Acta Biomaterialia
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2022
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IF 10.633
Meiyang Yang,Mariana Conceição,Weijun Chen,Fuwei Yang,Bingke Zhao,Matthew J.A. Wood,Lipeng Qiu,Jinghua Chen
Methods capable of distributing antitumour therapeutics uniformly throughout an entire tumour and that can suppress metastasis at the same time, would be of great significance in improving cancer treatment. Bacteria-mediated synergistic therapies have been explored for better specificity, temporal and spatial controllability, as well for providing regulation of the immune microenvironment, in order to provide improved cancer treatment. To achieve this goal, here we developed an engineered bacteria delivery system ( [email protected] ) using synthetic biology and interfacial chemistry technologies. The engineered bacteria were concurrently modified to express heparin sulfatase 1 (HSulf-1) inside (HSEc), to attach doxorubicin-loaded glycogen nanoparticles (GDOX NPs) on their surface. Here we demonstrate that HSEc can actively target and colonise tumour sites resulting in HSulf-1 overexpression, thereby suppressing angiogenesis and metastasis. Simultaneously, the GDOX NPs were able to penetrate into tumour cells, leading to intracellular DNA damage. Our results confirmed that a combination of biotherapy and chemotherapy using [email protected] resulted in significant melanoma suppression in murine models, with reduced side effects. This study provides a powerful platform for the simultaneous delivery of biomacromolecules and chemotherapeutic drugs to tumours, representing an innovative strategy potentially more effective in treating solid tumours. Statement of significance An original engineered bacteria-based system ( [email protected] ) was developed using synthetic biology and interfacial chemistry technologies to concurrently produce naturally occurring heparin sulfatase 1 (HSulf-1) inside and anchor doxorubicin-loaded glycogen nanoparticles on the surface. [email protected] allowed for combined local delivery of chemotherapeutic agents along with the enzymes and immunostimulatory bacterial adjuvants, which resulted in a synergistic action in the inhibition of tumour growth and metastasis. The study provides a potential therapeutic approach that allows therapeutic agents to be distributed in a spatiotemporally controllable manner in tumours for combinatorial enhanced therapy.
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高影响因子
Small
·
2022
·Vol. 19
·期 7
·2205414
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IF 15.153
Xiao Chu,Liufang Zhang,Yiling Li,Yue He,Yu Zhang,Chang Du
Osteosarcoma (OS) is the most serious bone malignancy, and the survival rate has not significantly improved in the past 40 years. Thus, it is urgent to develop a new strategy for OS treatment. Chemodynamic therapy (CDT) as a novel therapeutic method can destroy cancer cells by converting endogenous hydrogen peroxide (H 2 O 2 ) into highly toxic hydroxyl radicals (·OH). However, the therapeutic efficacy of CDT is severely limited by the low catalytic efficiency and overexpressed glutathione (GSH). Herein, an excellent nanocatalytic platform is constructed via a simple solvothermal method using F127 as a soft template to form the hollow copper ferrite (HCF) nanoparticle, followed by the coating of polydopamine on the surface and the loading of doxorubicin (DOX). The Fe 3+ and Cu 2+ released from HCF@polydopamine (HCFP) can deplete GSH through the redox reactions, and then trigger the H 2 O 2 to generate ·OH by Fenton/Fenton-like reaction, resulting in enhanced CDT efficacy. Impressively, the photothermal effect of HCFP can further enhance the efficiency of CDT and accelerate the release of DOX. Both in vitro and in vivo experiments reveal that the synergistic chemodynamic/photothermal/chemo-therapy exhibits a significantly enhanced anti-OS effect. This work provides a promising strategy for OS treatment.
