MOLECULES
·
2020
·Vol. 25
·期 2
·407
·
IF 3.267
Jiaguo Li,Dian Xiao,Lianqi Liu,Fei Xie,Wei Li,Wei Sun,Xiaohong Yang,Xinbo Zhou
In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug’s expected activity was lost after PPG protection. InBRCA1- andBRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP.Keywords:Talazoparib;PARP inhibitor;prodrug;o-nitro-benzyl;photoactivatable protecting groups
研究领域:
药物化学
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肿瘤学
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生物化学
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DOI
PubMed
高影响因子
ChemistrySelect
·
2024
·Vol. 9
·期 42
·e202401655
·
IF 1.9
Yang Lin,Ju Liang,Wenlan Wu,Yunyun Zhang,Fuqing Yan
Graphical In this study, the reduction responsive prodrug folic acid-polyethylene glycol-disulfide bond-curcumin (FA-PEG-SS-CUR) was synthesized. The prodrug could self-assemble into micelles in an aqueous solution. The chemical structure of the prodrug was determined using FTIR and NMR. Subsequently, the properties of the micelles were evaluated through TEM, particle size analysis, cell experiments, and in vitro drug release assessment. In order to improve the delivery performance of curcumin (CUR) in liver cancer cells, we prepared a targeted and reduction-sensitive prodrug, folic acid-polyethylene glycol-disulfide bond-curcumin (FA-PEG-SS-CUR). The synthesis involved the conjugation of CUR with NH 2 -PEG-NH 2 through a disulfide bond, followed by the connection of CUR-SS-PEG-NH 2 to FA-COOH via acylation. The resultant FA-PEG-SS-CUR prodrug self-assembled into nano micelles in aqueous solutions, displaying excellent dispersibility with an approximate particle size of 119 nm. In vitro drug release studies demonstrated the sensitivity of FA-PEG-SS-CUR to glutathione (GSH), displaying sustained release performance. After 72 h, FA-PEG-SS-CUR exhibited a drug release rate of 38% at low GSH concentration and 59% at high GSH concentration. Notably, FA-PEG-SS-CUR micelles exhibited favorable biocompatibility. The hemolysis rate resulting from co-incubation with red blood cells remained below 3%. Furthermore, cytotoxicity experiments unveiled the substantial cytotoxicity of FA-PEG-SS-CUR micelles against HepG2 tumor cells. Cellular uptake studies confirmed the greater internalization of FA-PEG-SS-CUR by HepG2 cells compared to the non-targeted PEG-SS-CUR. The findings highlight the potential of FA-PEG-SS-CUR as an ideal drug delivery system for CUR due to its facile synthesis and strong self-assembly performance.
研究领域:
药学
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癌症研究
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纳米技术
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产品关联
DOI
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 4
·511
·
IF 5.5
Qiao Qiao,Xian Wan,Jie Li,Weijun Chen,Enxuan Li,Lipeng Qiu,Huiming Tu
Background: Ulcerative colitis (UC), a subtype of chronic inflammatory bowel disease (IBD), is primarily treated with oral medications to reduce inflammation and alleviate symptoms. Celecoxib (CXB) is an attractive candidate for UC; however, its limited solubility and low bioavailability pose significant challenges to its clinical application.Methods: We reported a novel chondroitin sulfate A–Celecoxib (CSA-CXB) polymeric nanoprodrug to address the limited solubility and low bioavailability of CXB. CXB was conjugated to chondroitin sulfate A (CSA) via succinic anhydride (SA) and ethylenediamine to prepare CSA-CXB polymers, which can self-assemble into nanoparticle structural prodrugs in aqueous condition. We investigated the stability, blood compatibility, and responsiveness of the nanoparticles. The ability of the nanoparticles to treat UC in vitro and in vivo was then evaluated.Results: The CSA-CXB nanoprodrug was spherical with a mean particle size of 188.4 ± 2.2 nm, a zeta potential of −22.9 ± 0.1 mV, and sustained drug release behavior. Furthermore, CSA-CXB exhibited remarkable antioxidant and anti-inflammatory effects, as it can significantly increase the free radical scavenging rate and reduce the expression level of ROS, TNF-α, IL-6, nitric oxide (NO), and COX-2 protein in vitro. In vivo results demonstrated that CSA-CXB targeted the mice’s colon efficiently mitigate UC symptoms by inhibiting the expression of inflammatory cytokine.Conclusions: The CSA-CXB nanoprodrug can improve the therapeutic impact of CXB, and has potential as a new preparation for a clinical UC treatment nanoprodrug.
