CARBOHYDRATE POLYMERS
·
2024
·
IF 10.7
Yufan Guo,Xiuru Yang,Yihong Zhang,Fazhen Luo,Juan Yang,Xupeng Zhang,Jinxia Mi,Yan Xie
Cancer multidrug resistance (MDR) dramatically hindered the efficiency of standard chemotherapy. Mitochondria are highly involved in the occurrence and development of MDR; thus, inducing its malfunction will be an appealing strategy to treat MDR tumors. In this paper, a natural polysaccharides-based nanoplatform (TDTD@UA/HA micelles) with cell and mitochondria dual-targeting ability was facilely fabricated to co-deliver ursolic acid (UA) and doxorubicin (DOX) for combinatorial MDR therapy. TDTD@UA/HA micelles featured a spherical morphology, narrow size distribution (∼140 nm), as well as favorable drug co-loading capacity (DOX: 8.41 %, UA : 9.06 %). After hyaluronic acid (HA)-mediated endocytosis , the lysosomal hyaluronidase promoted the degradation of HA layer and then the positive triphenylphosphine groups were exposed, which significantly enhanced the mitochondria-accumulation of nano micelles . Subsequently, DOX and UA were specifically released into mitochondria under the trigger of endogenous reactive oxygen species (ROS), followed by severe mitochondrial destruction through generating ROS, exhausting mitochondrial membrane potential, and blocking energy supply, etc. ; ultimately contributing to the susceptibility restoration of MCF-7/ADR cells to chemotherapeutic agents. Importantly, TDTD@UA/HA micelles performed potent anticancer efficacy without distinct toxicity on the MDR tumor-bearing nude mice model. Overall, the versatile nanomedicine represented a new therapeutic paradigm and held great promise in overcoming MDR-related cancer.
研究领域:
药学
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纳米技术
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肿瘤学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-22
·
IF 9.429
Li Hanrui,Cai Xiaoxia,Yi Tong,Zeng Yun,Ma Jingwen,Li Lei,Pang Liaojun,Li Na,Hu Hao,Zhan Yonghua
Background Postoperative chemotherapy for gastric cancer often causes multidrug resistance (MDR), which has serious consequences for therapeutic effects. Individualized treatment based on accurate monitoring of MDR will greatly improve patient survival.Results In this article, a self-enhanced Mn3O4 nanoplatform (MPG NPs) was established, which can react with glutathione to produce Mn2+ to enhance T1-weighted magnetic resonance imaging (MRI) and mediate in vivo real-time MDR monitoring. In vitro MRI results showed that MRI signals could be enhanced in the presence of hydrogen peroxide and glutathione and at acidic pH. In vivo MRI results indicated that MPG NPs could specifically target MDR cells, thereby realizing real-time monitoring of MDR in gastric cancer. Furthermore, MPG NPs have good chemodynamic activity, which can convert the endogenous hydrogen peroxide of tumor cells into highly toxic hydroxyl radical through Fenton-like reaction at acidic pH to play the role of chemodynamic therapy. In addition, Mn3O4 can significantly enhance the chemodynamic therapy effect because of its good photothermal conversion effect. Furthermore, in situ photothermal/chemodynamic synergistic therapy obtained remarkable results, the tumors of the mice in the synergistic therapy group gradually became smaller or even disappeared.Conclusion sMPG NPs have good biocompatibility, providing a good nanoplatform for real-time monitoring and precise diagnosis and treatment of MDR in gastric cancer.Graphical Abstract
研究领域:
纳米技术
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癌症生物学
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诊疗一体化
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2017
·Vol. 5
·期 27
·5464-5472
·
IF 4.543
Zhipeng Zhang,Yun Wang,Shaohui Xu,Yanna Yu,Abid Hussain,Yuanyuan Shen,Shengrong Guo
The design of an ideal drug delivery system with targeted recognition and minimized premature release, especially controlled and specific release that is triggered by endogenous and exogenous dual-stimuli, is a great challenge. A biotin receptor-targeted, near-infrared (NIR) irradiation and redox responsive nano-system has now been developed. The nano-system was constructed by filling the interior of Au nanocages with doxorubicin as a chemotherapy agent trapped in tetradecanol, followed by surface conjugation of biotinylated poly(ethylene glycol)–poly(curcumin-dithiodipropionic acid) (Biotin–PEG–PCDA) as a macromolecular chemosensitizer. Once the nano-system had been delivered into MCF-7/ADR cells by biotin receptor mediated recognition and endocytosis, drug release was triggered by degradation of PCDA via a glutathione induced redox reaction in combination with a solid–liquid change of tetradecanol by photothermal effects under NIR irradiation, which could minimize premature drug release and then maximize the therapeutic efficacy.
