Abstract
Resistance to chemotherapy is a major problem facing current cancer therapy, which is continuously aiming at the development of new compounds that are capable of tackling tumors that developed resistance toward common chemotherapeutic agents, such as doxorubicin (DOX). Alongside the development of new generations of compounds, nanotechnology-based delivery strategies can significantly improve the in vivo drug stability and target specificity for overcoming drug resistance. In this study, multifunctional gold nanoparticles (AuNP) have been used as a nanoplatform for the targeted delivery of an original anticancer agent, a Zn(II) coordination compound [Zn(DION)2]Cl2 (ZnD), toward better efficacy against DOX-resistant colorectal carcinoma cells (HCT116 DR). Selective delivery of the ZnD nanosystem to cancer cells was achieved by active targeting via cetuximab, NanoZnD, which significantly inhibited cell proliferation and triggered the death of resistant tumor cells, thus improving efficacy. In vivo studies in a colorectal DOX-resistant model corroborated the capability of NanoZnD for the selective targeting of cancer cells, leading to a reduction of tumor growth without systemic toxicity. This approach highlights the potential of gold nanoformulations for the targeting of drug-resistant cancer cells.
Highlights
Chemotherapy agents, such as doxorubicin (DOX), are frequently used in first-line therapy against colorectal and lung cancer, but the efficacy of these agents is limited by the development of drug resistance
The impact of novel compounds in cancer chemotherapy is often challenged by stability and solubility issues and, more importantly, a lack of selectivity to cancer cells that induce undesirable deleterious effects to healthy cells and tissues
We presented a nanoformulation for the targeted delivery of a powerful anti-tumor water-soluble Zn(II) coordination compound ([Zn(DION)2]Cl2) (ZnD) toward colorectal carcinoma cells
Summary
Chemotherapy agents, such as doxorubicin (DOX), are frequently used in first-line therapy against colorectal and lung cancer, but the efficacy of these agents is limited by the development of drug resistance. A comparative proteomic analysis of the ZnD effect in HCT116 DR highlighted several molecular response profiles in clear agreement with the cell death mechanism identified earlier, such as an induction of cell death (via reactive oxygen species (ROS) induction and apoptosis) and cell cycle arrest as the main pathways involved (see Supplementary Material Section 4; Figure S4 and Table S1; STRING Analysis) Data show that these cancer cells have an efficient mechanism of ROS detoxification that allows them to survival under pro-oxidizing conditions [27], with higher activity for the DOX-resistant cells. The apoptotic and folding pathways that are activated upon ZnD treatment in HCT116 and HCT116 DR cells lead to a high loss of cell viability
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