Drug Design Development and Therapy
·
2022
·
IF 4.319
Ruifeng Wu,Zhiqiang Zhang,Baohua Wang,Ge Chen,Yaozhong Zhang,Haowen Deng,Zilong Tang,Junjie Mao,Lei Wang
Purpose Lung cancer is the leading cause of cancer mortality worldwide. Drug resistance is the major barrier for the treatment of non-small cell lung cancer (NSCLC). The aim of this research is to develop an aptamer-decorated hybrid nanoparticle for the co-delivery of docetaxel prodrug (DTXp) and cisplatin (DDP) and to treat lung cancer.Materials and Methods Aptamer-conjugated lipid–polymer ligands and redox-sensitive docetaxel prodrug were synthesized. DTXp and DDP were loaded into the lipid–polymer hybrid nanoparticles (LPHNs). The targeted efficiency of aptamer-decorated, DTXp and DDP co-encapsulated LPHNs (APT-DTXp/DDP-LPHNs) was determined by performing a cell uptake assay by flow cytometry-based analysis. In vivo biodistribution and anticancer efficiency of APT-DTXp/DDP-LPHNs were evaluated on NSCLC-bearing mice xenograft.Results APT-DTXp/DDP-LPHNs had a particle size of 213.5 ± 5.3 nm, with a zeta potential of 15.9 ± 1.9 mV. APT-DTXp/DDP-LPHNs exhibited a significantly enhanced cytotoxicity (drug concentration causing 50% inhibition was 0.71 ± 0.09 μg/mL), synergy antitumor effect (combination index was 0.62), and profound tumor inhibition ability (tumor inhibition ratio of 81.4%) compared with the non-aptamer-decorated LPHNs and single drug-loaded LPHNs.Conclusion Since the synergistic effect of the drugs was found in this system, it would have great potential to inhibit lung tumor cells and in vivo tumor growth.
研究领域:
肿瘤学
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药学
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纳米技术
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Si Zheng,Danping Wang,Zhiyu Kuang,Shengyao Xu,Wenxiao Li,Haiyu Zhao,Jingyi Zhang,Weiyao Li,Zhonggui He,Jin Sun,Lin Li,Bingjun Sun
Fatty acid modification enhances DTX affinity to phospholipids, increasing encapsulation efficiency and in vitro stability. • D-BC PLs with “structure-like” prodrugs enhance lipid interactions, showing modest redox sensitivity, good PK, and tolerance. • D-SC PLs with “length-like” prodrugs show high redox sensitivity, cytotoxicity, tumor suppression yet mild high-dose toxicity. Liposomes are one of the most promising nano-delivery systems to deliver chemotherapeutic drugs. Docetaxel (DTX) is a classic type of taxane drug widely used in clinical practice. However, no liposomal DTX formulation has been approved for marketing. It is speculated that the structure of DTX was highly rigid and hydrophobic, making it hard to encapsulate DTX in either lipid membranes nor aqueous phase. Therefore, designing novel DTX liposomes with high encapsulation efficiency and stability deserves further exploration. Phospholipid molecules have a hydrophilic head and two hydrophobic fatty acids as tail chains. Inspired by the structure of phospholipids, two fatty acid modification strategies were developed to construct length-like DTX prodrug (D-SC) and structure-like DTX prodrug (D-BC). Compared with DTX liposomes, two DTX prodrug liposomes (D-SC PLs and D-BC PLs) were equipped with improved drug-carrier affinity reflecting in higher encapsulation efficiency and stability in vitro. Moreover, both prodrug liposomes exhibited intelligent drug release in tumor cells. Further, D-BC PLs outperformed in the circulation stability and tolerance probably due to the improved affinity by structure-like modification strategy. In turn, D-SC PLs exhibited rapid DTX release to effectively inhibit tumor growth but cause reversible toxicity at high dosage. Overall, this work provides new insights to construct advanced prodrug liposomes for efficient cancer therapy.
