Boosting Doxorubicin‐Induced Mitochondria Apoptosis for the Monodrug‐Mediated Combination of Chemotherapy and Chemodynamic Therapy

Abstract

Doxorubicin (Dox)‐mediated generation of reactive oxygen radicals (ROS) for mitochondrial apoptosis is identified as a new cytotoxic mechanism in addition to the well‐established one via nuclear DNA replication interference. However, this mechanism contributes far less than the latter to Dox therapy. This newly identified pathway to make Dox therapy function like the combination of chemodynamic therapy (CDT) and chemotherapy‐mediated by Dox alone would be amplified. One‐pot nanoconstruction (HEBD) is fabricated based on the chemical reactions driven assemblies among epigallocatechin gallate (EGCG), buthionine sulfoximine (BSO) and formaldehyde in aqueous mediums followed by Dox adsorption. Acid tumor microenvironments allow the liberation of EGCG, BSO, and Dox due to the breakage of Schiff base bonds. EGCG component in HEBD is responsible for targeting mitochondria and disrupting mitochondrial electron transport chain (mETC) to compel electrons leakage in favor of their capture by Dox to produce more ROS. EGCG‐induced mETC disruption results in mitochondrial respiration inhibition with alleviated hypoxia in tumor cells while BSO inhibits glutathione biosynthesis to protect ROS from redox depletion, further boosting Dox‐induced CDT. This strategy of amplifying CDT pathway for the Dox‐mediated combined therapy could largely improve antitumor effect, extend lifespan of tumor‐bearing mice, reduce risks of cardiotoxicity and metastasis.

Hypoxia Inhibitor Combined with Chemotherapeutic Agents for Antitumor and Antimetastatic Efficacy against Osteosarcoma

“…As shown in Figure A–D, after treatment with AD@PLGA–PEG NPs, the intracellular ROS content increased significantly, and the mitochondrial membrane potential decreased, which indicated that AD@PLGA–PEG NPs could increase intracellular ROS production and destroy mitochondria to increase cell apoptosis. This may be because ABZ is an inhibitor of HIF-1α, which causes HIF-1α downregulation and reduces HIF-1α interference with electron transfer in the mitochondrial respiratory chain, thus providing more electrons for redox reactions. , Simultaneously, ABZ caused oxidative stress, increased the production of ROS, and promoted tumor cell apoptosis. ,, Besides, DOX also increased ROS production, and this result was consistent with the results of many other DOX nanoformulations reported in the literature …”

“…39 When DOX enters the mitochondria, electrons are obtained from the electron transport chain (ETC), semiquinone intermediates are formed, and then the electrons are transferred to oxygen (O 2 ) through a redox reaction to produce ROS. 11 Therefore, to explore the antitumor mechanism of AD@PLGA−PEG NPs, we first investigated their intracellular accumulation. As shown in Figure 2E, free DOX•HCl quickly entered the nucleus, while the AD@ PLGA−PEG NPs were mainly distributed in the cytoplasm.…”

“…As a first-line chemotherapeutic agent for osteosarcoma, doxorubicin (DOX) plays an important role in both preoperative neoadjuvant chemotherapy and postoperative chemotherapy. , Generally, DOX is believed to interfere with the transfer of oxidative respiratory electron chains in mitochondria and increase the production of reactive oxygen species (ROS). − Solid tumors, including osteosarcoma, usually exist in a hypoxic microenvironment . Hypoxia inducible factor-1α (HIF-1α) is a hypoxia-stable transcription factor that regulates the expression of multiple target genes involved in glycolysis, mitochondrial respiration, chemotherapy resistance, and tumor metastasis by binding to hypoxia-responsive elements. , Indeed, HIF-1α can also increase the expression of multidrug-resistant proteins, such as P-glycoprotein (P-gp), to pump chemotherapy drugs out of tumor cells and upregulate vascular endothelial growth factor (VEGF) to provide nutrients for tumor metastasis. − Meanwhile, the strategy of alleviating the hypoxia in the tumor microenvironment and inhibiting HIF-1α has achieved a significant effect in tumor treatment. − Therefore, treatment with DOX combined with HIF-1α inhibitors has great potential to enhance the efficacy of chemotherapy drugs and be used in osteosarcoma therapy. − However, traditional HIF-1α inhibitors have a certain toxicity when used in vivo, and direct oxygen administration has the problem of oxygen leakage.…”

Nucleus-Targeting Nanoplatform Based on Dendritic Peptide for Precise Photothermal Therapy

“…The dialysis membrane filter (MWCO: 3500 Da) containing 1 mL RDP/I was immersed in 10 mL buffer solution (pH 7.4, 6.5, or 5.0) and shaken at 37 °C for in vitro release simulation [ 27 ]. The encapsulation efficiency (EE) and loading level (LL) of IR780 are defined as below: EE = (mass of loaded IR780/mass of feed IR780) × 100% LL = (mass of IR780/mass of RDP/I) × 100% …”

ROS-scavenging hydrogel as protective carrier to regulate stem cells activity and promote osteointegration of 3D printed porous titanium prosthesis in osteoporosis

“…At present, active ingredients (such as anti-inflammatory agents, exosomes, and nanoparticles) provide a feasible strategy for combating chronic inflammation caused by ROS accumulation and accelerating tissue regeneration ( Zhao et al, 2021 ). Among them, natural compound, epigallocatechin-3-gallate (EGCG), the most abundant polyphenolic compound in green tea, has attracted considerable attention recently ( Liu T. et al, 2022 ; Zhichao et al, 2022 ). EGCG has been widely studied and applied in biomedical field due to its superior physical and chemical properties, including anti-inflammatory, anti-oxidant, bactericidal, anti-aging, promoting angiogenesis, anti-cancer effects, and easy crosslinking to prepare hydrogels ( Byun et al, 2021 ; Mi et al, 2021 ).…”