JOURNAL OF COLLOID AND INTERFACE SCIENCE
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2025
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IF 9.7
Chuan Hu,Jiaqi Ma,Ziye Su,Junyu Wang,Xueqian Zhang,Lin Pang,Yan Qu,Jinfeng Shi,Jinming Zhang
The combination of doxorubicin (Dox) and glycyrrhetinic acid (GA) has been widely explored for treating various cancers, while the heterogeneous distribution, uncontrolled release and acid tumor microenvironment often hinder their synergistic effects. Herein, we introduce an acid/glutathione (GSH)-dual responsive nano-prodrug (AS1411@Dox + GA/NPs) enabling precise co-delivery of Dox and GA for enhanced combination therapy. The GSH-activated Dox prodrug [Poly(lactic- co -glycolic acid)-disulfide-Dox, PLGA-ss-Dox], GA, and sulfur-terminated D-α-tocopherol polyethylene glycol succinate (TPGS-SH) are combined to form a nanoemulsion with sodium bicarbonate (NaHCO 3 ) in the aqueous phase. The AS1411 aptamer is modified on the surface for tumor-specific targeting. Upon reaching the tumor via enhanced penetration and retention effects, AS1411 aptamer medicates specific endocytosis of AS1411@Dox + GA/NPs into tumor cells. Intracellularly, the acidic endosomal environment promotes carbon dioxide (CO 2 ) production from NaHCO 3 , disrupting the nanoemulsion and causing a burst release of GA and PLGA-ss-Dox prodrug. Concurrently, high levels of GSH in the cytoplasm triggers the cleavage of the disulfide linker, thereby releasing Dox. Notably, the released NaHCO 3 consumed hydrogen ion (H + ), amplifying the sensitivity of tumor cells to Dox. As a consequence, AS1411@Dox + GA/NPs exhibits remarkable synergistic therapeutic efficacy on both liver cancer and breast cancer bearing mouse models. This work presents an appealing approach utilizing stimuli-sensitive nano-prodrug for advanced combinational cancer treatment.
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EUROPEAN POLYMER JOURNAL
·
2022
·
IF 5.546
Shuang Han,Aixin Yao,Yuxin Ding,Qiuxue Leng,Fu Teng,Le Zhao,Ruonan Sun,Hongzhou Bu
In this study, a dual-template molecularly imprinted polymer (UIO-66@DMIPs) was synthesized using deep-eutectic solvents (DES) as functional monomer and doxorubicin (DOX) and phycocyanin (PC) as template molecules for the first time. The PC and DOX drugs were combined to obtain the synergistic effect by molecular imprinting technique (MIT). The novel deep-eutectic solvents (DES) as functional monomer can bind to the template molecules by electrostatic and hydrogen bonding forces to facilitate the formation of imprinted sites and increase the hydrophilicity of UIO-66@DMIPs, which improved the drugs release of UIO-66@DMIPs in aqueous media. The introduction of UIO-66-NH 2 in UIO-66@DMIPs reduced the encapsulation of the imprinted sites and resulted in better performance of the prepared UIO-66@DMIPs. The drugs-loaded UIO-66@DMIPs showed the maximum release of DOX and PC when the pH of the release medium was 5.0, with a release time of 20 h. UIO-66@DMIPs showed superior drugs loading and responsive drugs release for synergistic therapy during drugs delivery. As a drugs delivery system for compounded formulations, this study provides a reliable scheme with potential applications.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Jiadong Pang,Leilei Huang,Yating Lian,Zhijie Yuan,Fen Wang,Li-Ming Zhang
Astrocyte elevated gene-1 (AEG-1) oncogene is a notorious and evolving target in a variety of human malignancies including osteosarcoma. The RNA interference (RNAi) has been clinically proven to effectively knock down specific genes. To successfully implement RNAi in vivo, protective vectors are required not only to protect unstable siRNAs from degradation, but also to deliver siRNAs to target cells with controlled release. Here, we synthesized a Zein-poly( l -lysine) dendrons non-viral modular system that enables efficient siRNA-targeted AEG-1 gene silencing in osteosarcoma and encapsulation of antitumor drugs for controlled release. The rational design of the ZDP integrates the non-ionic and low immunogenicity of Zein and the positive charge of the poly( l -lysine) dendrons (DPLL) to encapsulate siRNA and doxorubicin (DOX) payloads via electrostatic complexes and achieve pH-controlled release in a lysosomal acidic microenvironment. Nanocomplexes-directed delivery greatly improves siRNA stability, uptake, and AEG-1 sequence-specific knockdown in 143B cells, with transfection efficiencies comparable to those of commercial lipofectamine but with lower cytotoxicity. This AEG-1-focused RNAi therapy supplemented with chemotherapy inhibited, and was effective in inhibiting the growth in of osteosarcoma xenografts mouse models. The combination therapy is an alternative or combinatorial strategy that can produce durable inhibitory responses in osteosarcoma patients.
