ACS Applied Bio Materials
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2020
·
IF 0
Ting Wu,Shaobin Yu,Dongzi Lin,Zhimin Wu,Jun Xu,Jinglin Zhang,Zefen Ding,Ying Miao,Tao Liu,Tao Chen,Xiang Cai
With double cross-linking of chitosan (CS) and sodium alginate (SALG), a colon-targeting CS/SALG hydrogel bead was prepared and used for the colon-targeted release of doxorubicin hydrochloride (DOX). The CS/SALG hydrogel bead showed the improved mechanical property to withstand the simulated colon intestinal fluid (SCF), small intestinal fluid (SIF), as well as gastric fluid (SGF). DOX was released slightly in SGF and SIF and rapidly in SCF, showing a controlled DOX release from the CS/SALG hydrogel bead under different physiological conditions. In vitro cytotoxicity and in vivo toxicity assays indicated that the DOX-loaded CS/SALG hydrogel bead displayed obvious inhibition to tumor cells. These results suggested that the CS/SALG hydrogel bead had the potential application as a colon-targeting oral formulation for DOX transport.
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TOXICOLOGY
·
2020
·
IF 4.099
Xueli Lv,Yaolu Zhu,Yingguang Deng,Shichang Zhang,Qing Zhang,Boxin Zhao,Guofeng Li
Doxorubicin (DOX) is one of the most effective and irreplaceable chemotherapeutic agents but its clinical use is limited due to its cardiotoxicity. Glycyrrhizin(GL) has been applied to liver disorders for long. However, little is known that if GL could be meaningful in attenuating cardiotoxicity. The aim of this study is to investigate the cardioprotective effects of GL in DOX-induced cardiotoxicity (DIC) and the underlying mechanism. Here, H9c2 cardiomyoblasts, Neonatal rat cardiomyocytes (NRCMs), and Rats were introduced as test models. A single dose of 20 mg/kg DOX (i.p.) was applied to induce acute cardiotoxicity in vivo, as reflected by growth inhibition, increased levels of AST and CK-MB, and reduction of SOD activity, while GL (25 or 50 mg/kg/d, 14 d, i.p.) could counteract these effects. Moreover, pre-incubation with GL (0.8 mM for 12 h) in H9c2 cells protected against DOX-induced cytotoxicity, oxidative stress and depolarization of mitochondrial membrane potential (MMP). Besides, Western blot analysis showed that DOX upregulated the expression of LC3 II and p62 whereas GL reversed that both in vitro and in vivo and improved the obstructed autophagy flux in DOX-treated H9c2 cells with an autophagy inhibitor Bafilomycin A1 (Baf A1, 50 nM, 2 h). It has been previously documented that High-mobility group box 1 (HMGB1) was involved in DIC. In our work, knockdown of HMGB1 significantly increased cell viability and LC3 II level in H9c2, suggesting HMGB1 was crucial in DOX-induced autophagy-triggering cell death. Intriguingly, GL is a direct inhibitor of HMGB1. We found that GL downregulated Akt/mTOR autophagy signaling pathway in DOX-treated H9c2 cells. More importantly, in non-silencing H9c2 cells (transfected with negative control siRNA) cells, the expression of phospho-Akt, phospho-mTOR, p62, and LC3 II was significantly decreased with GL pretreament compared to DOX alone. However, in H9c2/HMGB1 － (transfected with HMGB1 siRNA) cells exposed to DOX, the expression of p-Akt, p-mTOR, p62, LC3 II had no statistical difference with or without GL, revealing that HMGB1 mediated the cardioprotective action of GL in DIC. Taken together, our findings demonstrate that improved autophagy flux via HMGB1-dependent Akt/mTOR signaling pathway might contribute to attenuate DIC and go a novel insight into the underlying mechanisms of GL’s cardioprotective action. GL could be a potential candidate for the prevention of DIC.
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高影响因子
NEW JOURNAL OF CHEMISTRY
·
2020
·Vol. 44
·期 6
·2578-2586
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IF 3.288
Yuan Zhang,Omer Eltayeb,Yating Meng,Guomei Zhang,Yan Zhang,Shaomin Shuang,Chuan Dong
Chemodynamic therapy is a new antitumor strategy triggered by transition metal as chemodynamic agent via the in situ catalytic Fenton reaction. Herein, we engineer a smart nanocarrier activated by tumor microenvironment-specific weak acidic pH and high glutathione conditions for chemo/chemodynamic processes. This unique architecture orderly consists of mesosilica-encapsulated doxorubicin, self-polymerization of polydopamine Fe3+ clathrate, further bonding the targeting polymer MnO2 disguised albumin–folic acid. Polydopamine and albumin as intelligent nanovalves shield doxorubicin from premature leaking. Folic acid improves the targeting capability for folate receptor (FR) overexpressing cancer cells. After intake of the nanocarrier by tumor cells, the nanocarrier nanovalves are first biodegraded by native glutathione and pH, enabling on-demand anticancer drug escape, and also generate and release Fe3+ and Mn2+ (reduced by MnO2via glutathione depletion). Subsequently, the ions interact with H2O2, generating highly toxic hydroxyl radicals (˙OH) via a Fenton-like reaction to enhance the anticancer cell efficacy. This result proves that the designed nanocarrier more likely devours into FR-positive cancer cells and illustrates a high intracellular ˙OH generation, leading to the desired specific killing efficacy. We believe this innovative strategy will exhibit a new avenue for the potential of accurate chemo/chemodynamic co-therapy in cancer cells.
