Journal of Biomedical Nanotechnology
·
2017
·Vol. 13
·期 11
·1435-1445
·
IF 4.521
Wang Tingting,Song Yonghong,Zhang Wencheng,Wu Zeyu,Li Fei,Su Yang,Yang Yi,Li Fangyuan,Chen Pengpeng,Wang Jing,Wu Qiang,Sun Xiaolian,Lu Yang,Ling Daishun
As a phenyltetralin-type lignin isolated from roots and rhizomes of Podophyllum hexandrum, podophyllotoxin (POD) possesses a great deal of biological activities, especially the anticancer activity via preventing the division of cancerous cells. However, its practical clinical
application as an anticancer agent is hindered by its poor water solubility and serious side effects. Herein, we enclosed the POD into the hydrophobic cavity of natural phosphatidylcholine based liposomes to improve its solubility and thus, enhance the chemotherapeutic effect. Modified gold
nanorods (GNRs) were further conjugated onto the liposomal POD composite (GLP) for enhanced photothermal stability. The extinction coefficient of GLP aqueous dispersion at 808 nm was calculated to be 8.08 Lg–1 cm–1, and the photothermal conversion efficiency
was calculated to be 46.1%. In addition, the release of POD from GLP composite was effectively triggered by NIR irradiation. Compared with the cellular viabilities in the single chemotherapy group (54.6%) and the single photothermal therapy group (66.9%), only 10.3% 4T1 cells were survived
after photothermal and chemotherapy simultaneously in the GLP group after exposure to 808 nm NIR laser at an intensity of 1.0 W/cm2 for 5 min. The cytotoxicity and hemolysis assay further demonstrated the excellent biocompatibility of POD based liposomal composite. Overall, the
GNRs conjugated liposomal POD is a promising therapeutic nanoagent for synergistic chemo-thermal therapy.
研究领域:
药学
·
肿瘤学
·
纳米医学
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PubMed
高影响因子
Biomedical Materials
·
2023
·Vol. 18
·期 4
·045019
·
IF 4
Yingyu Ma,Lei Chen,Lian Deng,Xuebing Li,Xiu Zhao,Daobing Jiang,Jiabao Liu,Yang Song,Junda Liu,Nan Cui,Neng Qiu
Podophyllotoxin (PPT) is an active natural pharmaceutical component with potent anticancer activity. However, due to its poor water solubility and serious side effects, its medical applications are limited. In this work, we synthesized a series of PPT dimers, which can be self-assembled into stable nanoparticles of 124–152 nm in aqueous solution and can significantly increase the solubility of PPT in aqueous solution. In addition, PPT dimer nanoparticles exhibited high drug loading capacity (>80%) and could store at 4 °C in aqueous state with good stability for at least 30 d. In vitro release studies showed that nanoparticles with disulfide bonds (SS NPs) can quickly release (about 96.5% drug released within 24 h) the conjugated drug in PBS buffer (pH = 7.4) in the presence of DTT. Cell endocytosis experiments showed that SS NPs enhanced cell uptake (18.56 times higher than PPT for Molm-13, 10.29 times for A2780S and 9.81 times for A2780T) and maintained antitumor effect against human ovarian tumor cells (A2780S and resistant A2780T) and human breast cancer cells (MCF-7). In addition, the endocytosis mechanism of SS NPs was revealed that these nanoparticles were mainly up-taken by macropinocytosis-mediated endocytosis. We believe that these PPT dimer-based nanoparticles will become an alternative formula for PPT, moreover the assembly behavior of PPT dimer can be extended to other therapeutic drugs.
