Copper-Based Metal-Organic Framework Enables ROS Amplification and Drug Potency Activation.

Reactive oxygen species (ROS)-induced cancer therapy is extremely limited by tumor hypoxia, insufficient endogenous hydrogen peroxide (H2O2), overexpressed glutathione (GSH), and slower reaction rate. To address these challenges, in this paper, a hybrid nanomedicine (CaO2@Cu/ZIF-8-ICG@LA, CCZIL) is developed using a copper-based metal-organic framework (Cu/ZIF-8) for cancer synergistic therapy. H2O2/O2 self-supplementing, GSH-depleting, and photothermal properties multiply amplify ROS generation. Moreover, disulfiram (DSF) chemotherapy (CT) was activated by chelating with Cu2+ to synergize therapy. This novel strategy has enormous potential for ROS-involved synergistic antitumor therapy.

Amplification of Oxygen-Independent Free Radicals Based on a Glutathione Depletion and Biosynthesis Inhibition Strategy for Photothermal and Thermodynamic Therapy of Hypoxic Tumors.

Thermodynamic therapy (TDT) based on oxygen-independent free radicals exhibits promising potential for the treatment of hypoxic tumors. However, its therapeutic efficacy is seriously limited by the premature release of the drug and the free radical scavenging effect of glutathione (GSH) in tumors. Herein, we report a GSH depletion and biosynthesis inhibition strategy using EGCG/Fe-camouflaged gold nanorod core/ZIF-8 shell nanoparticles embedded with azo initiator 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH) and L-buthionine-sulfoximine (BSO) for tumor-targeting photothermal (PTT) and thermodynamic therapy (TDT). This nanoplatform (GNR@ZIF-8-AIPH/BSO@EGCG/Fe, GZABEF) endows a pH-responsive release performance. With the 67 kDa lamin receptor (67LR)-targeting ability of EGCG, GZABEF could selectively release oxygen-independent free radicals in tumor cells under 1064 nm laser irradiation. More importantly, Fe3+-mediated GSH depletion and BSO-mediated GSH biosynthesis inhibition significantly boosted the accumulation of alkyl radicals. In 4T1 cells, GZABEF induced cancer cell death via intracellular GSH depletion and GSH peroxidase 4 (GPX4) inactivation. In a subcutaneous xenograft model of 4T1, GZABEF demonstrated remarkable tumor growth inhibition (78.2%). In addition, excellent biosafety and biocompatibility of GZABEF were observed both in vitro and in vivo. This study provides inspiration for amplified TDT/PTT-mediated antitumor efficacy.

Engineering of a double targeting nanoplatform to elevate ROS generation and DSF anticancer activity.

Intracellular oxidative protection mechanisms and adverse systemic toxicity are major obstacles for the success of chemodynamic therapy (CDT)/chemotherapy (CT) synergistic therapy. To tackle the fundamental challenges of current CDT and circumvent the side effects of conventional CT, we developed a copper peroxide (CP) and disulfiram (DSF)-loaded 3-aminotriazole (3-AT) doped ZIF-8 (MAF) with partial sequence-specificity using hyaluronic acid (HA) and triphenylphosphine (TPP) in this study. Upon intravenous administration, CP@MAF-DSF@PEG-TPP@HA (CPMDTH) nanoparticles (NPs) were enriched in tumor tissues through HA-mediated endocytosis, followed by enhanced accumulation in mitochondria by the TPP target. The acidic tumor environment (TME) triggered the decomposition of MAF to release CP, DSF and 3-AT. Cu2+ and H2O2 hydrated from CP NPs produced ˙OH via a Fenton-like reaction. CAT activity inhibition and GSH consumption induced by 3-AT dramatically amplified mitochondrial oxidative stress, thereby promoting the overproduction of ˙OH. In addition, the accumulation of DSF and Cu2+ led to the formation of a cytotoxic bis(N,N-diethyldithiocarbamate) copper(II) complex (Cu(DTC)2) in situ, achieving efficient CT. CPMDTH NPs demonstrated significantly improved antitumor efficiency and excellent biosafety both in vitro and in vivo. This study offers a promising therapeutic strategy for CDT/CT synergistic oncotherapy.

pH-responsive nanocatalyst for enhancing cancer therapy via H2O2 homeostasis disruption and disulfiram sensitization.

Due to the powerful redox homeostasis and inefficiency of monotherapy, chemodynamic therapy (CDT) is clinically limited. Despite great efforts, the design of CDT nanosystems with specific H2O2 homeostasis and effective integration of multiple treatments remains a great challenge. Therefore, herein, we engineer a novel pH-responsive nanocatalyst to disrupt intracellular H2O2 homeostasis through consuming glutathione (GSH), elevating H2O2 and restraining H2O2 elimination, as well as achieving a combination of CDT and chemotherapy (CT) through sensitized DSF. In the formulation, amplified CDT synergized enhanced CT significantly, strengthening the tumor therapeutic efficacy in vitro and in vivo. This work not only solves intracellular redox homeostasis disruption, but also realizes the re-use of old drugs, providing new insights for CDT-based multimodal cancer therapy.