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JOURNAL OF ETHNOPHARMACOLOGY
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2020
·
IF 3.69
Qian Zhou,Ping Meng,Ya Zhang,Peng Chen,Haibo Wang,Guangguo Tan
Ethnopharmacological relevance Sini decoction (SND) is a famous Traditional Chinese Medicine (TCM) formula composed of Acontium carmichaeli , Zingiber officinale and Glycyrrhiza uralensis , which is considered as an efficient formula against doxorubicin (DOX)-induced heart failure. But the compatibility mechanism of SND remains unclear. Aim of the study The present study aimed to investigate the compatibility mechanism of SND against DOX-induced heart failure in rats. Materials and methods Mass spectrometry-based serum metabolomics were performed. The relative distance values (RDVs) of SND, A. carmichaeli -free decoction (ACFD), Z. officinale -free decoction (ZOFD) and G. uralensis -free decoction (GUFD) treated groups from the control/DOX groups in multidimensional space were calculated to provide a measure of compatibility effect of SND. SND, ACFD, ZOFD, GUFD-targeted metabolic pathways were identified and compared to investigate the synergistic mechanism of SND by computational systems analysis. Real-time quantitative PCR was further employed to validate the key metabolic pathways at the level of the gene. Results The RDVs combined with the hemodynamic and biochemical analysis showed that the protection effects were sorted as SND > GUFD > ZOFD > ACFD. It revealed that DOX-induced heart failure perturbed 16 metabolic pathways, and SND, GUFD, ZOFD and ACFD-treated groups could significantly reversed 12, 10, 7 and 6 metabolic pathways of these 16 metabolic pathways, respectively. Metabolic pathway and RT-PCR analysis indicated that both SND and GUFD could protect DOX-induced heart failure mainly by regulating PLA2-COX pathway and PLA2-CYP pathway. Conclusion It can be concluded that A. carmichaeli played an essential role in attenuation of DOX-induced heart failure among the three herb constituents of SND and the constituent herbs mutually reinforced each other. This work demonstrated that metabolomics combined with computational systems analysis was a promising tool for uncovering the compatibility effects of TCM.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2022
·
IF 5.999
Qiu-yue Wang,Yali-Xiang,Qiu-hui Hu,Shuang-hui Huang,Juan Lin,Qing-han Zhou
Recently, the stimulus-sensitive drug co-delivery system has gained increasing attentions in the clinic and exhibits improved efficiency rather than the mono-chemotherapy in anti-tumor therapy. Herein, the smart charge switchable nano-micelles (NMs) were fabricated for the endosomal escape mediated co-delivery of doxorubicin (DOX) and paclitaxel (PTX) in treatment of lung adenocarcinoma. The disulfide bonds were facilitated as the linker of the polymer backbone to achieve the redox-sensitive degradation by high intracellular GSH, and acid-liable DMMA was grafted onto DOX molecules for pH-triggered drug release under acidic tumoral microenvironment. Folic acid (FA) was utilized as targeting molecule for facilitating entry of the as prepared NMs into cancer cells. Remarkably, the as fabricated NMs exhibited surface charge-switch from negative to positive during transmitting from physiological pH to the tumor extracellular pH, which can improve the cellular internalization towards cancer cell. Subsequently, the “proton-sponge” effect mediated endosome escape of the NMs was facilitated in the acidic endo/lysosome environment. By the cell assay , the NMs possessed good biocompatibility, excellent cellular uptake, and improved inhibition rate against cancer cell. Moreover, the co-delivery of DOX/PTX exhibited synergistic and enhanced solid tumor inhibition efficiency comparing to mono-chemotherapy in A-549 tumor bearing mice model. Based on above experimental results, the as prepared drug co-delivery system showed promising biosafety and potentials for efficient lung adenocarcinoma treatment in clinic.