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DOI
高影响因子
COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
·
2024
·
IF 4.9
Yuan Lin,Chuangnan Li,Kaijie Cen,Jucai Xu,Jing Chen
Docetaxel (DTX) is a chemotherapeutic drug extracted from the needles of Taxus baccata with a broad anticancer spectrum that has been widely used for the treatment of various cancers. However, its high hydrophobicity and poor solubility results in low bioavailability that restricted clinical application. To circumvent these challenges, the present investigation was performed to develop DTX proliposomes mediated glycyrrhetinic acid ligand (glycyrrhetinic acid - diaminododecane - cholestrol, GADC) for the treatment of hepatocellular carcinoma. The optimal parameters of liposome formulation were egg phosphatidylcholine/cholesterol mass ratio of 9:1, the ratio of DTX to lipid substance within 1/10, the percent of GADC ligand (8 %), hydration time of 30 min and homogenization time of 10 min. To protect DTX liposomes from external environment during their storage, DTX proliposomes mediated GADC (GADC-DTX-PL), three optimum processing variables, lyoprotectants of sucrose and mannitol, the sucrose/mannitol ratio of 1:1, and the lyoprotectant/egg phosphatidylcholine of 8:1, were obtained after investigation. Under the optimum lyophilization conditions, GADC-DTX-PL was prepared and reconstituted proliposomes were determined to evaluate its physicochemical characterizations. These proliposomes showed that GADC-DTX-PL were spherical particles with an average size of 214.88 ± 11.00 nm, PDI value of 0.23 ± 0.00, zeta potential of –20.04 ±4.94 mV, encapsulation efficiency of 80.58 ± 0.91 %, and drug loading of 7.39 %. In addition, encapsulation of DTX in proliposomal formulation resulted in stable and slow drug release. Furthermore, in vitro bioactivity was evaluated, cytotoxicity effect and apoptosis efficiency of GADC-DTX-PL by HepG2 cells was significantly higher than that of DTX proliposomes without GADC. In the cell cycle assay, the results confirmed that the effect of GADC-DTX-PL regarding the initiation of apoptosis is accompanied with adjustment in the cell cycle progress via generating G2/M arrest. This potential of this novel approach for delivery DTX to hepatocellular cells lies in the ability to combine a targeted ligand of GADC and proliposomes simultaneously. Such formulation of GADC-DTX-PL enhances the selectivity of DTX delivery to hepatocellular cells, thereby improving the efficacy of chemotherapy.
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
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Lian Deng,Xiongjie Zhu,Zhongjian Yu,Ying Li,Lingyu Qin,Zhile Liu,Longbao Feng,Rui Guo,Yanfang Zheng
Background Although single-drug chemotherapy is still an effective treatment for esophageal cancer, its long-term application is limited by severe side-effects, poor bioavailability, and drug-resistance. Increasing attention has been paid to nanomedicines because of their good biological safety, targeting capabilities, and high-efficiency loading of multiple drugs. Herein, we have developed a novel T7 peptide-modified pH-responsive targeting nanosystem co-loaded with docetaxel and curcumin for the treatment of esophageal cancer.Methods Firstly, CM-β-CD-PEI-PEG-T7/DTX/CUR (T7-NP-DC) was synthesized by the double emulsion (W/O/W) method. The targeting capacity of the nanocarrier was then investigated by in vitro and in vivo assays using targeted (T7-NP) and non-targeted nanoparticles (NP). Furthermore, the anti-tumor efficacy of T7-NP-DC was studied using esophageal cancer cells (KYSE150 and KYSE510) and a KYSE150 xenograft tumor model.Results T7-NP-DC was synthesized successfully and its diameter was determined to be about 100 nm by transmission electron microscopy and dynamic light scattering. T7-NP-DC with docetaxel and curcumin loading of 10% and 6.1%, respectively, had good colloidal stability and exhibited pH-responsive drug release. Good biosafety was observed, even when the concentration was as high as 800 μg/mL. Significant enhancement of T7-NP uptake was observed 6 hours after intravenous injection compared with NP. In addition, the therapeutic efficacy of T7-NP-DC was better than NP-DC and docetaxel in terms of growth suppression in the KYSE150 esophageal cancer model.Conclusion The findings demonstrated that T7-NP-DC is a promising, non-toxic, and controllable nanoparticle that is capable of simultaneous delivery of the chemotherapy drug, docetaxel, and the Chinese Medicine, curcumin, for treatment of esophageal cancer. This novel T7-modified targeting nanosystem releases loaded drugs when exposed to the acidic microenvironment of the tumor and exerts a synergistic anti-tumor effect. The data indicate that the nanomaterials can safely exert synergistic anti-tumor effects and provide an excellent therapeutic platform for combination therapy of esophageal cancer.
