MACROMOLECULAR BIOSCIENCE
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2020
·Vol. 21
·期 3
·2000291
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IF 3.416
Zi-Hao Zhou,Jian-Guo Zhang,Qing Chen,Yan-Ling Luo,Feng Xu,Ya-Shao Chen
To well adapt to the complicated physiological environments, it is necessary to engineer dual- and/or multi-stimuli responsive drug carriers for more effective drug release. For this, a novel temperature responsive lateral chain photosensitive block copolymer, poly[(N-isopropylacrylamide- co -N,N-dimethylacrylamide) - block -propyleneacylalkyl-4-azobenzoate] (P(NIPAM- co -DMAA)- b -PAzoHPA), is synthesized by atom transfer radical polymerization. The structure is characterized by 1 H nuclear magnetic resonance spectrometry and laser light scattering gel chromatography system. The self-assembly behavior, morphology, and sizes of micelles are investigated by fluorescence spectroscopy, transmission electron microscope, and laser particle analyzer. Dual responsiveness to light and temperature is explored by ultraviolet–visible absorption spectroscopy. The results show that the copolymer micelles take on apparent light and temperature dual responsiveness, and its lower critical solution temperature (LCST) is above 37 °C, and changes with the trans-/cis- isomerization of azobenzene structure under UV irradiation. The blank copolymers are nontoxic, whereas the paclitaxel (PTX)-loaded counterparts possessed comparable anticancer activities to free PTX, with entrapment efficiency of 83.7%. The PTX release from the PTX-loaded micelles can be mediated by changing temperature and/or light stimuli. The developed block copolymers can potentially be used for cancer therapy as drug controlled release carriers.
研究领域:
药学
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材料科学
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纳米技术
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生物医学工程
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International Journal of Nanomedicine
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2023
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IF 8
Jinming Zhang,Xiaobin Fang,Zeyong Li,Hon Fai Chan,Zhixiu Lin,Yitao Wang,Meiwan Chen
Brusatol (Bru) exhibits promising anticancer effects, with both proliferation inhibition and chemoresistance amelioration activity. However, the poor solubility and insufficient intracellular delivery of Bru greatly restrict its application. Herein, to simultaneously utilize the advantages of Pluronics as drug carriers and tumor microenvironment-responsive drug release profiles, a flexible amphiphilic copolymer with a polymer skeleton, that is, Pluronic® F68 grafting with linoleic acid moieties by redox-reducible disulfide bonds (F68-SS-LA), was synthesized. After characterization by 1H-nuclear magnetic resonance and Fourier transform infrared spectroscopy, the redox-sensitive F68-SS-LA micelles were self-assembled in a much lower critical micelle concentration than that of the unmodified F68 copolymer. Bru was loaded in micelles (Bru/SS-M) with high loading efficiency, narrow size distribution, and excellent storage stability. The redox-sensitive Bru/SS-M exhibited rapid particle dissociation and drug release in response to a redox environment. Based on the enhanced cellular internalization, Bru/SS-M achieved higher cytotoxicity in both Bel-7402 and MCF-7 cells compared with free Bru and nonreducible micelles. The improved anticancer effect was attributed to the remarkably decreased mitochondrial membrane potential and increased reactive oxygen species level as well as apoptotic rate. These results demonstrated that F68-SS-LA micelles possess great potential as an efficient delivery vehicle for Bru to promote its anticancer efficiency via an oxidation pathway.