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CHINESE JOURNAL OF CHEMICAL ENGINEERING
·
2021
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IF 3.171
Dong Wan,Sunfan Li,Jianxin Zhang,Guilei Ma,Jie Pan
Compared with physical drug-loaded nanocarriers, polymeric prodrug micelles have many advantages such as high drug loading and enhanced stability in blood, so they have great potential in cancer therapy. However, these micelles have a big disadvantage, which cannot achieve long-term circulation in vivo and high absorption of tumor cells simultaneously, resulting in low administration efficiency and poor therapeutic effect on cancer. To solve problems of traditional polymeric prodrug micelles, novel polymeric micelles with tumor microenvironment response were designed in this work. The prodrug formed by covalently linking D-α-tocopherol polyethylene glycol succinate (TPGS 3350 ), peptide (Pep), and doxorubicin (DOX) (TPGS 3350 -Pep-DOX) was self-assembled into micelles by encapsulating DOX physically. When the micelles entered the tumor tissue, the long-chain polyethylene glycol (PEG) was sensitively cut by the matrix metalloproteinase 2/9 (MMP2/9) enzyme, exposing the targeting molecule folate, then it entered the cell through the endocytic pathway mediated by the folate receptor. The drug loading content, encapsulation efficiency, critical micelle concentration , and invitro release of the micelles invented in this study were measured to characterize their properties. The particle size and zeta potential of micelles were characterized by dynamic light scattering. Images were scanned by transmission electron microscopes. In vitro cytotoxicity, cellular uptake, and in vivo antitumor effect evaluation experiments were measured to show that smart micelles have made much progress in material chemistry and drug delivery, making it possible to apply a stimulus–response carrier drug delivery system in clinical application.
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Biomaterials Science
·
2019
·Vol. 8
·期 5
·1290-1297
·
IF 5.251
Xiao-Xiao Shi,Wei-Min Miao,Di-Wen Pang,Jia-Si Wu,Qi-Song Tong,Jia-Xian Li,Jia-Qi Luo,Wen-Yu Li,Jin-Zhi Du,Jun Wang
Primary central nervous system lymphoma (PCNSL) is a rare brain tumor. Its therapeutic efficacy is much lower than that of traditional lymphoma, largely due to the presence of the blood–brain barrier (BBB), which hinders the effective drug delivery and deposition on the disease site. Angiopep-2 (ANG) can target low-density lipoprotein receptor-related protein (LRP) on the surface of brain capillary endothelial cells (BCECs) and exhibits high BBB transport capability. In this study, we designed an ANG conjugated poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) (APP) nanoparticle to deliver doxorubicin (DOX) for the treatment of PCNSL. Our data indicated that the targeted APP nanoparticles showed significantly increased cellular uptake by BCECs compared with the control nanoparticles. In the intracranial SU-DHL-2-LUC lymphoma xenograft mice model, APP enhanced drug deposition in tumor tissues, and DOX-loaded APP (APP@DOX) exhibited a better therapeutic effect than free DOX and nontargeted PP@DOX, which significantly prolonged the survival time of mice.
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高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2019
·
IF 6.361
Chunzhi Huang,Xu Hu,Zhaosheng Hou,Jianbo Ji,Zhonghao Li,Yuxia Luan
Graphene oxide (GO), as a drug delivery carrier, has attracted considerable attention because of its interesting properties. However, GO tends to aggregate in aqueous solution. Amphiphilic molecules are usually necessary to stabilize GO. The introduction of these non-functional macromolecules on the one hand reduces drug loading, but on the other hand may cause unpredictable side effects. This study proposes a new strategy for stabilizing GO with a functional photothermal agent, IR820 (new indocyanine green) derivative. IR820 derivative results from the conjugation of active targeted lactobionic acid (LA) with IR820 for the formation of IR820-LA. IR820-LA features central aromatic groups that can associate with the GO basal plane through π-π interactions. The flanking moiety of hydrophilic LA and sulfonic groups thus provides steric stabilization of GO in aqueous solution. Moreover, IR820-LA endows GO/doxorubicin (GO/DOX) nanovehicles with fluorescence imaging ability and actively targeted chemo-photothermal therapy. Experimental results both in vitro and in vivo have indicated its good chemo-photothermal therapeutic effect according to its active tumor targeting ability and pH-sensitive drug release characteristics. Therefore, our GO/DOX/IR820-LA nanohybrids can be excellent nanoplatforms for active tumor-targeted chemo-photothermal therapy with imaging guidance.
