Doxorubicin-loaded human serum albumin nanoparticles overcome transporter-mediated drug resistance

Resistance to systemic drug therapies is a major reason for the failure of anti-cancer therapies. Here, we tested doxorubicin-loaded human serum albumin (HSA) nanoparticles in the neuroblastoma cell line UKF-NB-3 and its ABCB1-expressing sublines adapted to vincristine (UKF-NB-3 r VCR 1 ) and doxorubicin (UKF-NB-3 r DOX 20 ). Doxorubicin-loaded nanoparticles displayed increased anti-cancer activity in UKF-NB-3 r VCR 1 and UKF-NB-3 r DOX 20 cells relative to doxorubicin solution, but not in UKF-NB-3 cells. UKF-NB-3 r VCR 1 cells were resensitised by nanoparticle-encapsulated doxorubicin to the level of UKF-NB-3 cells. UKF-NB-3 r DOX 20 cells displayed a more pronounced resistance phenotype than UKF-NB-3 r VCR 1 cells and were not re-sensitised by doxorubicin-loaded nanoparticles to the level of parental cells. ABCB1 inhibition using zosuquidar resulted in similar effects like nanoparticle incorporation, indicating that doxorubicin-loaded nanoparticles circumvent ABCB1-mediated drug efflux. The limited re-sensitisation of UKF-NB-3 r DOX 20 cells to doxorubicin by circumvention of ABCB1-mediated efflux is probably due to the presence of multiple doxorubicin resistance mechanisms. So far, ABCB1 inhibitors have failed in clinical trials, probably because systemic ABCB1 inhibition results in a modified body distribution of its many substrates including drugs, xenobiotics, and other molecules. HSA nanoparticles may provide an alternative, more specific way to overcome transporter-mediated resistance.