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Biomaterials Advances
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2023
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IF 0
Yiqing Liu,Peiyong Guo,Xinhao Dong,Yina Xu,Dan Li,Hua Zheng,Jianhong Liao
Here, we combined reversible addition-fragmentation chain transfer (RAFT) polymerization and amide coupling reaction to develop a novel drug-polymer conjugate using poly(AMA- co -IMMA)-b-poly(OEGMA) (termed as PAIPO) as nanocarriers. In order to enhance cellular uptake and obtain subsequent endo/lysosomal escape capacity, the dual-drugs-conjugated prodrug was then coupled with 2,3-dimethylmaleimide (DA) moieties and implanted with imidazolyl groups, respectively. Paclitaxel (PTX) was conjugated to PAIPO via 3,3′-dithiodipropionic acid (DPA) to construct a GSH-responsive moiety, while doxorubicin (DOX) was conjugated to PAIPO via 4-formyl benzoic acid to construct a pH-responsive moiety, which synergistically enabled a synchronized and precise drug delivery. The micelles self-assembled from DOX/ [email protected] DA showed an ideal average diameter (163.2–178.3 nm), contributing to passive targeting by the EPR effect. Moreover, a switch of the surface Zeta potential of micelles from steady negatively charged (− 9.74 ± 0.54 mV) at pH 7.4 to positively charged (+ 6.33 ± 1.25 mV) at pH 6.5, facilitated the long blood circulation and cellular endocytosis of micelles, respectively. More importantly, in vitro studies confirmed that DA M(DOX n /PTX) exhibited a strong synergism against tumor cells, and under slightly acidic conditions (pH 6.5), the combination index (CI) values for DA M(DOX 1 /PTX) on HeLa and Skov-3 cells were estimated to be 0.47 and 0.49 (previous to be 0.50 and 0.56 at pH 7.4), respectively. And in vivo results showed effective tumor accumulation potential, remarkable biosafety, and biocompatibility. Combined, such synchronized delivery approach based on multi-responsive micelles might potentiate the efficacy of combination chemotherapy in clinical cancer treatment.
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CARBOHYDRATE POLYMERS
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2022
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IF 10.723
Yuhan Yang,Yangyi Chen,Dianpeng Li,Shiyuan Lin,Hui Chen,Wei Wu,Wei Zhang
A novel delivery system based on linolenic acid (LA) conjugated chitosan (CS) polymeric micelles were proposed for improving the oral absorption of doxorubicin (DOX) through targeting intestinal fatty acid transporter. LA, as a ligand of the transporter, was grafted into CS to construct CS-LA micelles, and DOX was encapsulated into the micelles. The synthesized micelle material was identified by 1 H NMR and FT-IR. The micelles showed regular spherical shapes with a particle size of 117.1 ± 1.6 nm, drug loading of 8.77 ± 0.02 %, and critical micelle concentration (CMC) of 23.6 μg/ml. The pharmacokinetics studies showed the relative bioavailability of 166 % versus DOX·HCl. The fatty acid transport protein 4-mediated intestinal uptake process of micelles was confirmed by the intracellular uptake, immunofluorescent imaging and permeation test. These findings confirmed the potential of CS-LA micelles as an effective oral delivery vehicle, and fatty acid transporter as a target spot for enhancing intestinal drug absorption.
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ACS Applied Materials & Interfaces
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2022
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IF 10.383
Jinsong Tao,Zhengjie Wei,Yaxin Cheng,Meng Xu,Qiuxia Li,Simon Ming-Yuen Lee,Wei Ge,Kathy Qian Luo,Xueqing Wang,Ying Zheng
A suitable animal model for preclinical screening and evaluation in vivo could vastly increase the efficiency and success rate of nanomedicine development. Compared with rodents, the transparency of the zebrafish model offers unique advantages of real-time and high-resolution imaging of the whole body and cellular levels in vivo. In this research, we established an apoptosis-sensing xenograft zebrafish tumor model to evaluate the anti-cancer effects of redox-responsive cross-linked Pluronic polymeric micelles (CPPMs) visually and accurately. First, doxorubicin (Dox)-loaded CPPMs were fabricated and characterized with glutathione (GSH)-responsive drug release. Then, the B16F10 xenograft zebrafish tumor model was established to mimic the tumor microenvironment with angiogenesis and high GSH generation for redox-responsive tumor-targeting evaluation in vivo. The high GSH generation was first verified in the xenograft zebrafish tumor model. Compared with ordinary Pluronic polymeric micelles, Dox CPPMs had a much higher accumulation in zebrafish tumor sites. Finally, the apoptosis-sensing B16F10-C3 xenograft zebrafish tumor model was established for visual, rapid, effective, and noninvasive assessment of anti-cancer effects at the cellular level in vivo. The Dox CPPMs significantly inhibited the proliferation of cancer cells and induced apoptosis in the B16F10-C3 xenograft zebrafish tumor model. Therefore, the redox-responsive cross-linked Pluronic micelles showed effective anti-cancer therapy in the xenograft zebrafish tumor model. This xenograft zebrafish tumor model is available for rapid screening and assessment of anti-cancer effects in preclinical studies.
