MOLECULAR PHARMACEUTICS
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2013
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IF 4.57
He Lian,Tianhong Zhang,Jin Sun,Xiaohong Liu,Guolian Ren,Longfa Kou,Youxi Zhang,Xiaopeng Han,Wenya Ding,Xiaoyu Ai,Chunnuan Wu,Lin Li,Yongjun Wang,Yinghua Sun,Siling Wang,Zhonggui He
In addition to being a physiological protective barrier, the gastrointestinal mucosal membrane is also a primary obstacle that hinders the oral absorption of many therapeutic compounds, especially drugs with a poor permeability. In order to resolve this impasse, we have designed multifunctional nanomicelles based on the acetylcysteine functionalized chitosan-vitamin E succinate copolymer (CS-VES-NAC, CVN), which exhibit marked bioadhesion, possess the ability to penetrate mucus, and enhance the oral absorption of a hydrophobic drug with a poor penetrative profile, paclitaxel. The intestinal absorption (Ka = 0.38 ± 0.04 min–1, Papp = 0.059 cm·min–1) of CVN nanomicelles was greatly improved (4.5-fold) in comparison with paclitaxel solution, and CLSM (confocal laser scanning microscope) pictures also showed not only enhanced adhesion to the intestinal surface but improved accumulation within intestinal villi. The in vivo pharmacokinetics indicated that the AUC0–t (586.37 ng/mL·h) of CVN nanomicelles was markedly enhanced compared with PTX solution. In summary, the novel multifunctional CVN nanomicelles appear to be a promising nanocarrier for insoluble and poorly permeable drugs due to their high bioadhesion and permeation-enhancing capability.
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MATERIALS & DESIGN
·
2024
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IF 7.6
Zhining Zhuo,Yuehan Ouyang,Xiyue Zheng,Xiaobang Chen,Zequan Lin,Ruitian Zhu,Lan Lan,Dongyang Qian,Rongrong Li,Jixiang Zhu,Yuanye Dang,Yan Wang,Sida Liao,Xiumei Tian,Fanwen Yang
Airway stenosis, a significant cause of dyspnea, is commonly managed with airway stents. However, conventional stents frequently lead to restenosis. Excessive proliferation of fibroblasts and smooth muscle cells during abnormal repair processes is a key factor in airway restenosis. To address this challenge, a novel drug-loaded airway stent has been designed with personalized tailoring for the patient. This stent features a three-layered structure: an outer layer made from a blend of thermoplastic polyurethane (TPU) and Poloxamer 407 (P407), a drug-loading intermediate layer, and an inner layer made of TPU. This design aims to minimize airway irritation and enable adjustable drug release rates by adjusting the drug carrier and/or the content of P407 in the stent’s outer layer. Drug release profile conforms to the Improved First-Order model. Notably, P407 is released from the stent, serving a dual purpose: it creates micropores to regulate the drug release rate and synergizes with PTX to inhibit the proliferation of fibroblasts. This combination significantly enhances the inhibitory effect on the proliferation of fibroblasts and smooth muscle cells, without adversely affecting airway epithelial cells. This may represent a novel approach to reducing restenosis by addressing a critical complication associated with the use of airway stents.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Qingyu Lu,Wenhao Gao,Zhenzhen Chen,Zhihong Liu,Jie Wang,Lingjun Zeng,Xiaomu Hu,Enqin Zheng,Qian Zhang,Hongtao Song
Ovarian cancer is a malignant tumor that seriously endangers the lives of women, with chemotherapy being the primary clinical treatment. However, chemotherapy encounters the problem of generating multidrug resistance (MDR), mainly due to drug efflux induced by P-glycoprotein (P-gp), which decreases intracellular accumulation of chemotherapeutic drugs. The drugs efflux mediated by P-gp requires adenosine triphosphate (ATP) hydrolysis to provide energy. Therefore, modulating energy metabolism pathways and inhibiting ATP production may be a potential strategy to reverse MDR. Herein, we developed a PTX-ATO-QUE nanoparticle (PAQNPs) based on a PLGA-PEG nanoplatform capable of loading the mitochondrial oxidative phosphorylation (OXPHOS) inhibitor atovaquone (ATO), the glycolysis inhibitor quercetin (QUE), and the chemotherapeutic drug paclitaxel (PTX) to reverse MDR by inhibiting energy metabolism through multiple pathways. Mechanistically, PAQNPs