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2016
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IF 3.902
Jing Li,Xiaotong Du,Nan Zheng,Lu Xu,Jinghua Xu,Sanming Li
In this study, dual functionalized mesoporous silica nanoparticle (Dual-MSN) with functions of carboxyl modification and chirality was successfully developed and its special contribution in delivering doxorubicin hydrochloride (DOX) in vitro was mainly studied. Characteristics of Dual-MSN and its application as DOX carrier were intensively explored by comparing with naked non-functionalized MSN (Naked MSN). The results indicated that both Naked MSN and Dual-MSN significantly controlled DOX release due to the release hindrance caused by mesopores. As expected, Dual-MSN exhibited obvious enhanced pH-response because of its negative charges of carboxyl groups. DOX loaded Naked MSN and DOX loaded Dual-MSN presented better cytotoxicity than DOX due to carrier-mediated endocytosis and the favorable intercalation of DOX into DNA in the nuclei. The cytotoxicity of DOX loaded Dual-MSN was better than DOX loaded Naked MSN owing to its enhanced cellular uptake induced by chirality of Dual-MSN, demonstrating that double functions of Dual-MSN had unique advantages in improving antitumor effect of DOX towards MCF-7 cells and thus confirming its special contribution in DOX delivery.
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MATERIALS TECHNOLOGY
·
2025
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IF 3.7
Dan Jin,Song Wu,Linyang Dai,Ling Li
The high recurrence and metastasis rates of renal cell carcinoma (RCC) necessitate novel therapeutic strategies. Although chemotherapy is widely used, it often leads to systemic toxicity and acute kidney injury (AKI). This study developed a near-infrared (NIR)-responsive two-dimensional black phosphorus (BP) nanosheet drug delivery system loaded with doxorubicin (DOX) for photothermal therapy (PTT) of RCC, aiming to reduce nephrotoxicity. BP nanosheets exhibit excellent photothermal conversion efficiency under NIR irradiation, enabling localized hyperthermia for tumor ablation and triggering DOX release. Both in vitro and in vivo experiments demonstrated that BP-DOX induces apoptosis in RCC cells and suppresses tumor growth upon NIR irradiation. This study further revealed that this nanocomposite alleviates oxidative stress and inflammation in renal tissues, thereby preserving renal function. This work highlights the potential of the BP nanoplatform for synergistic chemotherapy–photothermal therapy in RCC while mitigating kidney damage, offering a new approach to overcome chemotherapy-related complications.
