Materials Science & Engineering C-Materials for Biological Applications
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2020
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IF 5.88
Ke Zhou,Yixin Zhu,Xuling Chen,Lingbing Li,Wei Xu
Tumor-responsive nanocarriers are highly valuable and demanded for smart anticancer drug delivery, where a quick release of chemotherapeutic drugs in tumors is preferred. Herein, a redox and MMP-2 sensitive nanoparticle has been designed for targeted delivery of PTX. Bovine serum albumin as a targeting ligand and gelatin as a hydrophilic carrier and MMP-2 sensitive reagent were used to construct the nanoparticles. Disulfide containing prodrug (PTX-SS-COOH) was grafted to the sulfhydryl modified gelatin to form the redox sensitive amphiphilic polymer. The nanoparticles were formed by self-assembly of amphiphilic polymer and BSA covering. Furthermore the modified sulfhydryl group on the gelatin can form a disulfide bond by self-crosslinking in the air, which endows the nanoparticle with a stable structure. The nanoparticle was sensitive to changes in MMP-2 concentration and redox potential, resulting in multiple responsive drug delivery to the tumor microenvironment. We further verified the anticancer effect of the nanoparticles both in vitro and in vivo , the nanoparticle (BSA/Gel-SS-PTX/PTX-SS-COOH NPs) demonstrated an excellent anticancer efficiency.
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Theranostics
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2021
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IF 11.556
Xin Wang,Bin Yang,Lingxiao Li,Tian Liu,Shiyi Zuo,Dongxu Chi,Zhonggui He,Bingjun Sun,Jin Sun
Rationale: Small-molecule prodrug nanoassembly is emerging as an efficient platform for chemotherapy. The self-assembly stability plays a vital role on the drug delivery efficiency of prodrug nanoassembly. It is reported that fluoroalkylation could improve the self-assembly stability of amphiphilic polymers by utilizing the unique fluorination effect. But the application of fluoroalkylation on small-molecule prodrug nanoassembly has never been reported. Methods: Here, fluoro-modified prodrug was developed by conjugating paclitaxel with perfluorooctanol (F 8 -SS-PTX), and the paclitaxel-octanol prodrug (C 8 -SS-PTX) was used as control. The fluoro-mediated self-assembly mechanisms were illustrated using molecular dynamics simulation. In addition, the impacts of fluoroalkylation on the pharmacy characters, in vivo fate and antitumor effect of small-molecule prodrug nanoassembly were investigated in details. Results: Fluoroalkylation significantly improved the self-assembly stability of F 8 -SS-PTX NPs both in vitro and in vivo , which could be attributed to the fluoro-mediated hydrophobic force and halogen bonds. The AUC 0-24h and tumor accumulation of F 8 -SS-PTX NPs was 6-fold and 2-fold higher than that of C 8 -SS-PTX NPs, respectively. As a result, F 8 -SS-PTX NPs exhibited much better antitumor effect than C 8 -SS-PTX NPs and Abraxane. Conclusion: Fluoroalkylation could improve the self-assembly stability, in vivo fate, and antitumor efficacy of small-molecule prodrug nanoassemblies, which could be an effective strategy for the rational design of advanced nanomedicines.
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2019
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IF 3.973
Lingli Zhang,Chengguang Wu,Shansong Mu,Wei Xue,Dong Ma
To enhance the chemotherapy effect to MDA-MB-231, a glutathione (GSH)-sensitive amphiphilic hyperbranched poly (amide-amine) (mPEG-PLGA-HPAA) was synthesized, and the anti-cancer drug, paclitaxel (PTX) was then encapsulated into the mPEG-PLGA-HPAA micelles. The mPEG-PLGA-HPAA containing a large number of disulfide bonds could degrade and then consume the GSH intracellularly, which was expected to enhances the sensitivity of MDA-MB-231 cells to PTX. It was found that the mPEG-PLGA-HPAA/PTX nanoparticles could respond to the GSH and showed a GSH-controlled PTX release. Simultaneously, the mPEG-PLGA-HPAA/PTX nanoparticles significantly enhanced the efficacy of PTX by inhibiting MDA-MB-231 cells proliferation and inducing cells apoptosis, performing the self-sensitization effect of chemotherapy. Moreover, the drug carrier of mPEG-PLGA-HPAA exhibited excellent biocompatibility in vitro and in vivo . These results indicated that the self-sensitized drug carrier is a promising route to maximize the therapeutic effect and minimize the side effects of chemotherapy drugs used currently in clinical.
