Pharmaceuticals
·
2025
·Vol. 18
·期 8
·1109
·
IF 4.8
Lingxin Zhuo,Mingxuan Ma,Jiayi Zhang,Jiayu Zhou,Yuqi Zheng,Aiyin Liang,Qingqing Sun,Jia Liu,Wenting Liao
Background/Objectives: Sepsis-induced cardiomyopathy (SIC) is a serious clinical disorder with a high death rate. Qifu decoction (QFD) is a renowned traditional Chinese medicine with documented pharmacological actions, such as anti-inflammatory, anti-oxidant and anti-apoptosis activities, and it has good therapeutic effects on cardiovascular diseases. This study aimed to reveal the cardioprotective effects and underlying mechanisms of QFD against SIC.Methods: Electrocardiography, histopathological examination, and biochemical indicator determination were carried out to investigate the cardioprotective effects of QFD in the treatment of LPS-induced SIC mice. Metabolomics and network pharmacology strategies were employed to preliminarily analyze and predict the mechanisms of QFD against SIC. Molecular docking and Western blot were further applied to validate the core targets and potential pathways for the treatment of SIC in in vitro and in vivo models.Results: It was found that QFD considerably enhanced cardiac function; attenuated myocardial injury; and reduced the serum levels of LDH, CK-MB, IL-1β, and TNF-α by 28.7%, 32.3%, 38.6%, and 36.7%, respectively. Metabolomic analysis showed that QFD could regulate seven metabolic pathways, namely, glutathione metabolism; alanine, aspartate, and glutamate metabolism; arachidonic acid metabolism; glycerophospholipid metabolism; purine metabolism; sphingolipid metabolism; and fatty acid metabolism. Network pharmacology suggested that the anti-SIC effect of QFD may be mediated through the TNF, toll-like receptor, NOD-like receptor, NF-κB, and PPAR signaling pathways. Additionally, 26 core targets were obtained. Molecular docking revealed that active ingredients such as formononetin, kaempferol, quercetin, and (R)-norcoclaurine in QFD had a high affinity for binding to PPARα and TLR4. Further Western blot validation indicated that QFD could regulate the protein levels of NLRP3, TLR4, NF-κB, IL-6, TNF-α, COX2, sPLA2, PPARα, CPT1B, and CPT2.Conclusions: This study demonstrates that QFD can alleviate SIC by suppressing the TLR4/NF-κB/NLRP3 inflammatory pathway and modulating impaired FAO through the activation of the PPARα/CPT pathway, highlighting QFD as a promising candidate drug for SIC treatment.
研究领域:
心脏病学
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药理学
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中医学
·
分子生物学
·
免疫学
·
代谢组学
·
网络药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Chuyao Liao,Di Wang,Siyuan Qin,Ying Zhang,Jie Chen,Ruijie Xu,Fengguo Xu,Pei Zhang
Irinotecan (CPT-11) in combination with 5-fluorouracil and leucovorin is a first-line chemotherapy regimen for the treatment of colorectal cancer; however, its clinical application is limited by the dose-limiting gastrointestinal toxicity of colitis. In our previous studies, several bile acids (BAs) were found significantly elevated in the colon of the CPT-11-induced rat colitis model. On the other hand, NLRP3 inflammasome has been reported to play important roles in mediating colitis. Interestingly, BA was stated to activate the NLRP3 inflammasome in some studies, while in some other reports, it showed an inhibitory effect. We assumed that the inflammatory status in different circumstances might have contributed to the controversial findings. In this study, we first discovered, under non-inflammatory conditions, that supplementing BA could activate the NLRP3 inflammasome in THP-1-differentiated macrophages and promote inflammation. In lipopolysaccharide (LPS)-induced inflammatory macrophages, however, BA inhibited the NLRP3 inflammasome and reduced inflammation. Further experiments demonstrated that Takeda G protein-coupled receptor 5 (TGR5) is essential in mediating the inhibitory effect of BA, while phospho-SP1 (p-SP1) is key to the activation. Furthermore, we applied the above findings to ameliorate CPT-11-caused colitis in rats by inhibiting SP1 with mithramycin A (MitA) or activating TGR5 using oleanolic acid (OA). Our findings may shed light on the discovery of effective interventions for reducing dose-limiting chemotherapy-induced colitis.
