EUROPEAN JOURNAL OF LIPID SCIENCE AND TECHNOLOGY
·
2021
·Vol. 123
·期 5
·2000337
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IF 2.679
Filipe Olim,Ana Rute Neves,Mariana Vieira,Helena Tomás,Ruilong Sheng
Developing new easy-to-prepare functional drug delivery nanosystems with good storage stability, low hemotoxicity, as well as controllable drug delivery property, has attracted great attention in recent years. In this work, a cholesterol-based prodrug nanodelivery system is prepared by self-assembly of cholesterol-doxorubicin prodrug conjugates (Chol-Dox) and tocopherol polyethylene glycol succinate (TPGS) using thin-film hydration method. The Chol-Dox/TPGS assemblies (molar ratio 2:1, 1:1, and 1:2) are able to form nanoparticles with average hydrodynamic diameter of ≈140–214 nm, surface zeta potentials of ≈−24.2–−0.3 mV, and remarkable solution stability in 0.1 m PBS, 16 days). The Chol-Dox/TPGS assemblies show low hemotoxicity and different cytotoxicity profiles in breast cancer cells (MCF-7 and MDA-MB-231), which are largely dependent on the molar ratio of Chol-Dox and TPGS. The Chol-Dox/TPGS assemblies tend to enter into MCF-7 and MDA-MB-231 cells through non-Clathrin-mediated multiple endocytosis and lysosome-dependent uptake pathways, moreover, these nanoassemblies demonstrate lysosome-dependent intracellular localization, which is different from that of free DOX (nuclear localization). The results demonstrate that the Chol-Dox/TPGS assemblies are promising cholesterol-based prodrug nanomaterials for breast cancer chemotherapy. Practical Applications : This work demonstrates a lipid prodrug-based nanotherapeutic system. Herein the Chol-Dox/TPGS nanoassemblies could serve as promising and controllable cholesterol-based prodrug nanomaterials/nano-formulations for potential breast cancer chemotherapy.
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Bioengineered
·
2021
·
IF 3.269
Yan Wang,Zhiqiang Cheng,Jing Xu,Meina Lai,Liming Liu,Min Zuo,Lin Dang
Excessive activation of signal transducer and activator of transcription 3 (STAT3) is implicated in breast cancer (BC) chemoresistance, but its underlying mechanism is not fully understood. There are STAT3 binding sites in fat mass and obesity-associated protein (FTO) promoter region, thus STAT3 may regulate the transcription of FTO. This study aimed to investigate the correlation between FTO and STAT3 in BC chemoresistance. Herein, FTO and STAT3 were highly expressed in doxorubicin-resistant BC (BC-DoxR) cells. CHIP assay verified the binding between STAT3 and FTO promoter in BC-DoxR cells. Dual luciferase reporter assay showed that FTO promoter activity was inhibited by S3I-201 (STAT3 inhibitor) but enhanced by epidermal growth factor (EGF, STAT3 activator) in BC-DoxR and BC cells. FTO mRNA and protein expression were suppressed by S3I-201 in BC-DoxR cells and EGF-stimulated BC cells. Notably, FTO regulated total N6-methyladenosine (m6A) levels in BC-DoxR and BC cells but could not affect STAT3 mRNA expression, indicating that FTO was not involved in the m6A modification of STAT3. However, FTO could activate STAT3 signaling in BC-DoxR and BC cells. Besides, FTO knockdown inhibited the doxorubicin resistance of BC-DoxR cells, while FTO overexpression enhanced the doxorubicin resistance and weakened the doxorubicin sensitivity of BC cells. Moreover, decreased doxorubicin resistance by STAT3 knockdown was abolished by FTO overexpression and decreased doxorubicin sensitivity by STAT3 overexpression was reversed by FTO knockdown, indicating that FTO was implicated in STAT3-mediated doxorubicin resistance and impairment of doxorubicin sensitivity of BC cells. Altogether, our findings provide a mechanism underlying BC doxorubicin resistance.
