Redox-responsive Drug Delivery System Research Articles

Construction of an Innovative Nanogel and Its Applications for Achieving Chemo-Immunotherapy of Tumors.

Malignant tumors, also known as cancers, are a global public health problem. Nanogels are promising carriers for the delivery of anticancer medicines. Therefore, based on the unique microenvironment of tumor cells and the advantages of nanogels, a simple and economical one-pot synthesis method was designed to construct natural polysaccharide-based redox-responsive nanogels (LDD NGs). The enhanced permeability and retention (EPR) effect enriched LDD NGs in tumor cells, which then rapidly collapsed and released the natural antitumor drug diosgenin (DG) and the natural polysaccharide lentinan (LNT) via the depletion of a high level of reduced glutathione (GSH) in tumor cells, resulting in a synergistic therapeutic effect of chemotherapy and immunotherapy. In vivo antitumor experiments showed that LDD NGs could inhibit the proliferation and metastasis of the A549 lung cancer cells. Further studies indicated that LDD NGs could increase the production of ROS and induce apoptosis of A549 cells. In addition, LNT released from LDD NGs could promote the proliferation of dendritic cells, increase the production of NO, and upregulate the expressions of the costimulatory molecules CD40, CD80, CD86, and MHC-II. The construction of LDD NGs was a novel drug synthesis approach that could provide fresh ideas for the development of polysaccharide-based redox-responsive drug delivery systems.

Diselenide-Bridged Doxorubicin Dimeric Prodrug: Synthesis and Redox-Triggered Drug Release.

The diselenide bond has attracted intense interest in redox-responsive drug delivery systems (DDSs) in tumor chemotherapy, due to its higher sensitivity than the most investigated bond, namely the disulfide bond. Here, a diselenide-bridged doxorubicin dimeric prodrug (D-DOXSeSe) was designed by coupling two doxorubicin molecules with a diselenodiacetic acid (DSeDAA) molecule via α-amidation, as a redox-triggered drug self-delivery system (DSDS) for tumor-specific chemotherapy. The drug release profiles indicated that the D-DOXSeSe could be cleaved to release the derivatives selenol (DOX-SeH) and seleninic acid (DOX-SeOOH) with the triggering of high GSH and H2O2, respectively, indicating the double-edged sword effect of the lower electronegativity of the selenide atom. The resultant solubility-controlled slow drug release performance makes it a promising candidate as a long-acting DSDS in future tumor chemotherapy. Moreover, the interaction between the conjugations in the design of self-immolation traceless linkers was also proposed for the first time as another key factor for a desired precise tumor-specific chemotherapy, besides the conjugations themselves.

PEGylated mesoporous silica core–shell redox-responsive nanoparticles for delivering paclitaxel to breast cancer cells

Controlling the drug release and restricting its presence in healthy organs is extremely valuable. In this study, mesoporous silica nanoparticles (MSN) as the core, loaded with paclitaxel (PTX), were coated with a non-porous silica shell functionalized with disulfide bonds. The nanoparticles were further coated with polyethylene glycol (PEG) via disulfide linkages. We analyzed the physicochemical properties of nanoparticles, including hydrodynamic size via Dynamic Light Scattering (DLS), zeta potential, X-ray Diffraction (XRD) patterns, Fourier-Transform Infrared (FTIR) spectra, and imaging through Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM). The drug release profile in two distinct glutathione (GSH) concentrations of 2 µM and 10 µM was measured. The cellular uptake of nanoparticles by MCF-7 cell line was determined using Confocal Laser Scanning Microscopy (CLSM) images and flow cytometry. Furthermore, the cell viability and the capability of nanoparticles to induce apoptosis in MCF-7 cell line were studied using the MTT assay and flow cytometry, respectively. Our investigations revealed that the release of PTX from the drug delivery system was redox-responsive. Also, results indicated an elevated level of cellular uptake and efficient induction of apoptosis, underscoring the promising potential of this redox-responsive drug delivery system for breast cancer therapy.

Calcium phosphate hybrid micelles inhibit orthotopic bone metastasis from triple negative breast cancer by simultaneously killing cancer cells and reprogramming the microenvironment of bone resorption and immunosuppression.