研究领域:
药学
·
纳米技术
·
癌症研究
·
药物递送系统
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Mo Liu,Zi-xu Zhang,Jia-hua Wang,Rui-bo Guo,Lu Zhang,Liang Kong,Yang Yu,Juan Zang,Yang Liu,Xue-tao Li
Ovarian cancer, a highly lethal form of gynecological cancer globally, has witnessed notable advancements in its treatment through the integration of nanotechnology and immunotherapy. Here, we designed a novel astragalus polysaccharide vector (PDA), encapsulating podophyllotoxin (PPT), and modifying methotrexate (DSPE-PEG 2000 -MTX) on its surface for targeting ovarian cancer cells with high folate receptor expression. We prepared novel MTX-modified PPT-loaded astragalus polysaccharide micelles (MTX-PPT-micelles) by dialysis method and evaluated their characterization, stability, safety and targeting ability. EDU proliferation, apoptosis, wound healing, and macrophage polarization experiments were performed, and a mouse ectopic tumor model and a lung metastasis model were established to evaluate the antitumor effects of MTX-PPT-micelles. The prepared MTX-PPT-micelles had appropriate particle size, good stability and safety, and were able to achieve slow drug release. In vitro and in vivo experiments showed that MTX-PPT-micelles significantly enhanced tumor uptake and apoptosis, and significantly inhibited tumor proliferation, invasion and metastasis processes. In addition, MTX-PPT-micelles could improve tumor immunosuppression by shifting tumor-associated macrophages from M2 to M1 phenotype. In conclusion, this study successfully constructed a novel nano-delivery system to achieve targeted therapy for ovarian cancer by combating tumor cells with immunomodulatory effects on tumor-associated macrophages.
研究领域:
肿瘤学
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药剂学
·
免疫学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2026
·
IF 6
Chunpeng Yang,Mengdi Wu,Min Li,Wenbin Niu,Yinan Zhao,Shubiao Zhang
MST and CD quantitatively confirmed that the flexible ADH-DTDPA spacer preserves strong CD44 binding ( K D = 15.3 μM). • HPMs showed pH/redox-triggered release, with 78.2% payload release in 72 h under tumor-mimicking conditions. • HPMs achieved superior antitumor efficacy at a lower dose while reducing systemic toxicity in vivo . Clinical application of podophyllotoxin (PPT) is significantly hampered by poor aqueous solubility and considerable systemic toxicity. Herein, we engineered dual-targeting and dual-cleavable prodrug micelles (HPMs) by conjugating PPT to hyaluronic acid (HA) backbone via a flexible, dual-responsive spacer, adipic dihydrazide–3,3′-dithiodipropionic acid (ADH-DTDPA). In vitro , HPMs demonstrated efficient CD44-mediated internalization in NCI-H1299 cells and rapidly disassembled under tumor microenvironment (TME) conditions (pH 5.0/GSH). Crucially, microscale thermophoresis (MST) provided quantitative evidence of the targeting mechanism, revealing a high binding affinity ( K D = 15.3 μM) for the CD44 receptor. In vivo , this design achieved effective accumulation of the micelles at tumor sites. Notably, HPMs (10 mg/kg) achieved superior tumor inhibition compared to free PPT (15 mg/kg) without inducing hepatotoxicity or nephrotoxicity. These findings provide a safe delivery strategy to overcome the clinical limitations of PPT and offer quantitative molecular insights into the rational design of targeted nanomedicines for lung cancer therapy. Download: Download high-res image (244KB) Download: Download full-size image
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2012
·
IF 4.447
Juan Li,Cai-Xia Dai,Hua Sun,Lu Jin,Chong-Yi Guo,Wei Cao,Jie Wu,Hai-Yan Tian,Cheng Luo,Wen-Cai Ye,Ren-Wang Jiang
Podophyllotoxin (POD) is a naturally occurring lignan with pronounced antineoplastic and antiviral properties. POD binds to tubulin and prevents the formation of mitotic spindle . Although cases of overdose or accidental ingestion are quite often, no specific therapy is currently available to treat the POD intoxication. In the current investigation, the protective effects and mechanisms of curcumin (CUR) on podophyllotoxin toxicity were evaluated in vitro and in vivo . The results showed that CUR could protect POD-induced cytotoxicity by recovering the G2/M arrest and decrease the changes of membrane potential and microtubule structure in Vero cells. A significant decrease of mortality rates was observed in Swiss mice treated by intragastrical administration of POD + CUR as compared with POD alone. The POD + CUR group also exhibited decreases in plasma transaminases , alkaline phosphatase , lactate dehydrogenase , plasma urea , creatinine and malondialdehyde level but elevated superoxide dismutase and glutathione levels as compared to the POD group. Histological examination of the liver and kidney demonstrated less morphological changes in the treatment of POD + CUR as compared with POD alone. The mechanism of the protective effects might be due to the competitive binding of CUR with POD in the same colchicines binding site as revealed by the tubulin polymerization assay and the molecular docking analysis, and the antioxidant activity against the oxidative stress induced by POD. In summary, both in vitro and in vivo data indicated the promising role of CUR as a protective agent against the POD poisoning.
