Repurposing disulfiram for cancer therapy via targeted nanotechnology through enhanced tumor mass penetration and disassembly

5 years ago

Repurposing disulfiram for cancer therapy via targeted nanotechnology through enhanced tumor mass penetration and disassembly

Disulfiram (DSF), an FDA approved drug for the treatment of alcoholism, degrades to therapeutically active diethyldithiocarbamate (DDTC) in the body by reduction. Hereby, we developed a redox sensitive DDTC-polymer conjugate for targeted cancer therapy. It was found that the DDTC-polymer conjugate modified with a β-d-galactose receptor targeting ligand can self-assemble into LDNP nanoparticle and efficiently enter cancer cells by receptor-mediated endocytosis. Upon cellular uptake, the LDNP nanoparticle degrades and releases DDTC due to the cleavage of disulfide bonds, and subsequently forms copper (II) DDTC complex to kill a broad spectrum of cancer cells. 3D cell culture revealed that this nanoparticle shows much stronger tumor mass penetrating and destructive capacity. Furthermore, LDNP nanoparticles exhibited much greater potency in inhibiting tumor growth in a peritoneal metastatic ovarian tumor model.

Statement of Significance

The β-d-galactose receptor targeted disulfiram loaded nanoparticle (LDNP) is novel in the following aspects:

1. Lactobionic acid (LBA) targets β-d-galactose receptor, which is a surface lectin that is overexpressed in various types of cancer cells, such as liver and ovarian cancers. The introducing of LBA ligand, endows the LDNP/Cu nanoparticle with stronger penetrating and destructive capacity in a tumor spheroid model.

2. The premature release of disulfiram from the nanoparticle can be minimized through the formation of polymer-prodrug based LDNP.

3. The LDNP nanoparticle fabricated from a polymer-disulfiram derivative conjugate can selectively kill a broad spectrum of cancer cells, while sparing normal cells.

4. In vivo study carried out in a clinically relevant orthotopic ovarian tumor model revealed that LDNP/Cu exhibits stronger efficacy in inhibiting the progression of metastatic ovarian cancer than a dosage form used in clinical trial, while not inducing side effects.

Publisher URL: www.sciencedirect.com/science

DOI: S1742706117307894