Doxorubicin-loaded human serum albumin nanoparticles overcome transporter-mediated drug resistance in drug-adapted cancer cells

Resistance to systemic drug therapy is a major reason for the failure of anticancer 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 anticancer 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 re-sensitised 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 successfully 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.