研究领域:
纳米医学
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肿瘤学
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药学
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分子生物学
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DOI
PubMed
高影响因子
Biomaterials Science
·
2018
·Vol. 7
·期 3
·1117-1131
·
IF 5.831
Weiping Cui,Shenwu Zhang,Hanqing Zhao,Cong Luo,Bingjun Sun,Zhenbao Li,Mengchi Sun,Qing Ye,Jin Sun,Zhonggui He
Oral chemotherapy of docetaxel (DTX) is restricted by active P-glycoprotein (P-gp) efflux, hepatic first-pass metabolism and then poor oral absorption. Herein, a lipophilic thioether-bridged oleate prodrug (DTX-S-OA) and an ester-bond linked oleate prodrug of docetaxel (DTX-OA) were synthesized and efficiently incorporated into a self-nanoemulsifying drug delivery system (SNEDDS) using core-matching technology with a high drug-loading rate. DTX-S-OA SNEDDS produced a uniform droplet size of about 30 nm and a significantly high drug loading capability (60 mg mL−1), compared with DTX SNEDDS (20 mg mL−1). Additionally, DTX-S-OA SNEDDS exhibited a markedly slower drug release property and higher (>2-fold) drug solubilization in the aqueous phase after 60 min lipolysis compared with DTX SNEDDS. In situ single-pass intestinal perfusion and intestinal biodistribution studies demonstrated that the membrane permeability and intestinal bioadhesion of SNEDDS were significantly increased. Moreover, DTX-S-OA showed a comparable ability with verapamil in inhibiting P-gp efflux. Lymphatic transport studies confirmed that DTX-S-OA SNEDDS could significantly enhance intestinal lymphatic transport. Notably, the bioavailability of DTX-S-OA SNEDDS was 6.2-fold and 2.0-fold higher than that of the DTX solution and DTX SNEDDS, respectively. Furthermore, DTX-S-OA achieved a more rapid release of free DTX from the prodrug in systemic circulation than DTX-OA. Therefore, such a unique combination strategy of the single thioether-bridged DTX-oleate prodrug and SNEDDS is a promising platform to enable effective oral delivery of DTX.
研究领域:
药剂学
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药物递送
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药代动力学
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DOI
PubMed
高影响因子
Biomaterials Science
·
2019
·Vol. 8
·期 5
·1418-1430
·
IF 5.251
Tiankuan Li,Zhongqian Hu,Chao Wang,Jian Yang,Chuhui Zeng,Rui Fan,Jinhe Guo
Immunotherapy is gradually becoming as important as traditional therapy in the treatment of cancer, but adverse drug reactions limit patient benefits from PD1/PD-L1 checkpoint inhibitor drugs in the treatment of non-small cell lung cancer (NSCLC). As a chemotherapeutic drug for NSCLC, docetaxel (DTX) can synergize with PD1/PD-L1 checkpoint inhibitors but increase haematoxicity and neurotoxicity. Herein, anti-PD-L1 monoclonal antibody (mAb)-conjugated and docetaxel-loaded multifunctional lipid-shelled microbubbles (PDMs), which were designed with biologically safe phospholipids to produce synergistic antitumour effects, reduced the incidence of side effects and promoted therapeutic effects under ultrasound (US) irradiation. The PDMs were prepared by the acoustic-vibration method and then conjugated with an anti-PD-L1 mAb. The material features of the microbubbles and their cytotoxic effects, cellular apoptosis and cell cycle inhibition were studied. A subcutaneous tumour model was established to test the drug concentration-dependent and antitumour effects of the PDMs combined with US irradiation, and an orthotopic lung tumour model simultaneously confirmed the antitumour effect of this synergistic treatment. The PDMs achieved higher cellular uptake than free DTX, especially when combined with US irradiation. The PDMs combined with US irradiation also induced an increased rate of cellular apoptosis and an elevated G2-M arrest rate in cancer cells, which was positively correlated with PD-L1 expression. An in vivo study showed that synergistic treatment had relatively strong effects on tumour growth inhibition, increased survival time and decreased adverse effect rates. Our study possibly provides a well-controlled design for immunotherapy and chemotherapy and has promising potential for clinical application in NSCLC treatment.
研究领域:
肿瘤学
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药学
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生物医学工程
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免疫学
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DOI
PubMed
高影响因子
PULMONARY PHARMACOLOGY & THERAPEUTICS
·
2019
·
IF 2.669
Xiaojie Zhu,Ying Kong,Qi Liu,Yayuan Lu,Han Xing,Xiaoyu Lu,Yue Yang,Jiaqiu Xu,Ning Li,Di Zhao,Xijing Chen,Yang Lu
Pulmonary delivery of anti-cancer drugs in the form of nanoparticulate dry powders is considered a promising modality for treating lung cancer. However, it is not known whether the pharmacodynamics and pharmacokinetics of nano-preparations are altered after co-spray drying. In this study, we compared the physicochemical property, anti-cancer activity, tumor targeting and pharmacokinetic behavior of docetaxel-loaded folic acid-conjugated liposomes (LPs-DTX-FA) with those of dry powder prepared by co-spray-drying LPs-DTX-FA. The particle size and PDI after re-dispersion of the powder were increased. The re-dispersed liposomes showed increased cellular uptake via micropinocytosis and exhibited higher cytotoxicity than LPs-DTX-FA. Tumor targeting of re-dispersed liposomes was less effective compared with LPs-DTX-FA but the metabolism of re-dispersed liposomes was decreased. Tracheal administration resulted in a 45-fold higher concentration of docetaxel in the lung of Sprague Dawley rats at 30 min as compared with intravenous administration . Our results indicated that co-spray drying did change the properties, while tracheal administration of the dry powder provided higher drug exposure at the tumor site without increasing the exposure of other organs. Thus, inhaled dry powders might be clinically effective for treatment of lung cancer .