could effectively inhibit the OXPHOS and glycolytic pathways of A2780/Taxol cells by suppressing the activities of mitochondrial complex III and hexokinase II (HK II), respectively, ultimately decreasing intracellular ATP levels in tumor cells. Energy depletion can effectively inhibit cell proliferation and reduce P-gp activity, increasing the chemotherapeutic drug PTX accumulation in the cells. Moreover, intracellular reactive oxygen species (ROS) is increased with PTX accumulation and leads to chemotherapy-resistant cell apoptosis. Furthermore, PAQNPs significantly inhibited tumor growth in the A2780/Taxol tumor-bearing NCG mice model. Immunohistochemical (IHC) analysis of tumor tissues revealed that P-gp expression was suppressed, demonstrating that PAQNPs are effective in reversing MDR in tumors by inducing energy depletion. In addition, the safety study results, including blood biochemical indices, major organ weights, and H&E staining images, showed that PAQNPs have a favorable in vivo safety profile. In summary, the results suggest that the combined inhibition of the two energy pathways, OXPHOS and glycolysis, can enhance chemotherapy efficacy and reverse MDR in ovarian cancer.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2025
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IF 4.9
Shuo Tang,Lujun Wang,Wenjie Lu,Lingzhen Ding,Xia Liu,Yu Tao,Mingchao Xu,Wenyou Fang,Shengqi Chen,Rongfeng Hu
Solid self-microemulsifying drug delivery systems (SMEDDS) offer unique advantages over conventional liquid formulations, including enhanced physical stability, simplified storage/transportation, and improved drug delivery efficiency. In this study, we developed a paclitaxel (PTX)-loaded SMEDDS using Ganoderma lucidum spore oil (GLSO) as a multifunctional oil phase. Through formulation screening and optimization, the PTX-GLSO-SMEDDS was successfully converted into a solid powder. Solid-state analyses confirmed the amorphous dispersion of PTX within the matrix, while the powder exhibited favorable fluidity, stability, and rapid in vitro drug release kinetics. PTX-GLSO-SMEDDS demonstrated potent antitumor effects by inducing apoptosis and suppressing metastasis in colorectal cancer (CRC) cells. In vivo studies revealed dual therapeutic advantages: enhanced tumor suppression and synergistic immunomodulation via GLSO-mediated activation of tumor-associated cytotoxic T lymphocytes regulation. Notably, the formulation reduced systemic toxicity compared to conventional PTX injections. By integrating GLSO's inherent bioactivity with SMEDDS technology, this work establishes a robust platform that synergizes chemotherapy and immunotherapy, offering a clinically translatable strategy for CRC treatment with improved safety and therapeutical outcomes. The findings underscore GLSO's potential as a natural, multifunctional excipient for advanced drug delivery systems.
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Acta Biomaterialia
·
2017
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IF 6.319
Ziqi Wang,Xinru Li,Dishi Wang,Yang Zou,Xiaoyou Qu,Chuyu He,Yunqiang Deng,Yao Jin,Yuanhang Zhou,Yanxia Zhou,Yan Liu
To concurrently suppress multidrug resistance (MDR) and metastasis of breast cancer cells, paclitaxel (PTX) and honokiol (HNK) were coencapsulated into pH-sensitive polymeric micelles based on poly(2-ethyl-2-oxazoline)-poly( d , l -lactide) (PEOz-PLA). The physicochemical properties of dual drug-loaded PEOz-PLA micelles were characterized in size, drug loading and in vitro release. The efficiency of MDR reversal for the micelles was testified by synergetic enhancement of cytotoxicity and uptake by MCF-7/ADR cells. The flow cytometry and fluorescence polarization measurement results reinforced the conclusion that down-regulation of P-gp expression and increase of plasma membrane fluidity appeared to be possible mechanisms of MDR reversal by dual drug-loaded PEOz-PLA micelles. Further, the efficient inhibition of tumor metastasis by dual drug-loaded PEOz-PLA micelles was demonstrated by in vitro anti-invasion and anti-migration assessment in MDA-MB-231 cells and in vivo bioluminescence imaging in nude mice . The suppression of MDR and metastasis by the micelles was assigned to synergistic effects of pH-triggered drug release and HNK/PEOz-PLA-aroused P-gp inhibition, and pH-triggered