Doxorubicin Intercalated Copper Diethyldithiocarbamate Functionalized Layered Double Hydroxides Hybrid Nanoparticles for Targeted Therapy of Hepatocellular Carcinoma
Disulfiram (DSF), a traditional FDA approved drug for the treatment of alcohol dependence, has been explored for cancer treatment for years. It has found that the antitumor activity of DSF is Cu2+ dependent and copper diethyldithiocarbamate (Cu(DDC)2) formed by DSF and Cu2+ or DDC (a metabolite of DSF) and Cu2+ is a major active ingredient for the anticancer activity of DSF. Although many clinical trials were conducted by administration of DSF and copper in com¬bination, no successful news has been announced. This is probably because that the formation of Cu(DDC)2 in tumor is insufficient. It is a promising strategy for direct delivery of Cu(DDC)2 to enhance the anticancer efficacy of DSF. However, efficient drug delivery remains a significant challenge because of the inherent aqueous insolubility of Cu(DDC)2. Herein, a kind of hexagonal Cu-Al LDH nanoparticle was prepared by the co-precipitation method for the first time. Subsequently, DDC was introduced into Cu-Al LDH to form Cu(DDC)2 in situ and doxorubicin (DOX) was also added into LDH for the synergistic treatment of hepatocellular carcinoma (HCC). The optimal ratio of Cu(DDC)2/DOX was investigated and used for the preparation of dual drug-loaded nanoparticles, which were further coated with polyethylene glycol-graft-polyglutamic acid (PEG-PLG) and hyaluronic acid (HA) to improve the stability of formulation and targeting of HCC. The dual drug-loaded nanoparticles showed good stability in both neutral and mild acidic solutions while accelerated drugs release in the solution of simulated lysosomes or tumor cells. In In vitro cellular assays, the nanoparticles co-delivering Cu(DDC)2 and DOX showed an improved synergistic effect of antitumor efficacy and HA coated nanoparticles presented rapid and massive cellular uptake in Hep G2 cells, which could be great benefit for the treatment of HCC in vivo. The in vivo antitumor results demonstrated that the HA/PEG-PLG@LDH@DDC/DOX nanoparticles with extremely low dose showed superior antitumor efficacy to PEG-PLG@LDH@DDC/DOX and the mixture of free drugs. This work provides an effective strategy for intravenous delivery of Cu(DDC)2 and shows a great potential for cancer synergistic therapy with the novel DOX intercalated Cu(DDC)2 functionalized layered double hydroxides hybrid nanoparticles.