自组装刺激响应型金刚烷胺-鬼臼毒素共轭物/β-环糊精包合物，提高溶解度和抗癌活性

IF 4 2区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Molecular Structure Pub Date : 2024-11-16 DOI:10.1016/j.molstruc.2024.140752

Lei Chen , Yang Song , Lian Deng , Jianpeng Liu , Jiabao Liu , Daobing Jiang , Xiaoshuang Dai , Ke Mei , Junda Liu , Neng Qiu

{"title":"自组装刺激响应型金刚烷胺-鬼臼毒素共轭物/β-环糊精包合物，提高溶解度和抗癌活性","authors":"Lei Chen , Yang Song , Lian Deng , Jianpeng Liu , Jiabao Liu , Daobing Jiang , Xiaoshuang Dai , Ke Mei , Junda Liu , Neng Qiu","doi":"10.1016/j.molstruc.2024.140752","DOIUrl":null,"url":null,"abstract":"<div><div>Podophyllotoxin (PPT) has excellent antitumor activity. However, poor water solubility and severe adverse effects hinder its extensive clinical applications. To effectively utilize PPT to fight against cancer, PPT was conjugated with adamantanamine (Ad) via glutathione (GSH) response disulfide bond and the resulting PPT-SS-AD was incorporated in β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) to generate high-affinity PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes. By conjugating with AD, the stability constants (<em>K</em><sub>s</sub>) of PPT-SS-AD/β-CDs were notably higher than that of PPT/β-CDs. In addition, the water solubility of PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD increased 5.1-fold and 8.71-fold compared to free PPT, respectively. Both PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes exhibited accelerated release in the presence of DTT and at acidic condition. The inclusion complex with hydrophilic CD and hydrophobic PPT could self-assemble into nanosized particles with spherical shape. Cell uptake studies showed that uptake of PPT-SS-AD/β-CD NPs was 2.12-fold greater than that of PPT. Moreover, the <em>in vitro</em> studies showed that the cytotoxic effects of PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes were also enhanced compared to free PPT and the most significant cell growth inhibition was observed in Hela cells. Our study demonstrates the potential of utilizing adamantanamine modification to enhance the complexation of anticancer drugs with cyclodextrins and subsequently boosting the anticancer efficacy.</div></div>","PeriodicalId":16414,"journal":{"name":"Journal of Molecular Structure","volume":"1324 ","pages":"Article 140752"},"PeriodicalIF":4.0000,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Self-assembled stimuli-responsive adamantanamine-podophyllotoxin conjugate/β-cyclodextrins inclusion complex for enhanced solubility and anticancer activity\",\"authors\":\"Lei Chen , Yang Song , Lian Deng , Jianpeng Liu , Jiabao Liu , Daobing Jiang , Xiaoshuang Dai , Ke Mei , Junda Liu , Neng Qiu\",\"doi\":\"10.1016/j.molstruc.2024.140752\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Podophyllotoxin (PPT) has excellent antitumor activity. However, poor water solubility and severe adverse effects hinder its extensive clinical applications. To effectively utilize PPT to fight against cancer, PPT was conjugated with adamantanamine (Ad) via glutathione (GSH) response disulfide bond and the resulting PPT-SS-AD was incorporated in β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) to generate high-affinity PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes. By conjugating with AD, the stability constants (<em>K</em><sub>s</sub>) of PPT-SS-AD/β-CDs were notably higher than that of PPT/β-CDs. In addition, the water solubility of PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD increased 5.1-fold and 8.71-fold compared to free PPT, respectively. Both PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes exhibited accelerated release in the presence of DTT and at acidic condition. The inclusion complex with hydrophilic CD and hydrophobic PPT could self-assemble into nanosized particles with spherical shape. Cell uptake studies showed that uptake of PPT-SS-AD/β-CD NPs was 2.12-fold greater than that of PPT. Moreover, the <em>in vitro</em> studies showed that the cytotoxic effects of PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes were also enhanced compared to free PPT and the most significant cell growth inhibition was observed in Hela cells. Our study demonstrates the potential of utilizing adamantanamine modification to enhance the complexation of anticancer drugs with cyclodextrins and subsequently boosting the anticancer efficacy.</div></div>\",\"PeriodicalId\":16414,\"journal\":{\"name\":\"Journal of Molecular Structure\",\"volume\":\"1324 \",\"pages\":\"Article 140752\"},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-11-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Molecular Structure\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0022286024032605\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Molecular Structure","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0022286024032605","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}