Triple negative breast cancer (TNBC) is prone to develop drug resistance and metastasis. Bone is the most common distant metastasis site of breast cancer cell. Patients with bone metastasis from TNBC suffer from unbearable pain due to the growth of bone metastasis and bone destruction. Simultaneously blocking the growth of bone metastasis and reprogramming the microenvironment of bone resorption and immunosuppression is a promising strategy to treat bone metastasis from TNBC. Herein, we prepared a pH and redox responsive drug delivery system, named DZ@CPH, by encapsulating docetaxel (DTX) with hyaluronic acid-polylactic acid micelle then reinforcing with calcium phosphate and zoledronate for targeting to bone metastasis from TNBC. DZ@CPH reduced the activation of osteoclast and inhibited bone resorption by decreasing the expression of nuclear factor κB receptor ligand and increasing the expression of osteoprotegerin in drug-resistant bone metastasis tissue. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the apoptosis-related and invasion-related protein expression. It also increased the sensitivity of orthotopic drug-resistant bone metastasis to DTX by inhibiting the expression of P-glycoprotein, Bcl-2 and transforming growth factor-β in tissue of drug-resistant bone metastasis. Moreover, the ratio between M1 type macrophage to M2 type macrophage in bone metastasis tissue was increased by DZ@CPH. In a word, DZ@CPH blocked the growth of bone metastasis from drug-resistant TNBC through inducing the apoptosis of drug-resistant TNBC cells and reprogramming the microenvironment of bone resorption and immunosuppression. DZ@CPH has a great potential in clinical application for the treatment of bone metastasis from drug-resistant TNBC. STATEMENT OF SIGNIFICANCE: Triple negative breast cancer (TNBC) is prone to develop bone metastasis. Now bone metastasis is still an intractable disease. In this study, docetaxel and zoledronate co-loaded calcium phosphate hybrid micelles (DZ@CPH) were prepared. DZ@CPH reduced the activation of osteoclasts and inhibited bone resorption. At the same time, DZ@CPH inhibited the invasion of bone metastatic TNBC cells by regulating the expression of apoptosis and invasion related protein in bone metastasis tissue. Moreover, the ratio between M1 type macrophages to M2 type macrophages in bone metastases tissue was increased by DZ@CPH. In a word, DZ@CPH blocked vicious cycle between the growth of bone metastasis and bone resorption, which greatly improved the therapeutic effect on bone metastasis from drug-resistant TNBC.

Redox-Responsive Drug Delivery Systems: A Chemical Perspective.

With the widespread global impact of cancer on humans and the extensive side effects associated with current cancer treatments, a novel, effective, and safe treatment is needed. Redox-responsive drug delivery systems (DDSs) have emerged as a potential cancer treatment with minimal side effects and enhanced site-specific targeted delivery. This paper explores the physiological and biochemical nature of tumors that allow for redox-responsive drug delivery systems and reviews recent advances in the chemical composition and design of such systems. The five main redox-responsive chemical entities that are the focus of this paper are disulfide bonds, diselenide bonds, succinimide–thioether linkages, tetrasulfide bonds, and platin conjugates. Moreover, as disulfide bonds are the most commonly used entities, the review explored disulfide-containing liposomes, polymeric micelles, and nanogels. While various systems have been devised, further research is needed to advance redox-responsive drug delivery systems for cancer treatment clinical applications.

Development of Surface Chemical Strategies for Synthesizing Redox-Responsive Diatomite Nanoparticles as a Green Platform for On-Demand Intracellular Release of an Antisense Peptide Nucleic Acid Anticancer Agent.

Redox-responsive silica drug delivery systems are synthesized by aeco-friendly diatomite source to achieve on-demand release of peptide nucleic acid (PNA) in tumor reducing microenvironment, aiming to inhibit the immune checkpoint programmed cell death 1 receptor/programmed cell death receptor ligand 1 (PD-1/PD-L1) in cancer cells. The nanoparticles (NPs) are coated with polyethylene glycol chains as gatekeepers to improve their physicochemical properties and control drug release through the cleavable disulfide bonds (S-S) in a reductive environment. This study describes different chemical conditions to achieve the highest NPs' surface functionalization yield, exploring both multistep and one-pot chemical functionalization strategies. The best formulation is used for covalent PNA conjugation via the S-S bond reaching a loading degree of 306 ± 25µg PNA mg-1 DNPs . These systems are used for in vitro studies to evaluate the kinetic release, biocompatibility, cellular uptake, and activity on different cancer cells expressing high levels of PD-L1. The obtained results prove the safety of the NPs up to 200µg mL-1 and their advantage for controlling and enhancing the PNA intracellular release as well as antitumor activity. Moreover, the downregulation of PD-L1 observed only with MDA-MB-231 cancer cells paves the way for targeted immunotherapy.

