A Rapid Dual-Responsive Releasing Nano-Carrier by Decomposing the Copolymer and Reversing the Core Dissolution.

Sen Liu,Can Shen,Zhihao Wang,Changjiang Pan,Jianquan Wang,Xuecong Tang,Qiuyang Zhang,Wei Ye,Cheng Qian

doi:10.3389/fbioe.2021.784838

Abstract

The accumulation of nanotechnology-based drugs has been realized in various ways. However, the concentration of drugs encapsulated by nanomaterials is not equal to the concentration of effective drugs; often, the drugs become effective only when they are released from the nanomaterials as free drugs. This means only when the drugs are rapidly released after the accumulated drug-encapsulating nanomaterials can they truly achieve the purpose of increasing the concentration of drugs in the tumor. Therefore, we herein report a dual-response nano-carrier of glutathione and acid to achieve the rapid release of encapsulated drug and increase the effective drug concentration in the tumor. The nano-carrier was constructed using a dual-responsive amphiphilic copolymer, composed of polyethylene glycol and hydrophobic acetylated dextran and connected by a disulfide bond. In the tumor microenvironment, disulfide bonds could be biodegraded by glutathione that is overexpressed in the tumor, exposing the core of nano-carrier composed of acetylated dextran. Then the acidic environment would induce the deacetylation of acetylated dextran into water-soluble dextran. In this way, the nano-carrier will degrade quickly, realizing the purpose of rapid drug release. The results showed that the drug release rate of dual-responsive nano-carrier was much higher than that of glutathione or acid-responsive nano-carrier alone. Furthermore, both in vitro and in vivo experiments confirmed that dual-responsive nano-carrier possessed more efficient anti-tumor effects. Therefore, we believe that dual-responsive nano-carriers have better clinical application prospects.

Highlights

Nano-carriers have played significant roles in improving the therapeutic effects of tumor chemotherapy in the past decades (Petros and Desimone, 2010; Shi et al, 2016)
The mean hydrodynamic diameter of these PSA NPs was measured by dynamic light scattering (DLS), which was 55 nm with a polydispersity index (PdI) of 0.068
This might be attributed to the transition from hydrophobic acetylated dextran (AD) to hydrophilic Dex in the acidic environment and the nano-carriers dissolved by the solvent

Summary

INTRODUCTION

Nano-carriers have played significant roles in improving the therapeutic effects of tumor chemotherapy in the past decades (Petros and Desimone, 2010; Shi et al, 2016). The rapid dual-responsive releasing nano-carrier (PSA NPs) was formed by the self-assembly of PEG-SS-AD. The byproduct was dialyzed and lyophilized to obtain disulfide bond-functionalized PEG (mPEG-SS, polymer 2). PTX@PSA NPs were obtained by adding 10 mg of PEG-SS-AD and 2 mg of PTX in 1 ml of DCM, and the steps above were followed. Non-responsive PTX@ PPD NPs were obtained by adding 10 mg of PEG-PD and 2 mg of PTX to 1 ml of DCM. After the acetylated dextran, the absorption peak of methyl (-CH3, the red part of polymer five in Figure 2A) appeared at 1.33 ppm, and the absorption peaks of -OH in Dex weakened, indicating the successful preparation of AD These findings showed that the GSH and pH dual-responsive PEG-SS-AD were successfully synthesized according to the synthetic route

RESULTS AND DISCUSSION

CONCLUSION

ETHICS STATEMENT