JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2026
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IF 5.2
Xiao-Qing Ling,Xin-Yan Zhao,Qi-Yan Lv,Jun-Yang Chen,Hai-Yang Dai,Hui-Fang Cui,XiaoJie Song
Cuproptosis has gained significant attention in cancer therapy. Use of copper-overloaded combination therapy that employs a variety of cell death mechanisms has emerged as a promising avenue in the treatment of cancer. However, integrating different modes in a system with optimal synergy and minimal side effects remains a challenge. In this study, a multifunctional copper ion-overloaded nanoparticle was fabricated via one-pot self-assembly for enhanced cuproptosis, chemo- and phototherapy. Molecular dynamics simulation was performed to study the self-assembly mechanism, demonstrating they assembled into stable nanoparticles (NPs) in 50 ns. The NPs possess dual-targeting capabilities towards tumor cells and mitochondria, and exhibit excellent stability in neutral PBS, while showing responsive payload release under acidic conditions or NIR laser irradiation. Upon reaching the mitochondria, the NPs release their payloads, where accumulated copper ions trigger aggregation of lipoylated proteins, etc. Released disulfiram chelates excessive copper ion to form toxic Cu(DTC) 2 , which induces apoptosis combining with hydroxycamptothecin. Meanwhile, indocyanine green-generated ROS and photothermal effects further enhance cuproptosis for synergistic therapy. In vitro results revealed potent cytotoxicity of the NPs against CT26 cells while negligible effects on normal cells. Furthermore, significant reactive oxygen species generation, mitochondrial membrane potential alteration, increased apoptosis, and modulated protein mRNA expression levels, confirmed the synergistic combination of chemotherapy, cuproptosis, and photothermal/photodynamic therapies. Notably, in vivo experiments demonstrated selective tumor accumulation and outstanding antitumor efficacy (89.5% inhibition rate) with excellent biosafety profile. The NPs provide a novel strategy for cuproptosis-based combination cancer therapy and shows significant clinical translation potential.
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ACS Biomaterials Science & Engineering
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2023
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IF 5.8
Jialin Chen,Qingyun Mo,Qiuzi Long,Renwang Sheng,Zhixuan Chen,Yifan Luo,Chuanquan Liu,Ludvig J. Backman,Yanan Zhang,Wei Zhang
Corneal fibrosis is a common outcome of inappropriate repair associated with trauma or ocular infection. Altered biomechanical properties with increased corneal stiffness is a feature of fibrosis that cause corneal opacities, resulting in severe visual impairment and even blindness. The present study aims to determine the effect of hydroxycamptothecin (HCPT) and matrix stiffness on transforming growth factor-β1 (TGF-β1)-induced fibrotic processes in human corneal fibroblasts (HTK cells). HTK cells were cultured on substrates with different stiffnesses (“soft”, ∼261 kPa; “stiff”, ∼2.5 × 103 kPa) and on tissue culture plastic (TCP, ∼106 kPa) and simultaneously treated with or without 1 μg/mL HCPT and 10 ng/mL TGF-β1. We found that HCPT induced decreased cell viability and antiproliferative effects on HTK cells. TGF-β1-induced expression of fibrosis-related genes (FN1, ACTA2) was reduced if the cells were simultaneously treated with HCPT. Substrate stiffness did not affect the expression of fibrosis-related genes. The TGF-β1 induced expression of FN1 on both soft and stiff substrates was reduced if cells were simultaneously treated with HCPT. However, this trend was not seen for ACTA2, i.e., the TGF-β1 induced expression of ACTA2 was not reduced by simultaneous treatment of HCPT in either soft or stiff substrate. Instead, HCPT treatment in the presence of TGF-β1 resulted in increased gene expression of keratocyte phenotype makers (LUM, KERA, AQP1, CHTS6) on both substrate stiffnesses. In addition, the protein expression of keratocyte phenotype makers LUM and ALDH3 was increased in HTK cells simultaneously treated with TGF-β1 and HCPT on stiff substrate as compared to control, i.e., without HCPT. In conclusion, we found that HCPT can reduce TGF-β1-induced fibrosis and promote the keratocyte phenotype in a substrate stiffness dependent manner. Thus, HCPT stimulation might be an approach to stimulate keratocytes in the appropriate healing stage to avoid or reverse fibrosis and achieve more optimal corneal wound healing.