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高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2020
·
IF 5.88
Jumin Yang,Shuai Liu,Zhanpeng Ye,Liandong Deng,Anjie Dong,Jianhua Zhang
Various nanoparticles as drug delivery system provide significant improvements in the cancer treatment. However, their clinical success remains elusive in large part due to their inability to overcome both systemic and tumor tissue barriers. The nanosystems with nanoproperty-transformability (surface, size, stability and target) hold great promise for achieving enhanced delivery efficacy. However, currently available systems that are mainly polymer-based assemblies usually suffer from the intrinsic drawbacks of poor stability, premature leakage and low drug loading as well as limited transformability. In this study, we designed a facile strategy to build a novel multi-transformable MSNs@GO nanosystem for efficient doxorubicin (DOX) loading and delivery. This novel nanosystem was well characterized and investigated in vitro. The results indicated that the MSNs@GO can realize a very high drug loading ability due to the large pore surface area of MSNs and the demonstrated donor-acceptor (boron‑nitrogen) coordination interactions between phenylboronic acid-containing nanocarriers and electron donor-containing DOX. More importantly, the novel nanocarriers can simultaneously achieve charge reversal, size reduction and ligand reemergence by shielding/deshielding transition via acid-cleavable dynamic boronate bonds under in vitro simulated acidic microenvironment of tumor tissues, opening a new avenue for improving delivery efficiency of chemotherapeutics.
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高影响因子
MOLECULAR PHARMACEUTICS
·
2020
·
IF 4.321
Fabiao Hu,Ruihuan Zhang,Wei Guo,Ting Yan,Xiujuan He,Fengzhi Hu,Fuzheng Ren,Xingyuan Ma,Jiandu Lei,Wenyun Zheng
Biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) have been widely used as delivery vehicles for chemotherapy drugs. However, premature drug release in PLGA NPs can damage healthy tissue and cause serious adverse effects during systemic administration. Here, we report a tannic acid–Fe(III) (FeIII–TA) complex-modified PLGA nanoparticle platform (DOX-TPLGA NPs) for the tumor-targeted delivery of doxorubicin (DOX). A PEGylated-PLGA inner core and FeIII–TA complex outer shell were simultaneously introduced to reduce premature drug release in blood circulation and increase pH-triggered drug release in tumor tissue. Compared to the unmodified NPs, the initial burst rate of DOX-TPLGA NPs was significantly reduced by nearly 2-fold at pH 7.4. Moreover, the cumulative drug release rate at pH 5.0 was 40% greater than that at pH 7.4 due to the pH-response of the FeIII–TA complex. Cellular studies revealed that the TPLGA NPs had enhanced drug uptake and superior cytotoxicity of breast cancer cells in comparison to free DOX. Additionally, the DOX-TPLGA NPs efficiently accumulated in the tumor site of 4T1-bearing nude mice due to the enhanced permeability and retention (EPR) effect and reached a tumor inhibition rate of 85.53 ± 8.77% (1.31-fold versus DOX-PLGA NPs and 3.12-fold versus free DOX). Consequently, the novel TPLGA NPs represent a promising delivery platform to enhance the safety and efficacy of chemotherapy drugs.