研究领域:
药理学
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肿瘤学
·
药物递送系统
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产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2017
·
IF 4.811
Mengrui Liu,Hongliang Du,Abdur Rauf Khan,Jianbo Ji,Aihua Yu,Guangxi Zhai
In this report, redox/enzyme responsive chondroitin sulfate-ss-deoxycholic acid (CSCD) conjugates were synthesized using cystamine as the linkage which could self-assemble to form self-assembled nanoparticles (175.6 + 5.2 nm) in the aqueous environment. Docetaxel (DTX) was loaded in nanoparticles with desired loading efficiency for the inhibition of tumor growth and metastasis of melanoma. Interestingly, nanoparticles were demonstrated to respond to hyaluronidase-1 (Hyal-1) which could degrade chondroitin sulfate (CS) backbones. In this case, we designed dual-sensitive nanoparticles with enhanced drug release pattern under the presence of glutathione (GSH)/Hyal-1. Compared with Taxotere®, CSCD nanoparticles significantly improved the DTX distribution in tumors and lungs with about 4.4-fold higher area-under-the-curve (AUC) value. In situ tumor volume and pulmonary metastatic formation were reduced upon the administration of DTX-loaded CSCD nanoparticles via DTX-induced apoptosis and decreased metastasis-promotion protein expression. With only minor cytotoxicity, CSCD nanoparticles could be promising nano-drug delivery systems for successful management of melanoma.
研究领域:
药剂学
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肿瘤学
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生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular BioSystems
·
2017
·Vol. 13
·期 10
·2125-2134
·
IF 2.781
Qianqian Wang,Fei Lu,Rongfeng Lan
Overcoming chemoresistance will prevent cancer relapse and contribute to clinical chemotherapy. In order to explore the underlying mechanism of chemoresistance, we firstly incubated cancer cells with a combination of cisplatin + paclitaxel (C + P) or cisplatin + paclitaxel + docetaxel (C + P + D) to mimic the treatment of cancer therapy in the laboratory. We found that polyploidy is a recurring strategy that cells adopt in response to cisplatin-based treatments. RNA-sequencing was performed to identify differentially expressed genes (DEGs) that may contribute to drug resistance. 4830 and 5518 DEGs were discovered in C + P and C + P + D resistant cells, respectively, and 4384 (73.40%) genes were shared. Possible drug resistance genes like Atg14, Abcb1b, Tbx2, Slc2a9, Slc10a3 and Slc22a18 were up-regulated while Foxm1, Bcl2, Brca1, Chek1, Hiatl1 and Abcb9 were down regulated. Genes involved in the pathways of p53 signaling, lysosomes and apoptosis were up-regulated, and in contrast, genes in the cell cycle, DNA replication, and mismatch repair pathways were down-regulated. Moreover, representative proteins relative to DEGs were examined to validate the results of RNA-seq and RT-PCR. Taken together, these results will contribute to revealing the mechanism of chemoresistance and discovering potential prognostic factors for cancer medication.
