Dual-Responsive Alginate Hydrogel Constructed by Sulfhdryl Dendrimer as an Intelligent System for Drug Delivery

Abstract

Intelligent stimulus-triggered release and high drug-loading capacity are crucial requirements for drug delivery systems in cancer treatment. Based on the excessive intracellular GSH expression and pH conditions in tumor cells, a novel glutathione (GSH) and pH dual-responsive hydrogel was designed and synthesized by conjugates of glutamic acid-cysteine dendrimer with alginate (Glu-Cys-SA) through click reaction, and then cross-linked with polyethylene glycol (PEG) through hydrogen bonds to form a 3D-net structure. The hydrogel, self-assembled by the inner disulfide bonds of the dendrimer, is designed to respond to the GSH heterogeneity in tumors, with a remarkably high drug loading capacity. The Dox-loaded Glu-Cys-SA hydrogel showed controlled drug release behavior, significantly with a release rate of over 76% in response to GSH. The cytotoxicity investigation indicated that the prepared DOX-loaded hydrogel exhibited comparable anti-tumor activity against HepG-2 cells with positive control. These biocompatible hydrogels are expected to be well-designed GSH and pH dual-sensitive conjugates or polymers for efficient anticancer drug delivery.

Responsive Hydrogels Based on Triggered Click Reactions for Liver Cancer

“…[32] Copyright 2021, The Royal Society of Chemistry. Internal stimuli pH-responsive PEG, TEG Inward diffusion [47,100,118,123,126,129] Redox-responsive PEG Inward diffusion [56,136,156] Enzyme-responsive ALG Cross-linking-codependent [14,27,106,124,130,132,158] Electroresponsive PLGA, PEG Inward diffusion [70,146,196] ROS-responsive PEG, PLGA Self-assembled [149,150,160,162,165] External stimuli Thermoresponsive PEG, PLGA In situ formation [7,30,34,42,67,170,171,173,175,17 8,181] Light-responsive PLGA, ALG Self-assembled [9,28,113,183,185] Magnetic-responsive ALG, HA Cross-linking-codependent [29,166,193,194,195] Mechanoresponsive PEG, PCL Inward diffusion [146,148,197,199,200] Ultrasound-responsive PEG Inward diffusion [14,163,201,…”

“…[25,26] Due to the good biocompatibility of responsive hydrogels, it has been developed for triggered click reaction hydrogels for drug delivery and cancer therapy. [27] Click reaction is an efficient, practical, and reliable platform for robust delivery of activated medicine. [28] There are four main types of click reactions: nucleophilic cycloaddition reactions, nucleophilic ring-opening reactions, nonaldol carbonyl chemistry reactions, and carbon-carbon multiple bond addition reactions.…”

“…[ 25,26 ] Due to the good biocompatibility of responsive hydrogels, it has been developed for triggered click reaction hydrogels for drug delivery and cancer therapy. [ 27 ]…”

Progress of Research in In Situ Smart Hydrogels for Local Antitumor Therapy: A Review

“…For instance, Li et al designed and synthesized a novel glutathione (GSH) and pH dual-responsive hydrogel. Alginate was conjugated with glutamic acid–cysteine dendrimer (Glu-Cys-SA) via the click reaction and was then crosslinked with polyethylene glycol (PEG) via hydrogen bonds to form a hydrogel with a 3D network structure [ 112 ]. The inner disulfide bonds of the dendrimer were designed to respond to the GSH in the tumor, inducing disulfide cleavage and resulting in the deconstruction of the network structures and the gradual release of the loaded DOX, which was demonstrated in an in vitro experiment.…”

Stimuli-Responsive Dendritic Macromolecules for Optical Detection of Metal Ions and Acidic Vapors by the Photoinduced Electron Transfer Mechanism: Paper-Based Indicator for Food Spoilage Sensing

“…Dendritic macromolecules have lots of unique properties, which are well-defined nanostructures and unique morphologies, high concentration of functional groups at the surface, high solubility in aqueous media, high monodispersity, low viscosity, and modification ability with functional molecules. − These characteristics resulted in the development of dendritic nanostructures for a wide range of applications, including drug-delivery or gen-delivery systems, chemosensors, bioimaging, and tissue engineering. − Induction of stimuli-responsivity to dendrimers by their modification with intelligent molecules has been known as an attractive field of study. The pH- or temperature-responsive dendrimers are among the highly important smart nanocarriers in drug- or gen-delivery technology, − and the light-responsive dendrimers are highly applicable in bioimaging and photosensing applications. , Different types of dendrimers were modified with stimuli-responsive molecules using their surface functional groups, or in a classic approach, using a functional intelligent molecule as a core to growth of dendritic structures on the surface. − Therefore, the presence of acid, amine, or hydroxyl functional groups on dendrimers is inevitable for their reaction with functional molecules.…”