DRUG DELIVERY
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2023
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IF 6
Wen Zhang,Peng Zhang,Xiaopeng Xu,Minghui Li,Shasha Wang,Hongjie Mu,Kaoxiang Sun
Doxorubicin (DOX) is a commonly studied chemotherapeutic agent for the treatment of solid tumors, but the severe side effects limit its clinical application. It is shown that DOX-metal chelate has lower in vitro cytotoxicity compared with DOX, as the anthracyclines of DOX can form coordinative interaction with transition metal ions. In addition, the transition metal ions could catalyze the production of hydroxyl radicals (·OH) via Fenton/Fenton-like reactions to achieve antitumor chemodynamic therapy (CDT). In this study, copper ions (Cu2+) were applied to obtain DOX/Cu(II) prodrug, and a liposomal formulation was used to avoid the rapid blood clearance and optimize the biodistribution of this prodrug. In vitro and in vivo antitumor results demonstrated that this pH sensitive Cu-chelating prodrug can reduce adverse effects of DOX but improve the antitumor efficiency due to the combination of chemotherapy and chemodynamic therapy. Our study provided a facile and effective approach of metal-chelating prodrug strategy for combination cancer therapy strategy.
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Arabian Journal of Chemistry
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2023
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IF 6
Lei Yang,Hong Huang,Ting Wang,Danling Zhou,Qing Chen,Dan Li,Shuzi Chen,Ping Lin
Endoplasmic reticulum, the largest cellular organelle where protein synthesis, folding, transportation, and the maintenance of Ca 2+ homeostasis occurred, is sensitive to the imbalance of its inner environment. Particularly, overproduction of reactive oxygen species in endoplasmic reticulum region can initiate endoplasmic reticulum stress and is tightly related to many metabolic diseases. In this respect, to retain normal function of endoplasmic reticulum, it is highly important to synthesize antioxidants with endoplasmic reticulum-targeting capability for precisely clearing excessively generated reactive oxygen species in endoplasmic reticulum. Herein, we demonstrate the preparation of endoplasmic reticulum-targeting Se-doped carbon nanodots and assays with HeLa cells as well as in vivo tests with mice have shown that the prepared carbon nanodots can significantly eliminate both •OH and O 2 •− . Experimental results declared that the fabricated carbon nanodots with powerful scavenging capabilities toward •OH and O 2 •- , low cytotoxicity and endoplasmic reticulum targetability can be utilized to protect cells against raised levels of reactive oxygen species in endoplasmic reticulum. What’s more, the fabricated carbon nanodots effectively alleviated phorbol 12-myristate 13-acetate induced ear inflammation in live mice.
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Advanced Healthcare Materials
·
2023
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IF 10
Yi Lu,Xinni Pan,Cheng Cao,Shanshan Fan,Haisong Tan,Shengsheng Cui,Yanlei Liu,Daxiang Cui
As one of the most widely used drugs, acetaminophen, is the leading cause of acute liver injury. In addition, acetaminophen-induced liver injury (AILI) has a strong relationship with the overproduced reactive oxygen species, which can be effectively eliminated by nanozymes. To address these challenges, mesoporous PdPt@MnO 2 nanoprobes (PPM NPs) mimicking peroxide, catalase, and superoxide dismutase-like properties are synthesized. They demonstrate nontoxicity, high colloidal stability, and exceptional reactive oxygen species (ROS)-scavenging ability. By scavenging excessive ROS, decreasing inflammatory cytokines, and inhibiting the recruitment and activation of monocyte/macrophage cells and neutrophils, the pathology mechanism of PPM NPs in AILI is confirmed. Moreover, PPM NPs’ therapeutic effect and good biocompatibility may facilitate the clinical treatment of AILI.