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AAPS PHARMSCITECH
·
2019
·Vol. 21
·期 1
·1-10
·
IF 2.608
Yang Yue,Li Jinyu,Chen Fen,Qiao Sen,Li Yunjian,Pan Weisan
As a synthetic clay material, laponite RDS (LR) was investigated as an effective drug carrier as a result of the special nanodisk structure together with the negative-charged surface to achieve enhanced cellular uptake and targeted delivery. In this research work, the synthesized oligomeric hyaluronic acid-aminophenylboronic acid (oHA-APBA) was entangled onto LR nanodisks to fabricate a valid targeted platform for breast cancer therapy. Briefly, through the formation of amide bonds, 3-APBA was connected to the chain of oHA with a substituted ratio of 4.0 ± 0.2% to synthesize oHA-APBA copolymer. Thereafter, doxorubicin (DOX) was inserted into the interlayer space of LR by the way of the ion exchange process, followed by an assembly with oHA-APBA as a targeted protection layer. The satisfactory drug encapsulation efficiency (> 80%) and narrow size distribution were achieved. The in vitro drug release study demonstrated the release of DOX from DOX@LR/oHA-APBA was sustained and acid dependent. In addition, after fitting the drug cumulative release of DOX@LR/oHA-APBA under different pH conditions with several kinetic models, it was identified that drug release from DOX@LR/oHA-APBA nanohybrids at pH 5.0 was mainly dependent on both diffusion and ion exchange effects. However, under the condition of pH 7.4, the drug was most efficiently released by diffusion effect. Importantly, DOX@LR/oHA-APBA showed remarkable cellular uptake and intracellular drug distribution in MCF-7 cells, which were consistent with inhibitory ability against MCF-7 cells. Hence, the high DOX loading capacity and enhanced cellular tracking can enlighten LR/oHA-APBA as an effective drug delivery carrier for breast cancer therapy.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2023
·
IF 5
Yanan Bu,Hongcai Wang,Ting Wu,Xiuqiong Chen,Siyuan Zhao,Huiqiong Yan,Qiang Lin
Nowadays, self-assembled polymeric micelles from amphiphilic polymer conjugates are urgently needed to enhance drug targeting and release efficiency. On account of the excellent properties of alginate and the redox-responsiveness of disulfide bonds , a redox-sensitive alginate–SS–ibuprofen derivative (LSA–SS–IBU) based anti-tumor target drug delivery system was created by attaching the hydrophobic ibuprofen (IBU) onto the hydrophilic alginate molecular skeleton through disulfide linkages for glutathione (GSH) triggered delivery of doxorubicin hydrochloride (DOX). The structure and self-assembly behavior of the synthesized LSA–SS–IBU was systematically evaluated by FT-IR spectrometer, 1 H NMR spectrometer, fluorescence spectrophotometer (FM), transmission electron microscope (TEM) and dynamic light scattering (DLS). Furthermore, the in vitro release of drugs from the LSA–SS–IBU micelles loaded with DOX was examined, along with the assessment of their cytotoxicity to HeLa cells. The resultant LSA–SS–IBU had a critical micelle concentration (CMC) value of 0.19 mg/mL that was able to self-assemble into the spherical micelles with the particle size and zeta potential of 148.2 ± 4.3 nm (PDI = 0.25) and −47.2 ± 0.4 mV, respectively. At a mass ratio of 3:10 for DOX/LSA–SS–IBU, the LSA–SS–IBU micelles achieved drug loading ratio (DLR) and encapsulation efficiency (EE) values of 12.2 % and 46.3 %, respectively. Furthermore, the in vitro drug release study indicated that the total drug release percentage of the drug-encapsulated LSA–SS–IBU micelles in PBS with the presence of 10 mmol/L GSH for 12 h exceeded 67.0 %, demonstrating a substantial increase compared to that in GSH-free PBS. The in vitro cytotoxicity findings indicated that LSA–SS–IBU had good biocompatibility , while the IC 50 value and the cell viability of DOX-loaded LSA–SS–IBU micelles cultured with HeLa cells for 48 h was 2.2 μg/mL and less than 20.1 %, respectively, which could significantly inhibit the growth of HeLa cells. Therefore, redox-responsive LSA–SS–IBU micelles had potential applications in cancer therapy for hydrophobic anti-tumor drug delivery.
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高影响因子
ANTIOXIDANTS & REDOX SIGNALING
·
2023
·
IF 6.6
Dr. Jiedong Zhou,Dr. Jinjin Hao,Dr. Zuoquan Zhong,Dr. Juntao Yang,Dr. Tingting Lv,Mr. Bingjie Zhao,Dr. Hui Lin,Dr. Jufang Chi,Dr. Hangyuan Guo
Aims: The relationship between gut microbiota and cardiovascular system has been increasingly clarified. Fecal microbiota transplantation (FMT), used to improve gut microbiota, has been applied clinically for disease treatment and has great potential in combatting doxorubicin (DOX)-induced cardiotoxicity. However, the application of FMT in the cardiovascular field and its molecular mechanisms are poorly understood.