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CARBOHYDRATE POLYMERS
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2022
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IF 10.723
Yang Xu,Na Liang,Jiyang Liu,Xianfeng Gong,Pengfei Yan,Shaoping Sun
In this study, cetyl 4-formylbenzoate alkyl and 4-(2-hydroxyethoxy) benzophenonesalicylaldazide modified biotinylated chitosan (CS-BT-HBS-CB) featured with aggregation-induced emission (AIE) characteristic, active tumor-targeting ability and pH-responsive drug release property was designed and synthesized. The polymer was fabricated by introducing hydrophobic segment, tumor targeting ligand, acid-sensitive bond and AIE fluorophore to the backbone of chitosan. Due to its amphiphilicity, the polymer could self-assemble into micelles and encapsulate paclitaxel (PTX) to form PTX-loaded CS-BT-HBS-CB micelles. The mean size of the micelles was 167 nm, which was beneficial to the EPR effect . Moreover, with the help of above functional groups, the micelles exhibited excellent AIE effect, triggered drug release behavior by acidic condition, selective internalization by MCF-7 cells and excellent cellular imaging capability. In vivo studies revealed that the PTX-loaded CS-BT-HBS-CB micelles could enhance the antitumor efficacy with low systemic toxicity. This micellar system would be a potential candidate for cancer therapy and bioimaging.
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ACS Applied Materials & Interfaces
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2022
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IF 10.383
He Ren,Jiexin Li,Gengqi Liu,Yaping Sun,Xingyue Yang,Zhen Jiang,Jingyu Zhang,Jonathan F. Lovell,Yumiao Zhang
The development of nanocarriers capable of codelivering antigens and immune-activating adjuvants is an emerging area of research and is relevant for cancer vaccines that target induction of antigen-specific CD8+ T-cell responses. Here, we report a system for delivery of short peptide antigens to dendritic cells for strong cellular immune responses, based on block copolymers chemically modified with a hydrophobic and self-immolative linker. After modification, micelles effectively and reversibly capture antigens and adjuvants via a covalent bond within several minutes in an aqueous solution. After uptake in antigen presenting cells, the polymer disulfide bond is cleaved by intracellular glutathione, leading to release of pristine antigens, along with the upregulated expression of costimulatory molecules. The induced antigen-specific CD8+ T cells have strong tumor cell killing efficacy in the murine B16OVA and human papilloma virus-E6/E7 subcutaneous and lung metastasis tumor models. In addition, delivery to lymph nodes can be imaged to visualize vaccine trafficking. Taken together, multifunctional self-immolative micelles represent a versatile class of a vaccine delivery system for the generation of a cellular immune response that warrants further exploration as a component of cancer immunotherapy.
