Thermo/pH dual-responsive core–shell particles for apatinib/doxorubicin controlled release: preparation, characterization and biodistribution

Abstract

Dual-drug loaded and dual-responsive core–shell particles (DD particles) were synthesized via an electrospray method in one step. First, 4-CBS-chitosan was synthesized by conjugating an aromatic sulfonamide group at the C2-N position of chitosan. Then, poly(nisopropylacylamide) (PNIPAM) containing apatinib model drug solution as the outer solution and 4-CBS-chitosan containing doxorubicin (DOX) as the inner solution were injected through a coaxial tube into a high voltage electric field. The formulation conditions of the DD particles were tuned to obtain spherical particles with narrow size distributions (94.97 ± 33.75 nm in diameter). The particles showed excellent responses to changes in pH and temperature: the releases of entrapped apatinib and doxorubicin (DOX) were accelerated when the solution temperature was above its lower critical solution temperature (LCST) (34 °C) or when the solution pH was acidic (pH 1.2). Degradation studies indicated that the DD particles degraded; the inner layer sank and the outer layer fragmented. In vivo biodistribution was studied by intragastric administration; it was found that the retention time of the drugs in the stomach was significantly improved and the initial burst release decreased, while a higher drug concentration level was maintained for a long time. These particles can exploit triggering mechanisms for release of the entrapped drugs from the particles, indicating their great potential for use in controlled release applications.