研究领域:
肿瘤学
·
胃肠病学
·
免疫学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2013
·
IF 3.554
Fang Du,Haijing Meng,Ke Xu,Yanyun Xu,Ping Luo,Yu Luo,Wei Lu,Jin Huang,Shiyuan Liu,Jiahui Yu
This research is aimed to develop a nanoparticle delivery system based on β-cyclodextrin-grafted diblock copolymer and camptothecin (CPT) inclusion complexes with the purpose of enhancing the stability of CPT in aqueous media. Firstly, mPEG-PBLG diblock copolymer was synthesized by the ring-opening polymerization of γ-benzyl- l -glutamate-N-carboxyanhydride (BLG-NCA) initiated with amine terminated poly (ethylene glycol) monomethyl ether (mPEG-NH 2 ). After removal of benzyl groups, mono-6-amine-β-cyclodextrin (EDA-β-CD) units were coupled to the carboxyl groups of the copolymer as side groups to produce the host macromolecule mPEG-PLG(CD). The highly hydrophobic anticancer drug CPT was employed as the guest component which could be included into the host macromolecule to form supramolecular inclusion-complex mPEG-PLG(CPT@CD). Interestingly, the supramolecular complexes were able to form spherical nanoparticles with an average size of 98 nm in aqueous media confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM), suggesting their passive targeting potential to tumor tissue. Due to the protection effect from a dual lock system (the environment of nanoparticles and the exterior surface of β-CD), the active lactone ring of CPT showed remarkably enhanced stability against hydrolysis under physiological condition. The release profile of the mPEG-PLG(CPT@CD) nanoparticles in PBS buffer was found to be gradual and sustaining. It was worthy to note that the release could be accelerated by addition of adamantane carboxylate (ADC) as competitive guest compound, demonstrating the chemically stimulated release behavior of the nanoparticles. Compared with free CPT, the mPEG-PLG(CPT@CD) nanoparticles displayed essentially decreased cytotoxicity against MCF-7 cell line in 24 h because of a sustained release profile of CPT from the nanoparticles, moreover, the carrier mPEG-PLG(CD) itself showed almost no cytotoxicity, indicating its great potential as tumor tissue targeted drug delivery system.
研究领域:
药剂学
·
生物材料
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Yadong Liu,Yifan Xue,Junjie Tang,Peng Zhang,Changjiang Liu,Dalin Wu,Jie Liu
Porphyrin-based photosensitizers are extensively utilized in the realm of photodynamic therapy, capitalizing on their advantageous optical, chemical, and electronic properties. Nonetheless, their application is often constrained by their pronounced hydrophobicity. Structures with a high load capacity and excellent biocompatibility are preferred options to circumvent this obstacle. Herein, we constructed a novel porphyrin–camptothecin (CPT) polymer, which is composed of amphiphilic oxazoline segments, and the drug monomers containing disulfide bonds are modified on the hydrophobic chain of polyoxazoline. The polyoxazoline–porphyrin–CPT (OPC) polymer can self-assemble into nanoparticles in the aqueous phase, possesses excellent stability, and generates abundant singlet oxygen (1O2) under laser irradiation. Additionally, the OPC nanoparticles exhibit satisfactory biocompatibility and high light toxicity against 4T1 cells. In the microenvironment of the tumor, drugs were released from the OPC nanoparticles owing to the high concentration of GSH, causing direct damage to the tumor cell, achieving the combination of photo-chemotherapy. The findings of this research indicate that polyoxazoline porphyrin demonstrates adaptability as a nanoplatform for cancer treatment.
研究领域:
药学
·
纳米技术
·
生物医学工程
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Wen Li,Jin-Xuan Fan,Ji-Yan Qiao,Qi-Wen Chen,Yun-Xia Sun,Xian-Zheng Zhang
The endogenous H 2 S plays an important role in the occurrence and development of colon cancer , and is related to the abnormal blood vessels. Here, we reported on a sulfhydryl hyaluronid-based hydrogel (HA-SH) synthesized by amide reaction and further obtained a bacterial hydrogel by loading Thiobacillus denitrificans to the hydrogel for targeting adhesion to the colon. It was found that the loaded bacteria in HA-SH hydrogel can scavenge excess H 2 S in colon cancer, then promote tumor vascular normalization and improve the delivery of chemotherapy drug CPT to inhibit tumor progression. Both in vivo and in vitro experiments show that the self-crosslinked bacterial hydrogel has satisfactory effects in inhibiting tumor progression and promoting tumor vascular normalization in colon cancer. This study presents an efficient method to target the colon and consume overexpressed H 2 S in colon cancer to inhabit tumor progression, providing a new way for oral drug treatment of colon cancer.