Rational design of ibuprofen-based redox-responsive anti-cancer polymeric drug delivery systems

Rational design of ibuprofen-based redox-responsive anti-cancer polymeric drug delivery systems

Prodrug nanoassemblies bridged by Mono-/Di-/Tri-sulfide bonds: Exploration is for going further

Sulfur bonds, including thioether bond and disulfide bond, have been widely used to develop tumor redox-responsive drug delivery systems. Recently, trisulfide bond was also introduced into the construction of prodrug nanoassemblies. However, the integrated effects of these sulfur bonds on prodrug nanoassemblies remain elusive. Here, three paclitaxel homodimeric prodrugs are synthesized using thioether bond, disulfide bond or trisulfide bond as linkages. Interestingly, the sulfur bonds significantly changed the molecular assembly of prodrugs, thereby influencing the colloidal stability and in vivo destiny of prodrug nanoassemblies. More importantly, the trisulfide bond is found to be a novel redox dual-sensitive linkage, and the responsive mechanism is illustrated. The differences of thioether/disulfide/trisulfide bond are investigated in-depth, and their effect on the antitumor efficacy of prodrug nanoassemblies is also clarified. Our findings provide deep insights into the impacts of sulfur bonds on prodrug nanoassemblies, and highlight the potential of trisulfide bond for the development of redox dual-responsive nanomedicines.

Construction of a redox-responsive drug delivery system utilizing the volume of AS1411 spatial configuration gating mesoporous silica pores.

In recent years, diverse redox-responsive drug delivery systems have emerged to prevent premature drug release and reduce drug toxicity in the human body in cancer treatment. In this paper, we put forward a view of directly utilizing the spatial structure size of the AS1411 aptamer as the nano-gatekeeper on the pore openings of MCM-41 type mesoporous silica and thus constructed a redox-responsive drug delivery system named MCM-41-SS-AS1411. The particles obtained at each step were characterized by TEM, FTIR, SXRD, TGA and zeta potential measurement. The characterization data confirmed that the particles were successfully prepared. The binding amount of the aptamer was ca. 3.1 × 103 for each carrier particle averagely. The anticancer drug Dox was regarded as a drug model to investigate the redox-controlled drug release behavior by fluorescence measurements. The investigation results demonstrate that the spatial volume of aptamer AS1411 can block the mesopore, and this drug-carrier can realize controlled drug release by GSH. We hope this idea can play a prompt role in relevant research. Meanwhile, the preparation steps of this DDS are simplified.

Dual CEA/CD44 targeting to colorectal cancer cells using nanobody-conjugated hyaluronic acid-modified mesoporous silica nanoparticles with pH- and redox-sensitivity

Mesoporous silica nanoparticles (MSNs) loaded with doxorubicin and then modified with hyaluronic acid (HA) and nanobody (DOX@MSNs-HA-11C12) is a pH- and redox-responsive drug delivery system, resulting in over 90% of LoVo cell apoptosis within 48 h.

A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity

Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA2-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug.Graphical

In vivo therapeutic evaluation of a novel bis-lawsone derivative against tumor following delivery using mesoporous silica nanoparticle based redox-responsive drug delivery system

