COLLOIDS AND SURFACES B-BIOINTERFACES
·
2018
·
IF 3.997
Xin Jin,Sajid Asghar,Mei Zhang,Zhipeng Chen,Lin Huang,Qineng Ping,Yanyu Xiao
N -acetylcysteine modified hyaluronic acid-paclitaxel (NAC-HA-PTX) conjugate was designed to improve the water solubility and oral bioavailability of PTX through mucosal bioadhesion ability. The average size of spherical NAC-HA-PTX micelles was 187 nm with a zeta potential of -25.38 mV. Mucin adhesion study showed that the amount of mucin adhered to NAC-HA-PTX micelles was 1.98-fold greater than that of hyaluronic acid-paclitaxel (HA-PTX) micelles. The fluorescence micrographs showed that the biodistribution sequence of coumarin 6-loaded micelles in the gastrointestinal tract was duodenum > jejunum > ileum, and NAC-modified micelles significantly exhibited better mucoadhesive properties than the corresponding unmodified ones. The pharmacokinetic study showed that the area under the curve (AUC 0-24h ) of NAC-HA-PTX micelles was 2.32-fold and 2.56-fold higher compared to that of HA-PTX micelles and PTX solution (Taxol) after oral administration, respectively. NAC-HA-PTX micelles appear to be a promising drug delivery system to improve the bioavailability of insoluble drugs for efficient tumor therapy via oral administration.
研究领域:
药剂学
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肿瘤学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2018
·
IF 3.466
Xian Tang,Jingdong Rao,Sheng Yin,Jiaojie Wei,Chunyu Xia,Man Li,Ling Mei,Zhirong Zhang,Qin He
The Cancer-Immunity Cycle is a series of anticancer immune responses initiated and allowed to proceed and expand iteratively. Paclitaxel (PTX) is a classic chemotherapeutic agent, which could induce immunogenic cell death (ICD) to trigger the Cancer-Immunity Cycle. However, the Cycle is severely impaired by tumor cell immunosuppression of host T cell antitumor activity through the programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) (PD-1/PD-L1) immune checkpoint pathway. Here, we demonstrated that PTX mediated the Cancer-Immunity Cycle could be enhanced by PD-L1 knockdown (KD) and followed mTOR pathway inhibition in tumor cells. PD-L1 siRNA (siP) and the hydrophobic chemotherapy drug PTX were co-delivered with a rationally designed hybrid micelle (HM). We showed clear evidence that the HM-siP/PTX is capable of delivering siP and PTX simultaneously to the B16F10 cells both in vitro and in vivo . We demonstrated that HM-PTX/siP reduced the expression of PD-L1 and p-S6K (a marker of mTOR pathway activation) both in vitro and in melanoma-bearing mice and attenuated synergistically tumor growth by chemical toxicity , promoting cytotoxic T-cell immunity and suppressing the mTOR pathway.
研究领域:
肿瘤学
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免疫治疗
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2018
·
IF 3.997
Min Yang,Houqiang Ding,Yixin Zhu,Yanxiu Ge,Lingbing Li
A strategy of preparing mixed micelles containing both DOX prodrug and PTX prodrug was developed, i.e., synthesizing a DOX conjugate and a PTX conjugate started with the same biocompatible amphiphilic copolymer, TPGS and DTDPA, a linker containing disulfide bond. The mixed micelles were prepared by co-assembling the two conjugates with a particle size about 98.5 nm. The mixed micelles could release anticancer drug DOX and PTX upon cellular reduction once they came into the cancerous cells. Moreover, the mixed micelles displayed synergistic effect in vitro and the combination therapy in micellar dosage-form led to reduced systematic toxicity and enhanced antitumor efficacy in vivo .
