Molecular Medicine Reports
·
2014
·Vol. 11
·期 4
·3078-3086
·
IF 1.484
Ai‑Jun Li,Yue‑Hua Zheng,Guo‑Dong Liu,Wei‑Sheng Liu,Pei‑Cheng Cao,Zhen‑Fu Bu
The treatment of glioblastoma, and other types of brain cancer, is limited due to the poor transport of drugs across the blood brain barrier and poor penetration of the blood‑brain‑tumor barrier. In the present study, cyclic Arginine‑Glycine‑Aspartic acid‑D‑Tyrosine‑Lysine [c(RGDyK)], that has a high binding affinity to integrin αvβ3 receptors, that are overexpressed in glioblastoma cancers, was employed as a novel approach to target cancer by delivering therapeutic molecules intracellularly. The c(RGDyK)/docetaxel polylactic acid‑polyethylene glycol (DTX‑PLA‑PEG) micelle was prepared and characterized for various in vitro and in vivo parameters. The specific binding affinity of the Arginine‑Glycine‑Aspartic acid (RGD) micelles, to the integrin receptor, enhanced the intracellular accumulation of DTX, and markedly increased its cytotoxic efficacy. The effect of microtubule stabilization was evident in the inhibition of glioma spheroid volume. Upon intravenous administration, c(RGDyK)/DTX‑PLA‑PEG showed enhanced accumulation in brain tumor tissues through active internalization, whereas non‑targeted micelles showed limited transport ability. Furthermore, RGD‑linked micelles showed marked anti‑glioma activity in U87MG malignant glioma tumor xenografts, and significantly suppressed the growth of tumors without signs of systemic toxicity. In conclusion, the results of the present study suggest that ligand‑mediated drug delivery may improve the efficacy of brain cancer chemotherapy.
研究领域:
药学
·
肿瘤学
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
Materials
·
2015
·Vol. 8
·期 2
·379-391
·
IF 2.651
Yanchao Liang,Zhihui Su,Yao Yao,Na Zhang
A novel polymer-drug conjugate was prepared by the chemical reaction between the copolymer Pluronic P123 and the docetaxel via a pH sensitive hydrazone bond. These pluronic P123-docetaxel (DTX) conjugates (P123-DTX) could form the stable drug-loaded materials that can self-assemble into the defined nano-micelles in aqueous solution because of their obvious amphiphilic property and low critical micelle concentration. The spherical morphology and particle size of the prepared nano-micelles were characterized by transmission electron microscopy and dynamic light scattering, respectively. Moreover, after the introduction of pH sensitive hydrazone bond, P123-DTX micelle showed a pH dependent drug release behavior. At pH 5.0 (in 48 h), the cumulative release amount of DTX were ~84.9%, which is about six times higher than that at pH 7.4. The prepared novel p123-DTX conjugates may offer a great benefit for drug delivery and controlling the drug release.Keywords:docetaxel;conjugates;nano-micelles;stability;pH controlled release
研究领域:
药剂学
·
生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2015
·Vol. 3
·期 20
·4259-4271
·
IF 4.726
Chunhuan Shi,Zhiqing Zhang,Fang Wang,Xiaoqing Ji,Zhongxi Zhao,Yuxia Luan
There are two major hurdles for the current anti-cancer drug delivery systems. One is the emergence of multidrug resistance (MDR) and the other is the conflict between long-circulation and cellular uptake. In the present study, the anticancer drug docetaxel (DTX) was successfully loaded into three series of micelles via self-assembly using a mixture of PEO–PPO–PCL and D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS), for the purpose of prolonging the blood circulation time as well as overcoming MDR of DTX. Three series of copolymers with different PCL molecular weights, PEO68–PPO34–PCL9, PEO68–PPO34–PCL18 and PEO68–PPO34–PCL36, were synthesized. The prepared spherical mixed micelles (MM) were found to possess nanoscale size (25–135 nm). The PEO–PPO–PCL/TPGS mixed micelles had a low critical micelle concentration (∼10−6 g mL−1) and a low hemolysis rate (<5%), which has proved that they are safe for use in vivo. Moreover, they had obvious sustained release behavior in vitro and a longer circulation time than free DTX in vivo. The P-gp inhibition assay, cellular uptake and MTT assay in cancer cells exhibited that DTX-loaded MM could overcome MDR, show higher cellular uptake and higher antitumor efficacy than free DTX. The IC50 values demonstrated that the three series of DTX-loaded MM were 69, 82 and 100 fold effective than free DTX after 72 h treatment with MCF-7 cells, respectively. Therefore, these results demonstrated that the prepared DTX-loaded MM provide desirable application in cancer chemotherapy.