Herein, we have evaluated the in vivo therapeutic efficacy and systemic toxicity profile of a synthetic anticancer compound [3,3′-((4-(trifluoromethyl)phenyl)methylene)bis(2-hydroxynaphthalene-1,4-dione)]. A multifunctional mesoporous silica nanoparticle (MSN) based drug delivery network was also fabricated which specifically showed targeting nature towards the cancer cell. The mesopores of silica nanoparticles were tagged with phenyl boronic acid (PBA) for targeted drug delivery into tumor tissue. 1j was then loaded inside the nanocarriers followed by pore blocking with gold nanoparticles (GN) to attain a redox-responsive controlled drug delivery pattern. The synthesized nanocarriers (1j@-MSN-PBA-GN) having mean diameter of ~86 nm exhibited a moderate 1j loading content of 13.68% with overall negative surface charge. Both the targeted and non-targeted nanoformulations were tested for their anticancer activities both in vitro and in vivo models, and found more effective as compared with free 1j treatment. However, the targeted nanoformulations showed higher therapeutic effect due to increased cellular internalization and caused mitochondria-dependent apoptosis in MCF-7 cells via oxidative stress. Besides, the targeted nanoformulation significantly inhibited in the development of solid tumor in comparison to non-targeted nanoformulations and free 1j as a consequence of increased internalization of the drug-candidate in tumor tissue. Therefore, this study proposes that 1j can be considered as a potent anti-carcinogenic compound in vivo and its therapeutic potential is further increased by using PBA functionalized and GN gated MSN-based controlled drug delivery system without showing any significant systemic toxicity.

Multi-stimuli-responsive magnetic hydrogel based on Tragacanth gum as a de novo nanosystem for targeted chemo/hyperthermia treatment of cancer

A novel magnetic pH- and redox-responsive drug delivery system (DDS) based on natural Tragacanth gum (TG) was developed for targeted chemo/hyperthermia treatment of cancer. Firstly, acrylic acid (AA) monomer was grafted onto a maleic anhydride-functionalized TG macromonomer (MATGM) through a free radical copolymerization. Magnetic nanoparticles (MNPs) were synthesized through chemical co-precipitation, and subsequently were modified using (3-aminopropyl)triethoxysilane coupling agent. The magnetic stimuli-responsive hydrogel for targeted cancer therapy was synthesized by the incorporation of modified-MNPs and folic acid (FA), and simultaneous crosslinking of TG-g-PAA copolymer using cystamine (Cys) moiety. Doxorubicin hydrochloride (Dox) was loaded into the fabricated magnetic hydrogel (MH), and its release was studied under pH- and redox-triggered condition. The anti-cancer activity of the Dox-loaded DDS was examined against MCF7 cells through MTT assay by both chemotherapy and chemo/hyperthermia therapy approaches. It was revealed that the developed DDS has higher anti-cancer activity (~ 24%) owing to its “smart” and slow drug release behavior as well as synergic effect of hyperthermia therapy. A novel magnetite pH- and redox-responsive drug delivery system (DDS) based on natural Tragacanth gum (TG) was design and developed for targeted chemo/hyperthermia therapy of solid tumors.

DOX-Loaded Gelatin Composite Hydrogels with Oxidation-Triggered Drug Release Property

Hydrogels developed as stimuli-responsive drug delivery systems (DDSs) are increasingly concerned research focus in many fields such as chemistry, functional materials and biomedicine. Herein, we report the fabrication, characterization and drug release property of new gelatin composite hydrogels by using biocompatible gelatin and the doxorubicin (DOX)-loaded micelles of a redox-responsive side-chain ferrocene (Fc)-containing amphiphilic diblock copolymer PNFc-b-PNTEG (Fig. 1). The self-assembly method was firstly adopted to prepare the DOX-loaded micelles of PNFc-b-PNTEG with oxidation-sensitive release property, and the DOX-loaded gelatin composite hydrogels were then successfully fabricated by using blending and soaking methods, respectively. The formed hydrogels were characterized by many techniques including scanning electron microscope, energy-dispersive spectroscopy, differential scanning calorimetry, thermogravimetry and swelling test. The successful encapsulation of the DOX-containing micelles in the gelatin matrix was demonstrated, and the prepared composite hydrogels exhibited improved thermal stability, faster swelling speed and higher swelling ratios. The oxidation-triggered controlled in vitro release of DOX from the composite hydrogels was confirmed by using FeCl3 at different concentrations as an oxidizing agent. The composite hydrogels could act as excellent solid carriers to guarantee the sustained-release effect of DOX, and it is feasible to keep the DOX molecules with high concentration at the specific site for a long period (20 days or so). Thus, the present composite hydrogels are anticipated to be good candidates as redox-responsive DDSs.

