Branched worm-like nanoparticles featured with programmed drug release for synergistic castration-resistant prostate cancer therapy

Co-delivery systems with programmed release of combined drugs are of great value for combination cancer therapy. However, design of such co-delivery systems for potent synergistic cancer therapy is still a great challenge. In the present work, dimethylcurcumin (DMC) and docetaxel (DTX) co-loaded branched worm-like nanoparticles (NPs) with programmed release of DMC and DTX were developed for potent synergistic castration-resistant prostate cancer (CRPC) therapy. (2-Hydroxypropyl)-β-cyclodextrin-retinoic acid (HP-β-CD-RA) conjugates with different molar ratios of RA to HP-β-CD were synthesized and used for the preparation of DMC and DTX co-loaded NPs. The as-prepared DMC and DTX co-loaded NPs ( D h 170–190 nm) have branched worm-like morphologies, and DMC/DTX@HP-β-CD-RA 3.0 NPs show the highest drug loading content and encapsulation efficiency. DMC/DTX@HP-β-CD-RA 3.0 NPs exhibit programmed drug release patterns with DTX released much faster than DMC, which could be ascribed to the difference between DMC and DTX in the interaction with HP-β-CD-RA 3.0 as analyzed by molecular simulation, phase solubility method, and fluorescence spectra. DMC/DTX@HP-β-CD-RA 3.0 NPs exhibit enhanced cellular uptake as compared to DMC/DTX. Mechanism dissection reveals that the cellular uptake of DMC/DTX@HP-β-CD-RA 3.0 NPs is energy-dependent in which macropinocytosis and clathrin- and caveolae-independent endocytosis pathways are involved. Benefited from their enhanced cellular uptake and programmed drug release, DMC/DTX@HP-β-CD-RA 3.0 NPs exhibit significantly enhanced antitumor effect as compared to DMC/DTX. Such mechanisms for potent synergistic antitumor effect, by enhancing cellular uptake of DMC and DTX together with programmed drug release, may provide new therapeutic options for CRPC.