Redox dual-stimuli responsive drug delivery systems for improving tumor-targeting ability and reducing adverse side effects

Abstract

Cancer is a big challenge that has plagued the human beings for ages and one of the most effective treatments is chemotherapy. However, the low tumor-targeting ability limits the wide clinical application of chemotherapy. The microenvironment plays a critical role in many aspects of tumor genesis. It generates the tumor vasculature and it is highly implicated in the progression to metastasis. To maintain a suitable environment for tumor progression, there are special microenvironment in tumor cell, such as low pH, high level of glutathione (GSH) and reactive oxygen species (ROS), and more special enzymes, which is different to normal cell. Microenvironment-targeted therapy strategy could create new opportunities for therapeutic targeting. Compared to other targeting strategies, microenvironment-targeted therapy strategy will control the drug release into tumor cells more accurately. Redox responsive drug delivery systems (DDSs) are developed based on the high level of GSH in tumor cells. However, there are also GSH in normal cell though its level is lower. In order to control the release of drugs more accurately and reduce side effects, other drug release stimuli have been introduced to redox responsive DDSs. Under the synergistic reaction of two stimuli, redox dual-stimuli responsive DDSs will control the release of drugs more accurately and quickly and even increase the accumulation. This review summarizes strategies of redox dual-stimuli responsive DDSs such as pH, light, enzyme, ROS, and magnetic guide to delivery chemotherapeutic agents more accurately, aiming at providing new ideas for further promoting the drug release, enhancing tumor-targeting and improving anticancer effects. To better illustrate the redox dual-stimuli responsive DDS, preparations of carriers are also briefly described in the review.

Keywords: Chemotherapy; Drug delivery system; Dual-stimuli responsive; Redox responsive; Tumor-targeting.

Graphical abstract

Fig. 1

The release mechanism of redox sensitive DDS.

Fig. 2

(A) Delivering photosensitizer and chemotherapeutic agent simultaneously. (B) Layer-by-layer structure. (C) Shell-core structure.

Fig. 3

Application of PTX/CHT nanoparticles in tumor NIR fluorescence imaging and synergistic photodynamic/chemotherapy. (Adapted with permission from .Copyright 2018 The Authors).

Fig. 4

Synthetic line to PCL-SS-PDEASB. (Adapted with permission from . Copyright 2015 Elsevier B.V.).

Fig. 5

Schematic illustration of the formation, tumor-targeted accumulation and redox/enzyme-responsive drug release of self-assembled nanoparticles. (Adapted with permission from . Copyright 2018 Elsevier B.V.).

Fig. 6

The mechanism of enhancing internalization by changing particle size.

Fig. 7

Schematic illustration of (A) chemical structure of mPEG-b-P(Des-alt-Cys) copolymer and (B) dual redox-responsive micelles and CPT release triggered by ROS and GSH. (Adapted with permission from . Copyright 2015 Elsevier B.V.).

Fig. 8

The drug distribution of magnetic and redox responsive DDS.

Fig. 9

Schematic illustration of the nanaoparticles’ fabrication. (Adapted with permission from . Copyright 2012 Wiley Online Library.).