DOX-Loaded Gelatin Composite Hydrogels with Oxidation-Triggered Drug Release Property

Hydrogels developed as stimuli-responsive drug delivery systems (DDSs) are increasingly concerned research focus in many fields such as chemistry, functional materials and biomedicine. Herein, we report the fabrication, characterization and drug release property of new gelatin composite hydrogels by using biocompatible gelatin and the doxorubicin (DOX)-loaded micelles of a redox-responsive side-chain ferrocene (Fc)-containing amphiphilic diblock copolymer PNFc-b-PNTEG (Fig. 1). The self-assembly method was firstly adopted to prepare the DOX-loaded micelles of PNFc-b-PNTEG with oxidation-sensitive release property, and the DOX-loaded gelatin composite hydrogels were then successfully fabricated by using blending and soaking methods, respectively. The formed hydrogels were characterized by many techniques including scanning electron microscope, energy-dispersive spectroscopy, differential scanning calorimetry, thermogravimetry and swelling test. The successful encapsulation of the DOX-containing micelles in the gelatin matrix was demonstrated, and the prepared composite hydrogels exhibited improved thermal stability, faster swelling speed and higher swelling ratios. The oxidation-triggered controlled in vitro release of DOX from the composite hydrogels was confirmed by using FeCl3 at different concentrations as an oxidizing agent. The composite hydrogels could act as excellent solid carriers to guarantee the sustained-release effect of DOX, and it is feasible to keep the DOX molecules with high concentration at the specific site for a long period (20 days or so). Thus, the present composite hydrogels are anticipated to be good candidates as redox-responsive DDSs.

Disulfur-bridged polyethyleneglycol/DOX nanoparticles for the encapsulation of photosensitive drugs: a case of computational simulations on the redox-responsive chemo-photodynamic drug delivery system.

Tumor redox stimulus-responsive nanoparticulate drug delivery systems (nano-DDSs) have attracted considerable attention due to their thermodynamically stable microstructures and well-controlled drug release properties. However, drug-loading nanoparticle conformation and redox-triggered drug release mechanisms at the molecular level remain unclear. Herein, doxorubicin-conjugated polymers were constructed using disulfide bonds as linkages (PEG–SS–DOX), which loaded photosensitizer chlorin e6 (Ce6). We integrated multiple scale dynamic simulations (density functional theory (DFT) calculation, atomistic molecular dynamics (MD) simulation and dissipative particle dynamics (DPD) simulations) to elucidate the assembly/drug release dynamic processing. First, it was revealed that the emergence of the calculated bond flexible angle of disulfide bonds facilitated the assembly behavior and improved the stability of conformation. Sorted by the binding model, hydrogen bonding accounted for the major interactions between polymers and photosensitive drugs. DPD simulations were further delved into to acquire knowledge regarding the drug-free self-aggregation and Ce6-loaded assembly mechanism. The results show that nano-assembly conformation not only depended on the concentration of polymers, but also were associated with the polymer–drug ratio. Different from dicarbon bond-bridging polymers, disulfide bonds would contribute to the breakage of the polymer and the rapid release of DOX and Ce6. Our findings provide deep insights into the influence of redox-responsive chemical linkages and offer theoretical guidance to the rational design of specific stimulus-responsive nano-DDSs for cancer therapy.

Targeted and redox-responsive drug delivery systems based on carbonic anhydrase IX-decorated mesoporous silica nanoparticles for cancer therapy

In this work, we developed a new antibody-targeted and redox-responsive drug delivery system “MSNs-CAIX” by binding the anti-carbonic anhydrase IX antibody (A-CAIX Ab) on the surface of mesoporous silica nanoparticles (MSNs) via disulfide linkages. The design of the composite particles “MSNs-CAIX” involved the synthesis and surface functionalization with thiol groups, 2,2′-dipyridyl disulfide and CAIX antibody. In vitro, CAIX capping the doxorubicin hydrochloric (DOX)-loaded nanoparticles (DOX@MSNs-CAIX) exhibited effectively redox-responsive release in the presence of glutathione (GSH) owing to the cleavage of the disulfide bond. Compared with CAIX negative Mef cells (mouse embryo fibroblast), remarkably more DOX@MSNs-CAIX was internalized into CAIX positive 4T1 cells (mouse breast cancer cells) by receptor-mediation. Tumor targeting in vivo studies clearly demonstrated DOX@MSNs-CAIX accumulated in tumors and induced more tumor cells apoptosis in 4T1 tumor-bearing mice. With great potential, this drug delivery system is a promising candidate for targeted and redox-responsive cancer therapy.