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JOURNAL OF MOLECULAR LIQUIDS
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2022
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IF 6.633
Qiulan Zhang,Linghong Liu,Yongnian Ni
10-hydroxycamptothecin (HCPT) is a natural alkaloid which has strong antitumor activity by inhibiting the degradation of the cleaved DNA strand. As a rich plasma protein, human serum albumin is a medium for transporting of various drugs and endogenous compounds. Due to its high water dispensability and good biocompatibility, reduced graphene oxide (rGO) is an eminent candidate for delivery of medicinal molecules. In cancer therapy, ferrosoferric oxide (Fe 3 O 4 ) could be used to improve the therapeutic action and the imaging-guided delivery. In this work, Fe 3 O 4 was anchored onto rGO nanosheets, and the formed Fe 3 O 4 /rGO nanocomposite showed efficient tumor targeting. The binding interaction between HCPT with HSA was investigated and the magnetic reduced graphene oxide (MrGO) had strong effect on the binding interaction. The comet assay results showed that MrGO had low toxicity, and the main binding forces between HCPT and HSA or HSA-HCPT were hydrogen bond and van der Waals force. In addition, it was found that the added MrGO greatly enhanced the binding of HCPT with HSA. The results offer some insight on the interaction between nanomaterials loaded with medicinal molecules and serum albumin at a molecular level.
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Asian Journal of Pharmaceutical Sciences
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2022
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IF 9.273
Qiongzhe Ren,Xuefeng Tang,Yi Lu,Qing Li,Zhiqian Liao,Shinan Jiang,Haoli Zhang,Zhigang Xu,Lei Luo
The use of nanocrystal technology to manufacture drug delivery systems intended to enhance therapeutic efficacy has attracted the attention of the pharmaceutical industry. However, the clinical application of nanocrystal drugs for injection is restricted by Ostwald ripening and the large-scale use of stabilizers such as polysorbate and lecithin, which have potential toxicity risks including hemolysis and allergies. Here, we designed an amorphous nanocrystal drug complex (IHNC), which is stabilizer-free and composed of indocyanine green (ICG) framework loading with a chemotherapeutic agent of 10-hydroxycamptothecin (HCPT). Considering the possibility of industrial manufacturing, IHNC was simply prepared with the assistance of ferric ion (III) via supramolecular assembly strategy. The theoretical result of Materials Studio simulation indicated that the prepared ICG-Fe(III) framework showed a stable spherical structure with the appropriate cavity for encapsulating the two drugs of HCPT and ICG with equal mass ratio. The IHNC was stable at physiological pH, with excellent PTT/PDT efficacy, and in vivo probing characteristics. The nanoscale size and reductive stimuli-responsiveness can be conducive to drug accumulation into the tumor site and rapid unloading of cargo. Moreover, such combination therapy showed synergistic photo/chemotherapy effect against 4T1 breast cancer and its tumor inhibition rate even up to 79.4%. These findings demonstrated that the nanocrystal drug delivery strategy could avoid the use of stabilizers and provide a new strategy for drug delivery for combination therapy.
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Frontiers in Oncology
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2022
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IF 5.738
Li Tian,Zhou An-Di,Bai Li-Fei,Zhang Xiao-Yang,Zhou Yu-Ting,Yang Hai-Li,Xu Le-Tian,Guo Xin-Qin,Zhu Xi-Yu,Wang Dong-Jin,Gu Hong-Wei,Wang Xiao-Ming
Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives.