drug release and PTX/HNK-aroused MMPs inhibition, respectively. In conclusion, our findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis. Statement of Significance Multidrug resistance (MDR) and metastasis are considered to be two of the major barriers for successful chemotherapy. The combination of a chemotherapeutic drug with a modulator has emerged as a promising strategy for efficiently treating MDR cancer and preventing tumor metastasis. Herein, a dual drug (paclitaxel and honokiol)-loaded pH-sensitive polymeric micelle system based on PEOz-PLA was successfully fabricated to ensure that tumor MDR and metastasis could be concurrently suppressed, therefore achieving distinguishing endo/lysosomal pH from physiological pH by accelerating drug release and then enhancing the cytotoxicity of paclitaxel to drug-resistant tumor cells MCF-7/ADR by increasing cellular uptake of paclitaxel, preventing in vitro invasion and migration for MDA-MB-231 cells and in vivo metastasis in nude mice. Further, the mechanism of MDR reversal by dual drug-loaded PEOz-PLA micelles was elucidated to be down-regulation of P-gp expression and increase of plasma membrane fluidity of MCF-7/ADR cells. The present findings strengthen the usefulness of co-delivery of PTX and HNK by pH-responsive polymeric micelles for suppression of tumor MDR and metastasis.
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Biomed Research International
·
2018
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IF 2.583
Huiling Lv,Chao Wu,Xuan Liu,Andi Bai,Yue Cao,Wenjing Shang,Lili Hu,Ying Liu
In this study, we prepared PTX-loaded mesoporous hollow SnO2 nanofibers conjugated with folic acid (SFNFP) for liver cancer therapy. According to SEM and TEM characterization, SFNF showed a mesoporous hollow structure. The average outer diameter was 200 nm, and the wall thickness was 50 nm. The DSC and XRD study showed that PTX in the channels of nanofibers was present in an amorphous state. The in vitro release experiments demonstrated that SFNF could efficiently improve the dissolution rate of PTX. Both in vitro cell experiments and in vivo antitumor experiments showed that SFNFP could efficiently inhibit the growth of liver cancer cells. Therefore, SFNF is a promising targeting antitumor drug delivery carrier.
研究领域:
纳米技术
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药学
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癌症研究
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材料科学
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International Journal of Nanomedicine
·
2023
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IF 8
Wen-jing Zhu,Shu-di Yang,Chen-xi Qu,Qiao-ling Zhu,Wei-liang Chen,Fang Li,Zhi-qiang Yuan,Yang Liu,Ben-gang You,Xue-nong Zhang
Multidrug resistance (MDR) is a major obstacle for the clinical therapy of malignant human cancers. The discovery of RNA interference provides efficient gene silencing within tumor cells for reversing MDR. In this study, a new “binary polymer” low-density lipoprotein–N-succinyl chitosan–cystamine–urocanic acid (LDL–NSC–SS–UA) with dual pH/redox sensitivity and targeting effect was synthesized for the co-delivery of breast cancer resistance protein small interfering RNA (siRNA) and paclitaxel (PTX). In vivo, the co-delivering micelles can accumulate in tumor tissue via the enhanced permeability and retention effect and the specific recognition and combination of LDL and LDL receptor, which is overexpressed on the surface of tumor cell membranes. The siRNA–PTX-loaded micelles inhibited gene and drug release under physiological conditions while promoting fast release in an acid microenvironment or in the presence of glutathione. The micelles escaped from the lysosome through the proton sponge effect. Additionally, the micelles exhibited superior antitumor activity and downregulated the protein and mRNA expression levels of breast cancer resistance protein in MCF-7/Taxol cells. The biodistribution and antitumor studies proved that the siRNA–PTX-loaded micelles possessed prolonged circulation time with a remarkable tumor-targeting effect and effectively inhibited tumor growth. Therefore, the novel dual pH/redox-sensitive polymers co-delivering siRNA and PTX with excellent biocompatibility and effective reversal of MDR demonstrate a considerable potential in cancer therapy.