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IMMUNOLOGICAL INVESTIGATIONS
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2023
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IF 2.8
Dongdong Dou,Meirong Bi,Xiuyun Li,Nan Zhang,Mi Xu,Aili Guo,Feng Li,Weiwei Zhu
Background Childhood asthma is a major global health concern. ADP-ribosylation factor 6 (ARF6) is a low-molecular-weight GTPase; however, its role in childhood asthma remains unclear.Methods Ovalbumin (OVA)-challenged neonatal mice and transforming growth factor-β1 (TGF-β1)-induced BEAS-2B cells were used as in vivo and in vitro models of childhood asthma, respectively.Results Upon OVA stimulation, ARF6 expression was upregulated in the lung tissue. Neonatal mice administered SehinH3 (an ARF6 inhibitor) exhibited improved pulmonary pathological injury, along with reduced inflammatory cell infiltration in the lungs and cytokine release in bronchial alveolar lavage fluid and serum (interleukin [IL]−3, IL−5, IL−13, IgE, and OVA-specific IgE). SehinH3 treatment restrained epithelial – mesenchymal transition (EMT) in the lungs of asthmatic mice, as evidenced by increased E-cadherin and decreased N-cadherin and α-smooth muscle actin expression. Different TGF-β1 exposures to BEAS-2B cells induced a time- and dose-dependent increase in ARF6 expression in vitro. Upon TGF-β1 stimulation, ARF6 knockdown repressed EMT and SehinH3 treatment caused similar results in BEAS-2B cells. The transcription factor E2F8 is involved in diverse biological functions and its increased expression was confirmed in vivo and in vitro. Dual-luciferase assays confirmed that E2F8 binds to the ARF6 promoter and promotes its transcriptional activity. In vitro results revealed that E2F8 silencing suppressed EMT, whereas rescue experiments showed that ARF6 overexpression partly reversed these phenomena.Conclusion Our study showed that ARF6 is associated with childhood asthma progression and may be positively regulated by E2F8. These results provide insight into the pathogenesis and treatment of childhood asthma.
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Advanced Healthcare Materials
·
2023
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IF 10
Fan Zhao,Hongyan Yu,Liying Liang,Chen Wang,Dier Shi,Xiangyu Zhang,Yao Ying,Wei Cai,Wangchang Li,Juan Li,Jingwu Zheng,Liang Qiao,Shenglei Che,Jing Yu
The combination of chemo/chemodynamic therapy is a promising strategy for improving antitumor efficacy. Herein, metal-phenolic network nanoparticles (NPs) self-assembled from copper ions and gallic acid (Cu-GA) are developed to evoke apoptosis and cuproptosis for synergistic chemo/chemodynamic therapy. The Cu-GA NPs are biodegraded in response to the highly expressed glutathione (GSH) in tumor cells, resulting in the simultaneous release of Cu + and GA. The intracellular GSH content is dramatically reduced by the released GA, rendering the tumor cells incapable of scavenging reactive oxygen species (ROS) and more susceptible to cuproptosis. Meanwhile, ROS levels within the tumor cells are significantly increased by the Fenton-like reaction of released Cu + , which disrupts redox homeostasis and achieves apoptosis-related chemodynamic therapy. Moreover, massive accumulation of Cu + in the tumor cells further induces aggregation of lipoylated dihydrolipoamide S-acetyltransferase and downregulation of iron-sulfur cluster protein, activating cuproptosis to enhance the antitumor efficacy of Cu-GA NPs. The experiments in vivo further demonstrate that Cu-GA NPs exhibited the excellent biosafety and superior antitumor capacity, which can efficiently inhibit the growth of tumors due to the activation by the tumor specific GSH and hydrogen peroxide. These Cu-based metal-phenolic network NPs provide a potential strategy to build up efficient and safe cancer therapy.