研究领域:
癌症治疗
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药物递送
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纳米技术
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材料科学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2017
·
IF 7.504
Ye Zhang,Congjun Zhang,Jing Chen,Li Liu,Mengyue Hu,Jun Li,Hong Bi
Multidrug resistance (MDR) has been recognized as a major obstacle to successful chemotherapy for cancer in the clinic. In recent years, more and more nanoscaled drug delivery systems (DDS) are constructed to modulate drug efflux protein (P-gp) and deliver chemotherapeutic drugs for overcoming MDR. Among them, d-α-tocopheryl polyethylene glycol succinate (TPGS) has been widely used as a drug carrier due to its capability of inhibiting overexpression of P-gp and good amphiphilicity favorable for improving permeation and long-circulation property of DDS. In the present work, a novel kind of mitochondria-targeting nanomicelles-based DDS is developed to integrate chemotherapeutics delivery with fluorescence imaging functionalities on a comprehensive nanoplatform. The mitochondria-targeting nanomicelles are prepared by self-assembly of triphenylphosphine (TPP)-modified TPGS and fluorescent carbon quantum dots (CQDs) in an n-hexane/H2O mixed solution, named CQDs-TPGS-TPP. Notably, although the drug loading content of doxorubicin (DOX) in the as-prepared nanomicelles is as low as 3.4%, the calculated resistant index (RI) is greatly decreased from 66.23 of free DOX to 7.16 of DOX-loaded nanomicelles while treating both parental MCF-7 cells and drug-resistant MCF-7/ADR cells. Compared with free DOX, the penetration efficiency of DOX-loaded nanomicelles in three-dimensional multicellular spheroids (MCs) of MCF-7/ADR is obviously increased. Moreover, the released DOX from the nanomicelles can cause much more damage to cells of drug-resistant MCs. These results demonstrate that our constructed mitochondria-targeting nanomicelles-based DDS have potential application in overcoming MDR of cancer cells as well as their MCs that mimic in vivo tumor tissues. The MDR-reversal mechanism of the DOX-loaded CQDs-TPGS-TPP nanomicelles is also discussed.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Weiguo Song,Hekai Yang,Ying Wang,Shuzhen Chen,Wenda Zhong,Qian Wang,Wenshuo Ding,Guangzhao Xu,Chen Meng,Ying Liang,Zhe-Sheng Chen,Shuhua Cao,Liuya Wei,Fahui Li
Multi-drug resistance (MDR) is a major cause of cancer therapy failure. Photodynamic therapy (PDT) is a promising modality that can circumvent MDR and synergize with chemotherapies, based on the generation of reactive oxygen species (ROS) by photosensitizers. However, overproduction of glutathione (GSH) by cancer cells scavenges ROS and restricts the efficacy of PDT. Additionally, side effects on normal tissues are unavoidable after PDT treatment. Here, to develop organic systems that deliver effective anticancer PDT and chemotherapy simultaneously with very little side effects, three GSH-sensitive photosensitizer-drug conjugates (CyR-SS-L) are designed and synthesized. CyR-SS-L localized in the mitochondria then is cleaved into CyR-SG and SG-L parts by reacting with and consuming high levels of intracellular GSH. Notably, CyR-SG generates high levels of ROS in tumor cells instead of normal cells and be exploited for PDT and the SG-L part is used for chemotherapy. CyR-SS-L inhibits better MDR cancer tumor inhibitory activity than indocyanine green, a photosensitizer (PS) used for PDT in clinical applications. The results appear to be the first to show that CyR-SS-L may be used as an alternative PDT agent to be more effective against MDR cancers without obvious damaging normal cells by the combination of PDT, GSH depletion, and chemotherapy.
