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Copper diethyldithiocarbamate (Cu(DDC) 2 ) has been demonstrated to possess excellent antitumor activity. However, the extremely poor water solubility of Cu(DDC) 2  bring difficulty for its formulation research. In this study, we aim to develop a novel nanocarrier for Cu(DDC) 2  delivery to overcome this obstacle and enhance antitumor activity. The SP94 modified asymmetrical bilayer lipid-encapsulated Cu(DDC) 2  nanoparticles (DCDP) was established by combining the method of inverse microemulsion aggregation and thin-film dispersion.  In vitro  cellular assays and  in vivo  tumor-xenograft experiments were conducted to evaluate the tumor chemotherapeutic effect of DCDP. And the vital role of copper ions played in DSF or DDC (DSF/DDC)-based cancer chemotherapy was also explored. DCDP with an encapsulation efficiency (EE%) of 74.0% were successfully prepared. SP94 modification facilitated cellular intake for DCDP, and promoted apoptosis to repress tumor cell proliferation (IC 50 , 200 nM). And DCDP effectively inhibited tumor growth with a high tumor inhibition rate of 74.84%. Furthermore, Cu(DDC) 2  was found to facilitate the copper ion accumulation in tumor tissues, which is beneficial to therapy with high potency. DCDP exhibited high-efficient tumor chemotherapeutic efficacy and provided a novel strategy for investigating the anticancer mechanism of Cu(DDC) 2 .

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The treatment of hepatocellular carcinoma with SP94 modified asymmetrical bilayer lipid-encapsulated Cu(DDC) 2  nanoparticles facilitating Cu accumulation in the tumor