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Nanomaterials
·
2021
·Vol. 11
·期 11
·2854
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IF 5.076
Yuqiong Shi,Wei Liu,Xiangrong Wu,Jinhua Zhu,Danyang Zhou,Xiuhua Liu
The poor water solubility and severe side effects of hydroxycamptothecin (HCPT) limit its clinical application; therefore, it is necessary to synthesize applicable nanodrug carriers with good solubility to expand the applications of HCPT. In this study, a hydrophilic metal–organic framework (MOF) with amphoteric carboxylic acid ligands as linkers was first synthesized and characterized. Then, water-soluble acrylamide and methacrylic acid were applied as monomers to prepare a water-soluble polyacid polymer MOF@P, which had a solubility of 370 μg/mL. The effects of the MOF@P material on the HCPT loading and solubility were investigated. The results showed that the polymer material could improve the HCPT solubility in water. Moreover, the in vitro release study indicated that the MOF@P polymeric composite exhibited a sustained-release effect on HCPT, with a cumulative release rate of 30.18% in 72 h at pH 7.4. Furthermore, the cytotoxicity test demonstrated that the hydrophilic MOF and the MOF@P had low cell toxicities. The results indicate that the prepared MOF@P polymeric complex can be applied for the sustained release of HCPT in clinics.Keywords:polyacid polymer;metal organic frameworks;HCPT delivery
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BIOMATERIALS
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2021
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IF 12.479
Liangliang Dai,Xiang Li,Xinmin Zheng,Zhenxiang Fu,Mengjiao Yao,Siyu Meng,Jiangong Zhang,Binbin Han,Quanli Gao,Jing Chang,Kaiyong Cai,Hui Yang
Immunosuppressive tumor microenvironment and low delivery efficiency severely impede the tumor chemotherapy effect. To address this issue, we develop a pH/ROS cascade-responsive prodrug micelle to deliver siTGF-β with size-shrinkage and charge-reversal property, leading to synergistical tumor microenvironment remodeling. The nanosystem highly improved endocytosis efficiency and tumor penetration depth through charge reversal and size reduction upon exposure to weakly acidic tumor microenvironment. Moreover, the nanocarrier would rapidly escape from endo/lysosome, disassemble and release siTGF-β and hydroxycamptothecin in response to high intracellular ROS. Furthermore, the nanosystem significantly boosted antitumor immune response and reduced immune tolerance with remodeling tumor microenvironment, which significantly prolonged the survival time of tumor-bearing mice (75% survival rate upon 35 days). It is realized by the combined effects of chemotherapy-enhanced immunogenicity and recruitment of effector T cells , TGF-β-blockade immunotherapy-activated inhibition immunosuppressive tumor microenvironment and epithelial-to-mesenchymal transition (EMT), and regulation physical tumor microenvironment via reducing the dense tumor extracellular matrix and the high tumor interstitial pressure obstacles. To this end, the nanosystem not only overcame biobarriers and reinforced antitumor immune response, but also effectively inhibited tumor growth, metastasis and recurrence in vivo .
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2021
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IF 5.875
Zhimei Xiao,Bo Zhuang,Guoli Zhang,Miao Li,Yiguang Jin
Sonodynamic therapy (SDT) has been tried for cancer treatment; however, sonosensitizers are usually administered by injection, leading to low distribution in the tumor tissue and compromised therapeutic effect, even serious side effect. Here, we combined cationic liposomal hydroxycamptothecin (CLH) and 5-aminolevulinic acid (5-ALA) via intratracheal (i.t.) administration for the chemo-sonodynamic (Chemo-SDT) therapy of metastatic lung cancer. CLH was prepared from HCPT and the lipid mixture of soybean lecithin/cholesterol/octadecylamine with a film method. The optimal pre-incubation time of 5-ALA with tumor cells before ultrasound exposure was 4 h, for sake of sonosensitizer accumulation, i.e., protoporphyrin IX, the metabolite of 5-ALA. In vitro studies showed the higher cytotoxicity of Chemo-SDT compared to the other treatments, including i.t. CLH, intravenous (i.v.) CLH, and SDT alone. The combination of pulmonary delivery and Chemo-SDT showed the highest anticancer effect among the treatments on the metastatic lung tumor-bearing mice, which was judged according to the tumor appearance and pathological sections. The major anticancer mechanism of Chemo-SDT included the improved apoptosis of cancer cells and the enhanced production of reactive oxygen species, and more importantly, the synergy of chemotherapy and SDT. Pulmonary delivery of chemotherapeutics and sonosensitizers is a promising strategy for the treatment of lung cancer.
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SENSORS AND ACTUATORS B-CHEMICAL
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2020
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IF 7.1
Ying Zhang,Xie-an Yu,Yiting Hu,Xuefei Bai,Ran Zhang,Mi Lu,Jianhui Sun,Jiangwei Tian,Bo-Yang Yu
Cell surface charge serves a significant role in maintaining cell membrane stability and integrity, affecting cell structure/functions and the expression of signaling molecules. With the aggravation of the cell injury, cell surface charge would have a difference, which could be treated as a vital indicator for the discernment of cell pathological states. Herein, we developed a novel and instantaneous response method for the determination of cell viability based on cell surface charge. This study introduced a fluorescence resonance energy transfer-based polydopamine-polyethyleneimine/quantum dot (PDA-PEI/QD) sensor constructed by PDA-PEI with positive charge and QD with negative charge via electrostatic interaction, which can be used to instantaneously read out the cell injured states through fluorescent signal change induced by the comprehensive charged materials on the cell surface. The resulting fluorescence signals induced by different hepatotoxic drugs showed the difference. Furthermore, it was worth noting that the fluorescence change induced by 12 hepatotoxic drugs had a close relationship with cellular states, presenting the consistent tendency with cell viability. Accordingly, this method may have applications in the fields of cell viability detection, drug toxicity evaluation, and even elucidating the mechanism of drug-induced liver injury in the future.