研究领域:
肿瘤学
·
药学
·
生物技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports Physical Science
·
2026
·
IF 6.9
Dian Jiao,Tao Wang,Yinghou Wang,Zhengdi Ma,Mingjia Sun,Chen Meng,Weihua Chen,Yaqi Wang,Yanxin Li,Yaru Song,Xinnan Hou,Zhong Wen,Jingdong Xiao,Zhonggui He,Tianhong Zhang,Jin Sun,Zhenbao Li,Qikun Jiang
Albumin-based drug-delivery systems garner attention due to their inherent biocompatibility and tumor-targeting potential. However, they are limited by weak human serum albumin (HSA) affinity for drugs like camptothecin (CPT). To address this, we synthesize five CPT prodrug derivatives (CPT-SA-C6–C14) with tunable aliphatic alcohol chains as HSA-binding motifs and a succinic acid linker for carboxylesterase (CES1/CES2)-mediated cascade activation. CPT-SA-C10, C12, and C14 achieve ultrahigh drug loading (>30%) in albumin nanoparticles (ANPs) via enhanced HSA affinity. Aliphatic chain length shows an inverted V-shaped correlation with both HSA-binding affinity and CES1-catalyzed hydrolysis. The resulting intermediate is hydrolyzed by CES2 to release CPT. CPT-SA-C12 ANPs exhibit the highest albumin affinity and fastest enzymatic conversion, yielding superior therapeutic efficacy and favorable tolerability. This work elucidates the structure-activity relationship of albumin-bound prodrugs and advances the design of CES-responsive nanomedicines.
✓ 已验证
产品关联
DOI
高影响因子
LANGMUIR
·
2023
·
IF 3.9
Hailiang Chen,Chenyu Liu,Simiao Yu,Hengjun Zhou,Farishta Shafiq,Weihong Qiao
The resistance of cancer cells to anticancer drugs has been recognized as one of the main reasons for chemotherapy failure. Multidrug combination therapy is one of the most effective ways to solve this problem. Therefore, in this article, we designed and synthesized a pH/GSH dual-responsive camptothecin/doxorubicin (CPT/DOX) dual pro-drug synergistic treatment system with the aim of overcoming the resistance of non-small cell lung cancer A549/ADR cells to DOX. The pro-drug cRGD-PEOz-S-S-CPT (cPzT) was obtained by linking CPT to poly(2-ethyl-2-oxazoline) (PEOz) with endosomal escape properties through a GSH-responsive disulfide bond and modifying it with the targeted peptide cRGD. The pro-drug mPEG–NH–N=C-DOX (mPX) was synthesized by attaching DOX to polyethylene glycol (PEG) through acid-sensitive hydrazone bonds. The dual pro-drug micelles cPzT/mPX configured according to the CPT/DOX mass ratio of 3:1 showed a strong synergistic therapeutic effect at IC50 with a combined therapy index CI = 0.49, far less than 1. Moreover, with the further improvement of the inhibition rate, the 3:1 ratio showed a stronger synergistic therapeutic effect than other ratios. The cPzT/mPX micelles not only had better targeted uptake ability but also showed a better therapeutic effect in both 2D and 3D tumor suppression assays relative to free CPT/DOX and significantly enhanced the penetration ability into solid tumors. In addition, the results of confocal laser scanning microscopy (CLSM) showed that cPzT/mPX could effectively overcome the resistance of A549/ADR cells to DOX by delivering DOX into the nucleus to exert its effect. Thus, this dual pro-drug synergistic therapy system combining targeting and endosomal escape ability provides a possible strategy to overcome tumor drug resistance.