研究领域:
肿瘤学
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分子生物学
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基因组学
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DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Ping Liu,Jiantao Jia,Yinliang Lu,Hanmin Tang,Chengyi Gao,Suxia Han
Cognitive impairment is a common side effect of docetaxel (DTX)-based chemotherapy. The novel neuroprotective agent edaravone dexborneol (ED) was found to alleviate the adverse phenotype caused by DTX. However, the underlying mechanism remains unexplored. By analyzing mRNA-sequencing data, we noticed that the expression of S100 calcium-binding protein A11 (S100A11), a protector of the nervous system, was decreased in DTX-treated rats with cognitive damage, but ED administration reversed the trend. Therefore, we speculated that S100A11 might be involved in the protective effects of ED on DTX-induced cognitive impairment. Sprague-Dawley rats were intraperitoneally injected with DTX to induce cognitive impairment, followed by intraperitoneal injection of ED after DTX induction. The results showed that ED treatment mitigated cognitive impairment caused by DTX. Next, adenoviruses carrying sequences encoding S100A11 were given to rats receiving DTX treatment. S100A11 overexpression alleviated cognitive dysfunction of DTX-treated rats, as evidenced by the decreased escape latency and swimming distance, and the increased number of platform crossings. Mechanically, S100A11 overexpression inhibited neuronal apoptosis by inactivating the MAPK signaling pathway. Further rescue experiments showed that S100A11 knockdown reversed the defensive role of ED in DTX-induced neuronal damage. In conclusion, ED ameliorates cognitive dysfunction caused by DTX by upregulating the S100A11 expression and subsequently inactivating the MAPK signaling pathway.
研究领域:
神经科学
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药理学
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分子生物学
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肿瘤学
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生物化学
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2026
·
IF 5.9
Ying He,Nengbin Wan,Hongwu Deng,Yi Zhang,Qiang Liu,Li Li,Hao Liu,Xiao He,Qing Zhu
Triple-negative breast cancer (TNBC) is an aggressive malignancy often characterized by chemoresistance, partly due to the overexpression of drug efflux transporters like ABCG2. To address this challenge, this study developed and evaluated a cRGD-modified, pH-sensitive liposomal system for the targeted co-delivery of docetaxel (DTX) and siRNA against ABCG2 (si-ABCG2). The synthesized nanoparticles (DTX/siRNA/cRGD-PLPs) exhibited optimal physicochemical properties, including a mean particle size of approximately 241.7 nm, efficient co-loading of DTX and siRNA, and pH-responsive cargo release, while protecting the siRNA from degradation in serum. Also, DTX/siRNA/cRGD-PLPs maintained homogeneous size distributions over the storage period and induced minimal hemoglobin release, with hemolysis rates remaining below safety threshold. These liposomes demonstrated enhanced, time-dependent uptake into TNBC cell lines HCC1937 and MDA-MB-231. In vitro , the DTX/siRNA/cRGD-PLPs formulation was significantly more effective at inhibiting cell viability, proliferation, migration, and invasion, and at inducing apoptosis, compared to the free drug combinations and other controls. Moreover, the dual-payload co-delivery liposomes (DTX/siRNA/cRGD-PLPs) exerted superior anti-tumor effects relative to single-agent formulations. In an MDA-MB-231 xenograft mouse model, the liposomal treatment was well-tolerated and resulted in marked tumor growth inhibition, which was associated with reduced cell proliferation (Ki67) and increased apoptosis (Caspase-3) within the tumor tissue. This targeted co-delivery system shows significant potential for improving TNBC treatment by synergistically enhancing therapeutic efficacy and overcoming chemoresistance.
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产品关联
DOI
PubMed
高影响因子
Micro & Nano Letters
·
2021
·Vol. 16
·期 6
·336-343
·
IF 1.102
Hang Hu,Defeng Xu
In the present work, docetaxel (DTX) and retinoic acid (RA) co-loaded micelles were developed for synergistic prostate cancer therapy. PEG-RA and RA-PEG-RA were synthesized and subsequently used for loading of DTX and RA. The as prepared DTX/RA@RA-PEG-RA micelles exhibit smaller size and higher drug loading capacity as compared to DTX/RA@PEG-RA micelles. The in vitro drug release study shows that DTX/RA@PEG-RA and DTX/RA@RA-PEG-RA micelles exhibit similar drug release behaviours in which DTX exhibits fast release and RA exhibits sustained release. Nile red (NR) was loaded into PEG-RA and RA-PEG-RA micelles to investigate the cellular uptake of the micelles by fluorescence microscope and flow cytometry. The results show that NR@RA-PEG-RA micelles exhibit slightly enhanced cellular uptake as compared to NR@PEG-RA micelles. The cellular uptake of DTX/RA@PEG-RA and DTX/RA@RA-PEG-RA micelles determined by HPLC also show similar results. In in vitro cytotoxicity against C4-2 and 22Rv1 cells, DTX in combination with RA exhibit synergistic antitumor effect, and DTX/RA@PEG-RA and DTX/RA@RA-PEG-RA micelles exhibit enhanced cytotoxicity against C4-2 cells and similar cytotoxicity against 22Rv1 cells as compared to DTX/RA. DTX/RA@PEG-RA and DTX/RA@RA-PEG-RA micelles show significant potential for prostate cancer therapy.
研究领域:
药剂学
·
肿瘤学
·
生物材料
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）