研究领域:
药学
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肿瘤学
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生物材料
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2015
·Vol. 5
·期 66
·53835-53845
·
IF 3.84
Weihua Jiang,Lei Yang,Lipeng Qiu,Jingwen Xu,Xiuchun Yang,Ju Wang,Hui Zhou,Dongkai Wang
Multifunctional hybrid nanoparticles (NPs) based on sodium carboxymethylcellulose-graft-histidine (CMH) and TPGS were designed for effective delivery and overcoming multidrug resistance (MDR) of docetaxel (DTX). An amphiphilic CMH copolymer with excellent biocompatibility, pH-sensitivity, and solubilizing capacity for poorly soluble drugs was firstly synthesized and characterized. TPGS incorporated into CMH copolymer facilitated lower critical aggregation concentration (CAC) (0.0074 mg mL−1), smaller particle size (147.8 ± 3.14 nm), higher drug encapsulation (88.3 ± 3.33%), and better controlled release rate. The NPs based on CMH copolymer showed a pH-dependent drug release manner. The DTX-loaded CHT-1.5 NPs could significantly enhance cytotoxicity against both MCF-7 and MCF-7/ADR cells when compared to DTX-loaded CMH NPs and free DTX. Furthermore, cellular uptake and P-gp inhibition assays confirmed that the enhanced MDR reversal effect of DTX-loaded CHT-1.5 NPs was caused by the combination of increased drug accumulation and inhibition of P-glycoprotein mediated drug efflux in drug-resistant MCF-7/ADR cells. Consequently, CHT-1.5 NPs can act as an effective nanocarrier for delivering antitumor drugs and overcoming P-gp overexpressing tumor cells.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
DRUG DELIVERY
·
2017
·
IF 6.402
Xiangyu Su,Chanchan Gao,Fangfang Shi,Xiaoyao Feng,Lin Liu,Ding Qu,Cailian Wang
Multidrug resistance (MDR) is the major underlying cause of the low 5-year survival rate of esophageal carcinoma. In this study, we developed a novel microemulsion system (SD-ME) co-loaded with docetaxel (DTX) and Schizandrin A, a potent chemotherapeutic agent and a potential drug resistance modulator, respectively. In the physicochemical characterization studies, SD-ME displayed a well-defined spherical shape and size (56.62 ± 4.16 nm), a narrow polydispersity index (PDI, 0.132 ± 0.002), and a negative surface charge (−19.81 ± 3.11 mv). In the cellular uptake studies, SD-ME with a DTX concentration of 30 μg/mL exhibited a 3.9-fold enhancement of DTX internalization in DTX-resistant EC109 (EC109/DDR) cells in comparison to that observed for EC109 cells, and the mechanisms were associated with reducing P-gp expression and inhibiting P-gp ATPease. The half-maximal inhibitory concentrations (IC50) of DTX and SD-ME against EC109/DDR cells were 40.57 ± 0.39 and 3.59 ± 0.06 μg/mL, respectively. Likewise, the apoptotic rate of EC109/DDR treated with SD-ME increased up to 20-fold compared to that observed with free DTX. In anticancer efficacy studies in vivo, SD-ME markedly retarded the tumor growth of nude mice bearing EC109/DDR tumor xenografts compared with D-ME and free DTX throughout the duration of study. Consequently, mice treated with SD-ME had the highest survival rate (37.5%) during the observation period (70 days). In addition, there were no apparent side effects after the administration of SD-ME. Overall, our study provides evidence for SD-ME as an effective drug delivery system for enhanced MDR tumor treatment.