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International Journal of Nanomedicine
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2020
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IF 5.115
Ting Zhou,Wei Zhang,Dongliang Cheng,Xin Tang,Jianfang Feng,Wei Wu
Purpose In this study, NK4-conjugated hydroxycamptothecin liposomes (NK4-HCPT-Lips) were prepared with the aim of improving drug targeting to the liver.Methods NK4-HCPT-Lips were prepared using the thin-film dispersion method. In vitro antitumor activities were evaluated by MTT assay. HCPT levels in plasma and tissues were determined via high-performance liquid chromatography (HPLC) with camptothecin as the internal standard, and the characteristics, pharmacokinetics, and bio-distribution of NK4-HCPT-Lips were evaluated.Results The liposomes showed a regular spherical-shaped morphology, and the entrapment efficiency and drug loading capacity reached 82.5 ± 2.4% and 3.01 ± 0.23%, respectively, with a particle size of 155.6 ± 2.6 nm and a zeta potential of −24.8 ± 3.3 mV. Inhibition effect experiments found that NK4-HCPT-Lips had a good inhibition on the HepG2 cells. Pharmacokinetic studies revealed an increase in the area under the curve and mean residence time as well as a decrease in plasma clearance (p < 0.05) of the NK4-HCPT-Lips compared to those of HCPT liposomes and a commercial HCPT injection. Tissue distribution studies showed that NK4-HCPT-Lips were present at high levels in the liver but were cleared from the kidneys.Conclusion These results demonstrate that NK4-HCPT-Lips possess excellent liver-targeting attributes, which could enhance the therapeutic effects of drug treatments for hepatic diseases.
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CHEMICAL ENGINEERING JOURNAL
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2019
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IF 8.355
Xunan Jing,Zhe Zhi,Ning Zhang,Huanhuan Song,Yanzi Xu,Guoqing Zhou,Daquan Wang,Yongping Shao,Lingjie Meng
It is of great importance to develop tumor microenvironment (TME) responsive and adjustable theranostic nano-systems for specific and efficient cancer treatment. However, carrier-based nanomedicines are often inefficacious in vivo due to low drug-loading efficiency, lack of synergistic effects, poor targeting specificity and limited drug accumulation in tumor tissues. Herein, we report a new multimodal theranostic nanoplatform which is assembled from Fe 3 O 4 nanoclusters , MnO 2 nanosheets with multifunctional and cross-linked polyphosphazene. This peanut-like nanoplatform exhibited enhanced chemo/photodynamic therapy (CT/PDT) effect as well as significant tumor-targeting capacity. In addition, Fe 3 O 4 cores and MnO 2 nanoshells enables T 1 / T 2 magnetic resonance imaging (MRI) of tumor tissues, while photosensitizer methylene blue (MB) allows for fluorescence imaging and PDT simultaneously. Importantly, nanopeanut agents could dual-regulate intracellular oxygen and glutathione (GSH) levels in TME by MnO 2 shells, to relieve hypoxic condition and produce enough ROS to induce cell apoptosis. Our research demonstrated that the multistage TME-responsive nanoplatform is ideally suitable for tumor specific drug delivery and real-time disease tracking with enhanced theranostic properties.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
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IF 8.2
Qingye Meng,Shuangling Zhong,Jia Wang,Yan Gao,Xuejun Cui
Controlled and accurate drug release at the target site have been the focus of research. Especially in cancer therapy, economical, convenient and accurate delivery strategies could help to reduce the toxic effects of drugs on normal tissues and improve drug availability. In the study, glutathione (GSH)-responsive microcapsules (FA-RSMCs) were prepared by sonochemical method based on thiolated modified starch . 10-Hydroxycamptothecin (HCPT) was designed as a reactive oxygen species (ROS)-responsive polyprodrug (polyHCPT), which was loaded into the core of the microcapsules to obtain stepwise released drug delivery carriers. In the tumor microenvironment, FA-RSMCs first triggered GSH-responsive cleavage to release polyHCPT, followed by ROS-responsive cleavage of polyHCPT to release intact HCPT drug molecules. The results of experiments in simulated tumor microenvironment showed that FA-RSMCs exhibited good cascade-response release properties in vitro . It exhibited good anti-tumor ability and protection of normal cells in cytotoxicity in vitro . This strategy enhanced the accuracy and safety of targeted delivery of HCPT via microcapsules, which has potential for clinical application.
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