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BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
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2021
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IF 3.77
O.Yu. Selyutina,P.A. Kononova,V.E. Koshman,E.A. Shelepova,M. Gholam Azad,R. Afroz,M. Dharmasivam,Paul V. Bernhardt,N.E. Polyakov,D.R. Richardson
Background Iron (Fe)-induced oxidative stress leads to reactive oxygen species that damage biomembranes, with this mechanism being involved in the activity of some anti-cancer chemotherapeutics. Methods Herein, we compared the effect of the ligand, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), or the potential ligand, Emodin, on Fe-catalyzed lipid peroxidation in cell membrane models (micelles and bicelles). These studies were performed in the presence of hydrogen peroxide (H 2 O 2 ) and the absence or presence of ascorbate. Results In the absence of ascorbate, Fe(II)/Emodin mixtures incubated with H 2 O 2 demonstrated slight pro-oxidant properties on micelles versus Fe(II) alone, while the Fe(III)-Dp44mT complex exhibited marked antioxidant properties. Examining more physiologically relevant phospholipid-containing bicelles, the Fe(II)- and Fe(III)-Dp44mT complexes demonstrated antioxidant activity without ascorbate. Upon adding ascorbate, there was a significant increase in the peroxidation of micelles and bicelles in the presence of unchelated Fe(II) and H 2 O 2 . The addition of ascorbate to Fe(III)-Dp44mT substantially increased the peroxidation of micelles and bicelles, with the Fe(III)-Dp44mT complex being reduced by ascorbate to the Fe(II) state, explaining the increased reactivity. Electron paramagnetic resonance spectroscopy demonstrated ascorbyl radical anion generation after mixing ascorbate and Emodin, with signal intensity being enhanced by H 2 O 2 . This finding suggested Emodin semiquinone radical formation that could play a role in its reactivity via ascorbate-driven redox cycling. Examining cultured melanoma cells in vitro , ascorbate at pharmacological levels enhanced the anti-proliferative activity of Dp44mT and Emodin. Conclusions and general significance Ascorbate-driven redox cycling of Dp44mT and Emodin promotes their anti-proliferative activity.
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高影响因子
LANGMUIR
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2023
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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.
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Acta Biomaterialia
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2023
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IF 9.7
Yifan Luo,Chao Li,Yiwen Zhang,Peixin Liu,Hongyi Chen,Zhenhao Zhao,Yu Wang,Zheng Zhou,Haolin Song,Boyu Su,Chufeng Li,Xuwen Li,Tongyu Zhang,Haoyu You,Yuxing Wu,Zonghua Tian,Shilin Zhang,Yun Guo,Hongrui Fan,Qinjun Chen,Chen Jiang,Tao Sun
The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is the main block for the penetration of chemotherapy. In the tumor microenvironment, a dense matrix composed of fibrin is formed on the exterior, while the interior is featured by high reduction, hypoxia and low pH. How to match the special microenvironment to on-demand drug release is the key to improve chemotherapeutic efficacy. Herein, a microenvironment-responsive micellar system is developed to deepen tumoral penetration. Briefly, the conjugation of a fibrin-targeting peptide to PEG-poly amino acid has been utilized to achieve accumulation of micelles in the tumor stroma. By modification of micelles with hypoxia-reducible nitroimidazole which becomes protonated under acidic conditions, their surface charge is more positive, facilitating deeper penetration into tumors. Paclitaxel was loaded onto the micelles via a disulfide bond to enable glutathione (GSH)-responsive release. Therefore, the immunosuppressive microenvironment is relived through the alleviation of hypoxia and depletion of GSH. Hopefully, this work could establish paradigms by designing sophisticated drug-delivery systems to tactfully employ and retroact the tamed tumoral microenvironment to improve the therapeutic efficacy based on understanding the multiple hallmarks and learning the mutual regulation. Statement of significance Tumor microenvironment(TME) is an unique pathological feature of pancreatic cancer and an inherent barrier to chemotherapy. Numerous studies regard TME as the targets for drug delivery. In this work, we propose a hypoxia-responsive nanomicellar drug delivery system that aiming hypoxia TME of pancreatic cancer. The nanodrug delivery system could respond to the hypoxic microenvironment and enhance the penetration of the inner tumor at the same time preserving the outer tumor stroma, thus achieving targeted treatment of PDAC by preserving the integrity of the outer stroma. Simultaneously, the responsive group can reverse the degree of hypoxia in TME by disrupting the redox balance in the tumor region, thus achieving precise treatment of PDAC by matching the pathological characteristics of TME. We believe our article would provide new design ideas for the future treatments for pancreatic cancer.
