Reversal of Cisplatin Resistance in Ovarian Cancer by the Multitargeted Nanodrug Delivery System Tf-Mn-MOF@Nira@CDDP

Abstract

Cisplatin (CDDP) is a widely used chemotherapeutic drug with proven efficacy for treating tumors. However, its use has been associated with severe side effects and eventually leads to drug resistance, thus limiting its clinical application in patients with ovarian cancer (OC). Herein, we aimed to investigate the success rate of reversing cisplatin resistance using a synthetic, multitargeted nanodrug delivery system comprising a Mn-based metal–organic framework (Mn-MOF) containing niraparib (Nira) and CDDP alongside transferrin (Tf) conjugated to the surface (Tf-Mn-MOF@Nira@CDDP; MNCT). Our results revealed that MNCT can target the tumor site, consume glutathione (GSH), which is highly expressed in drug-resistant cells, and then decompose to release the encapsulated Nira and CDDP. Nira and CDDP play a synergistic role in increasing DNA damage and apoptosis, exhibiting excellent antiproliferation, migration, and invasion activities. In addition, MNCT significantly inhibited tumor growth in tumor-bearing mice and exhibited excellent biocompatibility without side effects. Furthermore, it depleted GSH, downregulated multidrug-resistant transporter protein (MDR) expression, and upregulated tumor suppressor protein phosphatase and tensin homolog (PTEN) expression, consequently reducing DNA damage repair and reversing cisplatin resistance. These results indicate that multitargeted nanodrug delivery systems can provide a promising clinical approach to overcoming cisplatin resistance. This study provides an experimental basis for further investigation into multitargeted nanodrug delivery systems to reverse cisplatin resistance in patients with OC.

Surface functionalization of metal–organic framework nanoparticle for overcoming biological barrier in cancer therapy

“…9C). 81 Mn-MOF reacts with GSH present in cancer cells, leading to its degradation. This reaction reduces the intracellular GSH levels, inhibiting detoxification and efflux pump-mediated drug outflow.…”

A copper-loaded self-assembled nanoparticle for disturbing the tumor redox balance and triple anti-tumor therapy

“…17,18 One of the major factors is the antioxidant defense system, mainly attributed to the overexpressed glutathione (GSH) in tumor cells that can regulate the oxidative stress and bring anticancer drug resistance. 19,20 In particular, GSH, an important antioxidative molecule and one of the biomarkers overexpressed in cancer, has the ability to scavenge ROS and result in the reduction of ROS-related therapeutic efficiency. 21,22 Therefore, GSH-depletion agents show promise as a potential strategy to enhance the efficiency of anticancer therapeutics.…”

Homologous-magnetic dual-targeted metal-organic framework to improve the Anti-hepatocellular carcinoma efficacy of PD-1 inhibitor

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