomes for efficient delivery of MTX to the implantation site and its triggered release in placental cells. Fluorescence and photoacoustic imaging have confirmed that the developed polymersomes preferentially accumulate after systemic administration in the implantation site of pregnant mice at early gestational stages. The high concentrations of intracellular glutathione (GSH) reduce an incorporated disulfide bond within polymersomes upon internalization into placental cells, resulting in their disintegration and efficient drug release. Consequently, MTX delivered by polymersomes induces pregnancy demise in mice, as opposed to free MTX at the same dose regimen. To achieve the same therapeutic efficacy with free MTX, a sixfold increase in dosage is required. In addition, mice successfully conceive and birth healthy pups following a prior complete pregnancy demise induced by methotrexate polymersomes. Therefore, the developed MTX nanomedicine can potentially improve EP management and reduce associated mortality rates and related cost.
Funder
Eunice Kennedy Shriver National Institute of Child Health and Human Development
Subject
Biomaterials,Biotechnology,General Materials Science,General Chemistry