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ACS Applied Materials & Interfaces
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2018
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IF 8.097
Di Zhang,Jing Zhang,Qian Li,Hailong Tian,Na Zhang,Zhonghao Li,Yuxia Luan
The short lifetime and easy quick elimination of the near-infrared (NIR) dye new indocyanine green (IR820) in the body restrict its practical application as a photothermal agent in cancer therapy. Meanwhile, the drawback of poor water solubility of the chemotherapeutic drug paclitaxel (PTX) largely restricts its clinical applications. Herein, we, for the first time, combined IR820 and PTX in an “all-in-one” fluorescence imaging-guided chemo–photothermal therapy (PTT) platform by a rational design of a novel pH- and enzyme-sensitive IR820–PTX conjugate assembly. Specifically, the IR820–PTX conjugate nanoparticles exhibit an extremely high therapeutic agent content (IR820 and PTX, 95.7%). Besides the good stability in bloodstream, the IR820–PTX nanoparticles can target tumors for high accumulation via the enhanced permeation and retention effect. Particularly, our IR820–PTX nanoparticles simultaneously solve the obstacles of PTX poor solubility and the short lifetime of IR820 for cancer therapy. The simultaneous release of the free drug and dye can efficiently kill tumor cells by the combination of PTT and chemotherapy via NIR irradiation. Furthermore, the combined therapy can be imaging-guided by measuring the NIR fluorescence imaging resulting from the IR820 component. Therefore, our rationally designed pH- and enzyme-sensitive IR820–PTX conjugate nanoparticles provide an alternative “all-in-one” option for an efficient combinational dual-therapy and imaging.
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Cells
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2019
·Vol. 8
·期 8
·892
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IF 5.656
Dattatrya Shetti,Bao Zhang,Conghui Fan,Canlong Mo,Bae Hoon Lee,Kun Wei
Triple-negative breast cancer (TNBC) accounts for 15% of overall breast cancer. A lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2 receptor) makes TNBC more aggressive and metastatic. Wnt signaling is one of the important pathways in the cellular process; in TNBC it is aberrantly regulated, which leads to the progression and metastasis. In this study, we designed a therapeutic strategy using a combination of a low dose of paclitaxel and a Wnt signaling inhibitor (XAV939), and examined the effect of the paclitaxel-combined XAV939 treatment on diverse breast cancer lines including TNBC cell lines (MDA-MB-231, MDA-MB-468, and BT549) and ER+ve cell lines (MCF-7 and T-47D). The combination treatment of paclitaxel (20 nM) and XAV939 (10 µM) exerted a comparable therapeutic effect on MDA-MB-231, MDA-MB-468, BT549, MCF-7, and T-47D cell lines, relative to paclitaxel with a high dose (200 nM). The paclitaxel-combined XAV939 treatment induced apoptosis by suppressing Bcl-2 and by increasing the cleavage of caspases-3 and PARP. In addition, the in vivo results of the paclitaxel-combined XAV939 treatment in a mice model with the MDA-MB-231 xenograft further confirmed its therapeutic effect. Furthermore, the paclitaxel-combined XAV939 treatment reduced the expression of β-catenin, a key molecule in the Wnt pathway, which led to suppression of the expression of epithelial-mesenchymal transition (EMT) markers and angiogenic proteins both at mRNA and protein levels. The expression level of E-cadherin was raised, which potentially indicates the inhibition of EMT. Importantly, the breast tumor induced by pristane was significantly reduced by the paclitaxel-combined XAV939 treatment. Overall, the paclitaxel-combined XAV939 regimen was found to induce apoptosis and to inhibit Wnt signaling, resulting in the suppression of EMT and angiogenesis. For the first time, we report that our combination approach using a low dose of paclitaxel and XAV939 could be conducive to treating TNBC and an external carcinogen-induced breast cancer.Keywords:breast cancer;XAV939;apoptosis;EMT;pristane;angiogenesis;combination treatment;Wnt signaling