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ACS Nano
·
2023
·
IF 17.1
Hongrui Zhu,Chenqi Huang,Jingran Di,Zepu Chang,Ke Li,Shuo Zhang,Xueping Li,Daocheng Wu
To achieve the maximum therapeutic effects and minimize adverse effects of trimodal synergistic tumor therapies, a cost-effective programmed photothermal (PTT)-chemodynamic (CDT)-coordinated dual drug chemotherapy (CT) trimodal synergistic therapy strategy in chronological order is proposed. According to the status or volumes of the tumors, the intensity and time of each therapeutic modality are optimized, and three modalities are combined programmatically and work in chronological order. The optimal synergistic therapy begins with high-intensity PTT for 10 min to ablate larger tumors, followed by medium-intensity CDT for several hours to eliminate medium-sized tumors, and then low-intensity coordinated dual drugs CT lasts over 48 h to clear smaller residual tumors. Composite nanoparticles, made of Fe-coordinated polydopamine mixed with copper peroxide as the cores and their surface dotted with lots of doxorubicin-Fe(III)-gossypol infinite coordination polymers (ICPs), have been developed to implement the strategy. These composite nanoparticles show excellent synergistic effects with the minimum dose of therapeutic agents and result in nearly 100% tumor inhibition for mice bearing PC-3 tumors and no observed recurrence within 60 days of treatment. The ratios of the different therapeutic agents in the composite nanoparticles can be adjusted to accommodate different types of tumors with this cost-effective programmed trimodal therapy strategy.
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Acta Biomaterialia
·
2023
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IF 9.7
Zaixiang Fang,Ling Lin,Zhiqian Li,Lei Gu,Dayi Pan,Yunkun Li,Jie Chen,Haitao Ding,Xiaohe Tian,Qiyong Gong,Kui Luo
The combination of chemotherapy and photodynamic therapy (PDT) has the potential to complement single-drug therapies, but chemotherapeutic agents and photosensitizers often have compromised therapeutic efficacies and strong toxic effects. In this study, we exploited nanotechnology to address this challenge by utilizing heparin as a carrier for co-delivery of chemotherapeutic drugs and photosensitizers for synergistic cancer therapy. Specifically, heparin-paclitaxel (HP-PTX) and heparin-pyropheophorbide-a (HP-Ppa) were synthesized by attaching paclitaxel (PTX), a small molecular chemotherapeutic drug, through a reactive oxygen species (ROS)-responsive linker and Ppa, a photosensitizer, to heparin, respectively. Two conjugates were co-assembled into a nanomedicine , HP-PP nanoparticles (NPs), for controllable co-delivery of Ppa and PTX into tumor cells. HP-PP NPs significantly enhanced the in vitro stability of HP-Ppa and the photostability of Ppa, and the synergistic actions of chemotherapy and PDT were confirmed by both in vitro and in vivo antitumor studies. Notably, HP-PP NPs enhanced tumor accumulation of Ppa up to 11-fold and the treatment of 4T1 tumor-bearing mice with HP-PP NPs resulted in a tumor growth inhibition of 98.1% without systemic toxicity. The strategy of co-assembly of heparin conjugates may offer great potential in enhancing the efficacy of combination therapy. Statement of significance We proposed a nano-delivery system, HP-PP NPs, which was constructed by co-assembly of heparin-paclitaxel (HP-PTX) and heparin-pyropheophorbide-a (HP-Ppa), to co-deliver PTX and Ppa for synergistic cancer therapy. HP-PP NPs enhanced the photostability and the in vitro stability of Ppa and HP-Ppa, and induced greater cytotoxicity than HP-PTX NPs or HP-Ppa NPs. This co-delivery system displays enhanced tumor accumulation and has a remarkable synergistic antitumor effect with a tumor growth inhibition of 98.1%.