研究领域:
药剂学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2022
·Vol. 14
·期 3
·535
·
IF 6.525
Huiru Zhu,Li Kong,Xu Zhu,Tingting Ran,Xiaojuan Ji
A high incidence of restenosis has been reported at the site of inflammation following angioplasty and stent implantation. The anti-proliferative drug paclitaxel (PTX) could help to reduce inflammation and restenosis; however, it has poor water solubility and serious adverse side effects at high doses. Given the presence of metabolic acidosis at the site of inflammation, we hypothesized that nanoparticles that are responsive to low pH could precisely release the loaded drug at the target site. We successfully constructed pH-responsive poly(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles loaded with PTX and NaHCO3as a pH-sensitive therapeutic agent (PTX-NaHCO3-PLGA NPs). The NPs exhibited remarkable pH sensitivity and a good safety profile both in vitro in rat vascular smooth muscle cells and in vivo in Sprague Dawley rats after tail vein injection. In the rat model, the PTX-NaHCO3-PLGA NPs treatment group showed suppressed intimal proliferation following balloon-induced carotid artery injury compared with that of the saline-treated control. Overall, these results demonstrate that our newly developed pH-responsive nanodrug delivery platform has the potential to effectively inhibit restenosis.Keywords:vascular restenosis;pH-responsive nanoparticles;sodium bicarbonate;paclitaxel;drug delivery
研究领域:
医学
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药学
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生物材料
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
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2020
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IF 4.902
Tan Yang,Jianfang Feng,Qian Zhang,Wei Wu,Hailan Mo,Lanzhen Huang,Wei Zhang
A delivery system based on l-carnitine (LC) conjugated chitosan (CS)-stearic acid polymeric micelles has been developed for improving the oral bioavailability of paclitaxel (PTX) through targeting intestinal organic cation/carnitine transporter 2 (OCTN2). Stearic acid grafted chitosan (CS-SA), as micelle skeleton material, was synthesized by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated coupling reaction. The PTX-loaded micelles were prepared by solvent evaporation-hydration method, and the ligand LC was conjugated onto the micelle surface by anchoring its derivative stearoyl group to the lipophilic core of micelle. The modified polymeric micelles showed regular spherical shapes with small particle size of 157.1 ± 5.2 nm and high drug loading capacity of 15.96 ± 0.20 wt%, and the micelle stability in water was supported by low critical micelle concentration of 14.31 ± 0.21 μg/ml. The drug-loaded micelles presented a slow and incomplete in vitro release, and the pharmacokinetic studies indicated the micelle carriers increased the relative bioavailability of PTX to 165.8% against the commercial formulation. The enhancement effect on intestinal absorption was also confirmed by the intracellular uptake of Caco-2 cells. The proposed micelle carrier system manifested a prospective tool for oral drug delivery.
研究领域:
药剂学
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药物递送系统
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分子生物学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
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2020
·Vol. 10
·期 46
·27676-27687
·
IF 3.119
Jiang Yu,Shuang Zhou,Jinbo Li,Yingli Wang,Yujiao Su,Dongxu Chi,Jiamei Wang,Xue Wang,Zhonggui He,Guimei Lin,Dan Liu,Yongjun Wang
Liposomes are among the most successful nanocarriers; several products have been marketed, all of which were prepared by active loading methods. However, poorly water-soluble drugs without ionizable groups are usually incorporated into the lipid bi-layer of liposomes by passive loading methods, with serious drug leakage during blood circulation. Furthermore, there have been few improvements in their anti-cancer activity and safety. Herein, we designed and synthesized three weak-acid modified paclitaxel (PTX) derivatives with a one-step reaction for the remote loading of liposomal formulations. By comparison, PTX-succinic acid liposomes (PTX-SA LPs) exhibited the highest encapsulation efficiency (97.2 ± 1.8%) and drug loading (8.84 ± 0.16%); meanwhile, there was almost no change in their particle size or zeta potential within one month. Furthermore, compared with Taxol®, the PTX-SA LPs showed a 4.35-fold prolonged half-time, enhanced tumor accumulation, and an increased maximum tolerated dose (MTD) of more than 30 mg kg−1. As a result, the PTX-SA LPs displayed significantly improved in vivo anti-cancer efficacy in comparison with Taxol®. Therefore, weak-acid modification is proved to be a simple and effective method to achieve remote loading and high encapsulation efficiency of poorly soluble drugs, showing great potential for clinical application.
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
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2020
·
IF 4.389
Mengyao Liu,Manfei Fu,Xiaoye Yang,Guoyong Jia,Xiaoqun Shi,Jianbo Ji,Xianghong Liu,Guangxi Zhai
Multidrug resistance (MDR) in tumor has long been considered a major factor in the failure of tumor chemotherapy. P-glycoprotein (P-gp)-mediated drug efflux plays a significant role in the MDR of tumor. Herein, paclitaxel (PTX) and P-gp inhibitor quercetin (QC) co-loaded and chondroitin sulfate (ChS)-coated mesoporous silica nanoparticles (MSNs) ( [email protected] ) were developed to reverse MDR in breast cancer and improve chemotherapy efficacy. The dual drug-loaded nanoparticles (NPs) showed a nanoscale size of ∼ 227.2 nm and redox-responsive drug release property. In vitro cell experiments showed that NPs exhibited CD44 receptor-mediated active targeting in MCF-7/ADR cells. The dual drug-loaded NPs had lower IC 50 value, higher apoptosis rate, obvious G2M phase arrest as well as stronger microtubule destruction in MCF-7/ADR cells compared to PTX-loaded NPs, suggesting that QC addition, significantly, improved the sensitivity of MCF-7/ADR cells to PTX. Further study found that QC-loaded NPs down-regulated the expression of P-gp. Notably, the dual drug-loaded NPs exhibited tumor-targeting ability, prolonged tumor retention time and effective anti-tumor effect without obvious toxicity to normal tissues in vivo . Taken together, our research provides a viable approach to overcome MDR in breast cancer.
