Subcutaneous injection sites impact brain uptake of blood-brain barrier impermeable paclitaxel

Abstract

PurposeSystemic absorption is the process of drug movement from the site of drug administration to systemic circulation for therapeutic efficacy. Systemic absorption and distribution of therapeutics are affected by the route of administration and may further vary with different sites for the same route. Paclitaxel (PTX) remains one of the most powerful chemotherapeutic drugs to treat various tumors. Nevertheless, PTX has not been used to treat brain tumors because of its blood-brain barrier (BBB) impermeability and lack of drug accumulation in the brain. This study aimed to investigate systemic absorption and brain uptake of PTX following subcutaneous (SC) injection at different sites.MethodsA hydroxypropyl methylcellulose (HPMC) polymer was used to prepare the PTX-HPMC hydrogel. The PTX-HPMC hydrogel was characterized by sol-gel transition, drug release, and in situ hydrogel formation. Systemic absorption and distribution in the brain were investigated in mice after subcutaneous injection at three different sites (flank, head, and abdomen). The PTX concentrations in the plasma and brain homogenates were quantified using LC-MS/MS using the liquid-liquid extraction method.ResultsThe PTX-HPMC hydrogel showed sol-gel transition at 37 celcius and bi-phase release with burst and sustained release. Systemic absorption in the plasma at all SC injection sites showed no significant differences. However, the distribution to the brain after SC injection at the head was 2.5 times higher than at the flank, suggesting an injection site-dependent distribution of PTX.ConclusionDifferences in blood and lymph flow among SC sites are expected to contribute to PTX distribution. SC injection into the head may be a promising route for drug delivery to brain.