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JOURNAL OF CONTROLLED RELEASE
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2023
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IF 10.8
Yuxin Zhang,Jie Zhou,Xiaoting Chen,Zhiqian Li,Lei Gu,Dayi Pan,Xiuli Zheng,Qianfeng Zhang,Rongjun Chen,Hu Zhang,Qiyong Gong,Zhongwei Gu,Kui Luo
Interaction between carcinoma-associated fibroblasts (CAFs) and tumor cells leads to the invasion and metastasis of breast cancer. Herein, we prepared a redox-responsive chondroitin sulfate (CS)-based nanomedicine , in which hydrophobic cabazitaxel (CTX) was conjugated to the backbone of CS via glutathione (GSH)-sensitive dithiomaleimide (DTM) to form an amphipathic CS-DTM-CTX (CDC) conjugate, and dasatinib (DAS) co-assembled with the CDC conjugate to obtain [email protected] After CD44 receptor-mediated internalization by CAFs, the nanomedicine could reverse CAFs to normal fibroblasts, blocking their crosstalk with tumor cells and reducing synthesis of major tumor extracellular matrix proteins , including collagen and fibronectin . Meanwhile, the nanomedicine internalized by tumor cells could effectively inhibit tumor proliferation and metastasis, leading to shrinkage of the tumor volume and inhibition of lung metastasis in a subcutaneous 4T1 tumor model with low side effects. Collectively, the nanomedicine showed a remarkably synergistic therapy effect against breast cancer by modulating tumor-stromal crosstalk.
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DRUG DELIVERY
·
2023
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IF 6
Yaqin Tu,Wei Zhang,Guorun Fan,Chenming Zou,Jie Zhang,Nan Wu,Jiahui Ding,Wen Qing Zou,Hongjun Xiao,Songwei Tan
High intracellular reactive oxygen species (ROS) level is characteristic of cancer cells and could act as a target for the efficient targeted drug delivery for cancer treatment. Consequently, biomaterials that react to excessive levels of ROS are essential for biomedical applications. In this study, a novel ROS-responsive polymer based on D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly (β-thioester) (TPGS-PBTE) was synthesized for targeted delivery of the first-line antineoplastic drug, paclitaxel (PTX). The resultant TPGS-PBTE NPs showed good ROS-responsive capability in size change and drug release. Compared to PTX, PTX-loaded nanoparticles (PTX@TPGS-PBTE NPs) showed enhanced cytotoxicity and higher level of apoptosis toward squamous cell carcinoma (SCC-7) cells. Tumor-targeted delivery of the NPs was also observed, especially after being modified with a tumor-targeting peptide, cRGD. Enhanced tumor growth inhibition was also observed in head and neck cancer SCC-7 murine models. In summary, PTX@TPGS-PBTE NPs can achieve good therapeutic effects of PTX against head and neck cancer both in vitro and in vivo, especially when modified by cRGD for active targeting, which enriched the application of ROS responsive system utilized in the delivery of anticancer drugs.
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FOOD CHEMISTRY
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2023
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IF 8.8
Xi Peng,Xing Hu,Kai Liu,Deming Gong,Guowen Zhang
Inhibition of advanced glycation end products (AGEs) formed in protein glycosylation is crucial for minimizing diabetic complications. Herein, the anti-glycation potential of hesperetin-Cu (II) complex was investigated. Hesperetin-Cu (II) complex strongly inhibited three stages glycosylation products in bovine serum albumin (BSA)-fructose model, especially for the inhibition of AGEs (88.45%), which was stronger than hesperetin (51.76%) and aminoguanidine (22.89%). Meanwhile, hesperetin-Cu (II) complex decreased the levels of BSA carbonylation and oxidation products. 182.50 µg/mL of hesperetin-Cu (II) complex inhibited 66.71% β-crosslinking structures of BSA, and scavenged 59.80% superoxide anions and 79.76% hydroxyl radicals. Moreover, after incubating with methylglyoxal for 24 h, hesperetin-Cu (II) complex removed 85.70% methylglyoxal. The mechanisms of protein antiglycation by hesperetin-Cu (II) complex may be through protecting structure, trapping methylglyoxal, scavenging free radicals and interacting with BSA. This study may contribute to the development of hesperetin-Cu (II) complex as a functional food additive against protein glycation.