研究领域:
肿瘤学
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药剂学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Biomedical Nanotechnology
·
2017
·Vol. 13
·期 4
·393-408
·
IF 4.521
Tan LiWei,Ma BuYun,QianZhao .,LanZhang .,Chen LiJuan,Peng JinRong,Qian ZhiYong
In this work, docetaxel (DTX) was encapsulated in monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) micelles and monomethoxy poly(ethylene glycol)-poly(D, L-lactic acid) (mPEG-PLA) micelles, respectively. For the further application, the acute/genetic toxicity
evaluation and pharmacokinetic/pharmacodynamic study of the two kinds of micellar nanomedicines were performed. In the study of anticancer activity in vitro and in vivo, DTX micelles showed better tumorgrowth inhibition than free DTX. The pharmacokinetic and tissue distribution
studies showed that the DTX incorporated in micelles (especially in DTX-mPEG-PCL) retained significantly higher concentration in plasma and tumor tissue compared with free DTX. The acute toxicity and genotoxicity studies indicated that DTX micelles were safer than the docetaxel injection in
cancer therapy and DTX-mPEG-PCL had less damage to DNA than DTX-mPEG-PLA. So the micelles had a pronounced effect on reducing acute toxicity and genotoxicity of docetaxel. In conclusion, DTX micelles were efficient and safe on breast carcinoma chemotherapy.
研究领域:
药学
·
肿瘤学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
DRUG DELIVERY
·
2022
·
IF 6.819
Guolian Ren,Yujie Li,Canqi Ping,Danyu Duan,Ning Li,Jiaqi Tang,Rongrong Wang,Wenju Guo,Xiaomin Niu,Qiuyue Ji,Guoshun Zhang,Ruili Wang,Shuqiu Zhang
To realize the synergistic anti-tumor effect of chemotherapy and photodynamic therapy, the mono sulfide-modified docetaxel (DTX) prodrugs (DSD) provided by our laboratory and hematoporphyrin (HP) were used to physically prepare co-assembled nanoparticles (DSD/HP NPs) by nano-precipitation. For the first time, this study showed its characteristics, in vitro anti-tumor activity, pharmacokinetic behavior in rats, in vivo distribution, and pharmacodynamic effects on 4T1 tumor-bearing Bal b/c mice. DSD/HP NPs optimized by single-factor and response surface optimization had several distinct characteristics. First, it had dark purple appearance with particle size of 105.16 ± 1.24 nm, PDI of 0.168 ± 0.15, entrapment efficiency and drug loading of DSD and HP in DSD/HP NPs of 96.27 ± 1.03% and 97.70 ± 0.20%, 69.22 ± 1.03% and 20.03 ± 3.12%, respectively. Second, it had good stability and could release DTX and HP slowly in the media of pH 7.4 PBS with 10 mM DTT (H2O2). Moreover, DSD/HP NPs along with NiR treatment significantly inhibited 4T1 cells proliferation, and induced more reactive oxygen species and cells apoptosis. In vivo pharmacokinetic and pharmacodynamic studies showed that DSD/HP NPs could prolong the drug circulation time in rats, increase drug distribution in tumor site, obviously inhibit tumor growth, and decrease the exposure of drug to normal tissues. Therefore, DSD/HP NPs as a promising co-assembled nano-drug delivery system could potentially improve the therapeutic efficiency of chemotherapeutic drug and achieve better anti-tumor effects due to the combination of chemotherapy and photodynamic therapy.
