Orchestrating Precision within the Tumor Microenvironment by Biomimetic Nanoprodrugs for Effective Tumor Therapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Therapy

Background:

• Developing novel antitumor drugs faces significant challenges including lengthy trials and high costs.
• Repurposing existing drugs like disulfiram (DSF) offers a promising alternative for cancer treatment.
• Disulfiram metabolizes to diethyldithiocarbamate (DTC), which can chelate copper ions to form a cytotoxic complex (CuET).

Purpose of the Study:

• To develop a novel nanoprodrug system for enhanced antitumor efficacy using disulfiram and copper.
• To investigate the targeted delivery and in situ generation of the cytotoxic CuET complex within the tumor microenvironment.
• To evaluate the immunogenic effects and overall therapeutic potential of the M-MDTC nanoprodrugs in preclinical models.

Main Methods:

• Disulfiram (DSF) was loaded into mesoporous dopamine nanocarriers, surface-chelated with tannin and Cu2+, and camouflaged with tumor cell membranes to create M-MDTC nanoprodrugs.
• The M-MDTC nanoprodrugs were designed for targeted delivery to tumor sites via intravenous injection and subsequent release of DSF and Cu2+ under specific tumor microenvironment conditions (acidic pH, photothermal stimulation).
• In vitro and in vivo studies were conducted to assess the tumor-killing ability, solid tumor suppression, and immunogenic cell death induction of the M-MDTC nanoprodrugs.

Main Results:

• M-MDTC nanoprodrugs demonstrated successful accumulation at tumor sites and triggered the in situ formation of the highly toxic CuET complex.
• The generated CuET complex effectively killed tumor cells in situ and induced immunogenic cell death, characterized by increased CD86+ CD80+ cells and enhanced dendritic cell maturation.
• Both in vitro and in vivo experiments confirmed the excellent tumor-cell-killing capability and significant solid tumor suppression by the M-MDTC nanoprodrugs.

Conclusions:

• The developed M-MDTC nanoprodrug system effectively utilizes repurposed disulfiram and copper for targeted cancer therapy.
• This approach enables in situ amplification of chemotherapy within the tumor microenvironment, leading to potent antitumor effects.
• The strategy holds significant promise for developing effective and alternative cancer treatments by leveraging existing medications and advanced nanotechnology.