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Inorganic Chemistry Frontiers
·
2023
·Vol. 10
·期 14
·4045-4053
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IF 7
Zhaoguo Hong,Xin You,Jingjing Zhong,Di Yao,He-Dong Bian,Shulin Zhao,Liangliang Zhang,Hong Liang,Fu-Ping Huang
Chemodynamic therapy (CDT), in which highly toxic hydroxyl radicals (˙OH) could be triggered by a Fenton or Fenton-like reaction to kill cancer cells, has emerged recently. Compared to traditional CDT nanomaterials, herein, an atomically-precise biotinylated Cu(I/II) complex [CuICuIICl2(VBio)]·CH3OH (VBio = deprotonated O-vanillin biotinylhydrazone), denoted VBio-CuICuII, was rationally designed and synthesized successfully. This targeted Fenton-like agent, VBio-CuICuII, is constructed from a hydroxyl radical-producible CuI ion, a CuII center as a GSH depletor for an augmented CDT effect, and a biotin moiety as a cancer-targeting unit. Owing to the obvious cell selectivity discrepancy of biotin towards normal and cancerous cells, VBio-CuICuII was able to preferentially accumulate in tumor cells. Meanwhile, the CuI metal center could be used as a Fenton-like agent to generate ˙OH. Furthermore, the CuII in VBio-CuICuII was available for successive ˙OH production via a CuI/CuII-circulation strategy under a GSH-rich tumor site, thereby improving catalytic efficiency. More importantly, in vivo results further demonstrate that VBio-CuICuII could significantly inhibit tumor growth without obvious damage toward major organs. Therefore, this multiple-identity Fenton-like agent could provide an appreciable reference value for the design of atomically precise CDT agents.
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HUMAN & EXPERIMENTAL TOXICOLOGY
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2023
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IF 2.8
Yanli Song,Dongjie He,Shaoqi Shi,Tianwei Cui,Hui Zhang,Xianmin Zhao,Tingting Ni,Huidongzi Xiao,Aiwu Wei
BackgroundWomen with antiphospholipid syndrome (APS) or antiphospholipid antibodies (aPLs) are at high risk for obstetric complications, including recurrent pregnancy loss (RPL). However, effective treatments for RPL are lacking.ObjectiveThis study aimed to reveal the function and underlying mechanism of hyperoside (Hyp) in RPL associated with antiphospholipid antibodies (aCLs).MethodsThe pregnant rats (N = 24) were divided randomly into four groups: normal human-IgG (NH-IgG); aCL-pregnancy loss (aCL-PL); aCL-PL + Hyp (40 mg/kg/day); aCL-PL + low molecular weight heparin (LMWH, 525 μg/kg/day). HTR‐8 cells were treated with 80 μg/mL aCL to establish the cell models of miscarriage.ResultsIn pregnant rats, aCL-IgG injection raised the abortion rate of embryos, while Hyp treatment inhibited the effects. Additionally, Hyp inhibited the platelet activation and uteroplacental insufficiency caused by aCL. In vivo and in vitro experiments further suggested that Hyp suppressed aCL-induced inflammation and apoptosis by downregulating NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-related factors and decreasing apoptotic rates. After aCL administration, Hyp therapy downregulated the expression of purinergic ligand-gated ion channel 7 (P2X7), which is reported to induce cytokine release and apoptosis. Furthermore, we found that the treatment of 3′-O-(4-Benzoyl) benzoyl-ATP (BzATP, an agonist of the P2X7 receptor) reversed the inhibitory effects of Hyp on cell function.ConclusionsHyp exerts protective effects on aCL-induced pregnancy loss by preventing platelet activation-mediated P2X7/NLRP3 pathway. Therefore, Hyp may provide a feasible pharmaceutical strategy for the treatment of RPL.
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