Results: During DOX-induced stress, FMT alters the gut microbiota and serum metabolites, leading to a reduction in cardiac injury. Correlation analysis indicated a close association between serum metabolite Indole-3-propionic acid (IPA) and cardiac function. FMT and IPA achieves this by facilitating the translocation of Nfe2l2 (Nrf2) from the cytoplasm to the nucleus, thereby activating the expression of antioxidant molecules, reducing ROS production, and inhibiting excessive mitochondrial fission. Consequently, mitochondrial function is preserved, leading to the mitigation of cardiac injury under DOX-induced stress.
Innovation: FMT has the ability to modify the composition of the gut microbiota, providing not only protection to the intestinal mucosa but also influencing the generation of serum metabolites and regulating the Nrf2 gene to modulate the balance of cardiac mitochondrial fission and fusion. This study comprehensively demonstrates the efficacy of FMT in countering DOX-induced myocardial damage and elucidates the pathways linking the microbiota and the heart.
Conclusion: FMT alters the gut microbiota and serum metabolites of recipient mice, promoting nuclear translocation of Nrf2 and subsequent activation of downstream antioxidant molecule expression, while inhibiting excessive mitochondrial fission to preserve cardiac integrity. Correlation analysis highlights IPA as a key contributor among differentially regulated metabolites.
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高影响因子
FOOD HYDROCOLLOIDS
·
2018
·
IF 5.089
Jianzhong Zhu,Li Zhong,Wenxue Chen,Yizhe Song,Zhengming Qian,Xianying Cao,Qiang Huang,Bin Zhang,Haiming Chen,Weijun Chen
The objective of this study was to design a simple, colon targeted drug delivery system by using porous starch (PS), pectin and chitosan. Porous maize starch was prepared by hydrolysis with a combination of α-amylase and amyloglucosidase, and it was characterized by scanning electron microscopy, revealing the formation of porous structures in the starch granules. A Brunauer-Emmett-Teller (BET) specific surface area analysis indicated that the specific surface area of the PS (0.8768–0.9448 m 2 /g) was 19.88–21.42 times larger than that of native maize starch (0.0441 m 2 /g). The average pore diameter of the PS granules, as calculated by the Barrett-Joiner-Halenda (BJH) method, was 40.52–62.42 nm. A favorable adsorptive potential of the PS granules was verified by water and soybean oil tests. Doxorubicin was loaded into PS granules, which were then coated with a pectin/chitosan complex solution. The results of confocal laser scanning microscopy (CLSM) demonstrated that doxorubicin was successfully absorbed into the PS granules. In addition, an in vitro simulated digestion method demonstrated the effectiveness of this delivery design, as only a 13.80% release rate of doxorubicin was observed in the upper gastrointestinal tract, whereas release rates of 17.56% and 67.04% were observed for pectin/PS/doxorubicin and pectin/doxorubicin beads, respectively. It was concluded that the use of PS and a pectin/chitosan coating is an effective method for colon targeted drug delivery compared with the simple polysaccharide system.