Facile synthesis of redox-responsive paclitaxel drug release platform using metal-organic frameworks (ZIF-8) for gastric cancer treatment

This paper investigated the dual-role of cystamine as a surface modification linker and stimuli-responsive material, and simplify redox-responsive drug delivery system synthesis. ZIF-8 is used as the drug delivery vehicle (due to its exceptional biocompatibility), cystamine is used as the linker and redox-sensitive material, and paclitaxel (PTX) is selected as the anti-tumor drug. Redox-responsive paclitaxel drug delivery platform based on metal-organic frameworks (MOFs) was synthesized by using ZIF-8 as the drug delivery vehicle, and cystamine as the linker and redox-sensitive material. The morphology of ZIF-8 was determined by the Transmitting Electron Microscope (TEM), and the crystal structure was determined by x-ray diffraction (XRD). The surface modification of ZIF-8 was studied by the Fourier-transform infrared (FT-IR) spectroscopy. The Brunauer–Emmett–Teller (BET) study indicated that surface modification has little impact on the specific surface area and pore size distribution of ZIF-8. The drug release of ZIF-8/cystamine/paclitaxel was studied under different pH and glutathione concentrations. The cytotoxicity was investigated with human gastric cancer cells. Higher glutathione (GSH) concentration and lower pH were favorable to the release of paclitaxel from ZIF-8/cystamine/paclitaxel, and the drug release platform provided a higher tumor-killing effect than free paclitaxel solution.

Disulfide Bond-Responsive Nanotherapeutic Systems for the Effective Payload in Cancer Therapy.

The progressive treatment of cancer using disulfide bond-based therapeutics offers improvement in therapeutic potency of active, reduction in adverse events, prolongation of drug release pattern and on-site action by interacting with neoplastic cell microenvironment. The objective of this article is to highlight the research carried out on disulfide bond-based drug delivery systems as a potential candidate for cancer treatment. The article provides an overview of the importance of disulfide bonds in cancer treatment in terms of their properties, mechanism of formation/fragmentation and applications. Properties of disulfide bonds, such as pKa, entropy, and dihedral angle contribute to the structural stability of the bonds in a nanotherapeutic system, while their formation and fragmentation are attributed to the presence of a high concentration of GSH in cancer cells. The article further focuses on various drug delivery systems like dendrimers, liposomes, micelles, etc. involving disulfide cross-linked polymers for the preparation of redox-responsive drug delivery systems. The use of nanotechnology with disulfide bond creates an anticancer drug delivery system with higher target specificity, improved bioavailability, and good therapeutic efficacy. In the near future, the combination of DSB with active, cellular material, stem cell and biological fluid will be considered as a new thrust area for research in healthcare.

Redox-Responsive Coordination Polymers of Dopamine-Modified Hyaluronic Acid with Copper and 6-Mercaptopurine for Targeted Drug Delivery and Improvement of Anticancer Activity against Cancer Cells.

Dopamine-modified hyaluronic acid (HA-DOP) was chosen as the drug carrier in this study, and Cu2+ was selected from among Cu2+, Zn2+, Fe2+, and Ca2+ as the central atom. 6-Mercaptopurine (6-MP) was conjugated with HA through a coordination reaction. HA-DOP-copper-MP (HA-DOP-Cu-MP), a redox-responsive coordination polymer prodrug, was prepared. The drug loading was 49.5 mg/g, the encapsulation efficiency was 70.18%, and the particle size was 173.5 nm. HA-DOP-Cu-MP released rapidly in the release medium containing reduced glutathione (GSH), and the accumulated release exceeded 94% in 2 h. In the release medium without GSH, the drug release rate was slow, with only 15% of the 6-MP released in 24 h. Cell uptake experiments revealed the CD44 targeting of HA. Cell viability assays showed that the cytotoxicity of HA-DOP-Cu-MP was higher than that of free 6-MP. Indeed, HA-DOP-Cu-MP is very toxic to cancer cells. In this paper, the redox-responsive drug delivery system was synthesized by a coordination reaction. The tumour targeting and tumour cytotoxicity of 6-MP were improved.