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2017
·
IF 3.234
Yushu Huang,Ya Gao,Tiandong Chen,Yanyun Xu,Wei Lu,Jiahui Yu,Yi Xiao,Shiyuan Liu
The aim of this research is to develop a novel type of camptothecin (CPT) prodrug micelles bearing boronate ester bonds as a smart nanosystem with enhanced cellular uptake and controlled drug release based on diblock copolymer abbreviated as PEG-BC-PGlu-ss-CPT. Particularly, boronate ester bond was introduced to achieve acid-triggered de-PEGylation and succeeding boronic acid-mediated enhanced cellular uptake. Besides, CPT was conjugated to the prodrug monomer through a disulfide bond to realize reduction-responsive drug release. The resultant copolymer PEG-BC-PGlu-ss-CPT could self-assemble into spherical nanomicelles in water. The degradation half-life time of PEG-BC-PGlu-ss-CPT copolymer decreased sharply from 96.27 h to only 5.7 h with pH value decreasing from 7.4 to 5.0, indicating the acid-degradable potential, which corresponded to size change monitoring. The cumulative CPT release from prodrug micelles increased significantly from 8.5 ± 1.73 to 82.9 ± 2.29% with an increase of dithiothreitol (DTT) concentration from 20 μM to 10 mM at pH 7.4, illustrating the reduction-responsive drug release property of prodrug micelles. The half maximal inhibitory concentration (IC50) value of prodrug micelles against HepG2 cells decreased from 1.06 to 0.68 μg/mL with the decrement of pH value from 7.4 to 6.0, proving that the utilization of boronate ester bonds was beneficial for enhancing antiproliferative activity. Interestingly, prodrug micelles exhibited enhanced cellular uptake ability against HepG2 cells compared to that of HL7702 cells, further confirming boronic acid-mediated enhanced endocytosis. In brief, this novel type of intelligent prodrug micelles possessed great potential as a smart nanosystem for antitumor drug delivery.
研究领域:
药剂学
·
肿瘤学
·
生物材料
✓ 已验证
DOI
PubMed
高影响因子
INORGANIC CHEMISTRY COMMUNICATIONS
·
2025
·
IF 5.4
Xiaoyu Li,Guangru Chu,Zhen Zhou,Jiashen Fan,Liying Cui,Zhongkai Liu,Shengkai Liu,Yujie Fu,Zhiguo Liu
In this study, chitooligosaccharide (CHO) was used as a template to synthesis of 50 nm mesoporous silica nanoparticles (MSNs) with high specific surface area and pore volume. The MSNs nanopaticles have been characterized by SEM, TEM, DLS, FTIR, TGA, XRD and XPS spectrometry. The CHO templated MSNs nanoparticles featured with very high specific surface area (1443.7 m 2 g −1 ) and pore volume (2.171 cm 3 g −1 ). The MSNs surface was further modified by the chitosan (CHI) layer and the folic acid (FA). Under the optimized conditions, the anticancer drug CPT-11 has a loading efficiency of 378 mg/g and the drug release efficiency is 40.8 % in 24 h. In vitro tests on the prepared MSNs-CHI-FA loaded with CPT-11 against human breast cancer cells indicated that the nano-formulation with drug concentration of 20 μg/mL successfully enhanced folate receptor-mediated endocytosis by the cellular uptake and significantly improved CPT-11 inhibitory against the cancer cells to 58.1 %
研究领域:
材料科学与工程
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Yu Xia,Xiaojie Song,Rui Bian,Junyang Chen,Qian Guo,Qi-Yan Lv,Hui-Fang Cui
Combined use of different drugs and therapy modes has been effective in improving tumor therapy efficiency and reducing side effects. However, synergistic anticancer efficiency and highly responsive drug release still remain challenging. Herein, we found that camptothecin (CPT), doxycycline (DOXY), and IR780 exhibit a synergistic anticancer effect on CT26 colorectal cancer cells. Thereafter, a redox dual-responsive CPT/DOXY hybrid dimer, CPT-SeSe-DOXY, was synthesized via the –SeSe– linkage. As a control, CPT-SS-DOXY was also synthesized. Both dimers were able to self-assemble with IR780 and DSPE-PEG-iRGD into multifunctional, stimuli-responsive, aqueous-dispersible, and spherical nanoparticles (NPs) with diameters of 83–87 nm. The C-SeSe-D/I/RGD NPs showed significantly stronger responsiveness to glutathione, H2O2, and near-infrared (NIR) lasers, reflected by dramatically higher responsive drug release ratios and stronger generation of 1O2 upon NIR laser irradiation, than the C–SS–D/I/RGD NPs. They can be highly taken up by CT26 cells, while hardly taken up by normal colorectal cells. In addition, they exhibited a very efficacious killing property against CT26 cells. The cell viability with C-SeSe-D/I/RGD NPs (with NIR laser) at 4.0 μg·mL–1 equivalent CPT at hypoxic conditions reached as low as ∼7.8%. The treatment can induce strong mitochondrial depolarization, ATP depletion, reactive oxygen species (ROS) generation, and therefore high cell apoptosis, even in hypoxic cultures. They can highly accumulate in tumors and lead to as high as 90.8% tumor growth inhibition under an NIR laser. Collectively, the C-SeSe-D/I/RGD NPs possess sensitive multistimuli-responsive capabilities and efficacious chemo/photothermal/photodynamic combined tumor therapy, exhibiting great potential in clinical applications.