Sarika Sabnis,1 Nirupama A Sabnis,1 Sangram Raut,2 Andras G Lacko1,3 1Institute of Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, 2Department of Physics, Texas Christian University, 3Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, TX, USA Abstract: Current cancer chemotherapy is frequently associated with short- and long-term side effects, affecting the quality of life of cancer survivors. Because malignant cells are known to overexpress specific surface antigens, including receptors, targeted drug delivery is often utilized to reduce or overcome side effects. The current study involves a novel targeting approach using specifically designed nanoparticles, including encapsulation of the anti-cancer drug valrubicin into superparamagnetic iron oxide nanoparticle (SPION) containing reconstituted high-density lipoprotein (rHDL) nanoparticles. Specifically, rHDL–SPION–valrubicin hybrid nanoparticles were assembled and characterized with respect to their physical and chemical properties, drug entrapment efficiency and receptor-mediated release of the drug valrubicin from the nanoparticles to prostate cancer (PC-3) cells. Prussian blue staining was used to assess nanoparticle movement in a magnetic field. Measurements of cytotoxicity toward PC-3 cells showed that rHDL–SPION–valrubicin nanoparticles were up to 4.6 and 31 times more effective at the respective valrubicin concentrations of 42.4 µg/mL and 85 µg/mL than the drug valrubicin alone. These studies showed, for the first time, that lipoprotein drug delivery enhanced via magnetic targeting could be an effective chemotherapeutic strategy for prostate cancer. Keywords: drug delivery, nanoparticles, rHDL, magnetic nanoparticles, SPION