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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生物医学工程
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产品关联
DOI
PubMed
高影响因子
Small Methods
·
2022
·Vol. 6
·期 7
·2101531
·
IF 15.367
Shuqi Jiang,Xiaohu Li,Fang Zhang,Jiaji Mao,Minghui Cao,Xinna Zhang,Siming Huang,Xiaohui Duan,Jun Shen
Chemotherapy plays an important role in treating cancers in clinic. Hypoxia-mediated chemoresistance remains a major hurdle for effective tumor chemotherapy. Herein, a new class of tLyP-1-modified dopamine (DOPA)-β-cyclodextrin (CD)-coated paclitaxel (PTX)- and manganese dioxide (MnO 2 )-loaded nanoparticles (tLyP-1-CD-DOPA-MnO 2 @PTX) is developed to enhance glioma chemotherapy. The nanomedicine delivered to the tumor site decomposes in response to the weak acidity and high hydrogen peroxide in the tumor microenvironment (TME), resulting in collapse of the system to release PTX and generates Mn 2+ and O 2 . In a rat model of intracranial glioma, tLyP-1-CD-DOPA-MnO 2 @PTX can efficiently pass through the blood-brain-barrier to accumulate in tumor sites. The hypoxia in TME can be relieved via O 2 generated by MnO 2 and the reactive oxygen species produced by Mn 2+ can kill tumor cells. The tLyP-1-CD-DOPA-MnO 2 @PTX nanoparticles exert a remarkable antitumor effect by promoting apoptosis and inhibiting proliferation of tumor cells in addition to enabling real-time tumor monitoring with magnetic resonance imaging. This MnO 2 -based theranostic medicine will offer a novel strategy to simultaneously enhance chemotherapy and achieve real-time imaging of therapeutic process in glioma treatment.
研究领域:
纳米技术
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癌症治疗
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神经科学
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药学
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医学成像
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2022
·
IF 10.723
Dan Gao,Sajid Asghar,Junxiu Ye,Mei Zhang,Rongfeng Hu,Yadong Wang,Lin Huang,Chengjun Yuan,Zhipeng Chen,Yanyu Xiao
In this study, a CD44 and biotin receptors dual-targeted enzyme-sensitive hyaluronic acid nanogel loading paclitaxel (PTX/Bio-NG) for targeting breast cancer was constructed. Spherical nanogels with a mean particle size of 149.1 ± 1.6 nm, higher entrapment efficiency (90.17 ± 0.52 %) and drug loading (15.28 ± 0.10 %) were obtained. PTX/Bio-NG quickly released drugs under the catalysis of hyaluronidase and/or lipase . Cell studies revealed that the uptake of Bio-NG by 4T1 cells was mediated by CD44 receptor and Bio-specific receptor. Compared with PTX-loaded biotin-free NG (PTX/NG), PTX/Bio-NG had higher cytotoxicity against breast cancer cells (4T1 cells). The rats pharmacokinetic profile indicated higher AUC 0-t but lower clearance rates of PTX/NG (6.24 times and 15.96 %, respectively) and PTX/Bio-NG (6.66 times and 14.89 %, respectively) than control group (Taxol). In vivo studies showed that PTX/Bio-NG possessed excellent therapeutic efficacy in 4T1 tumor-bearing Balb/c mice, which suggest that PTX/Bio-NG could be an excellent candidate for the treatment of breast cancer.