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ACS Biomaterials Science & Engineering
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2020
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IF 4.152
Bai-Yi Yan,Bai-Lu Liu,Ling-Yu Yi,Gui-Ling Wang,Bai-Zhong Xue,Ying Xie
Biodegradable hemostatic gauze used for surgical hemostasis has attracted great interest due to its excellent compliance and local anti-inflammatory and therapeutic effects when combined with drugs. Herein, we demonstrate the successful fabrication of water-soluble absorbed cellulose hemostatic material by introducing a biocompatible hydroxyethyl cellulose (HEC) hemostasis gauze into doxorubicin-loaded in situ gel (GEL(DOX)) for the prevention of breast cancer recurrence after surgical tumor resection. The present results show that HEC has a shorter metabolic period, no anaphylaxis and peripheral nerve toxicity, and possesses more advantages than oxidative regenerated cellulose hemostasis gauze, a commercially available product in market. HEC is of the physical hemostasis in mechanism, which does not induce physiological hemostasis and hemolysis. In addition, the combination of HEC with GEL(DOX) not only stops the bleeding efficiently, but also effectively reduces the proliferation of tumor with no cardiac toxic and bone marrow suppression. After treatment, the tumor inhibition rate is up to 90%, resulting in prolonged survival time to 58 days. In conclusion, HEC hemostatic gauze has a broad prospect in clinical application due to its perfect biocompatibility, and we envision that it is a new strategy for the prevention of breast cancer to implant HEC hemostatic gauze containing GEL(DOX) at the postoperative site after surgery.
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MOLECULES
·
2024
·Vol. 29
·期 4
·775
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IF 4.2
Liyuan Ma,Qiaoling Yu,Meng Zhuang,Chen Yang,Yuan Liu,Yuling Li,Cheng Liu,Xiaoyan Shen,Yan Chang
Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies.
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Food Bioscience
·
2026
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IF 6.2
Zhiyuan Li,Lei Jiang,Yuqi Li,Huifen Li,Shihan Zhang,Lijuan Han
Chemotherapy-induced mesenchymal stem cell (MSC) senescence impairs tissue repair and limits regenerative therapies. Probiotic-derived extracellular vesicles (EVs) have emerged as biocompatible nanocarriers, yet the molecular determinants of their therapeutic efficacy remain poorly defined.Culturing Lactobacillus rhamnosus PB LR76 with mangiferin (MGF) loads MGF into extracellular vesicles (EVs, 2.66% w/w) and remodels their proteome, generating multimodule anti senescence cargo. PB LR76 MGF EVs (50 μg/mL protein, 1.33 μg/mL MGF) significantly attenuated doxorubicin induced mesenchymal stem cell (MSC) senescence: they reduced ROS, DNA damage (γ-H2AX), and p53/p21 activation, while preserving mitochondrial membrane potential. In an eight group, three strain comparison (PB LR76, probiotic LGG, nonprobiotic ATCC 4356), only probiotic strain EVs preserved osteogenic and chondrogenic differentiation (Alizarin Red S/Alcian Blue; Runx2, ALP, COL1A1, OSX, ACAN, COL2A1, SOX9), confirming strain specificity. DIA Hyper quantitative proteomics (549 proteins, n = 3) identified 134 differentially abundant proteins enriched in PB LR76 MGF EVs, coordinated across four functional modules: redox/stress proteins (thioredoxin, NADH dehydrogenase FC = 30.8), six glycolytic moonlighting enzymes, DnaK GrpE/GroEL chaperones, and metabolic/ribosomal moonlighting proteins. PubMed cross referencing mapped 21 of 26 probiotic EV effector categories, 11 enriched in PB LR76 MGF EVs, to 10 human pathways, including TLR2/NF-κB, integrin/FAK survival, and NAD+/sirtuin dependent p53 deacetylation. These findings establish a proteome to phenotype framework for probiotic EV bioactivity and position PB LR76 MGF EVs as a food grade nanotherapeutic strategy against chemotherapy induced tissue damage.