研究领域:
肿瘤学
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药学
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生物医学工程
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治疗学
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产品关联
DOI
PubMed
高影响因子
NATURAL PRODUCT RESEARCH
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2022
·
IF 2.488
Xin Liu,Zhihong Cheng
Euphorbia factor L1 (EFL1, 1) is a natural tri-ester of 6,17-epoxylathyrol with cancer multidrug resistance (MDR) reversal activity. Several EFL1 derivatives (2–9) were prepared by chemical and microbial transformations and their ability to inhibit P-glycoprotein (P-gp) activity was estimated. Six de-acylated derivatives (2–7) were obtained through base-hydrolysis of 1, and the base-catalysed hydrolysis via KOH and NaOH yielded different hydrolysed products of 1. Two biotransformed products (8–9) were directly obtained via microbial transformation of 1, and 8 was also formed by microbial conversion of the hydrolysed product 3. The P-gp modulation of 1–9 was assessed by a zebrafish model. The substrate 1 and its biotransformed product 9 as the tri-esters of lathyranes possessed the highest P-gp inhibitory activity with IC50 values of 34.97 and 15.50 µM, respectively, through down-regulating P-gp expression at the protein level rather than at MDR1 mRNA level.
研究领域:
药理学
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生物化学
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毒理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2025
·
IF 5.4
Yang Yu,Lixin Fan,Chunling Gao,Yang Ping,Liting Mu,Weitong Sun
Despite the advances made in cancer treatment, malignant tumors remain a significant threat to human health. Tumor multidrug resistance (MDR) constitutes a significant impediment to the effectiveness of chemotherapy. Thus, the reversal of MDR has become a critical research domain for medical professionals. Now, paclitaxel (PTX) is encapsulated in a reduction-sensitive polymer pre-drug micelle called mPEG-SS-IND(PSI), which reduces the MDR of PTX and enhances its anti-tumor efficacy. The PSI/PTX micelles show excellent reduction sensitivity and stability. In vitro , the harmful effect of PTX on MCF-7/PTX cells is enhanced by the PSI/PTX micelles, while its damaging effect on normal cells is decreased. Furthermore, compared to PTX solution, PTX encapsulated in PSI/PTX micelles exhibits reduced volume distribution and clearance, longer blood circulation time, and greater drug concentration area under the curve. Furthermore, in vivo studies using BALB/c subcutaneous tumor-bearing mice demonstrate decreased systemic toxicity and enhanced therapeutic effectiveness of PTX. This study proves that the potential utility of reduction-sensitive polymer pre-drug micelles as a delivery method for overcoming MDR for PTX and targeting tumors.