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DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
·
2019
·
IF 2.367
Xin-Cheng Zhong,Wen-Hong Xu,Zi-Ting Wang,Wang-Wei Guo,Jie-Jian Chen,Ning-Ning Guo,Tian-Tian Wang,Meng-Ting Lin,Zhen-Tao Zhang,Yi-Ying Lu,Qi-Yao Yang,Min Han,Dong-Hang Xu,Jian-Qing Gao
Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor.Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR.Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo.Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs.Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.
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ACS Applied Bio Materials
·
2019
·
IF 0
Xiaomin Zhi,Yuqian Jiang,Linlin Xie,Yanbo Li,Chen-Jie Fang
Multidrug resistance (MDR) and adverse effects of chemotherapeutic agents are severe issues in clinical cancer treatment. Due to the dysregulation of enzymes in the cancer cells, enzyme-responsive drug delivery systems (DDSs) have been considered as a viable technology for cancer chemotherapy. In the present work, doxorubicin (DOX) is visible after leaving from AuNR–LAX. After treatment with AuNR–LAX, the drug resistance index of DOX-resistant MCF-7/ADR cells was reduced from extremely high 955.0 to 1.7, implying high potential of AuNR–LAX in the MDR phenotype cancer treatment. In addition, the cellular viability of both MCF-7 and MCF-7/ADR cells decreased from 50% to 80% after treatment with AuNR–LAX along (equivalent DOX concentration = 2.3 μg/mL, Au concentration = 30 μg/mL) to below 10% after AuNR–LAX treatment plus radiation of 808 nm, due to the NIR photothermal effect of AuNRs. Human bronchial epithelial cell line 16HBE was chosen to evaluate the adverse effect of AuNR–LAX on the normal cells. At the low concentration, the cytotoxicity of LAX and AuNR–LAX is comparable for breast cancer cell MCF-7 and normal cell 16HBE. It is noted that, at high concentration (with equivalent DOX concentration = 13.1 μg/mL, Au concentration = 167.7 μg/mL), the cellular viability of 16HBE cells is over 50%, whereas that of MCF-7 cancer cells is close to 0, implying the potential of AuNR–LAX in reducing the adverse effects of DOX against normal cells/tissues. Overall, AuNR–LAX showed high potential in overcoming MDR and alleviating adverse effect on normal cells.
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ADVANCED ENGINEERING MATERIALS
·
2018
·Vol. 20
·期 7
·1701151
·
IF 2.576
Yanan Xue,Lijun Tao,Yang Zhou,Jie Liu,Bo Yu,Sihui Long,Shiwen Huang,Faquan Yu
To elevate the efficacy and to attenuate the adverse effects remain a tough challenge in exploring anticancer drug delivery systems. A nanocarrier characteristic of acid induced charge reversal and acid/redox/magnetic combinational stimuli-responsiveness is designed. This system exhibits weaker repulsion between the carrier and the cancer cell membrane, resulting in enhanced uptake. After nanocarriers enter the cell, the system exhibits negative-to-positive charge reversal in response to the low intracellular pH value. Moreover, after the uptake, the carrier will be further dissociated by glutathione in cytoplasm via the reduction of the disulfide bond, leading to the rapid release of the encapsulated DOX into the nuclei. In vitro release study expresses the sequent stimulus release profile. The antitumor activity tested in CT26 tumor-bearing mice reveals efficient therapeutic efficacy and as low adverse effect as PBS. H&E staining and immunohistochemical analysis of tumor tissues as well as pathological test of tissue sections of vital organs confirm the high antitumor activity and low tissue toxicity. Thus, the belief that this system has a good prospect in the field of cancer clinical chemotherapy.