研究领域:
药学
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纳米技术
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肿瘤学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Fangqian Sui,Zengjun Fang,Lingjun Li,Xinhuan Wan,Yongqing Zhang,Xiaoqing Cai
Multifunctional nanoparticles have attracted significant attentions for oncology and cancer treatment. In fact, they could address critical point for tumour treatment by creating a stimuli-responsive targeted drug delivery system that can exist stably in the systemic circulation, efficiently penetrate the tumour tissue, and then accumulate in tumour cells in large quantities. A novel stepwise pH-responsive multifunctional nanoparticles (FPDPCNPs/DTX) for targeted delivery of the antitumour drug docetaxel (DTX) is prepared by coating a tumour acidity-sensitive “sheddable” FA modified β-carboxylic amide functionalized PEG layer (folic acid-polyethylene glycol-2,3-dimethylmaleic anhydride, FA-PEG-DA) on the cationic drug-loaded core (poly(β-amino ester-cholesterol, PAE-Chol) through electrostatic interaction in this study. The charge shielding behaviour of the FPDPCNPs/DTX was confirmed by zeta potential assay. The surface charges of the nanoparticles can change from positive to negative after PEG coating. The IC 50 values of FPDPCNPs/DTX was 3.04 times higher than that of PEG “unsheddable” nanoparticles in cytotoxicity experiments. The results of in vivo experiment further showed that FPDPCNPs/DTX had enhanced tumour targeting effect, the tumour inhibition rate of FPDPCNPs/DTX was as high as 81.99%, which was 1.51 times that of free DTX. Under a micro acidic environment and folate receptor (FR)-mediated targeting, FPDPCNPs/DTX contributed to more uptake of DTX by MCF-7 cells. In summary, FPDPCNPs/DTX as a multifunctional nano-drug delivery system provides a promising strategy for efficiently delivering antitumour drugs.
研究领域:
肿瘤学
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癌症治疗
·
药物递送系统
·
纳米技术
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2025
·
IF 5.1
Wenjing Wang,Shuo Wang,Shengyao Xu,Rong Chai,Jun Yuan,Hao Zhang,Yaqi Li,Xiaohui Pu,Xin Li,Jin Sun,Zhonggui He,Bingjun Sun
The self-assembly prodrugs usually consist of drug modules, activation modules, and assembly modules. The selection of suitable modules to construct prodrug nanoassemblies with self-assembly stability and intelligent activation is still a challenge. As a common assembly module, oleic acid can provide a driving force and steric hindrance for prodrugs self-assembly. However, unsaturated double bond of oleic acid is easily oxidized to affect its chemical stability. Herein, two docetaxel (DTX) prodrugs were designed using disulfide bonds as activation modules and two different fatty acids (isostearic acid and oleic acid) as assembly modules, respectively. Compared with oleic acid, isostearic acid has the advantage of higher chemical stability. At the same time, the terminal propyl structure of isostearic acid makes up for the steric hindrance without double bond. Overall, this structural deformation improved the self-assembly ability and chemical stability of the prodrug nanoassemblies, thus balancing the effectiveness and safety of the prodrugs. Our findings reveal the importance of the assembly modules and provide a guidance for the rational design of prodrug nanoassemblies.
研究领域:
药学
·
纳米医学
·
肿瘤治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2018
·
IF 5.08
Xiang Feng,Yunfeng Zhou,Xin Xie,Ming Li,Hao Huang,Liangliang Wang,Xiao Xu,Jingmou Yu
In this study, prostate-specific membrane antigen (PSMA)-targeted and core-crosslinked micelles were developed based on prostate cancer-binding peptide (PCP) modified glycol chitosan-lipoic acid (PGC-LA) conjugate. The degree of substitution was 5.2 PCP groups and 10.7 lipoic acid groups per 100 sugar residues of glycol chitosan in PGC-LA copolymer. Docetaxel (DTX) was chosen as a model anti-tumor drug. The DTX-loaded micelles were prepared by an o/w method, and core-crosslinked micelles were further constructed by using a catalytic amount of dithiothreitol. The mean diameter of DTX-loaded core-crosslinked PGC-LA (DTX-PGC-LA/cc) micelles was 397 nm determined by dynamic light scattering (DLS). In vitro DTX released from core-crosslinked micelles was slower than that from non-crosslinked counterpart. Blank micelles exhibited good biocompatibility. Additionally, cellular uptake and cytotoxcity of PCP-modified micelles were higher than those of micelles without PCP in PSMA-positive LNCaP cells. Importantly, DTX-PGC-LA/cc demonstrated the stronger anti-tumor efficacy against LNCaP tumor xenograft models than DTX injection and other DTX-loaded micelles. Taken together, this study provides a potential way in developing actively targeted and core-crosslinked micelles for hydrophobic drug delivery in cancer therapy.