研究领域:
药理学
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毒理学
·
分子生物学
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PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2015
·
IF 2.793
Cheng-Ting Zi,Dan Yang,Fa-Wu Dong,Gen-Tao Li,Yan Li,Zhong-Tao Ding,Jun Zhou,Zi-Hua Jiang,Jiang-Miao Hu
A series of perbutyrylated glycosides of podophyllotoxin and its derivatives were synthesized and evaluated for their antitumor activity in vitro. Most of them exhibit cytotoxic activity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assays . Among the synthesized compounds, epipodophyllotoxin α- d -galactopyranoside 8b , epipodophyllotoxin α- d -arabinopyranoside 8e , and podophyllotoxin β- d -glucopyranoside 11a show the highest potency of anticancer activity with their IC 50 values ranging from 0.14 to 1.69 μM. Structure activity relationship analysis indicates that the type of glycosidic linkage , the configuration at C-4 of the podophyllotoxin scaffold, and the substitution at 4′-position (OH vs OCH 3 ) can all have significant effect on the potency of their anticancer activity. Several compounds are more active than the control drugs Etoposide and Cisplatin , suggesting their potential as anticancer agents for further development.
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高影响因子
JOURNAL OF NANOPARTICLE RESEARCH
·
2020
·Vol. 22
·期 9
·1-13
·
IF 2.132
Liu Yajing,Lv Xiaoguang,Xia Shengli,Hao Bingjie,Huang Xiaoyu,Shi Ping
Efficient drug delivery systems are required to increase drug concentrations at tumor sites and to reduce the side effects on normal cells. In this work, we developed a nanoscale drug delivery system based on graphene oxide (GO) and used it to load a disulfide prodrug of podophyllotoxin (DCM-S-PPT), which was linked by a thiol-specific cleavable disulfide bond. In order to improve the biocompatibility in physiological solution, GO was functionalized with 6-armed polyethylene glycol (PEG) and characterized by UV-Vis spectroscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis. By atomic force microscopy, the size distribution of the nanoparticles was shown to be 25~250 nm. DCM-S-PPT was loaded on GO-PEG via p–p stacking and hydrophobic interactions. The loading rate reached 138%. In vitro cytotoxicity assay showed that GO-PEG/DCM-S-PPT inhibited the proliferation of human cervical adenocarcinoma HeLa cells more than that of human normal kidney 293T cells, which was attributed to the different intracellular concentrations of GSH. After intravenous injection in mice bearing tumors, GO-PEG/DCM-S-PPT showed the better antitumor activity and less side effects than those of DCM-S-PPT and PPT. Compared with DCM-S-PPT or PPT, GO-PEG/DCM-S-PPT complex showed the best tumor-targeting and specific drug release. Our results provide a novel strategy for the combination of nanocarriers and modified chemotherapy drugs in the future.
