Doxorubicin intercalated copper diethyldithiocarbamate functionalized layered double hydroxide hybrid nanoparticles for targeted therapy of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to its long incubation period and low cure rate. Layered double hydroxide (LDH) nanoparticles have attracted considerable research interest in the field of nanomedicine owing to their surface effects and good biocompatibility. In this research, we synthesized a hexagonal nanoparticle by the co-precipitation method, referred to as Cu–Al LDH. As an alternative to traditional drug-loading methods, sodium diethyldithiocarbamate (DDC) was introduced and combined with Cu²⁺ in LDHs to form a diethyldithiocarbamate–copper complex (Cu(DDC)₂), which was not only the composition of carrier materials but also an effective component for cancer therapy. Doxorubicin (DOX) was also encapsulated into LDHs due to the clinical relevance of DOX treatment for HCC. Formulations of the Cu(DDC)₂ and DOX co-loaded nanoparticles were optimized to precisely control the Cu(DDC)₂/DOX ratio. The nanoparticles were coated with polyethylene glycol-graft-polyglutamic acid (PEG-PLG) through electrostatic adsorption to improve the stability of the nanoparticles. The outer layer was decorated with hyaluronic acid (HA) to achieve specific targeting of tumors. Compared with non-HA coated nanoparticles, HA coated nanoparticles showed greater cellular uptake in Hep G2 cells, which could cause higher cytotoxicity. In addition, targeted nanoparticles effectively inhibited tumor growth in mouse models of ectopic hepatocellular carcinoma. It can be concluded that there is a great potential for synergistic cancer therapy using the novel DOX intercalated Cu(DDC)₂ functionalized layered double hydroxide hybrid nanoparticles.