Reactive Oxygen Species-Responsive Nanococktail With Self-Amplificated Drug Release for Efficient Co-Delivery of Paclitaxel/Cucurbitacin B and Synergistic Treatment of Gastric Cancer.

Lijun Pang,Tengyun Li,Ling Cao,Lei Zhang,Hong Zhou,Yueqin Shao

doi:10.3389/fchem.2022.844426

Lijun Pang, Tengyun Li + Show 4 more

Open Access

https://doi.org/10.3389/fchem.2022.844426

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Abstract

Application of drug combinations is a powerful strategy for the therapy of advanced gastric cancer. However, the clinical use of such combinations is greatly limited by the occurrence of severe systemic toxicity. Although polymeric-prodrug-based nanococktails can significantly reduce toxicity of drugs, they have been shown to have low intracellular drug release. To balance between efficacy and safety during application of polymeric-prodrug-based nanococktails, a reactive oxygen species (ROS)-responsive nanococktail (PCM) with self-amplification drug release was developed in this study. In summary, PCM micelles were co-assembled from ROS-sensitive cucurbitacin B (CuB) and paclitaxel (PTX) polymeric prodrug, which were fabricated by covalently grafting PTX and CuB to dextran via an ROS-sensitive linkage. To minimize the side effects of the PCM micelles, a polymeric-prodrug strategy was employed to prevent premature leakage. Once it entered cancer cells, PCM released CuB and PTX in response to ROS. Moreover, the released CuB further promoted ROS generation, which in turn enhanced drug release for better therapeutic effects. In vivo antitumor experiments showed that the PCM-treated group had lower tumor burden (tumor weight was reduced by 92%), but bodyweight loss was not significant. These results indicate that the developed polymeric prodrug, with a self-amplification drug release nanococktail strategy, can be an effective and safe strategy for cancer management.

Highlights

In 2020, over 1,080,000 new cases of gastric cancer (GC) were diagnosed and 768,000 mortalities were reported making it the sixth most common cancer and the third cause of cancer-related deaths in the world (Sung et al, 2021)
The polymeric prodrugs were prepared by modifying PTX or cucurbitacin B (CuB) to DEX though an reactive oxygen species (ROS)-sensitive TK linker via a two-step esterification reaction
The structure of TK-modified PTX (TK-PTX) and TK-CuB were verified through 1H NMR (Figures 1A,B) and MS (Supplementary Figure S1)

Summary

INTRODUCTION

In 2020, over 1,080,000 new cases of gastric cancer (GC) were diagnosed and 768,000 mortalities were reported making it the sixth most common cancer and the third cause of cancer-related deaths in the world (Sung et al, 2021). CuB-based nanococktail increases the ROS to promote drug release in cancer cells and achieve a synergistic effect for the treatment of GC. A self-amplification release nanococktail (PCM) was developed by self-assembling of both ROS-responsive CuB (DEX-TK-CuB) and PTX (DEX-TK-PTX) polymeric prodrugs (Scheme 1). Reactive oxygen species (ROS)-responsive CuB (DEX-TK-CuB) and DEX-TK-PTX can co-assembly into micelles in an aqueous solution to form a selfamplification release nanococktail (PCM). The drug loading content (DLC) of PTX and CuB was detected by HPLC and calculated using the following Eq 1: DLC(%) Mass of drug in micelles × 100%. Freshly prepared PCM (containing 30 μg of PTX and 15 μg of CuB) was dissolved in 4 ml of release medium and cultured at 37°C with slight shaking. Inferential statistics were carried out using the t-test or one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test to compare the means. p < 0.05 was defined as a statistically significant difference

RESULTS AND DISCUSSION

CONCLUSION

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