Delivery of Anticancer Gold-Dithiocarbamate via Thiolated Chitosan Nanoparticles

Thiolated chitosan nanoparticles (TCNs) are versatile biomaterials with applications in tissue engineering, coatings, wound healing, and drug delivery. Their biodegradability and ability to conjugate sulfhydryl-containing payloads make TCNs attractive as carriers for controlled therapeutic delivery. However, the nanodelivery of metallodrugs remains challenging because of instability and premature ligand exchange under physiological conditions. Developing robust strategies that enable the delivery of intact metal-based therapeutics is, therefore, of significant interest. Here, we exploit the redox properties of a gold-(III)-dithiocarbamate complex (AuDCN1) to enable the covalent attachment of its sulfhydryl ligand to the thiolated chitosan polymer backbone through disulfide bond formation. Nanoparticles were subsequently prepared via an ionic gelation method to generate AuDCN1-conjugated thiolated chitosan nanoparticles (Au-TCNs). Cargo release was characterized by LC-MS and spectroscopic methods under reducing conditions triggered by l-glutathione, a biologically relevant nucleophile. Biological evaluation demonstrated that Au-TCN nanoparticles exhibit potent activity against triple-negative breast cancer cells, inducing mitochondrial dysfunction through depolarization of the mitochondrial membrane potential and increased levels of mitochondrial reactive oxygen species production. Furthermore, Au-TCN significantly inhibited mammosphere formation in a three-dimensional culture, indicating activity against stem-like tumor cell populations. Collectively, these results highlight thiolated chitosan nanoparticles as a promising redox-responsive platform for delivering gold-based metallodrugs, expanding therapeutic strategies for the treatment of triple-negative breast cancer.