研究领域:
药学
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Xiaoying Wang,Yaling Zheng,Liangzhen Qiu,Huizhi Ouyang,Xueya Xu,Wen Xu,Yuqin Zhang,Wei Xu
D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS)-modified carboxymethyl chitosan-rhein (TCR) polymeric micelles (PMs) self-assembled by TCR conjugate were constructed for oral delivery of paclitaxel (PTX). PTX-loaded TCR PMs with a drug loading capacity of 47.52 ± 1.65 % significantly improved the intestinal absorption and oral bioavailability of PTX. TCR PMs loaded with PTX displayed time- and concentration-dependent cytotoxicity in Caco-2, MCF-7 and Taxol-resistant MCF-7 (MCF-7/Taxol) cells. In MCF-7/Taxol cells, PTX-loaded TCR PMs promoted apoptosis and changed cell cycle, and TCR conjugate exhibited a P-gp inhibition ability and caused ATP depletion. Moreover, confocal imaging of intestinal sections, Caco-2 cell uptake assay and in vivo bioimaging using environmental response fluorescence probe suggested that TCR PMs loaded with drugs can be absorbed as a whole through the intestinal epithelium after oral administration, enter systemic circulation, and then get to the tumor site. Remarkably, PTX-loaded TCR PMs displayed a significant antitumor effect in H22 tumor xenograft mice and the MCF-7 or MCF-7/Taxol xenograft zebrafish model, which was related to the inhibitory function of TCR conjugate for P-gp activity and P-gp and MDR1 expression. Functionalized TCR PMs are expected to improve the oral therapeutic efficacy of poorly water-soluble antitumor drugs and treat drug-resistant tumors.
研究领域:
药学
·
肿瘤学
·
生物技术
·
药物递送系统
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2021
·
IF 5.875
Xiaoyu Lu,Hangyi Wu,Yiping Liang,Zhenhai Zhang,HuiXia Lv
Most anticancer drugs are not orally bioavailable due to their undesirable physicochemical properties and inherent physiological barriers. In this study, a polymeric prodrug strategy was presented to enhance the oral bioavailability of BCS class IV drugs using paclitaxel (PTX) as the model drug. PTX was covalently conjugated with cholic acid-functionalized PEG by a redox-sensitive disulfide bond . Cholic acid-functionalized PEGylated PTX (CPP) achieved remarkably improved PTX solubility (>30,000-fold), as well as favorable stability under the physiological environment and controlled drug release in the tumor. Meanwhile, CPP could self-assemble into nanoparticles with an average size of 56.18 ± 2.06 nm and drug loading up to 17.6% (w/w). Then, permeability study on Caco-2 cell monolayers demonstrated that CPP obtained an approximately 4-fold increase by apical sodium-dependent bile acid transporter (ASBT) mediated transport, compared with Taxol®. Pharmacokinetic studies carried out in rats confirmed that the oral bioavailability of CPP was 10-fold higher than that of Taxol®. Finally, significant improvement in the antitumor efficacy of CPP against breast cancer was confirmed on MDA-MB-231 cells. In summary, this prodrug-based cascade strategy offers new ways for chemotherapeutic drugs whose oral delivery is limited by solubility and permeability, also endows drugs with the capacity of tumor-specific release.
研究领域:
药学
·
药物递送系统
·
癌症治疗
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2021
·Vol. 22
·期 13
·6659
·
IF 5.924
Yang Han,Jieyi Pan,Na Liang,Xianfeng Gong,Shaoping Sun
In this study, an amphiphilic conjugate based on mPEG and cholesterol-modified chitosan with hydrazone bonds in the molecules (mPEG-CS-Hz-CH) was successfully synthesized. Using the polymer as the carrier, the paclitaxel (PTX)-loaded mPEG-CS-Hz-CH micelles were prepared by an ultrasonic probe method. The mean particle size and zeta potential of the optimized PTX-loaded micelles were 146 ± 4 nm and +21.7 ± 0.7 mV, respectively. An in vitro drug release study indicated that the PTX-loaded mPEG-CS-Hz-CH micelles were stable under normal physiological conditions (pH 7.4), whereas rapid drug release was observed in the simulated tumor intracellular microenvironment (pH 5.0). An in vitro cytotoxicity study demonstrated the non-toxicity of the polymer itself, and the PTX-loaded micelles exhibited superior cytotoxicity and significant selectivity on tumor cells. An in vivo antitumor efficacy study further confirmed that the PTX-loaded micelles could improve the therapeutic efficacy of PTX and reduce the side effects. All these results suggested that the mPEG-CS-Hz-CH micelles might be promising pH-sensitive nanocarriers for PTX delivery.Keywords:chitosan;drug delivery;paclitaxel;pH-sensitive;polymeric micelles
研究领域:
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）