引用次数: 0

摘要

鬼臼毒素（PPT）具有出色的抗肿瘤活性。然而，水溶性差和严重的不良反应阻碍了它在临床上的广泛应用。为了有效利用鬼臼毒素抗癌，研究人员通过谷胱甘肽（GSH）反应二硫键将鬼臼毒素与金刚烷胺（Ad）共轭，并将生成的鬼臼毒素-SS-AD与β-环糊精（β-CD）和羟丙基-β-环糊精（HP-β-CD）结合，生成高亲和力的PPT-SS-AD/β-CD和PPT-SS-AD/HP-β-CD包合物。通过与 AD 共轭，PPT-SS-AD/β-CD 的稳定性常数（Ks）明显高于 PPT/β-CD。此外，与游离 PPT 相比，PPT-SS-AD/β-CD 和 PPT-SS-AD/HP-β-CD 的水溶性分别增加了 5.1 倍和 8.71 倍。PPT-SS-AD/β-CD 和 PPT-SS-AD/HP-β-CD 包合物在 DTT 存在和酸性条件下均表现出加速释放的特性。亲水性 CD 和疏水性 PPT 的包合物可自组装成球形的纳米颗粒。细胞摄取研究表明，PPT-SS-AD/β-CD NPs 的摄取量是 PPT 的 2.12 倍。此外，体外研究表明，与游离 PPT 相比，PPT-SS-AD/β-CD 和 PPT-SS-AD/HP-β-CD 包合物的细胞毒性作用也得到了增强，在 Hela 细胞中观察到了最显著的细胞生长抑制作用。我们的研究表明，利用金刚烷胺修饰可增强抗癌药物与环糊精的络合，从而提高抗癌疗效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Self-assembled stimuli-responsive adamantanamine-podophyllotoxin conjugate/β-cyclodextrins inclusion complex for enhanced solubility and anticancer activity

Podophyllotoxin (PPT) has excellent antitumor activity. However, poor water solubility and severe adverse effects hinder its extensive clinical applications. To effectively utilize PPT to fight against cancer, PPT was conjugated with adamantanamine (Ad) via glutathione (GSH) response disulfide bond and the resulting PPT-SS-AD was incorporated in β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) to generate high-affinity PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes. By conjugating with AD, the stability constants (K_s) of PPT-SS-AD/β-CDs were notably higher than that of PPT/β-CDs. In addition, the water solubility of PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD increased 5.1-fold and 8.71-fold compared to free PPT, respectively. Both PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes exhibited accelerated release in the presence of DTT and at acidic condition. The inclusion complex with hydrophilic CD and hydrophobic PPT could self-assemble into nanosized particles with spherical shape. Cell uptake studies showed that uptake of PPT-SS-AD/β-CD NPs was 2.12-fold greater than that of PPT. Moreover, the in vitro studies showed that the cytotoxic effects of PPT-SS-AD/β-CD and PPT-SS-AD/HP-β-CD inclusion complexes were also enhanced compared to free PPT and the most significant cell growth inhibition was observed in Hela cells. Our study demonstrates the potential of utilizing adamantanamine modification to enhance the complexation of anticancer drugs with cyclodextrins and subsequently boosting the anticancer efficacy.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Journal of Molecular Structure 化学-物理化学

CiteScore

7.10

自引率

15.80%

发文量

2384

审稿时长

45 days

期刊介绍： The Journal of Molecular Structure is dedicated to the publication of full-length articles and review papers, providing important new structural information on all types of chemical species including: • Stable and unstable molecules in all types of environments (vapour, molecular beam, liquid, solution, liquid crystal, solid state, matrix-isolated, surface-absorbed etc.) • Chemical intermediates • Molecules in excited states • Biological molecules • Polymers. The methods used may include any combination of spectroscopic and non-spectroscopic techniques, for example: • Infrared spectroscopy (mid, far, near) • Raman spectroscopy and non-linear Raman methods (CARS, etc.) • Electronic absorption spectroscopy • Optical rotatory dispersion and circular dichroism • Fluorescence and phosphorescence techniques • Electron spectroscopies (PES, XPS), EXAFS, etc. • Microwave spectroscopy • Electron diffraction • NMR and ESR spectroscopies • Mössbauer spectroscopy • X-ray crystallography • Charge Density Analyses • Computational Studies (supplementing experimental methods) We encourage publications combining theoretical and experimental approaches. The structural insights gained by the studies should be correlated with the properties, activity and/ or reactivity of the molecule under investigation and the relevance of this molecule and its implications should be discussed.