研究领域:
纳米技术
·
药学
·
癌症研究
·
药物递送系统
·
材料科学
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DOI
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2026
·
IF 4.9
Na Yao,Lian Deng,Ziqing Weng,Yang Song,Ning Lei,Junda Liu,Neng Qiu
Podophyllotoxin (PPT) is a natural lignan antitumor compound, but its clinical application is significantly limited by poor water solubility and lack of selectivity. To address these issues, PPT was conjugated with a tumor-targeting ligand, biotin (Bio), through different linkers to prepare three PPT-Bio conjugates: podophyllotoxin-biotin (PB), podophyllotoxin-6-aminohexanoic acid-biotin (PACAB), and podophyllotoxin-3,3’-dithiobispropionic acid-ethanolamine-biotin (PSSB). These conjugates were subsequently complexed with HP-β-CD to form the corresponding inclusion complexes, aiming to improve both tumor-targeting capability and water solubility of PPT. Among them, the PSSB/HP-β-CD complex exhibited 5.68-fold increase in solubility compared to free PPT. In vitro release studies demonstrated that the PSSB/HP-β-CD inclusion complex exhibited an accelerated release under both acidic and reductive environment. Cellular uptake studies revealed significantly higher internalization of all three inclusion complexes in Hela cells compared to free PPT. The targeting specificity of biotin was confirmed by competitive inhibition of the biotin receptor (BR). Further endocytosis pathway studies showed that the internalization process was energy-dependent and involved multiple endocytic pathways. Cytotoxicity assays indicated that all compounds and complexes exhibited concentration-dependent cytotoxicity, with the three inclusion complexes showing significantly stronger antitumor activity than free PPT. Notably, the PSSB/HP-β-CD complex demonstrated the highest potency (IC50 =17.03μM). Additionally, these complexes exhibited low toxicity on normal cells and good hemocompatibility. Preliminary pharmacokinetic evaluation indicated favorable tissue distribution of the biotinylated prodrug conjugates. Therefore, the biotinylated prodrug inclusion complexes, particularly PSSB/HP‑β‑CD, demonstrate great potential as targeted antitumor agents with improved solubility and efficacy.
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高影响因子
ANALYST
·
2011
·Vol. 136
·期 11
·2294-2305
·
IF 3.913
Ya Yuan,Yuzhi Wang,Ran Xu,Meidong Huang,Huan Zeng
A micelle-mediated extraction technique, i.e. ionic liquid-based microwave-assisted extraction (ILs-MAE) technique has been developed for the effective extraction of podophyllotoxin from three Chinese medicinal plants. Several operating parameters were successively optimized by single-factor and L9 (34) orthogonal array experiments. 1-Butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]), 1-decyl-3-methylimidazolium tetrafluoroborate ([demim][BF4]) and 1-allyl-3-methylimidazolium tetrafluoroborate ([amim][BF4]) were selected as the optimal surfactants for Dysosma versipellis, Sinopodophyllum hexandrum and Diphylleia sinensis, respectively. Compared with other extraction techniques, such as ionic liquids-based maceration extraction (ILs-ME), heat extraction (ILs-HE) and ultrasound-assisted extraction (ILs-UAE), the ILs-MAE technique not only took a shorter time but also afforded a higher extraction rate of podophyllotoxin from the herbs. Reversed phase high performance liquid chromatography was employed for the analysis of podophyllotoxin. The results showed that the linearity for analyzing podophyllotoxin in all three herbs was in the concentration range of 0.005–0.4 mg mL−1 with the correlation coefficient between 0.9993 and 0.9996. LODs were 2.05–2.58 μg mL−1 and RSDs of inter-day stability were less than 5.8%. Repeatability and intermediate precision were separately lower than 3.3% and 6.3%. The recoveries for podophyllotoxin extracted with the ILs-MAE technique were in the range of 97.1–102% and all RSDs were lower than 3.0%. Furthermore, the mechanism of ILs-MAE was preliminarily studied by means of kinetic mechanism, surface structures and chemical compositions of samples before and after different extraction techniques. On the basis of the destruction of herb surface microstructures and high solubility of ILs, the ILs-MAE technique eventually got the maximum yield value.
