A Novel NQO1 Enzyme-Responsive Polyurethane Nanocarrier for Redox-Triggered Intracellular Drug Release

Abstract

The design of nano-drug delivery vehicles responsive to tumor microenvironment stimuli has become a crucial aspect in developing cancer therapy in recent years. Among them, the enzyme-responsive nano-drug delivery system is particularly effective, as it utilizes tumor-specific and highly expressed enzymes as precise targets, leading to increased drug release at the target sites, reduced nonspecific release, and improved efficacy while minimizing toxic side effects on normal tissues. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an important reductase associated with cancer and is overexpressed in some cancer cells, particularly in lung and breast cancer. Thus, the design of nanocarriers with high selectivity and responsiveness to NQO1 is of great significance for tumor diagnosis and treatment. It has been reported that under physiological conditions, NQO1 can specifically reduce the trimethyl-locked benzoquinone structure through a two-electron reduction, resulting in rapid lactonization via an enzymatic reaction. Based on this, a novel reduction-sensitive polyurethane (PEG-PTU-PEG) block copolymer was designed and synthesized by copolymerizing diisocyanate, a reduction-sensitive monomer (TMBQ), and poly(ethylene glycol). The successful synthesis of monomers and polymers was verified by nuclear magnetic resonance (1H NMR) and gel permeation chromatography (GPC). Then, the PEG-PTU-PEG micelles were successfully prepared by self-assembly, and their reductive dissociation behavior in the presence of Na2S2O4 was verified by dynamic light scattering (DLS), 1H NMR, and GPC. Next, the model drug doxorubicin (DOX) was encapsulated into the hydrophobic core of this polyurethane micelles by microemulsion method. It was observed that the drug-loaded micelles could also achieve a redox response and rapidly release the encapsulated substances. In vitro cell experiments demonstrated that PEG-PTU-PEG micelles had good biocompatibility and a low hemolysis rate (<5%). Furthermore, in the presence of an NQO1 enzyme inhibitor (dicoumarol), lower drug release from micelles was observed in A549 and 4T1 cells by both fluorescence microscopy and flow cytometry assays, but not in NIH-3T3 control cells. Predictably, DOX-loaded micelles also showed lower cytotoxicity in 4T1 cells in the presence of NQO1 enzyme inhibitors. These results indicate that drug-loaded polyurethane micelles could accomplish specific drug release in the reducing environment in the presence of NQO1 enzymes. Therefore, this study provides a new option for the construction of polyurethane nanocarriers for precise targeting and reductive release, which could benefit the intracellular drug-specific release and precision therapy of tumors.

Polyurethane Nanoparticles as Versatile Tools in Nanomedicine: A Review

“…Additionally, the findings suggested that the novel enzyme-sensitive polyurethane nanocarrier holds the promise of precisionregulated drug release and a reduction in adverse effects in the context of chemotherapy treatment. 95 The DLS study and TEM images showed that the particle size distribution was narrow and the shape of the particles was spherical (Figure 5A,B). The breakdown of the sample during sample preparation resulted in a comparatively smaller micelle size assessed by TEM than by DLS.…”

“…Xie et al 95 successfully designed a series of amphiphilic block polyurethanes (PEG-PTU-PEG) with the monomer Llysine diisocyanate (natural amino acid derivative) and a trimethyl-locked benzoquinone diol monomer (TMBQ) nanodrug delivery system. This reduction-responsive behavior was confirmed by a few in vitro characterizations.…”

Designing polyurethane-based microcapsules with tailored swelling behaviours for enhanced oil recovery

“…Considering the versatility of PU microcapsules, they have been widely used in various fields such as biology and drug delivery. 18,19 Besides that, PU microcapsules have gained gradual attention in the petroleum industry in recent years. For instance, by using IPDI and polyethylene glycol (PEG) as reaction monomers, Gong et al employed emulsion reversed-phase polymerization to synthesize PU-shell microcapsules for enhancing polymer flooding.…”

A Novel Redox-Sensitive Drug Delivery System Based on Trimethyl-Locked Polycarbonate

“…Currently, most of the reported redox-sensitive motifs focus on the disulfide bond or diselenide bond. , Until now, a series of redox-sensitive polymer nanocarriers have been developed by introducing disulfide or diselenide bonds into biodegradable polymers, including polycarbonate or polypeptide nanocarriers. , Notably, recent studies have shown that lactonized trimethyl-locked (TML) compounds with high reactivity through unfavorable steric interactions between the three pendant methyl groups can be chemically or enzymatically transformed. , This simple lactonization system can prevent the reactivity of the TML system by using different esters, ethers, or benzoquinone structures to protect the dihydroquinone moiety. Under different specific environmental conditions (such as enzymes, , cytochrome, light, electrochemistry, and redox chemicals), this system can exhibit different sensitivities. In addition, this multifunctional system designed with stimuli-responsive conjugations using the TML system holds great potential for diverse applications in the fields of polymer prodrugs, drug delivery nanocarrier systems, fluorescent and luminescent probes, and smart materials .…”

“…28,29 This simple lactonization system can prevent the reactivity of the TML system by using different esters, ethers, or benzoquinone structures to protect the dihydroquinone moiety. Under different specific environmental conditions (such as enzymes, 30,31 cytochrome, 32 light, 33 electrochemistry, 34 and redox chemicals 35 ), this system can exhibit different sensitivities. In addition, this multifunctional system designed with stimuli-responsive conjugations using the TML system holds great potential for diverse applications in the fields of polymer prodrugs, drug delivery nanocarrier systems, fluorescent and luminescent probes, and smart materials.…”