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Materials Today Communications
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2022
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IF 3.662
Lianlian Yang,Junhong Ling,Nan Wang,Yongjun Jiang,Yuqing Lu,Li-Ye Yang,Xiao–kun Ouyang
Here, glycidyl methacrylate (GMA) was used for modification of carboxymethyl chitosan (CMCS). The double bond on the side group of CMCS was polymerized and cross-linked with N-N′-bis(acryloyl) cysteamine (BAC), containing a disulfide bond, and modified with folic acid (FA) to obtain nanogels for the targeted delivery of doxorubicin (DOX). Effectiveness of DOX delivery and release were subsequently investigated. The drug encapsulation efficiency (EE) and loading capacity (LC) of DOX were 94.77 ± 0.83% and 15.6 ± 0.12%, respectively. The particle size of the GCMCS-FA-DOX nanoparticles loaded with DOX was 220.4 ± 38.4 nm. The experimental results showed that GCMCS-FA-DOX had a high glutathione and pH response performance. GCMCS-FA-DOX showed an improved inhibitory effect on tumor cell proliferation compared to free DOX. GCMCS-FA-DOX significantly improved the efficiency of drug uptake by cells, and the cytotoxicity of GCMCS-FA-DOX in HCT-116 tumor cells was higher than that in HepG-2 tumor cells.
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Pharmaceuticals
·
2022
·Vol. 15
·期 9
·1104
·
IF 5.215
Yin Huang,Fang Yang,Linling Guo,Yan Xu,Xiaxia Yu,Zunjian Zhang,Yuxin Zhang
Doxorubicin (DOX) is an essential component in chemotherapy, and Astragali Radix (AR) is a widely used tonic herbal medicine. The combination of DOX and AR offers widespread, well-documented advantages in treating cancer, e.g., reducing the risk of adverse effects. This study mainly aims to uncover the impact of AR on DOX disposition in vivo. Rats received a single intravenous dose of 5 mg/kg DOX following a single-dose co-treatment or multiple-dose pre-treatment of AR (10 g/kg × 1 or × 10). The concentrations of DOX in rat plasma and six tissues, including heart, liver, lung, kidney, spleen, and skeletal muscle, were determined by a fully validated LC-MS/MS method. A network-based approach was further employed to quantify the relationships between enzymes that metabolize and transport DOX and the targets of nine representative AR components in the human protein–protein interactome. We found that short-term (≤10 d) AR administration was ineffective in changing the plasma pharmacokinetics of DOX in terms of the area under the concentration–time curve (AUC, 1303.35 ± 271.74 μg/L*h versus 1208.74 ± 145.35 μg/L*h,p> 0.46), peak concentrations (Cmax, 1351.21 ± 364.86 μg/L versus 1411.01 ± 368.38 μg/L,p> 0.78), and half-life (t1/2, 31.79 ± 5.12 h versus 32.05 ± 6.95 h,p> 0.94), etc. Compared to the isotype control group, DOX concentrations in six tissues slightly decreased under AR pre-administration but only showed statistical significance (p< 0.05) in the liver. Using network analysis, we showed that five of the nine representative AR components were not localized to the vicinity of the DOX disposition-associated module. These findings suggest that AR may mitigate DOX-induced toxicity by affecting drug targets rather than drug disposition.Keywords:Adriamycin;drug disposition;combination therapy;LC-MS/MS;network
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AAPS PHARMSCITECH
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2022
·Vol. 23
·期 6
·1-12
·
IF 4.026
Hu Mengru,Zhang Wenjing,Chen Weidong,Chen Yunna,Huang Qianqian,Bao Qianqian,Lin Tongyuan,Wang Lei,Zhang Shantang
