Self-assembled leuprolide-oleic acid nanoparticles encapsulating docetaxel for synergistic drug delivery.

In the present study, an amphiphilic leuprolide acetate (LEU)-oleic acid (OA) conjugate (LOC) was synthesized by conjugating the peptide drug LEU with OA to form self-assembled nanoparticles (LON). This may maximize the synergistic effectiveness of fatty acids and anticancer drugs in prostate cancer. Docetaxel (DTX)-encapsulating LON (LOND) have also been developed for triple-synergistic drug delivery. LON and LOND retained a uniformly spherical morphology and had particle sizes ranging 130.6-159.1 ± 3.1 nm, depending on the freeze drying or redispersion process. Neither LON nor encapsulation of DTX into LON altered the structural behavior of LEU circular dichroism (CD). The nanoparticles were also stable in terms of particle size and polydispersity index (PDI) during storage. LOND exhibited excellent membrane permeability using a Franz diffusion cell. In addition, high lymphatic uptake was observed using an Intralipid®-based absorption assay. LEU and DTX from LON or LOND were released in a controlled manner for 7 d. Notably, the esterase (5 U/mL) significantly decreased the release of LEU, DTX, and LOC. As LOC from LON was enzymatically cleaved, a higher release rate of LEU was achieved. In contrast, a higher release rate of DTX but a lower LEU from LOND was achieved by losing the nanoparticle structure. In a cytotoxicity assay, LOND exhibited significantly higher cytotoxicity against PC3 human prostate cancer cells than LEU or DTX alone, whereas no significant cytotoxicity was observed in normal human foreskin fibroblast (HFF-1) cells. Furthermore, confocal microscopy confirmed the cellular uptake of the nanoparticles in both PC-3 and RAW 264.7 macrophage cells. Based on these findings, LOND, simultaneously releasing LEU, DTX, and fatty acids (such as OA), provides a promising drug delivery platform for triple synergy in the treatment of prostate cancer.