Abstract
Diagnosis and treatment of breast cancer in pregnancy can result in morbidity and mortality for the mother and fetus. Many new paclitaxel nanoformulations commercially available worldwide for breast cancer treatment are being adopted due to favorable dosing regimens and side effect profiles, but their transplacental transport and resultant fetal exposure remain unknown. Here, we examine three formulations: Taxol (paclitaxel dissolved in Kolliphor EL and ethanol); Abraxane (albumin nanoparticle); and Genexol-PM (polymeric micelle). In the ex vivo dually perfused human placental cotyledon, placental accumulation of Genexol-PM is higher than Taxol, and both nanoformulations have lower maternal concentrations of paclitaxel over time. In vitro studies of these formulations and fluorescent nanoparticle analogs demonstrate that Genexol-PM allows paclitaxel to overcome P-glycoprotein efflux, but Abraxane behaves as a free drug formulation. We anticipate that these findings will impact future development of rational and safe treatment strategies for pregnancy-associated breast cancer and other diseases.
We tested two nanoformulations of paclitaxel (Genexol-PM and Abraxane) against Taxol in ex vivo dually perfused human placental cotyledons, and found that polymeric micelles caused increased placental accumulation of paclitaxel. Further in vitro studies revealed this is likely due to shielding of encapsulated paclitaxel from efflux by P-glycoprotein. Abraxane, on the other hand, acts as a free drug formulation and does not shield paclitaxel from efflux. [Display omitted]
•Nanoparticle formulations of drugs alter their permeability across human placenta.•Encapsulation of paclitaxel in micelles prevents placental efflux by P-glycoprotein.•Reduced efflux of paclitaxel leads to increased placental accumulation.