研究领域:
药剂学
·
肿瘤学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2017
·
IF 6.402
Shenwu Zhang,Jibin Guan,Mengchi Sun,Dong Zhang,Haotian Zhang,Bingjun Sun,Weiling Guo,Bin Lin,Yongjun Wang,Zhonggui He,Cong Luo,Jin Sun
Breast cancer leads to high mortality of women in the world. Docetaxel (DTX) has been widely applied as one of the first-line chemotherapeutic drugs for breast cancer therapy. However, the clinical outcome of DTX is far from satisfaction due to its poor drug delivery efficiency. Herein, a novel disulfide bond bridged oleate prodrug of DTX was designed and synthesized to construct self-delivering prodrug-based nanosystem for improved anticancer efficacy of DTX. The uniquely engineered prodrug-nanoassemblies showed redox-responsive drug release, increased cellular uptake and comparable cytotoxicity against 4T1 breast cancer cells when compared with free DTX. In vivo, oleate prodrug-based nanoparticles (NPs) demonstrated significantly prolonged systemic circulation and increased accumulation in tumor site. As a result, prodrug NPs produced a notable antitumor activity in 4T1 breast cancer xenograft in BALB/c mice. This prodrug-based self-assembly and self-delivery strategy could be utilized to improve the delivery efficiency of DTX for breast cancer treatment.
研究领域:
肿瘤学
·
药剂学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
·
2021
·
IF 3.534
Hong Wang,Wanghao Chen,Guojian Wu,Jun Kong,Shaofei Yuan,Lukui Chen
Glioma-targeted drug delivery is a hugely challenging task because of the multibarrier in the brain. In this study, we report a magnetic T7 peptide&AS1411 aptamer-modified microemulsion for triple glioma-targeted delivery of shikonin and docetaxel (Fe 3 O 4 @T7/AS1411/DTX&SKN-M). Such a system comprises two tumor-targeted ligands (T7 peptide and AS1411 aptamer), ultra-small superparamagnetic iron oxide nanoparticle (Fe 3 O 4 ), and shikonin&docetaxel-coloaded microemulsion (SKN&DTX-M). Fe 3 O 4 @T7/AS1411/DTX&SKN-M is capable of stably circulating in the blood, accumulating around the brain under an external magnetic field, distributing inside the glioma via the affinity to nucleolin/transferrin receptor, and retarding the growth of orthotopic glioma. Fe 3 O 4 @T7/AS1411/DTX&SKN-M encapsulated Fe 3 O 4 nanoparticles in the core to obtain the superparamagnetism, which did not influence the main surface properties. Introducing 6% (wt%) of DSPE-PEG 2000 -T7 and 180 nM of AS1411 collaboratively enhanced the murine glioma (G422) cellular uptake of Fe 3 O 4 @T7/AS1411/DTX&SKN-M and thereby achieved the strongest antiproliferation among all the groups. Notably, the drug distribution at the brain sites of orthotopic Luc-G422 glioma tumor-bearing nude mice treated with Fe 3 O 4 @T7/AS1411/DTX&SKN-M was overwhelming among all the treatments. Most importantly, Fe 3 O 4 @T7/AS1411/DTX&SKN-M not only significantly reduced the luminescence signal at the brain areas of orthotopic Luc-G422 glioma mice but also prolonged the overall survival period. The enhancement of anti-glioma efficacy was associated with down-regulating the population of CD133- and CD44-positive cells within the tumors. In summary, such a triple glioma-targeted delivery of shikonin and docetaxel using combinational magnetism and T7/AS1411 modification strategies provides a promising method for synergistic and precise glioma therapy.
研究领域:
药学
·
肿瘤学
·
纳米医学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）