A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer

Abstract

One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug-loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX-DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer.

A highly integrated precision nanomedicine strategy to target esophageal squamous cell cancer molecularly and physically

“…Therefore, we decided to provide more flexibility by loading two drugs separately for our study. As previously described [30], we successfully loaded AZD8186 and DTX in disulfide cross-linked micelles (DCMs) to prepare AZD8186-DCMs and DTX-DCMs. The average particle size of AZD8186-DCMs and DTX-DCMs were 20± 6 nm and 21± 7 nm, respectively (Fig 2A).…”

Novel Nanococktail of a Dual PI3K/mTOR Inhibitor and Cabazitaxel for Castration‐Resistant Prostate Cancer

“…[ 42–45 ] To date, very few nanomedicines have been approved for clinical use, including albumin‐bound paclitaxel, polymeric micelle‐formulated paclitaxel, and non‐PEGylated liposomal doxorubicin. [ 46 ]…”

Telodendrimers: Promising Architectural Polymers for Drug Delivery

“…As the general chemical methodologies involved in the synthesis of telodendrimers were becoming available, the biological perspective of their applications became the next focus [ 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 ]. As noted by Newkome in 1985, it was the search for an architectural outline with the ability to form micelles that inspired the scientific community about these hybrid structures.…”