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Nanoscale
·
2018
·Vol. 10
·期 18
·8536-8546
·
IF 7.233
Daquan Wang,Lingjie Meng,Zhaofu Fei,Chen Hou,Jiangang Long,Leli Zeng,Paul J. Dyson,Peng Huang
Multi-layered single-walled carbon nanotubes, termed SWNT@BSA@Au-S-PEG-FA@DOX, which integrate photothermal therapy with small molecule drug delivery, were prepared using a facile layer-by-layer assembly process. Oxidized and cut single-walled carbon nanotubes (SWNTs) were coated with bovine serum albumin (BSA) to provide abundant active sites for the nucleation of Au seeds, which are subsequently converted into gold nanoparticles (Au NPs) by in situ reduction. The resulting SWNT@BSA@Au material exhibits ideal photothermal properties. Further modification of the nanomaterial with folic acid terminated-polyglycol (FA-PEG-SH) and subsequent loading with doxorubicin (DOX) afford the SWNT@BSA@Au-S-PEG-FA@DOX. The FA terminated PEG endows the material with high water-dispersibility, biocompatibility and cancer cell selectivity. A high drug loading ratio for DOX of up to 590% was achieved, with the drug release being pH and temperature dependent, adding to the selectivity of the system. High efficacy of the SWNT@BSA@Au-S-PEG-FA@DOX material, when combined with photothermal therapy (irradiation of the tumor with an 808 nm laser, 1 W cm−2 for 5 min, 24 h after systemic injection of the nanomedicine), was demonstrated in vivo, resulting in complete tumor eradication. Remarkably, the side effects are negligible with only minor damage to normal tissues including the liver and kidneys being observed.
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高影响因子
Nanoscale
·
2018
·Vol. 10
·期 24
·11418-11429
·
IF 7.233
Yuxia Pei,Menghuan Li,Yanhua Hou,Yan Hu,Guangyu Chu,Liangliang Dai,Ke Li,Yuxin Xing,Bailong Tao,Yonglin Yu,Chencheng Xue,Ye He,Zhong Luo,Kaiyong Cai
The precise tumor cell-specific delivery of therapeutic proteins and the elimination of side effects associated with routine chemotherapeutic agents are two current critical considerations for tumor therapy. In this study, we report a reactive oxygen species (ROS)-activated yolk–shell nanoplatform for the tumor-specific co-delivery of cytochrome c (Cyt c) prodrug and doxorubicin, in which the bioactivity of Cyt c could be restored by the intracellular ROS-trigger and readily initiate the sequential doxorubicin release. The DOX-loaded lactobionic acid-modified yolk–shell mesoporous silica nanoparticles were first encapsulated with 4-nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl carbonate (NBC)-modified Cyt c via boronic ester linkages, and functionalized again with lactobionic acid to further shield Cyt c and confer the selective tumor targeting against liver cancer cells. The key feature in this design is that by taking advantage of the boronic ester linkage, the cytotoxicity of Cyt c capped on the nanoparticle could be temporarily deactivated during blood transportation and rapidly restored upon exposure to the ROS-rich microenvironment within liver cancer cells, thereby simultaneously achieving the protein therapy and stimuli-responsive doxorubicin release. This study presents a novel strategy for the development of tumor-sensitive co-delivery nanoplatforms.
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高影响因子
RSC Advances
·
2015
·Vol. 5
·期 112
·92292-92302
·
IF 3.84
Meng Cai,Mengyuan Ye,Xingxing Shang,Honghao Sun,Mingxing Liu,Hongmei Sun,Zhuo Ma,Hongda Zhu
Polymeric micelles as nanocarrier-based drug delivery systems provide an innovative platform for selectively delivering active molecules and offer better antitumour activity. However, circulation stability in vivo, controllable drug intracellular release and high targeting efficiency are several practical challenges for micelles. Therefore, we developed cRGD-modified and shell crosslinked micelles (RSCMs) based on amphiphilic poly(styrene-co-maleic anhydride) (SMA). RSCMs exhibited a spherical shape and were homogeneous with an average diameter of 106.1 nm and a low polydispersity of 0.087. In comparison, after crosslinking the micelles possessed better stability against dilution and stronger redox-response towards dithiothreitol (DTT). The SMA micelles displayed high drug loading capacity for hydrophobic DOX with a drug loading of approximately 14.1–19.2% (w/w) and an encapsulation efficiency of 72.1–82.7% (w/w). The in vitro release studies of shell crosslinked micelles showed that DOX release was minimal (<25%, 24 h) under physiological conditions. However, in the presence of 10 mM DTT, accelerated release of DOX was achieved (60%, 24 h). MTT assays in B16F10 cells indicated that RSCMs displayed low cytotoxicity up to a concentration of 500 μg ml−1. Moreover, the IC50 value showed that cRGD-DOX-ss-M could be more effective than other groups. In vitro, cellular uptake was further studied with confocal laser scanning microscopy and flow cytometry, both the qualitative and quantitative results demonstrated that cRGD-DOX-ss-M possessed much better specificity to cancer cells and superior stimulated release property in cytoplasm. Notably, cRGD-DOX-ss-M could more efficiently be delivered to and release into the nuclei of αvβ3 integrin over expressing tumor cell line (B16F10) than counterparts of integrin-deficient tumor cells (Hela). Thus, these cRGD-modified redox-sensitive micelles have appeared as a technology platform with great potential for targeted anticancer drug delivery and release for integrin over expressing tumor cells.
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