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Epigallocatechin gallate-zinc oxide co-crystalline nanoparticles as an anticancer drug that is non-toxic to normal cells.

ABSTRACT: Decreased uptake and cellular accumulation of zinc is a common characteristic in cancer of the liver, pancreas and prostate, because these malignant cells are intolerant to the physiological concentrations of zinc. A tea polyphenol, epigallocatechin-3-gallate (EGCG), can enhance the cytotoxicity of zinc ions to cancer, but the application of this is limited by the low stability of EGCG. In this work, we have prepared a material that can simultaneously preserve the EGCG stability and facilitate zinc uptake and accumulation in cancer cells, under conditions that are not harmful to normal cells. Thus, we co-crystallize zinc oxide with EGCG to obtain hybrid EGCG-ZnO crystalline nanoparticles of 16.5 ± 5.3 nm in diameter. The EGCG-ZnO particles effectively kill PC-3 prostate adenocarcinoma cells at concentrations that are not cytotoxic to normal cells, WI-38 human embryonic lung fibroblasts. The EGCG-ZnO particles are two times more cytotoxic against PC-3 cells than the standard ZnO particles. In PC-3 cells, the EGCG-ZnO particles are taken up by endocytosis, followed by lysosomal disruption to release zinc and EGCG into the cytoplasm, finally resulting in nuclear accumulation of zinc.

SUBMITTER: Samutprasert P

PROVIDER: S-EPMC9078484 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Epigallocatechin gallate-zinc oxide co-crystalline nanoparticles as an anticancer drug that is non-toxic to normal cells.

Samutprasert Pawatsanai P Chiablaem Khajeelak K Teeraseranee Chanon C Phaiyarin Punnawich P Pukfukdee Puttikorn P Pienpinijtham Prompong P Svasti Jisnuson J Palaga Tanapat T Lirdprapamongkol Kriengsak K Wanichwecharungruang Supason S

RSC advances 20180215 14

Decreased uptake and cellular accumulation of zinc is a common characteristic in cancer of the liver, pancreas and prostate, because these malignant cells are intolerant to the physiological concentrations of zinc. A tea polyphenol, epigallocatechin-3-gallate (EGCG), can enhance the cytotoxicity of zinc ions to cancer, but the application of this is limited by the low stability of EGCG. In this work, we have prepared a material that can simultaneously preserve the EGCG stability and facilitate z ...[more]

PMID: 35539101

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Project description:Intimal macrophages play a critical role in atherosclerotic lesion initiation and progression by taking up oxidized low-density lipoprotein (oxLDL) and promoting inflammatory process. 1-(Palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdiA-PC), a major type of oxidized phosphatidylcholines (PC) found on oxLDL, has a high binding affinity to the macrophage scavenger receptor CD36 and participates in CD36-mediated recognition and uptake of oxLDL by intimal macrophages. We successfully synthesized epigallocatechin gallate (EGCG)-loaded nanoparticles (Enano), which were composed of EGCG, PC, (+) alpha-tocopherol acetate, and surfactant. We also incorporated KOdiA-PC on the surface of Enano to make ligand-coated Enano (L-Enano) to target intimal macrophages. The objectives of this study were to determine the anti-atherogenic effects of Enano and L-Enano in LDL receptor null (LDLr-/-) mice. Our in vitro data demonstrated that L-Enano had a higher binding affinity to mouse peritoneal macrophages than Enano. This high binding affinity was diminished by CD36 antibodies or knockdown of the CD36 receptor in mouse peritoneal macrophages, confirming the specific binding of L-Enano to the macrophage CD36 receptor. LDLr-/- mice were randomly divided to six groups and received weekly tail vein injection with PBS, EGCG, void nanoparticles (Vnano), Enano, ligand-coated Vnano (L-Vnano), or L-Enano once per week for 22 weeks. The dose of EGCG was 25 mg per kg body weight. L-Enano at 20 μg/mL significantly decreased production of monocyte chemoattractant protein-1, tumor necrosis factor alpha, and interleukin-6 from mouse macrophages, while having no effect on their plasma levels compared to the PBS control. There were no significant differences in blood lipid profiles among six treatment groups. Mice treated with L-Enano also had significantly smaller lesion surface areas on aortic arches compared to the PBS control. Liver EGCG content was decreased by treatments in the order of EGCG>Enano>L-Enano. Native EGCG had inhibitory effects on liver and body fat accumulation. This molecular target approach signals an important step towards inhibiting atherosclerosis development via targeted delivery of bioactive compounds to intimal macrophages.

Project description:Numerous therapeutic agents and strategies were designed targeting the therapies of Alzheimer's disease, but many have been suspended due to their severe clinical side effects (such as encephalopathy) on patients. The attractiveness for small molecules with good biocompatibility is therefore restarted. Epigallocatechin-3-gallate (EGCG), extracted from green tea, is expected to be a promising small-molecule drug candidate, which can remodel the structure of preformed β-sheet-rich oligomers/fibrils and then effectively interfere with neurodegenerative processes. However, as the structure of non-fibrillary aggregates cannot be directly characterized, the atomic details of the underlying inhibitory and destructive mechanisms still remain elusive to date. Here, all-atom molecular dynamics simulations and experiments were carried out to elucidate the EGCG-induced remodeling mechanism of amyloid β (Aβ) fibrils. We showed that EGCG was indeed an effective Aβ fibril inhibitor. EGCG was capable of mediating conformational rearrangement of Aβ1-42 fibrils (from a β-sheet to a random coil structure) and triggering the disintegration of fibrils in a dose-dependent manner. EGCG redirected the structure of Aβ by breaking the β-sheet structure and hydrogen bonds between peptide chains within the Aβ protofibrils, especially the parallel β-strand (L17VFFAEDVGS26). Moreover, reduced solvent exposure and multisite binding patterns all tended to induce the conformation conversion of Aβ17-42 pentameric protofibrils, destroying pre-formed fibrils and inhibiting continued fibril growth. Detailed data analysis revealed that structural features of EGCG with abundant benzene ring and phenolic hydroxyl moieties preferentially interact with the parallel β-strands to effectually hinder the interaction of the interpeptide chain and the growth of the ordered β-sheet structure. Furthermore, experimental studies confirmed that EGCG was able to disaggregate the preformed fibrils and alter the protein structure. This study will enable a deeper understanding of fundamental principles for design of structural-based inhibitors.

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Epigallocatechin gallate-zinc oxide co-crystalline nanoparticles as an anticancer drug that is non-toxic to normal cells.

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Epigallocatechin gallate-zinc oxide co-crystalline nanoparticles as an anticancer drug that is non-toxic to normal cells.

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