研究领域:
药理学
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肿瘤学
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药物递送系统
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癌症治疗
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Liucan Wang,Haidi Guan,Zhenqiang Wang,Yuxin Xing,Jixi Zhang,Kaiyong Cai
Combination chemotherapy with a modulator and a chemotherapeutic drug has become one of the most promising strategies for the treatment of multidrug resistance (MDR) in cancer therapy. However, the development of nanocarriers with a high payload and sequential release of therapeutic agents poses a significant challenge. In this work, we report a type of hybrid nanocarriers prepared by polydopamine (PDA) mediated integration of the mesoporous MSN core and the microporous zeolite imidazolate frameworks-8 (ZIF-8) shell. The nanocarriers exploit storage capacities for drugs based on the high porosity and molecular sieving capabilities of ZIF-8 for sequential drug release. Particularly, large amounts of an anticancer drug (DOX, 607 μg mg–1) and a MDR inhibitor curcumin (CUR, 778 μg mg–1) were sequentially loaded in the mesoporous core via π–π stacking interactions mediated by PDA and in the microporous shell via the encapsulation during ZIF-8 growth. The sustained release of DOX was observed to follow earlier and faster release of CUR by acid-sensitive dissolution of the ZIF-8 shell. Furthermore, the nanoparticles showed good biocompatibility and effective cellular uptake in in vitro evaluations using drug-resistant MCF-7/ADR cancer cells. More importantly, the preferentially released CUR inhibited the drug efflux function of the membrane P-glycoprotein (P-gp), which subsequently facilitated the nuclear transportation of DOX released from the PDA-MSN core, and, in turn, the synergistic effects on killing MDR cancer cells. The hybrid mesoporous–microporous nanocarrier holds great promise for combination chemotherapy applications on the basis of sequential drug release.
研究领域:
癌症治疗
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纳米技术
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药学科学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Hongyan Zhang,Jiandong Yu,Lisha Ma,Yue Zhao,Shujun Xu,Jingbin Shi,Ke Qian,Mancang Gu,Hongsheng Tan,Li Xu,Yun Liu,Chaofeng Mu,Yang Xiong
Multi-drug resistance (MDR) in breast cancer poses a great threat to chemotherapy. The expression and function of the ATP binding cassette (ABC) transporter are the major cause of MDR. Herein, a linear polyethylene glycol (PEI) conjugated with dicyandiamide, which called polymeric metformin (PolyMet), was successfully synthesized as a simple and biocompatible polymer of metformin. PolyMet showed the potential to reverse MDR by inhibiting the efflux of the substrate of ATP-binding cassette (ABC) transporter from DOX resistant MCF-7 cells (MCF-7/DOX). To test its MDR reversing effect, PolyMet was combined with DOX to treat mice carrying MCF-7/DOX xenografts. In order to decrease the toxicities of DOX and delivery PolyMet and DOX to tumor at the same time, PolyMet was complexed with poly-γ-glutamic acid-doxorubicin (PGA-DOX) electrostatically at the optimal ratio of 2:3, which were further coated with lipid membrane to form lipid/PolyMet-(PGA-DOX) nanoparticles (LPPD). The particle size of LPPD was 165.8 nm, and the zeta potential was +36.5 mV. LPPD exhibited favorable cytotoxicity and cellular uptake in MCF-7/DOX. Meanwhile, the bioluminescence imaging and immunohistochemical analysis indicated that LPPD effectively conquered DOX-associated MDR by blocking ABC transporters (ABCB1 and ABCC1) via PolyMet. Remarkably, LPPD significantly inhibited the tumor growth and lowered the systemic toxicity in a murine MCF-7/DOX tumor model. This is the first time to reveal that PolyMet can enhance the anti-tumor efficacy of DOX by dampening ABC transporters and activating the AMPK/mTOR pathway, which is a promising strategy for drug-resistant breast cancer therapy.
研究领域:
肿瘤学
·
药理学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2022
·
IF 5.895
Yajing Fang,Weiwei Cao,Mengmeng Xia,Siyi Pan,Xiaoyun Xu
This study aims to evaluate the interaction of flavonoid–flavonoid by inhibiting the function of P-glycoprotein (P-gp). The cellular uptake of seven substrates and eleven co-incubated inhibitors was measured in KB/MDR cells. The effect of galangin or morin on the absorption of silibinin or wogonin was carried out in the rat everted gut sacs. Docking was performed to evaluate the interactions between inhibitors and P-gp. Most substrates were greatly enhanced by at least five co-incubated inhibitors. Conversely, the increased uptake of substrates coincided with a decrease or without affecting the uptake of inhibitors, implying a competitive/non-competitive inhibition on P-gp. The enhancement effect by galangin or morin on the transport of silibinin or wogonin was verified in everted gut sacs. Docking explained the inhibition of flavonoids on P-gp by competitively binding to the ATP site. These results provide a strategy for increasing the absorption of flavonoids by co-administration.