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Frontiers in Chemistry
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2023
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IF 5.5
Jiapeng Deng,Su Liu,Guoqing Li,Yien Zheng,Weifei Zhang,Jianjing Lin,Fei Yu,Jian Weng,Peng Liu,Hui Zeng
Introduction: Chemotherapy is a common strategy for the treatment of osteosarcoma. However, its therapeutic efficacy is not ideal due to the low targeting, lowbioavailability, and high toxicity of chemotherapy drugs. Nanoparticles can improve the residence time of drugs at tumor sites through targeted delivery. This new technology can reduce the risk to patients and improve survival rates. To achieve this goal, we developed a pHsensitive charge-conversion polymeric micelle [mPEG- b -P(C7- co -CA) micelles] for osteosarcoma-targeted delivery of cinnamaldehyde (CA). Methods: First, an amphiphilic cinnamaldehyde polymeric prodrug [mPEG- b -P(C7- co -CA)] was synthesized through Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) polymerization and post-modification, and self-assembled into mPEG- b -P(C7- co -CA) micelles in an aqueous solution. The physical properties of mPEG- b -P(C7- co -CA) micelles, such as critical micelle concentration (CMC), size, appearance, and Zeta potential were characterized. The CA release curve of mPEG- b -P(C7- co -CA) micelles at pH 7.4, 6.5 and 4.0 was studied by dialysis method, then the targeting ability of mPEG- b -P(C7- co -CA) micelles to osteosarcoma 143B cells in acidic environment (pH 6.5) was explored by cellular uptakeassay. The antitumor effect of mPEG- b -P(C7- co -CA) micelles on 143B cells in vitro was studied by MTT method, and the level of reactive oxygen species (ROS) in 143B cells after mPEG- b -P(C7- co -CA) micelles treatment was detected. Finally, the effects of mPEG- b -P(C7- co -CA) micelles on the apoptosis of 143B cells were detected by flow cytometry and TUNEL assay. Results: An amphiphilic cinnamaldehyde polymeric prodrug [mPEG- b -P(C7- co -CA)] was successfully synthesized and self-assembled into spheric micelles with a diameter of 227 nm. The CMC value of mPEG- b -P(C7- co -CA) micelles was 25.2 mg/L, and it showed a pH dependent release behavior of CA. mPEG- b -P(C7- co -CA) micelles can achieve chargeconversion from a neutral to a positive charge with decreasing pHs. This charge-conversion property allows mPEG- b -P(C7- co -CA) micelles to achieve 143B cell targeting at pH 6.5. In addition, mPEG- b -P(C7- co -CA) micelles present high antitumor efficacy and intracellular ROS generation at pH 6.5 which can induce 143B cell apoptosis. Discussion: mPEG- b -P(C7- co -CA) micelles can achieve osteosarcoma targeting effectively and enhance the anti-osteosarcoma effect of cinnamaldehyde in vitro . This research provides a promising drug delivery system for clinical application and tumor treatment.
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CHEMISTRY OF MATERIALS
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2021
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IF 9.811
Jiexin Li,He Ren,Yaping Sun,Gengqi Liu,Xingyue Yang,Qian Qiu,Yuanmeng Ding,Jonathan F. Lovell,Yumiao Zhang
Cancer peptide vaccines face challenges for antigen delivery and presentation. In the present work, we develop a self-assembled magnetic micelle delivery system for CD8+ T-cell epitopes that produces strong cellular immune responses. Hydrophobically modified imiquimod R837 and Zn1.15Fe1.85O4 are coencapsulated in the core of Pluronic F127 block copolymer micelles. Magnetic Zn1.15Fe1.85O4 enables externally targeted delivery and enrichment of micelles in lymph nodes. Furthermore, metal ions are found to enhance vaccine immunogenicity. F127 micelles were chemically modified by a self-immolative linker so that antigens are rapidly and reversibly grafted on micelles in an aqueous solution. With the assistance of an external magnetic field, once the magnetic micelles are delivered to lymph nodes and taken up by immune cells, intracellular glutathione cleaves the disulfide bond and releases pristine short peptide antigen. Delivery to lymph nodes is tracked by magnetic resonance and fluorescence imaging. The use of this vaccine system eradicated tumors in a murine tumor model. Thus, integrating multiple functionalities in a single micellar delivery system, including responsive linkage, multiple immunostimulatory molecules, targeted delivery, and bimodal imaging, demonstrates the potential for theranostic approaches to develop a new generation of cancer vaccines.
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