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高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2017
·
IF 4.164
Aili Suo,Junmin Qian,Minghui Xu,Weijun Xu,Yaping Zhang,Yu Yao
Co-delivery of chemotherapeutic drug and small interfering RNA (siRNA) within a single nanovehicle has emerged as a promising combination therapy approach to treating cancers because of their synergistic effect. Nanocarrier delivery systems with low cytotoxicity and high efficiency are needed for such a purpose. In this study, a novel folate-conjugated PEGylated cationic triblock copolymer, poly(acrylhydrazine)- block -poly(3-dimethylaminopropyl methacrylamide)- block -poly(acrylhydrazine) (PAH- b -PDMAPMA- b -PAH), was synthesized and evaluated as a stimuli-sensitive vehicle for the targeted co-delivery of doxorubicin (DOX) and Bcl-2 siRNA into breast cancer MCF-7 cells. The synthetic process of the PEGylated triblock copolymer involved sequential reversible addition-fragmentation chain transfer polymerization, PEGylation and removal of tert -butoxy carbamate protecting groups. Folate-conjugated and/or -unconjugated poly(ethylene glycol) segments were grafted onto PAH- b -PDMAPMA- b -PAH via a reduction-sensitive disulfide linkage. The synthetic polymers were characterized by 1 H NMR and gel permeation chromatography. The PEGylated triblock copolymer could chemically conjugate DOX onto PAH blocks via pH-responsive hydrazone bonds and simultaneously complex negatively charged Bcl-2 siRNA with cationic PDMAPMA blocks through electrostatic interactions at N/P ratios ≥ 32:1 to form multifunctional nanomicelleplexes. The nanomicelleplexes exhibited spherical shape, possessed a positively charged surface with a zeta potential of + 22.5 mV and had a desirable and uniform particle size of 187 nm. In vitro release studies revealed that the nanomicelleplexes could release DOX and Bcl-2 siRNA in a reduction and pH dual-sensitive manner and the payload release was significantly enhanced in a reductive acidic environment mimicking the endosomes/lysosomes of cancer cells compared to under physiology conditions. Furthermore, the release of both DOX and siRNA was found to follow Higuchi kinetic model. Confocal laser scanning microscopy, flow cytometry and MTT analyses confirmed that, compared with folate-undecorated nanomicelleplexes, folate-decorated nanomicelleplexes could more effectively co-deliver DOX and Bcl-2 siRNA into MCF-7 cells and showed a stronger cell-killing effect. The pristine PEGylated triblock copolymer exhibited good cytocompatibility. Moreover, co-delivery of DOX and Bcl-2 siRNA achieved a significant synergistic antitumor efficacy. These findings suggested that the folate-decorated PEGylated cationic triblock copolymer might be a promising vehicle for targeted intracellular co-delivery of DOX and siRNA in MCF-7 cells, representing a potential clinical combination therapy for breast cancer treatment.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2016
·
IF 3.994
Lele Wang,Baocheng Tian,Jing Zhang,Keke Li,Yan Liang,Yujie Sun,Yuanyuan Ding,Jingtian Han
Multifunctional polymeric micelles self-assembled from a DOX-conjugated methoxypolyethylene glycols- b -poly (6- O -methacryloyl- d -galactopyranose)-disulfide bond-DOX (mPEG- b -PMAGP-SS-DOX) copolymer were prepared as an antitumor carrier for doxorubicin delivery, of which the chemical modification with disulfide bonds and hydrazone bonds allowed micelles to release doxorubicin (DOX) selectively at acidic pH and high redox conditions. The resulting micelles exhibited coordinated pH/redox dual-sensitive and hepatoma-targeted multifunction with sustaining stability in aqueous media. The multifunctional micelles showed spherical shapes with a mean diameter of 93 ± 2.08 nm, a low polydispersity index (PDI) of 0.21, a low CMC value of 0.095 mg/mL, a high drug grafting degree of 56.9% and a drug content of 39.0%. Remarkably, in vitro drug release studies clearly exhibited a pH and redox dual-sensitive drug release profile with significantly accelerated drug release treated with pH 5.0 and 10 mM GSH (88.4% in 72 h) without drug burst release. The tumor proliferation assays indicated that DOX-grafted micelles, along with low cytotoxicity and well biocompatibility to normal cells up to a concentration of 10 μg/mL, inhibited the proliferation of HepG2 cells in a formulation-, time- and concentration-dependent manner in comparison with MCF-7 cells which was similar to free DOX. Anticancer activity releaved that the disulfide-modified micelles possessed much higher anti-hepatoma activity with a low IC 50 value of 1.1 μg/mL following a 72 h incubation. Furthermore, the intracellular uptake tested by CLSM and FCM demonstrated that multifunctional polymeric micelles could be more efficiently taken up by HepG2 cells compared with MCF-7 cells, agreed well with MTT assays, suggesting these well-defined micelles provide a potential drug delivery system for dual-responsive controlled drug release and enhanced anti-hepatoma therapy.