Abstract. The combination of functionalized nanoparticles and chemotherapy drugs can effectively target tumor tissue, which can improve efficacy and reduce toxicity. In this article, pPeptide-PDA@HMONs-DOX nanoparticles (phosphopeptide-modified polydopamine encapsulates doxorubicin-loaded hollow mesoporous organosilica nanoparticles) were constructed that based on multiple modification hollow mesoporous organosilica nanoparticles (HMONs). The pPeptide-PDA@HMONs-DOX nanoparticles retain the biological functions of phosphorylated peptide while exhibiting biological safety that are suitable for effective drug delivery and stimulus responsive release. The degradation behaviors showed that pPeptide-PDA@HMONs-DOX has dual-responsive to drug release characteristics of pH and glutathione (GSH). In addition, the prepared pPeptide-PDA@HMONs-DOX nanoparticles have good biological safety, and their anti-tumor efficacy was significantly better than doxorubicin (DOX). This provided new research ideas for the construction of targeted nanodrug delivery systems based on mesoporous silicon. Graphical Abstract
Scheme 1 The preparation of pPeptide-PDA@HMONs-DOX and the process of drug release under multiple responses. (A) Schematic diagram of the synthesis process of pPeptide-PDA@HMONs-DOX. (B) The process in which nanoparticles enter the cell and decompose and release DOX in response to pH and GSH
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ACS Applied Nano Materials
·
2021
·
IF 5.097
Li Zhang,Huaizhong Xing,Wei Liu,Zihan Wang,Yumin Hao,Huiping Wang,Wenjuan Dong,Yang Liu,Shaomin Shuang,Chuan Dong,Xiaojuan Gong
A ratiometric optical dual-mode probe was first designed for the detection of doxorubicin (DOX) based on 11-mercaptoundecanoic acid-functionalized carbon dots (MUA-CDs). The carbon dots (CDs) were synthesized via hydrothermal carbonization of m-phenylenediamine and p-aminobenzoic acid, and then it was reacted with 11-mercaptoundecanoic acid by the amide reaction to obtain the MUA-CDs. The as-synthesized MUA-CDs have a high fluorescence quantum yield (59.4%) with bright green emission. Based on a specific electrostatic interaction and the fluorescence resonance energy transfer (FRET) between MUA-CDs and DOX, a ratiometric optical dual-mode probe was constructed for the detection of DOX with good selectivity, high sensitivity, and excellent anti-interference performance. When DOX was mixed the MUA-CDs, the fluorescence of the MUA-CDs at 513 nm decreased, while the fluorescence at 590 nm increased. With this information, a ratiometric fluorescent method was established to determine DOX with a linear range and limit of detection (LOD) of 0.25–19.96 and 0.66 μM and 50.33–80.88 and 0.23 μM, respectively. Meanwhile, the color of the MUA-CDs varied from colorless to dark yellow in the presence of DOX, and therefore, a ratiometric colorimetric method was applied to determine DOX in a range of 2.50–29.80 μM with a LOD of 0.75 μM. Finally, the as-constructed probe was successfully used to determine DOX in serum, urine, and live cells with satisfactory results. This work will contribute to the specific design of functional CDs and broaden the application of functional CDs in analytical detection and biological imaging.
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JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
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2021
·
IF 3.517
Jinsong Du,Lijuan Wang,Xiao Han,Jie Dou,Jiang Yuan,Jian Shen
Drug-loaded nanoparticles have been widely used in the field of tumor treatment due to their low side effects and reduced frequency of administration. In this study, pH and glutathione (GSH) dual-responsive keratin-tannic acid (TA) complex nanoparticles were established to trigger drug release under tumor microenvironments. Reductive keratin was first extracted using a reduction method. Then, keratin-TA complex nanoparticles (KNPs) were self-assembled via non-covalent interaction and further stabilized by self-crosslinking of thiols. This method was facile and green without chemicals during the whole procedure. KNPs exhibited pH and GSH dual responsiveness as well as charge reversibility in the simulated tumor microenvironment. The anticancer drug of doxorubicin (DOX) was loaded on KNPs by hydrophobicity and hydrogen bonds. Drug-loaded KNPs accelerated drug release under mimicked tumor microenvironments, performing high toxic against A549 cells while low toxic on normal cells. Besides, drug-loaded nanoparticles could be endocytosed by tumor cells. Based on these results, KNPs may serve as drug carriers for therapeutic delivery.