研究领域:
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
·
2024
·
IF 6.1
Qi Shang,Ziyan Chen,Jing Li,Mingmei Guo,Jiapei Yang,Zhu Jin,Yuanyuan Shen,Shengrong Guo,Feihu Wang
Chemotherapy treatment outcomes are severely restricted by multidrug resistance (MDR), in which tumors develop a multiple cross-resistance toward drug involving the pump and nonpump resistance mechanisms, resulting in drug efflux and defending against drug toxicity. Herein, we constructed a pH and near infrared (NIR) light responsive nanomedicine DOX@FG based on gold nanorods (GNRs) that demonstrated the potential to improve chemotherapy outcomes by overcoming MDR. DOX@FG was constructed by conjugating folic acid (FA) and doxorubicin (DOX) derivatives onto GNRs, where the DOX derivatives possessed an acid-labile hydrazone bond. Stimulated by the acidic media in endocytic organelles, DOX@FG exhibited a responsive dissociation for the controlled release of chemotherapeutic DOX. Surprisingly, we found the mild photothermal effect elicited by GNRs under NIR irradiation simultaneously inhibited the pump and nonpump resistance mechanisms, enhancing the intracellular DOX accumulation and sensitizing the cancer cells to DOX, collectively amplify the chemotherapy efficacy and delay the MCF-7/ADR breast tumor growth. This intelligent DOX@FG nanomedicine with the potential for two-pronged reversal of MDR may provide a prospective way to encourage chemotherapy efficacy.
研究领域:
纳米医学
·
癌症治疗
·
光热疗法
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药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2024
·
IF 5.3
Liqiao Zhang,Xinyu Cao,Jiayi Chen,Yanyan Dong,Wenwen Chen,Yu Gao,Jingjing Guo,Haiqin Huang
Multidrug resistance (MDR) poses a significant impediment to the efficacy of chemotherapy in clinical settings. Despite Paclitaxel (PTX) being designated as the primary pharmaceutical agent for treating recurrent and metastatic breast cancer, the emergence of PTX resistance frequently results in therapeutic shortcomings, representing a substantial obstacle in clinical breast cancer management. In response, we developed a delivery system exhibiting dual specificity for both tumors and mitochondria. This system facilitated the sequential administration of small interfering B-cell lymphoma-2 (siBcl-2) and PTX to the tumor cytoplasm and mitochondria, respectively, with the aim of surmounting PTX resistance in tumor cells through the activation of the mitochondrial apoptosis pathway. Notably, we employed genetic engineering techniques to fabricate a recombinant ferritin containing the H-subunit (HFn), known for its tumor-targeting capabilities, for loading siBcl-2. This HFn-siBcl-2 complex was then combined with positively charged Triphenylphosphine-Liposome@PTX (TL@PTX) nanoparticles (NPs) to formulate HFn/siBcl-2@TL/PTX. Guided by HFn, these nanoparticles efficiently entered cells and released siBcl-2 through the action of triphenylphosphine (TPP)-mediated “proton sponge,” thereby precisely modulating the expression of Bcl-2 protein. Simultaneously, PTX was directed to the mitochondria through the accurate targeting of TL@PTX, synergistically initiating the mitochondrial apoptosis pathway and effectively suppressing PTX resistance both in vitro and in vivo . In conclusion, the development of this dual-targeting delivery system presents a promising therapeutic strategy for overcoming PTX resistance in the clinical treatment of breast cancer.
研究领域:
肿瘤学
·
药学
·
分子生物学
·
纳米技术
✓ 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）