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BIOMACROMOLECULES
·
2015
·
IF 5.75
Zhao Wang,Ting Luo,Ruilong Sheng,Hui Li,Jingjing Sun,Amin Cao
In this work, a series of diblock terpolymer poly(6-O-methacryloyl-d-galactopyranose)-b-poly(methacrylic acid-co-6-cholesteryloxy hexyl methacrylate) amphiphiles bearing attached galactose and cholesterol grafts denoted as the PMAgala-b-P(MAA-co-MAChol)s were designed and prepared, and these terpolymer amphiphiles were further exploited as a platform for intracellular doxorubicin (DOX) delivery. First, employing a sequential RAFT strategy with preliminarily synthesized poly(6-O-methacryloyl-1,2:3,4-di-O-isopropylidene-d-galactopyranose) (PMAIpGP) macro-RAFT initiator and a successive trifluoroacetic acid (TFA)-mediated deprotection, a series of amphiphilic diblock terpolymer PMAgala-b-P(MAA-co-MAChol)s were prepared, and were further characterized by NMR, Fourier transform infrared spectrometer (FTIR), gel permeation chromatography (GPC), differential scanning calorimetry (DSC), and a dynamic contact angle testing instrument (DCAT). In aqueous media, spontaneous micellization of the synthesized diblock terpolymer amphiphiles were continuously examined by critical micellization concentration assay, dynamic light scattering (DLS), and transmission electron microscopy (TEM), and the efficacies of DOX loading by these copolymer micelles were investigated along with the complexed nanoparticle stability. Furthermore, in vitro DOX release of the drug-loaded terpolymer micelles were studied at 37 °C in buffer under various pH conditions, and cell toxicities of as-synthesized diblock amphiphiles were examined by MTT assay. Finally, with H1299 cells, intracellular DOX delivery and localization by the block amphiphile vectors were investigated by invert fluorescence microscopy. As a result, it was revealed that the random copolymerization of MAA and MAChol comonomers in the second block limited the formation of cholesterol liquid-crystal phase and enhanced DOX loading efficiency and complex nanoparticle stability, that ionic interactions between the DOX and MAA comonomer could be exploited to trigger efficient DOX release under acidic condition, and that the diblock terpolymer micellular vector could alter the DOX trafficking in cells. Hence, these suggest the pH-sensitive PMAgala-b-P(MAA-co-MAChol)s might be further exploited as a smart nanoplatform toward efficient antitumor drug delivery.
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BIOMACROMOLECULES
·
2013
·
IF 5.371
Yuefang Zhao,Yuting Qin,Yang Liang,Haijuan Zou,Xiao Peng,Huan Huang,Ming Lu,Min Feng
Short interfering RNAs (siRNAs) as chemotherapeutic RNAi agents hold great promise for a significant improvement in cancer therapy. Despite the promise, effective transport of siRNA with minimal side effects remains a challenge. The common problem associated with the low delivery efficiencies of current polycation-based gene delivery systems is their low stability in the presence of salt and serum. In the present study we developed the polyglutamate derivatives (PGS) polyelectrolyte brushes for NF-κB p65 siRNA delivery. The PGS polyelectrolyte brushes/siRNA polyplex was colloidally stable (150 nm diameter) in physiological saline (150 mM NaCl), likely due to the osmotic brushes of PGS. The size-controlled siRNA/PGS polyplex also showed the serum resistance resulting in their efficient cellular uptake was not negatively influenced by the presence of serum. The endothermic profile of ITC, their low values of Gibbs free energy and binding constants Kb under salt conditions provided the direct evidence that PGS polyelectrolyte brushes had a much lower binding affinity for serum proteins, compared with PEI 25KDa. PGS polyelectrolyte brushes delivering NF-κB p65 siRNA achieved efficient down-regulation of NF-κB p65 protein in HeLa cells. The NF-κB p65 down-regulation mediated by PGS polyelectrolyte brushes was more significant than PEI 25KDa and comparable to Lipofectamine 2000. Furthermore, the combination treatment with PGS polyelectrolyte brushes/NF-κB p65 siRNA polyplex and doxorubicin demonstrated synergistic apoptotic and cytotoxic effects on HeLa cancer cells. The high stability in physiological saline and salt-induced serum resistance of PGS polyelectrolyte brushes/siRNA polyplex has potential applications together with standard chemotherapies such as doxorubicin to be a viable method to improve the clinical outcomes in cancer therapies.
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