研究领域:
药剂学
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炎症性肠病治疗
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生物材料
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产品关联
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2025
·
IF 3
Jiangye Zhang,Rui Cai,Changxu Ning,Zhongxiang Zhou,Yibo Zhang,Shisheng Wang,Yueqing Li,Xiuhan Guo
Ferroptosis is a newly discovered form of cell death that is closely related to the occurrence of various diseases, such as neurodegenerative diseases, cardiovascular and cerebrovascular ischemic damage, and organ fibrosis. Therefore, the discovery of new active compounds with ferroptosis inhibitory activity is regarded as a new strategy for the clinical treatment of these diseases. In this study, a multifunctional prodrug molecule PNX-B2 with a phenoxazine structure was designed based on the oxidative microenvironment characteristic of ferroptosis. PNX-B2 can recognize the ferroptosis-associated oxidative conditions and simultaneously release compounds with ferroptosis-inhibitory activity. Moreover, it integrates diagnostic and therapeutic functions and offers a fluorescent indication of the ferroptosis microenvironment. PNX-B2 has demonstrated excellent ferroptosis-inhibitory activity with an EC 50 value of 1.7 nM. This intelligent multifunctional compound shows great potential as a novel clinical agent for ferroptosis inhibition and presents broad prospects for future development.
研究领域:
医学
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生物学
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药物化学
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DOI
PubMed
高影响因子
BIOMACROMOLECULES
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2024
·
IF 5.5
Yufei Cao,Moujiang Zheng,Jiahong Shi,Jiale Si,Guopu Huang,Yuanyuan Ji,Yuzhu Hou,Zhishen Ge
X-ray-induced photodynamic therapy (XPDT) can penetrate deeply into the tumor tissues to overcome the disadvantage of conventional PDT. However, the therapeutic efficacy of XPDT in cancer therapy is still restricted due to the insufficient reactive oxygen species (ROS) generation at a relatively low irradiation dosage. Herein, we present the tumor pH and ROS-responsive polyprodrug micelles to load the X-ray photosensitizer verteporfin (VP) as an ROS production enhancer. The block copolymer polyprodrug consisting of hydrophilic poly(ethylene glycol) (PEG) as well as the segments of thioketal-linked camptothecin (CPT) methacrylate (CPTKMA) and 2-(pentamethyleneimino)ethyl methacrylate (PEMA) (PEG-b-P(CPTKMA-co-PEMA)) can self-assemble into micelles in aqueous solution and encapsulate VP with a high loading efficiency of 67%. Inside tumor tissues, the zeta potential of the micelles can transform from neutral to positive for promoted cellular internalization under tumor acidity. Followed by X-ray irradiation at the dose of 4 Gy, efficient ROS generation in the presence of VP triggers CPT release. The VP-loaded polyprodrug micelles can finally ablate tumors efficiently via synergistic radiochemotherapy due to deep penetration of X-ray inside tumor tissues, ROS generation enhancement, and triggered CPT release. Consequently, this promising strategy represents a robust therapeutic modality for the enhanced radiochemotherapy of cancers.
研究领域:
肿瘤学
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药剂学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
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2025
·
IF 3.8
Xiaotian Wan,Xiyu Liu,Pan Wu,Yongmei Li,Yuanyuan Shi,Yueli Nie,Keyong Zhang,Ze Jin,Ruiyun Song,Zhikun Zhang,Lu Gan,Jian He
Objective Exploring the role and mechanism of a novel bioorthogonal system using transition metals as catalysts in the treatment of hepatocellular carcinoma (HCC). Methods Initially, a catalytic ruthenium (Ru) complex and the substrate alloc-RH 110 were synthesized, followed by the identification of their structures utilizing mass spectrometry and nuclear magnetic resonance (NMR) techniques. The catalytic efficacy of the Ru complex was then assessed using a fluorescence spectrophotometer. Subsequently, employing HepG2 cells as the cellular source, cell-derived vesicles encapsulating the Ru complexes, designated as EVs@Ru, were prepared. The EVs@Ru were characterized by measuring their particle size and Zeta potential, observing morphological features under transmission electron microscopy (TEM), and detecting specific protein expressions via Western blot analysis. Drug loading within the EVs@Ru was quantified using inductively coupled plasma mass spectrometry (ICP-MS), and their catalytic efficiency was evaluated. In vitro, the low-activity prodrug alloc-DOX was synthesized and its toxicity, along with the drug concentration in EVs@Ru, was determined. Further, the catalytic cytotoxicity of alloc-DOX against HepG2 cells encapsulated in EVs@Ru was analyzed through microscopic observation, CCK-8 assays, and apoptosis experiments. For in vivo studies, a tumor-bearing mouse model was established using human liver cancer HepG2 cells to observe