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高影响因子
DRUG DELIVERY
·
2021
·
IF 6.419
Mingming Song,Wentao Xia,Zixuan Tao,Bin Zhu,Wenxiang Zhang,Chang Liu,Siyu Chen
Malignant melanoma is a life-threatening form of skin cancer with a low response rate to single-agent chemotherapy. Although combined therapies of metformin (MET) and doxorubicin (DOX) are effective in treating a variety of cancers, including breast cancer, their different physicochemical properties and administration routines reduce the effective co-accumulation of both drugs in tumors. Nanoparticles (NPs) have been demonstrated to potentially improve drug delivery efficiency in cancer therapy of, for example, liver and lung cancers. Hence, in this study, we prepared pH-sensitive, biocompatible, tumor-targeting NPs based on the conjugation of biomaterials, including sodium alginate, cholesterol, and folic acid (FCA). As expected, since cholesterol and folic acid are two essentials, but insufficient, substrates for melanoma growth, we observed that the FCA NPs specifically and highly effectively accumulated in xenograft melanoma tumors. Taking advantage of the FCA NP system, we successfully co-delivered a combination of MET and DOX into melanoma tumors to trigger pyroptosis, apoptosis, and necroptosis (PANoptosis) of the melanoma cells, thus blocking melanoma progression. Combined, the establishment of such an FCA NP system provides a promising vector for effective drug delivery into melanoma and increases the possibility and efficiency of drug combinations for cancer treatment.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2021
·
IF 6.514
Quanling Guo,Lu Zhang,Mengmeng He,Xiaohua Jiang,Jingrui Tian,Qiurong Li,Zhiwei Liu,Longgang Wang,Haotian Sun
Development of a simple method to enhance targeting and anti-tumor effect of the chemotherapeutic agents in vivo is a major problem. Amphipathic and natural daptomycin is biocompatible antibacterial polypeptide used in clinical practice. Herein, doxorubicin (DOX) was stabilized by zwitterionic daptomycin (Dap) micelles in aqueous solution to form a zwitterionic nanodrug (Dap-DOX micelles). The hydrodynamic size and zeta potential of Dap-DOX micelles were 85 nm and −10 mV, respectively. The study on the controlled release showed that more DOX molecules were released from Dap-DOX micelles at acidic condition of tumor tissue than that at neutral condition of normal tissue which was due to pH responsiveness of Dap-DOX micelles. Dap-DOX micelles exhibited good stability in fibrinogen solution. Moreover, MTT studies showed that Dap-DOX micelles had higher cytotoxicity than free DOX. Notably, the results of flow cytometry indicated that the average fluorescence intensity of Dap-DOX micelle-treated cells was higher than that of free DOX-treated cells, and acidic conditions were more favorable for Dap-DOX micelles than normal pH in cell uptake assay. More importantly, Dap-DOX micelles were biocompatible in vivo based on the changes of weight and blood indexes of mice. Dap-DOX micelles were selectively accumulated at tumor sites in vivo through EPR effect , which reduced the toxicity of free DOX and achieved excellent tumor inhibition effect. The tumor inhibition rate of Dap-DOX micelles reached 96%. Dap-DOX micelles also effectively inhibited the growth of bacterial. Taken together, Dap-based drug delivery systems are promising and effective in cancer therapy.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2020
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IF 2.734
Miaomiao Long,Shenhuan Liu,Xiaotian Shan,Jing Mao,Fuwei Yang,Xiaoyu Wu,Lipeng Qiu,Jinghua Chen
Polymeric micelles have attracted much attention in the field of anticancer drug delivery system because of their special properties. However, the slow drug release rate of micelles after reaching tumor cells is still considered to be a major problem. Therefore, we constructed a new orthoester-based pH-sensitive polyethylene glycol–hydroxydodecanoic acid (PAE) polymer to form doxorubicin-loaded micelles (DOX/PAE). DOX/PAE micelles with uniform particle size showed pH-sensitive drug release behavior in vitro . And the in vitro cytotoxicity studies showed that blank PAE micelles were nontoxic to cells while DOX/PAE micelles could inhibit the growth of tumor cells in a concentration-dependent manner. Furthermore, cellular uptake studies showed that DOX/PAE micelles were uptaken by tumor cells and transported into the nucleus to achieve the effect of killing tumor cells. The results of the uptake mechanism showed that clathrin and macrophage mediated endocytic pathways played important roles in internalization of DOX/PAE micelles. Altogether, the above results show that pH-sensitive PAE micelles have potential in anticancer drug delivery.
