pH-Responsiveness of Hexosomes and Cubosomes for Combined Delivery of Brucea Javanica Oil and Doxorubicin.

We report pH-responsive liquid crystalline lipid nanoparticles, which are dual loaded by Brucea javanica oil (BJO) and doxorubicin hydrochloride (DOX) and display a pH-induced inverted hexagonal (pH=7.4) to cubic (pH=6.8) to emulsified microemulsion (pH=5.3) phase transition with a therapeutic application in cancer inhibition. Brucea javanica oil is a traditional herbal medicine that strongly inhibits the proliferation and metastasis of various cancers. Doxorubicin is an anti-tumor drug, which prevents DNA replication and hampers protein synthesis through intercalation between the base pairs of the DNA helices. Its dose-dependent cardiotoxicity imposes the need of safe delivery carriers. Here pH-induced changes in the structural and interfacial properties of designed multicomponent drug delivery (monoolein-oleic acid-BJO-DOX) systems are determined by synchrotron small-angle X-ray scattering (SAXS) and the Langmuir film balance technique. The nanocarrier assemblies displayed good physical stability in the studied pH range and adequate particle sizes and zeta potentials. Their interaction with model lipid membrane interfaces was enhanced under acidic pH conditions, which mimic the microenvironment around tumor cells. In vitro cytotoxicity and apoptosis studies with BJO-DOX dual-loaded pH-switchable liquid crystalline nanoparticles (BJO-DOX-LCNPs) were performed with the human breast cancer MCF-7 cells line and MCF-7 cells with doxorubicin resistance (MCF-7/DOX), respectively. The obtained pH-sensitive nanomedicines demonstrated enhanced anti-tumor efficacy. The performed preliminary studies suggested a potential reverse of the resistance of the MCF-7/DOX cells to DOX. These results highlighted the necessity of further understanding of the link between the established pH-dependent drug release profiles of the nanocarriers and the role of their pH-switchable inverted hexagonal, bicontinuous cubic, emulsified microemulsion inner organizations for the therapeutic outcomes.