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RSC Advances
·
2022
·Vol. 12
·期 50
·32534-32551
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IF 4.036
Huanli Yin,Qi Yan,Yuan Liu,Lan Yang,Yang Liu,Yujie Luo,Tianyu Chen,Ningxi Li,Min Wu
A dual-loaded multi-targeted drug delivery nanosystem was constructed to simultaneously load paclitaxel (PTX) and 5-fluorouracil (5-FU) for targeted delivery and sustained release at tumor sites. Hollow mesoporous silica nanoparticles (HMSNs) were prepared by the inverse microemulsion method, then modified with folic acid and pH- and temperature-responsive materials, co-loaded with PTX and 5-FU, and finally encapsulated into lipid membranes. The obtained nanosystem was selectively internalized by human breast cancer MCF-7 cells that overexpress folate receptors through an energy-dependent process, and it released both drugs in vitro in a simulated tumor microenvironment. Moreover, the inhibitory effect of the dual-loaded nanoparticles was significantly better than that of the free drugs, suggesting that the composite nanosystem has the potential to selectively target tumor sites and perform the synergistic effect of PTX and 5-FU, while reducing their toxic effects on normal tissues.
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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
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2026
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IF 2.5
Yu Miao,Ning Zhang,Guolei Zhang,Runyi Ye,Linrui Li,Hongyu Xue,Lei Yin,Meiyun Shi
Ultrafiltration with UPLC-MS/MS assay simultaneously quantifies free, protein-bound, total paclitaxel in biosamples. • PTX-Nab in vivo shows sustained release, lower systemic exposure, longer half-life, lung/spleen accumulation. • The primary excretion pathway of paclitaxel shifts from renal to hepatobiliary following albumin nanoparticle formulation. Paclitaxel (PTX) has poor water solubility. Traditional formulations requiring solubilizers can induce allergic reactions and disrupt pharmacokinetics. Albumin-bound PTX nanoparticles (PTX-Nab) provide a solvent-free nanodelivery system that enhances solubility and may enable receptor-mediated tumor targeting. Comprehensive studies comparing its systemic pharmacokinetics, particularly the dynamics of free versus total drug concentrations and excretion routes, are still lacking. This study established a sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method coupled with ultrafiltration to simultaneously quantify free, protein-bound, and total PTX in rats following intravenous administration of PTX-Nab and conventional PTX-injection. PTX-Nab profoundly altered the pharmacokinetic profile. Despite a double dose (10 mg/kg), it exhibited significantly lower dose-normalized initial concentration ( C 0 /Dose) and systemic exposure (AUC/Dose) along with a longer elimination half-life (t 1/2 ) than the injection group (5 mg/kg), indicating sustained drug release and prolonged circulation. Tissue distribution showed preferential accumulation of PTX-Nab in lung and spleen. Excretion studies showed a change in the primary excretion route. Unlike the renal-excreted conventional injection, PTX-Nab enhanced fecal excretion (56.14% versus 16.50%). These findings elucidate how the albumin carrier reshapes the in vivo fate of PTX through sustained release, tissue targeting, and clearance redirection, providing crucial pharmacokinetic evidence for its clinical application and future nanocarrier development.
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EUROPEAN JOURNAL OF PHARMACOLOGY
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2021
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IF 4.432
Liwei Ni,Jianhao Xu,Fenglun Zhao,Xiaoxiao Dai,Jialong Tao,Jie Pan,Aiming Shi,Zhu Shen,Cunjin Su,Yusong Zhang
MicroRNAs (miRNAs) are involved in the initiation and development of cancer and participate in drug resistance. Paclitaxel (PTX) is a first-line chemotherapy drug for advanced non-small cell lung cancer (NSCLC). The abnormal miRNA expression in NSCLC and its association with chemotherapy drug resistance remains largely unknown. The study aimed to investigate the aberrant expression of miR-221–3p in NSCLC and to elucidate its molecular mechanisms in relation to PTX resistance. PTX increased miR-221–3p expression and regulated MDM2/P53 expression in the PTX-sensitive NSCLC strain (A549). Meanwhile, miR-221–3p was rarely expressed and not interfered by PTX in PTX-resistant A549 cells (A549/Taxol). Dual-luciferase reporter assay confirmed that miR-221–3p specifically binds to MDM2 messenger RNA and inhibited MDM2 expression. The expression of MDM2 and P53 showed a negative correlation in NSCLC cell lines. MiR-221–3p down-regulation reduced the sensitivity of A549 cells to PTX, whereas its up-regulation partially reversed the A549/Taxol cells resistance to PTX and increased the chemosensitivity of A549/Taxol cells to PTX in xenograft models. Quantitative polymerase chain reaction analysis revealed that miR-221–3p expression increased, whereas the MDM2 level decreased in human NSCLC tumor tissues. Moreover, Western bolt analysis showed that P53 was lowly expressed in tumor tissues with MDM2 overexpression. Low expression of miR-221–3p in NSCLC tissues might indicate a poor T staging. In conclusion, miR-221–3p overexpression could regulate MDM2/p53 signaling pathway to reverse the PTX resistance of NSCLC and induce apoptosis in vitro and vivo.
