Preparation, characterization, and toxicity assessment of carfilzomib-loaded nickel-based metal-organic framework: Evidence from in-vivo and in-vitro experiments

Abstract

The introduction of innovative medications such as proteasome inhibitors (PIs) has significantly increased the response rate and overall survival of cancer patients. Carfilzomib (CFZ) is a second-generation PI that has shown favorable outcomes in treating relapsed/refractory and newly diagnosed multiple myeloma patients in clinical trials. In the present study, novel nickel-based metal-organic frameworks (Ni-MOFs) were designed, loaded with CFZ, and utilized for the first time as a drug delivery platform for targeted cancer therapy. Ni-MOFs were prepared via a simple bottom-up solvothermal method, and characterized in terms of morphology, size distribution, porosity, and release behavior. They have a mesoporous structure with a mean pore diameter of 16.2 nm. Both unloaded and CFZ-loaded Ni-MOFs exhibit nanocube and nanorod-like morphologies and a size range of 150–500 nm. The in-vitro and in-vivo effects of CFZ-loaded Ni-MOFs were compared with those of standard drugs. A high loading efficiency with a controlled release behavior was observed. MTT results demonstrated that CFZ-loaded Ni-MOFs exert higher cytotoxic effects than free CFZ against cancer cells, this effect being more pronounced in A549 lung cancer cells. Besides, they also lead to a stronger increase of the mRNA levels of TP53 in malignant cells. Rats treated with free and loaded CFZ significantly increased biochemical parameters, namely serum alanine aminotransferase (ALT), serum creatinine, blood urea nitrogen (BUN), aspartate aminotransferase (AST), and liver malondialdehyde (MDA). Moreover, a high dose of CFZ-loaded Ni-MOFs caused severe histopathological alterations. Altogether, our findings provide rational evidence for future studies using Ni-MOFs as promising carriers of PIs such as CFZ, for targeted drug delivery.