Tumor microenvironment (TME)-modulating nanoreactor for multiply enhanced chemodynamic therapy synergized with chemotherapy, starvation, and photothermal therapy.

The combination of chemotherapy (CT) and chemodynamic therapy (CDT) via nanoscale drug delivery systems has great potential for tumor therapy. Nevertheless, the low intracellular H2O2 and high reductive glutathione (GSH) levels, as well as the mildly acidic conditions (pH 5.8-6.8) of the tumor microenvironment (TME) still limit their further applications. To tackle these problems, a TME-modulating nanoreactor (denoted as Fe3O4-DOX@PDA-GOx@HA, FDPGH) was developed through a simple and practicable method to achieve multiply enhanced CDT synergized with CT, starvation therapy (ST), and photothermal therapy (PTT). Upon cellular uptake, the hyaluronic acid (HA) and PDA shells rapidly collapsed to release Fe3O4, glucose oxidase (GOx) and doxorubicin (DOX), and the overexpressed GSH could promote the reduction of Fe3+ to Fe2+, resulting in CDT activation. GOx-driven oxidation reaction not only produced H2O2 for enhanced CDT, but also killed tumor cells by initiating ST. In addition, the acid amplification caused by gluconic acid production in turn accelerated the degradation of FDPGH, promoting the Fenton reaction to enhance CDT. Most importantly, the nanoreactor had excellent photothermal performance to achieve PTT and PTT-enhanced CDT with the release of DOX into tumor tissue to achieve enhanced CT. This novel cascade nanoreactor with TME-modulating capability is intended to provide further inspiration for multimodal treatment paradigms.

Enzyme functionalized PEOz modified magnetic polydopamine with enhanced penetration for cascade-augmented synergistic tumor therapy.

In recent years, reactive oxygen species (ROS)-mediated cancer therapies have been widely recognized for their high selectivity and good biological safety. However, due to the difficulties of endogenous tumor microenvironment (TME), penetration of tumor tissues and integration of multimodal tumor ablation, the treatment with traditional therapies could not achieve satisfactory tumor inhibition effects. Here, a doxorubicin (DOX)-glucose oxidase (GOx) dual-loaded and poly (2-ethyl-2-oxazoline) (PEOz) decorated magnetic polydopamine nanoparticles (Fe3O4-DOX@PDA-GOx@PEOz, FDPGP) were constructed for tumor ablation. GOx-mediated cascade enzyme reactions could amplify oxidative stress damage and further synergistically inhibit breast cancer. Its pH-responsive charge reversal, drug-controlled release, photothermal, and cascade reactions were evaluated through extracellular experiments. Cellular uptake, cell cytotoxicity, tumor penetration and therapeutic efficacy of FDPGP were investigated through intracellular experiments. Finally, in vivo distribution, photothermal, synergistic antitumor therapeutic effect and biosafety were evaluated comprehensively by in vivo experiments. Excitingly, outstanding tumor enrichment and penetration, superior anticancer effects and biosafety were achieved by the combination of photothermal therapy (PTT)/starvation therapy (ST)/chemodynamic therapy (CDT)/chemotherapy (CT). As such, the FDPGP nanoplatform provides a new insight into the development of collaboratively multimodal enhanced tumor therapy.

The influence of UGT2B7 genotype on valproic acid pharmacokinetics in Chinese epilepsy patients.

PURPOSE: The aim of this study was to investigate the distribution and frequency of genetic polymorphisms in uridine diphosphate glucuronosyltransferase-2B7 (UGT2B7) in epilepsy patients and to evaluate the effect of these on the metabolism of valproic acid (VPA). METHODS: Single nucleotide polymorphisms in UGT2B7 were investigated in 102 epilepsy patients using DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis. The steady-state plasma concentrations of VPA were determined in these patients, who had received VPA (approx. 500-1000 mg/day) for at least 2 weeks. RESULTS: Fourteen patients had the CC genotype at UGT2B7 C802T, 46 carried CT, and 42 carried the TT genotype. At UGT2B7 G211T, 78 patients had the GG genotype, 23 carried GT, and one individual had the TT genotype. The standardized trough plasma concentration of VPA was much lower in those patients with a T allele at UGT2B7 C802T than in those with the CC genotype (TT, 2.11 ± 1.26; CT, 2.31 ± 1.25; CC, 3.02 ± 1.32 µg kg mL(-1) mg(-1), p < 0.01). However, UGT2B7 G211T polymorphisms had no influence on the plasma concentration of VPA (GG, 2.28 ± 1.32, GT, 2.303 ± 1.38 µg kg mL(-1) mg(-1)). CONCLUSION: These results suggested that UGT2B7 C802T may be an important determinant of individual variability in the pharmacokinetics of VPA and that it may be necessary to increase the VPA dose for individuals with a T allele in order to achieve the therapeutic range of 50-100 µg/mL.