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JOURNAL OF POLYMER SCIENCE PART A-POLYMER CHEMISTRY
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2015
·Vol. 54
·期 1
·99-107
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IF 3.113
Ying Huang,Rui Sun,Qiaojie Luo,Ying Wang,Kai Zhang,Xuliang Deng,Weipu Zhu,Xiaodong Li,Zhiquan Shen
In this study, a facile method to fabricate reduction-responsive core-crosslinked micelles via in situ thiol-ene “click” reaction was reported. A series of biodegradable poly(ether-ester)s with multiple pendent mercapto groups were first synthesized by melt polycondensation of diol poly(ethylene glycol), 1,4-butanediol, and mercaptosuccinic acid using scandium trifluoromethanesulfonate [Sc(OTf) 3 ] as the catalyst. Then paclitaxel (PTX)-loaded core-crosslinked (CCL) micelles were successfully prepared by in situ crosslinking hydrophobic polyester blocks in aqueous media via thiol-ene “click” chemistry using 2,2′-dithiodiethanol diacrylate as the crosslinker. These PTX-loaded CCL micelles with disulfide bonds exhibited reduction-responsive behaviors in the presence of dithiothreitol (DTT). The drug release profile of the PTX-loaded CCL micelles revealed that only a small amount of loaded PTX was released slowly in phosphate buffer solution (PBS) without DTT, while quick release was observed in the presence of 10.0 mM DTT. Cell count kit (CCK-8) assays revealed that the reduction-sensitive PTX-loaded CCL micelles showed high antitumor activity toward HeLa cells, which was significantly higher than that of reduction-insensitive counterparts and free PTX. This kind of biodegradable and biocompatible CCL micelles could serve as a bioreducible nanocarrier for the controlled antitumor drug release. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54 , 99–107
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DRUG DELIVERY
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2015
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IF 2.558
Yanxiu Ge,Yanli Zhao,Lingbing Li
In present study, two types of micelles based on sodium cholate (NaC) were prepared through non-covalent bonding interaction and the potential of micelles as oral drug delivery systems for paclitaxel (PTX) was evaluated. Pluronic–chitosan (F127–CS) and Pluronic–poly (acrylic acid) (F127–PAA) copolymers were synthesized. Electrostatic interaction and hydrogen bond were used to prepare F127–CS/NaC micelles and F127–PAA/NaC micelles, respectively. The physicochemical characteristics of micelles were determined. An average diameter of 67.5 nm and unimodal pattern of size distribution were observed for F127–CS/NaC micelles. While for F127–PAA/NaC micelles, an average diameter of 85.89 nm and non-unimodal pattern of size distribution were observed. The results revealed that F127–CS/NaC micelles were more integrated than F127–PAA/NaC micelles. Further experiments showed that the F127–CS/NaC micelles had a higher drug-loading content of 12.8% and a lower critical micelle concentration (CMC) of 2.5 × 10−3 mol/L compared with F127–PAA/NaC micelles. In vitro cytotoxicity analysis demonstrated that the PTX-loaded F127–CS/NaC micelles were of great efficiency in inhibiting the growth of drug-resistant breast cancer MCF-7 cells (MCF-7/Adr). The intragastric administration of the PTX-loaded F127–CS/NaC micelles in rats provided a 4.33-fold higher absolute bioavailability compared to commercial Taxol®, indicating an efficient oral absorption of PTX delivered by micelles. These findings signify that F127–CS/NaC micelle may be a promising carrier for the delivery of PTX.