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Frontiers in Pharmacology
·
2022
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IF 5.988
Liao Wenli,Rao Zhiwei,Wu Lingling,Chen Yong,Li Cairong
Background: Doxorubicin (DOX) is a potent chemotherapeutic agent with limited usage due to its cumulative cardiotoxicity. The Na+/H+ exchanger isoform 1 (NHE1) is a known regulator of oxidative stress, inflammation, and apoptosis. The present study was designed to investigate the possible protective effect of cariporide (CAR), a selective inhibitor of NHE1, against DOX-induced cardiotoxicity in rats.Methods: Male Sprague-Dawley rats were intraperitoneally injected with DOX to induce cardiac toxicity and CAR was given orally for treatment. The injured H9c2 cell model was established by incubation with DOX in vitro. Echocardiography, as well as morphological and ultra-structural examination were performed to evaluate cardiac function and histopathological changes. The biochemical parameters were determined according to the manufacturer’s guideline of kits. ROS were assessed by using an immunofluorescence assay. The serum levels and mRNA expressions of inflammatory cytokines were measured by using ELISA or qRT-PCR. Cardiac cell apoptosis and H9c2 cell viability were tested by TUNEL or MTT method respectively. The protein expressions of Cleaved-Caspase-3, Bcl-2, Bax, Akt, GSK-3β, and Sirt1 were detected by western blot.Results: Treatment with CAR protected against DOX-induced body weight changes, impairment of heart function, leakage of cardiac enzymes, and heart histopathological damage. In addition, CAR significantly attenuated oxidative stress and inhibited the levels and mRNA expressions of inflammatory cytokines (TNF-α, IL-6, IL-18, and IL-1β), which were increased by DOX treatment. Moreover, CAR significantly suppressed myocardial apoptosis and Cleaved-Caspase-3 protein expression induced by DOX, which was in agreement with the increased Bcl-2/Bax ratio. Also, DOX suppressed phosphorylation of Akt and GSK-3β, which was significantly reversed by administration of CAR. Furthermore, CAR treatment prevented DOX-induced down-regulation of Sirt1 at the protein level in vitro and in vivo. Finally, Sirt1 inhibitor reversed the protective effects of CAR, as evidenced by reduced cell viability and Sirt1 protein expression in vitro.Conclusion: Taken together, we provide evidence for the first time in the current study that CAR exerts potent protective effects against DOX-induced cardiotoxicity in rats. This cardio-protective effect is attributed to suppressing oxidative stress, inflammation, and apoptosis, at least in part, through regulation of Akt/GSK-3β and Sirt1 signaling pathway, which has not been reported to date.
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Scientific Reports
·
2020
·Vol. 10
·期 1
·1-14
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IF 3.998
Zhang Chao,Zhang Fanghua,Han Mengnan,Wang Xuming,Du Jie,Zhang Honglei,Li Wei
Combination chemotherapy is still of great importance as part of the standard clinical care for patients with HER2 positive breast cancer. As an attractive component, gold nanoparticles (AuNPs) have been extensively studied as biosafety nanomaterials, but they are rarely explored as drug nanocarriers for targeted co-delivery of multiple chemotherapeutics. Herein, a novel affibody-DNA hybrid strands modified AuNPs were fabricated for co-loading nucleoside analogue (5-fluorodeoxyuridine, FUdR) and anthracycline (doxorubicin, Dox). FUdRs were integrated into DNA hybrid strands decorated on AuNPs by DNA solid phase synthesis, and Dox molecules were intercalated into their duplex regions. Affibody molecules coupled to the DNA hybrid strands were distributed the surface of AuNPs, giving them targeting for HER2. The new dual-drug-containing affibody-DNA-AuNPs (Dox@affi-F/AuNPs) owned compact and stable spherical nanostructures, and precise drug loading. Cytotoxicity tests demonstrated that these nanoparticles caused a higher inhibition in HER2 overexpressing breast cancer cells, and showed better synergistic antitumor activity than simple mixture of the two drugs. The related mechanistic studies proved that Dox@affi-F/AuNPs achieved a remarkable combined antitumor activity of Dox and FUdR by promoting more cells to enter apoptosis pathway. Our work provided a nanomedicine platform for targeted co-delivery of nucleoside analog therapeutics and anthracycline anticancer drugs to achieve synergistic treatment of HER2 + cancer.
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