the antitumor effects. Finally, the primary organs of each group of tumor-bearing mice were assessed for in vivo safety. Results ESI-MS and 1H NMR confirmed the accurate structure of Ru complexes and alloc-RH 110. The Ru complexes achieved full catalytic conversion of alloc-RH 110 within 24 hours. EVs and EVs@Ru exhibited particle sizes of ∼116.85 nm and ∼281.88 nm, respectively, with Zeta potentials of ∼-20.86 mV and ∼-25.89 mV, both appearing quasi-circular under TEM. WB analysis verified the presence of vesicle-specific marker proteins in both, confirming their cell-derived nature. ICP-MS determined a drug loading of 21.90 μg/mL for EVs@Ru, with an encapsulation efficiency of ∼24.86%. Fluorescence spectrophotometry demonstrated 100% catalytic efficiency for EVs@Ru. Synthetic alloc-DOX validated by 1H NMR and ESI-MS matched literature data. MTT and CCK-8 assays confirmed low toxicity for alloc-DOX and Ru complexes, setting the experimental drug concentration at 4μM. In vitro, the EVs@Ru+alloc-DOX group exhibited potent HepG2 cell killing and apoptosis. In vivo, this group significantly inhibited tumor growth in tumor-bearing mice, with no observed toxicity to vital organs, indicating good biosafety. Conclusion The integration of bio-derived microvesicles (MVs) with transition metal catalysts has resulted in a biologically orthogonal system for efficient Ru complex delivery to tumor sites. This system facilitates controlled release of the Ru complexes, enabling tumor cell elimination. This innovative strategy holds great promise for enhancing tumor immunity and targeted therapeutic approaches.
研究领域:
肿瘤学
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药理学
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生物化学
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2019
·
IF 3.973
Fangyuan Lv,Dapeng Liu,Hailin Cong,Youqing Shen,Bing Yu
A bottlebrush polymer-cytotoxin prodrug, where a potent anticancer drug 10-hydroxycamptothecin (HCPT) and water-soluble methoxypolyethylene glycols (mPEG) were attached into the polyester backbone, was synthesized via thiol-ene reaction. The synthesized bottlebrush polymer-HCPT conjugate with drug loading content as high as ca. 20.4 wt% was characterized by NMR, IR, UV and fluorescence techniques. The prepared bottlebrush polymer-HCPT prodrug could self-assemble into nanosized micelles ( ca. 153 nm), which were uniform and stable in aqueous solution. Moreover, when exposed to esterase, the formed prodrug micelles as stimuli-responsive nanomaterials could release HCPT. In the cellar uptake and cytotoxicity experiments, the formed prodrug micelles exhibited effective internalization into tumor cells and excellent anticancer efficacies.
研究领域:
生物材料学
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药学
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肿瘤学
✓ 已验证
DOI
高影响因子
RSC Advances
·
2018
·Vol. 8
·期 1
·380-389
·
IF 2.936
Dongyang Tang,Xin Zhao,Tie Yang,Cheng Wang
An effective chemotherapy is usually subject to an insufficient loading of hydrophobic drugs as well as severe side effects. In order to address these dilemmas in one formulation, we herein construct paclitaxel prodrug based mixed micelles (MMs) for tumor-targeted chemotherapy. The paclitaxel prodrug containing a hydrophobic PTX and a hydrophilic PEG chain can self-assemble into uniform MMs with distearoyl phosphoethanolamine–polyethylene glycol–folate (DSPE–PEG–FA). The resultant MMs with preferable stability and hemolysis compatibility could improve the cellular uptake of nanoparticles via FA receptor-mediated endocytosis as compared to the single micelles (SMs). This tumor targetability was also confirmed in vivo by fluorescent imaging. MMs with a stable drug loading as well as tumor targetability displayed elevated in vitro cytotoxicity and in vivo antitumor efficacy compared with Taxol, which could be a potential formulation for cancer therapy.
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
NEW JOURNAL OF CHEMISTRY
·
2021
·Vol. 45
·期 18
·8306-8313
·
IF 3.591
Hui Xu,Yue Xiao,Jinlu Tang,Dongfang Liu,Xinxin Shi,Aaron Albert Aryee,Hongmin Meng,Lingbo Qu,Zhaohui Li
Chemotherapy for cancer treatment is widely used but remains restricted by several limitations, including inefficient drug delivery and concomitant adverse side effects. Herein, we report a new prodrug-based self-assembled nanoparticle for the efficient treatment of cancer. Amphiphilic prodrug molecules (3′,5′-dioleoyl floxuridine, DOF) were constructed to form prodrug nanoparticles (DOF NPs) through a self-assembly process in water via hydrophobic interactions. The DOF NPs with high stability can be quickly enriched in tumor cells and release the floxuridine drug via hydrolysis of ester bonds by esterase. In vitro experiments reveal that the DOF NPs possess satisfactory tumor killing effects and weak toxicity and side effects. These unique features could further promote the research progress of prodrug-based self-assembled strategies for the application of chemotherapy in cancer.