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ChemistryOpen
·
2019
·Vol. 8
·期 4
·451-456
·
IF 2.205
Joo Hee Jang,Sang Jin Han,Jung Young Kim,Kwang Il Kim,Kyo Chul Lee,Chi Soo Kang
Graphical Conjugate for double duty : A new antibody-drug conjugate composed of paclitaxel (PTX), deferoxamine (DFO) and trastuzumab (DFO-trastuzumab-PTX) was prepared using simple conjugation chemistry. The new conjugate displayed instant complexation kinetics with 89 Zr and showed feasible cytotoxic effect and binding property on HER2-positive MDA-MB-231 breast cancer cell showing promising potential as a theranostic agent utilizing chemo-drug and positron emission tomography (PET). The preparation and in vitro evaluation of a theranostic conjugate composed of trastuzumab, paclitaxel (PTX), and deferoxamine (DFO)-chelated 89 Zr have been reported. These comounds have potential applications against HER2 receptor positive breast cancers. We conjugated DFO and PTX to trastuzumab by exploiting simple conjugation chemistry. The conjugate (DFO-trastuzumab-PTX) showed excellent radiolabeling efficiency with 89 Zr and the labeled conjugate had high in vitro stability in human serum. Furthermore, DFO-trastuzumab-PTX displayed comparable cytotoxicity with PTX and 89 Zr-DFO-trastuzumab-PTX exhibited HER2 receptor-mediated binding on HER2-positive MDA-MB-231 breast cancer cells. The results of our in vitro study indicate high potential of 89 Zr-DFO-trastuzumab-PTX to be utilized in the theranostic application against HER2-postive breast cancers.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2019
·
IF 2.606
Meijia Song,Yan Liang,Keke Li,Jing Zhang,Nan Zhang,Baocheng Tian,Jingtian Han
Tumor targeted drug delivery system has been developed as a promising approach to improve cancer chemotherapy . The design of hyaluronic acid (HA)-modified nanocarriers has been proven to be effective for targeting CD44 overexpressing tumor cells. Moreover, combination therapy can improve the therapeutic effect and delay the development of drug resistance. In this study, doxorubicin (DOX) and paclitaxel (PTX) co-loaded liposomal delivery system modified with an acid-cleavable cholesterol-HA conjugate (Chol-HA) was prepared by post-insertion method. The dual-drug co-loaded HA modified liposome (HA-D/P-Lip), had a suitable particle size of 125.5 ± 0.79 nm with negative surface charge of −9.56 ± 0.62 mV, and acceptable encapsulation efficacy of 93.6 ± 0.51% (DOX) and 70.4 ± 1.46% (PTX). In vitro drug release study showed that the cumulative release of both drugs over 72 h were much higher in pH 5.5 phosphate buffer than that in pH 7.4 phosphate buffer. In vitro cytotoxicity study against MCF-7 breast cancer cells illustrated superior cytotoxicity and obvious synergistic effect in comparison to free drug or single drug loaded liposome via MTT assay. In vitro cellular uptake study demonstrated a higher cell internalization of HA-DOX-Lip compared with DOX loaded non-modified liposome (DOX-Lip) and free DOX. Therefore, the pH-sensitive HA-targeted liposome may be a useful targeted nanocarrier for efficient tumor therapy.
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