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Asian Journal of Pharmaceutical Sciences
·
2024
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IF 10.7
Fugen Wu,Xingsi An,Shize Li,Chenyu Qiu,Yixuan Zhu,Zhanzheng Ye,Shengnan Song,Yunzhi Wang,Dingchao Shen,Xinyu Di,Yinsha Yao,Wanling Zhu,Xinyu Jiang,Xianbao Shi,Ruijie Chen,Longfa Kou
Chemoimmunotherapy has the potential to enhance chemotherapy and modulate the immunosuppressive tumor microenvironment by activating immunogenic cell death (ICD), making it a promising strategy for clinical application. Alantolactone (A) was found to augment the anticancer efficacy of paclitaxel (P) at a molar ratio of 1:0.5 (P:A) through induction of more potent ICD via modulation of STAT3 signaling pathways. Nano drug delivery systems can synergistically combine natural drugs with conventional chemotherapeutic agents, thereby enhancing multi-drug chemoimmunotherapy. To improve tumor targeting ability and bioavailability of hydrophobic drugs, an amphiphilic prodrug conjugate (HA-PTX) was chemically modified with paclitaxel (PTX) and hyaluronic acid (HA) as a backbone. Based on this concept, CD44-targeted nanodrugs (A@HAP NPs) were developed for co-delivery of A and P in colorectal cancer treatment, aiming to achieve synergistic toxicity-based chemo-immunotherapy. The uniform size and high drug loading capacity of A@HAP NPs facilitated their accumulation within tumors through enhanced permeability and retention effect as well as HA-mediated targeting, providing a solid foundation for subsequent synergistic therapy and immunoregulation. In vitro and in vivo studies demonstrated that A@HAP NPs exhibited potent cytotoxicity against tumor cells while also remodeling the immune-suppressive tumor microenvironment by promoting antigen presentation and inducing dendritic cell maturation, thus offering a novel approach for colorectal cancer chemoimmunotherapy.
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JOURNAL OF CONTROLLED RELEASE
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2024
·
IF 10.5
Danping Wang,Yuetong Huang,Jun Yuan,Shuo Wang,Jingzhe Sheng,Yingjie Zhao,Hao Zhang,Xiyan Wang,Yuanhao Yu,Xianbao Shi,Zhonggui He,Tian Liu,Bingjun Sun,Jin Sun
In the prodrug-based self-assembled nanoassemblies, prodrugs usually consist of drug modules, response modules, and modification modules. Modification modules play a critical role in regulating the nano-assembly ability of the prodrugs. Herein, we carried out a “fatty alcoholization” strategy and chose various lengths of aliphatic alcohol chains (AC) as modification modules to construct disulfide bond bridged paclitaxel (PTX) prodrug nanoassemblies. The PTX-AC prodrugs would self-assemble into nanoassemblies (PTX-AC PNs) with higher drug loading, stability, and tumor selectivity than commercial preparations. After comprehensive exploration, we found the chain length (AC 12 , AC 16 , AC 20 , AC 24 ) of modification modules affected the assembly of PTX-AC PNs, further leading to disparate in vivo fate and antitumor efficacy. With the increase of the chain length of the modification modules (from AC 12 to AC 20 ), the assembly ability of the nanoassemblies was improved, attributed to the appropriate enhancement of hydrophobic force. When the chain length was further increased to AC 24 , the excessive hydrophobic force will lead to the aggregation of prodrugs and weaken the assembly ability. Therefore, PTX-AC 20 PNs with proper chain length may solve the paradox of efficacy and tolerance in 4 T1 breast tumor owing to their optimal nano-assembly stability and modest redox-sensitivity. In short, this work highlighted the importance of screening optimal modification modules in developing prodrug nanoassemblies.
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ACS Applied Nano Materials
·
2024
·
IF 5.3
Jiyang Xue,Hai Zhang
Immunotherapy has become a potential treatment technique for ovarian cancer. However, its improvement is impeded by obstacles such as immunosuppression and minimal tumor penetration. Inhibiting the chemokine receptor 4 (CXCR4)/chemokine ligand 12 (CXCL12) axis to enhance tumor infiltration and alleviate the immunosuppressive microenvironment holds promise for enhancing tumor immunotherapy. We developed a targeted drug delivery system by encapsulating the chemotherapeutic drug paclitaxel (PTX) in PEGylated albumin nanoparticles (NPs) modified with the tumor-specific CXCR4 inhibitor plerixafor (AMD3100) (AMD-NP-PTX). The effects of AMD-NPs on cell uptake and migration were investigated using ID8 cells. Subsequently, an ovarian cancer-bearing mouse model was developed to assess the targeting ability of AMD-NP-PTX and its repressive result on ovarian cancer. Lastly, the prospective healing system was investigated. The CXCR4 blocker-enriched NPs showed increased tumor cell uptake in vitro and significant inhibition of CXCL12-mediated immune cell migration. Moreover, this system not only properly targets tumors using AMD3100 but also hinders tumor growth by modulating the CXCR4/CXCL12 axis, hence boosting MAPK expression and lowering PI3K expression. Immune analysis showed that the medicine shipment system upregulates CD8+ T cells as well as natural killer cells in both growth tissues and the spleen, while all at once downregulating myeloid-derived suppressor cells and regulatory T cells. This study underscores the synergistic inflection of the immunosuppressive microenvironment within the tumor, triggering a durable and appropriate antitumor immune response. These findings underscore the potential of a tailored medication delivery system to enhance immunotherapy for ovarian cancer.