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PHARMACEUTICAL RESEARCH
·
2019
·Vol. 36
·期 12
·1-10
·
IF 3.896
Li Songtao,Zhao Hongling,Mao Xiaoxia,Fan Yanfang,Liang Xiujun,Wang Ruxing,Xiao Lijun,Wang Jianping,Liu Qi,Zhao Guiqin
Purpose Transferrin receptors (TfRs) are overexpressed in tumor cells but are scarce in normal tissues, which makes TfR an attractive target for drug treatment of cancer. The objective of this study was to evaluate the potential of BP9a (CAHLHNRS) as a peptide vector for constructing TfR targeted peptide-drug conjugates and selective drug delivery. Methods Doxorubicin (DOX) was connected to BP9a via a disulfide-intercalating linker to afford a reduction-responsive BP9a-SS-DOX conjugate. By using HepG2 human liver cancer cells and L-O2 normal hepatic cells as TfR over-expressing and low-expressing in vitro models, respectively, TfR mediated cellular uptake of this conjugate was studied by using flow cytometry and confocal laser scanning microscopy. The in vitro cytotoxicities of the conjugate against HepG2 and L-O2 cells were examined by cell counting kit-8 (CCK-8) assay to evaluate its tumorous specificity. Results Cellular uptake and TfR blockage test results showed that the BP9a-SS-DOX conjugate gained entry into HepG2 cells via endocytosis mediated by TfR and mainly accumulated in cytoplasm. The in vitro antiproliferative activity of this conjugate against HepG2 cells (IC 50 6.21 ± 1.12 μM) was approximately one-sixth of that of free DOX (IC 50 1.03 ± 0.13 μM). However, its cytotoxic effect on L-O2 cells was obviously reduced compared with that of free DOX. Conclusions The BP9a-SS-DOX conjugate showed specific antiproliferative activity against HepG2 liver cancer cells. Our study suggests that BP9a has the potential to target chemotherapeutic agents to tumor cells over-expressing TfR and facilitate selective drug delivery.
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EUROPEAN POLYMER JOURNAL
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2019
·
IF 3.621
Yanhai Li,Feng Gao,Jin Guo,Peng Ren,Zhenzhen Tian,Jianan Bai,Jie Hua
Natural polymers have shown special advantages in application as drug delivery carriers. However, microbial ε-polylysine seems to have been snubbed. In this study, we constructed a drug delivery system based on natural ε-polylysine. Amphipathic graft copolymer, methoxypoly(ethylene glycol)- graft -ε-polylysine-tetraphenylethylene (mPEG- g -Plys-TPE), was synthesized based on microbial ε-polylysine which was modified completely with PEG and TPE. MPEG- g -Plys-TPE could self-assemble into nanomicelles with stable shell-core structure. PEG served as the hydrophilic shell to provide long blood circulation and biocompatibility. TPE formed the hydrophobic core with aggregation-induced emission (AIE) effect to load drugs. The physical and chemical properties, including size distribution, morphology, stability and photoluminescent effect, were investigated in detail. In vitro drug release indicated pH-dependent patterns. Furthermore, cytotoxicity of doxorubicin (DOX)-loaded micelles against HT-29, HCT116 and SW480 was significantly higher than that of free DOX, which was explained by the mechanism of cellular uptake against tumor cells. In summary, all results suggested that mPEG- g -Plys-TPE as new type biomaterials exhibited great potential for drug delivery.
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危险品化学品经营许可证（带存储）