研究领域:
药学
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肿瘤学
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纳米医学
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产品关联
DOI
高影响因子
AAPS PHARMSCITECH
·
2016
·Vol. 18
·期 3
·729-737
·
IF 1.954
Li Yongquan,Xiao Yu,Yin Zongning
As an effective COX-2 inhibitor, celecoxib is widely used in anti-inflammation therapy. However, it may cause cardiovascular risks and renal adverse effects. In the present study, we aimed to construct a celecoxib prodrug with enhanced anti-inflammatory efficacy and reduced adverse effects using folate in order to target activated macrophages. Folate-glycine-celecoxib was synthesized and identified by 1 H-NMR, MS, and FTIR analyses. The cytotoxicity of folate-glycine-celecoxib was tested on murine macrophage cells (RAW264.7) using thiazolyl blue tetrazolium bromide. Cellular uptake studies were employed to determine targeting ability toward folate receptors via flow cytometry and confocal microscopy. Anti-inflammatory efficacy of folate-glycine-celecoxib was investigated by measuring the concentration of LPS-induced nitric oxide (NO). Folate-glycine-celecoxib exhibited lower cytotoxicity than conventional celecoxib, and this conjugate could be targetedly transported into RAW264.7 cells through binding with folate receptors on cell surface. Through targeting to RAW264.7 cells, folate-glycine-celecoxib exhibited better effects than equimolar celecoxib in NO inhibition, suggesting greater anti-inflammatory activity. These findings demonstrated that the prodrug folate-glycine-celecoxib had potential to treat inflammatory disease with low cytotoxicity and high targeting ability.
研究领域:
药理学
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免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Materials Science & Engineering C-Materials for Biological Applications
·
2014
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IF 2.736
Yi Ding,Wulian Chen,Jianhua Hu,Ming Du,Dong Yang
A polymerizable disulfide paclitaxel (PTX) prodrug was synthesized by the consequential esterification reactions of 3,3′-dithiodipropionic acid (DTPA), a disulfide compound containing two active carboxyl groups, with 2-hydroxyethyl methacrylate (HEMA) and PTX. The structure of the prodrug was confirmed by 1 H NMR characterization. Then, the polymerizable prodrug was copolymerized with poly(ethylene glycol) methyl ether methacrylate (PEGMEA) to obtain a copolymer with hydrophilic PEG side chains and PTX covalently linked onto the backbone via disulfide bonds. The loading content of PTX was 23%. In aqueous solution, this copolymer prodrug could self-assemble into micelles, with hydrophobic PTX as the cores and hydrophilic PEG-segment as the shells. In vitro cell assay demonstrated that this copolymer prodrug showed more apparent cytotoxicity to cancer cells than to human normal cells. After incubation for 48 h, the cell viability of HEK-293 cells (human embryo kidney cells) at 0.1 μg/mL PTX still remained more than 90%, however, that of HeLa cells (human cervical cancer cells) decreased to 52%.
研究领域:
药物化学
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生物材料学
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肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2015
·Vol. 3
·期 16
·3297-3305
·
IF 4.726
Haibo Wang,Xiangsheng Liu,Yin Wang,Yangjun Chen,Qiao Jin,Jian Ji
Ideal drug delivery systems should have prolonged circulation in blood, high accumulation in tumors with fast cellular uptake and burst drug release in cancer cells. Herein, a pH-sensitive small-molecule phospholipid prodrug based on phosphorylcholine (PC) was designed to overcome these challenges. The prodrug was synthesized by conjugating doxorubicin (DOX) to 11-mercaptoundecyl phosphorylcholine via an acid-labile hydrazone linker (UnPC-hyd-DOX). This phospholipid prodrug can self-assemble into core–shell micelles with exact and very high drug loading content (56.2%). Interestingly, the PC prodrug micelles can strongly minimize nonspecific phagocytosis by macrophages. They exhibited better ability to be internalized by cancer cells than that of the PEG prodrug micelles, which indicated that the PC shell facilitated cancer cell internalization. Moreover, in vitro results further demonstrated that DOX of phospholipid prodrug micelles can effectively escape from endo/lysosomes to the cytosol and enter the nucleus. An in vivo study demonstrated that these PC prodrug micelles exhibited much lower cardiotoxicity than free DOX. Importantly, PC prodrug micelles showed significantly slower blood clearance than PEG prodrug micelles and free DOX.
研究领域:
药学
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肿瘤学
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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）