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MICROCHEMICAL JOURNAL
·
2025
·
IF 5.1
Yu Zhong,An-Yang Li,Jun-Bin Dai,Chen Guo,Shan-Shan Chen,Li-Li Su,Qin-Ying Liu,Yang Sun
Sensitive and rapid quantification of chemotherapeutic drug paclitaxel (PTX) in human serum is crucial for enabling personalized dosing and minimizing severe toxicity. In this approach, an ultrasensitive electrochemical sensor was developed via facile one-step deposition method for rapid determination of PTX. The nitrogen-doped carbon quantum dots-multiwalled carbon nanotubes (NCQDs-MWCNT) nanocomposite, which modified on the screen-printed carbon electrode (SPCE), synergistically enhanced the active surface area, boosted the electrical conductivity and improved the detection sensitivity. Under the optimized conditions, the prepared NCQDs-MWCNT/SPCE exhibited good linearity in both 0.2 M phosphate buffer (pH 7.4) and human serum, and the limit of detection (LOD) reached as low as 1.0 nM and 2.3 nM, respectively. Additionally, the developed sensor possessed satisfactory repeatability, long-term storage property and anti-interference capability. The recovery rates were in the range of 107.73–114.05 % in human serum, indicating its accuracy of PTX measurement. In depth, the electrochemical behaviors of PTX at NCQDs-MWCNT/SPCE were examined. Collectively, the proposed ultrasensitive and facile sensor displays potential applications in therapeutic drug monitoring for PTX, facilitating individualized treatment in precision medicine.
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International Journal of Nanomedicine
·
2023
·
IF 8
Qiang Huo,Jianhua Zhu,Yimin Niu,Huihui Shi,Yaxiang Gong,Yang Li,Huihui Song,Yang Liu
Multidrug resistance (MDR) remains a major challenge for providing effective chemotherapy for many cancer patients. To address this issue, we report an intelligent polymer-based drug co-delivery system which could enhance and accelerate cellular uptake and reverse MDR. The nanodrug delivery systems were constructed by encapsulating disulfiram (DSF), a P-glyco-protein (P-gp) inhibitor, into the hydrophobic core of poly(ethylene glycol)-block-poly(l-lysine) (PEG-b-PLL) block copolymer micelles, as well as 2,3-dimethylmaleic anhydride (DMA) and paclitaxel (PTX) were grafted on the side chain of l-lysine simultaneously. The surface charge of the drug-loaded micelles represents as negative in plasma (pH 7.4), which is helpful to prolong the circulation time, and in a weak acid environment of tumor tissue (pH 6.5–6.8) it can be reversed to positive, which is in favor of their entering into the cancer cells. In addition, the carrier could release DSF and PTX successively inside cells. The results of in vitro studies show that, compared to the control group, the DSF and PTX co-loaded micelles with charge reversal exhibits more effective cellular uptake and significantly increased cytotoxicity of PTX to MCF-7/ADR cells which may be due to the inhibitory effect of DSF on the efflux function of P-gp. Accordingly, such a smart pH-sensitive nanosystem, in our opinion, possesses significant potential to achieve combinational drug delivery and overcome drug resistance in cancer therapy.
研究领域:
药剂学
·
纳米技术
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肿瘤学
·
药物递送系统
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