研究领域:
药学
·
分析化学
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DOI
PubMed
高影响因子
CHINESE JOURNAL OF CHEMISTRY
·
2016
·Vol. 34
·期 4
·425-431
·
IF 1.872
Yafei Guo,Yushun Zhang,Jiuling Li,Fen Zhao,Yang Liu,Min Su,Yubo Jiang,Yuqi Liu,Jihong Zhang,Bo Yang,Rui Yang
An inclusion complex of podophyllotoxin (PPT) with γ -cyclodextrin ( γ -CD) was prepared. The behavior, characterization, and water solubility of the inclusion complex were carefully investigated via fluorescence spectroscopy, thermogravimetry, differential scanning calorimetry, X-ray diffraction analysis, and 1 H and 2D nuclear magnetic resonance spectroscopy. Furthermore, antitumor activity to human cancer lines and toxicity in mice were studied. Results showed that the inclusion complex formed in a 1:1 ratio with a considerable apparent stability constant K s (4245.5 L·mol −1 ). Water solubility was considerably improved. In addition, the anticancer activity of the inclusion complex was better than that of cis -platinum (DDP, positive control). Most importantly, the toxicity of podophyllotoxin inclusion complex reduced and became more safety to mice which will be great valuable to research its applications as a kind of antitumor drug to human in the further.
研究领域:
药学
·
肿瘤学
·
药物化学
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DOI
高影响因子
JOURNAL OF NATURAL PRODUCTS
·
2023
·
IF 5.1
Hongyan Lin,Dongxuan Ai,Qingqing Liu,Xinling Wang,Jiale Gao,Qingqing Chen,Lingyu Ruan,Yuheng Tao,Jian Gao,Liqun Wang
Cancer is a major disease threatening human health worldwide, among which non-small-cell lung cancer (NSCLC) is the most deadly. Clinically, almost all anticancer drugs eventually fail to consistently benefit patients due to serious drug resistance. AKT is a key effector of the PI3K/AKT/mTOR pathway, which is closely related to the occurrence, development, and drug resistance of tumors. Herein, we first designed and synthesized 20 kinds of novel hybrid molecules targeting both tubulin and AKT based on a podophyllotoxin (PPT) skeleton through computer-aided drug design. By CCK8 assay, we screened the compound D1-1 (IC50 = 0.10 μM) with the strongest inhibitory activity against H1975 cells, and its activity was 100 times higher than PPT (IC50 = 12.56 μM) and 300 times higher than gefitinib (IC50 = 32.15 μM). Affinity analysis results showed that D1-1 not only retained the tubulin targeting of PPT but also showed strong AKT targeting. Subsequent pharmacological experiments showed that D1-1 significantly inhibited the proliferation and metastasis of H1975 cells and slightly induced their apoptosis by inhibiting both tubulin polymerization and the AKT pathway activation. Collectively, these data demonstrate that the novel hybrid molecule D1-1 may be an excellent lead compound for the treatment of human NSCLC as a dual inhibitor of tubulin and AKT.
研究领域:
肿瘤学
·
药理学
·
药物设计
·
癌症生物学
·
分子生物学
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DOI
PubMed
高影响因子
SYNTHETIC COMMUNICATIONS
·
2023
·
IF 2.1
Jun Yang,Guang-Ping Liang,Xiong-Li Liu
To investigate the effects and mechanisms of 4-(1H-indol-1-yl)-4-oxobutanoic acid spliced podophyllotoxin derivatives (3a–3l) on tumor cells. The MTT method was adopted to evaluate (3a–3l) antitumor activity in vitro against A549 cells, A549/DDP cells, MCF-7 cells. The results showed that compound 3l had the most prominent inhibitory effect and high selectivity with IC50 18.53 ± 1.51 µM against A549/DDP cells. Meanwhile, the effects of compound 3l on the nuclear state, cell cycle and apoptosis of A549/DDP cells showed that compound 3l induced apoptosis by delaying the G2/M phase of A549/DDP cell cycle. In addition, molecular docking of compound 3l also showed that it could form a good hydrogen bond with ARG-158 (d = 2.6, 2.7 Å) and HIS-406 (d = 2.5 Å) at the colchicine site of tubulin. Compound 3l could provide lead compound for the development of new multi-drug resistant anti-tumor drugs.
研究领域:
药理学
·
肿瘤学
·
化学
·
分子生物学
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高影响因子
危险品化学品经营许可证（带存储）