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Theranostics
·
2016
·
IF 8.854
Caixia Yue,Chunlei Zhang,Gabriel Alfranca,Yao Yang,Xinquan Jiang,Yuming Yang,Fei Pan,Jesús M. de la Fuente,Daxiang Cui
Many drug controlled release methods have been integrated in multifunctional nanoparticles, such as pH-, redox-, temperature-, enzyme-, and light-responsive release. However, few report is associated with the ROS responsive drug controlled release. Herein, a thioketal linker-based ROS responsive drug (camptothecin conjugated with thioketal linker, abbreviated as TL-CPT) was prepared and the thioketal linker could be cleaved by ROS(reactive oxygen species). To achieve cancer simultaneous optical imaging, photodynamic therapy and chemotherapy, the photosensitizer Chlorin e6(Ce6), TL-CPT and carboxyl-mPEG were loaded on the upconversion nanoparticles (UCNPs), which were named as Ce6-CPT-UCNPs. Under 980 nm laser irradiation, Ce6-CPT-UCNPs emitted a narrow emission band at 645-675 nm which was overlapped with Ce6 absorption peak. Ce6 absorbed the light to produce ROS, which was used for photodynamic therapy and to cleave the thioketal linker in Ce6-CPT-UCNPs to release camptothecin for chemotherapy. Meanwhile, Ce6 absorbed the light, was used for near-infrared fluorescence imaging. The in vivo biodistribution studies showed that the prepared nanoparticles had high orthotopic lung cancer targeting efficiency. The in vivo therapeutic results demonstrated that NCI-H460 lung cancers could be completely eliminated by combining chemo- and photodynamic therapy under 980 nm laser irradiation. The prepared multifunctional Ce6-CPT-UCNPs have great potential in applications such as cancer targeted fluorescent imaging, simultaneous ROS activated chemo- and photodynamic therapy in near future.
研究领域:
生物医学工程
·
肿瘤学
·
药剂学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2024
·Vol. 16
·期 10
·1327
·
IF 4.9
Huiping Zhang,Liang Li,Wei Li,Hongxia Yin,Huiyun Wang,Xue Ke
Background:CPT is a pentacyclic monoterpene alkaloid with a wide spectrum of antitumor activity. Its clinical application is restricted due to poor water solubility, instability, and high toxicity. We developed a new kind of multifunctional micelles to improve its solubility, reduce the side effecs, and obtain enhanced antitumor effects.Methods:We constructed HA-CPT nano-self-assembly prodrug micelles, which combined the advantages of pH-sensitivity, redox-sensitivity, and active targeting ability to CD44 receptor-overexpressing cancer cells. To synthesize dual sensitive HA-CPT conjugates, CPT was conjugated with HA by pH-sensitive histidine (His) and redox-sensitive 3,3′-dithiodipropionic acid (DTPA). In vitro, we studied the cellular uptake and antitumor effect for tumor cell lines. In vivo, we explored the bio-distribution and antitumor effects of the micelles in HCT 116 tumor bearing nude mice.Results:The dual-sensitive and active targeting HA-His-ss-CPT micelles was proved to be highly efficient in CPT delivery by the in vitro cellular uptake study. The HA-His-ss-CPT micelles escaped from endosomes of tumor cells within 4 h after cellular uptake due to the proton sponge effect of the conjugating His and then quickly released CPT in the cytosol by glutathione (GSH). In mice, HA-His-ss-CPT micelles displayed efficient tumor accumulation and conspicuous inhibition of tumor growth.Conclusions:The novel, dual-sensitive, active targeting nano-prodrug micelles exhibited high efficiency in drug delivery and cancer therapy. This “all in one” drug delivery system can be realized in an ingenious structure and avoid intricate synthesis. This construction strategy can illume the design of nanocarriers responding to endogenous stimuli in tumors.
研究领域:
药学
·
纳米技术
·
癌症治疗
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）