Aseel Kashkush, Judith Furth-Lavi, Jiri Hodon, Raphael I Benhamou
The interaction between proteins and RNA is crucial for regulating gene expression, with dysregulation often linked to diseases such as cancer. The RNA-binding protein (RBP) Lin28 inhibits the tumor suppressor microRNA (miRNA) let-7, making it a significant oncogenic factor in tumor progression and metastasis. In this study, a small molecule is used that binds Lin28 and blocks its inhibition of let-7. To enhance its efficay, the inhibitor is transformed into degraders via two degradation approaches: Proteolysis Targeting Chimera (PROTAC) and molecular glue. A series of PROTAC bifunctional molecules and molecular glues capable of degrading Lin28 in cells.is developed Both strategies significantly reduce overexpressed Lin28 and alleviate cancer cellular phenotypes. Notably, the molecular glue approach demonstrates exceptional potency, surpassing PROTAC in several aspects. This outcome underscores the superior efficiency of the molecular glue approach for targeted Lin28 degradation and highlights its potential for addressing associated diseases with small molecules. Innovative small molecule strategies such as molecular glue and PROTAC technology for targeted RBP degradation, hold promise for opening new avenues in RNA modulation and addressing related diseases.
{"title":"PROTAC and Molecular Glue Degraders of the Oncogenic RNA Binding Protein Lin28.","authors":"Aseel Kashkush, Judith Furth-Lavi, Jiri Hodon, Raphael I Benhamou","doi":"10.1002/mabi.202400427","DOIUrl":"https://doi.org/10.1002/mabi.202400427","url":null,"abstract":"<p><p>The interaction between proteins and RNA is crucial for regulating gene expression, with dysregulation often linked to diseases such as cancer. The RNA-binding protein (RBP) Lin28 inhibits the tumor suppressor microRNA (miRNA) let-7, making it a significant oncogenic factor in tumor progression and metastasis. In this study, a small molecule is used that binds Lin28 and blocks its inhibition of let-7. To enhance its efficay, the inhibitor is transformed into degraders via two degradation approaches: Proteolysis Targeting Chimera (PROTAC) and molecular glue. A series of PROTAC bifunctional molecules and molecular glues capable of degrading Lin28 in cells.is developed Both strategies significantly reduce overexpressed Lin28 and alleviate cancer cellular phenotypes. Notably, the molecular glue approach demonstrates exceptional potency, surpassing PROTAC in several aspects. This outcome underscores the superior efficiency of the molecular glue approach for targeted Lin28 degradation and highlights its potential for addressing associated diseases with small molecules. Innovative small molecule strategies such as molecular glue and PROTAC technology for targeted RBP degradation, hold promise for opening new avenues in RNA modulation and addressing related diseases.</p>","PeriodicalId":18103,"journal":{"name":"Macromolecular bioscience","volume":" ","pages":"e2400427"},"PeriodicalIF":4.4,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
As an exceptional carrier for localized drug delivery to tumors, hydrogels can achieve prolonged drug release through careful design and adjustments, effectively targeting cancer cells and minimizing side effects. This study investigates a novel dual-responsive hydrogel system designed for the delivery of nanomedicines, focusing on drug release and the local antitumor efficacy of SN-38-cholesterol nanoparticles (SN-38-chol NPs) and polydopamine NPs (PDA NPs)/poly(n-isopropylacrylamide) (pNIPAM) hydrogels. By combining the thermosensitive properties of pNIPAM with the near-infrared (NIR) responsiveness of PDA NPs, the hydrogel aims to enhance on-demand drug release. SN-38-chol NPs, known for their stability and small size, are incorporated into the hydrogel to improve drug release dynamics. The investigation reveals a drug release cycle of over three weeks, maintaining sensitivity to both temperature and NIR light for controlled drug release. In vivo studies demonstrate the high tumor growth inhibition performance of the system after photothermal treatment induced by 808 nm NIR light. These results suggest that the drug-carrying hydrogel system holds promise for diverse applications in chemical and physical therapies, including the treatment of malignant wounds, post-surgery wound healing, and direct tumor treatment. This study establishes the potential of SN-38-chol NPs and PDA NPs/pNIPAM hydrogels as effective platforms for chemo-phototherapy.
{"title":"Sustained Drug Release from Dual-Responsive Hydrogels for Local Cancer Chemo-Photothermal Therapy.","authors":"Zhixiang Liu, Yoshitaka Koseki, Ryuju Suzuki, Anh Thi Ngoc Dao, Hitoshi Kasai","doi":"10.1002/mabi.202400413","DOIUrl":"https://doi.org/10.1002/mabi.202400413","url":null,"abstract":"<p><p>As an exceptional carrier for localized drug delivery to tumors, hydrogels can achieve prolonged drug release through careful design and adjustments, effectively targeting cancer cells and minimizing side effects. This study investigates a novel dual-responsive hydrogel system designed for the delivery of nanomedicines, focusing on drug release and the local antitumor efficacy of SN-38-cholesterol nanoparticles (SN-38-chol NPs) and polydopamine NPs (PDA NPs)/poly(n-isopropylacrylamide) (pNIPAM) hydrogels. By combining the thermosensitive properties of pNIPAM with the near-infrared (NIR) responsiveness of PDA NPs, the hydrogel aims to enhance on-demand drug release. SN-38-chol NPs, known for their stability and small size, are incorporated into the hydrogel to improve drug release dynamics. The investigation reveals a drug release cycle of over three weeks, maintaining sensitivity to both temperature and NIR light for controlled drug release. In vivo studies demonstrate the high tumor growth inhibition performance of the system after photothermal treatment induced by 808 nm NIR light. These results suggest that the drug-carrying hydrogel system holds promise for diverse applications in chemical and physical therapies, including the treatment of malignant wounds, post-surgery wound healing, and direct tumor treatment. This study establishes the potential of SN-38-chol NPs and PDA NPs/pNIPAM hydrogels as effective platforms for chemo-phototherapy.</p>","PeriodicalId":18103,"journal":{"name":"Macromolecular bioscience","volume":" ","pages":"e2400413"},"PeriodicalIF":4.4,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Basak Coban, Mehmet Baskurt, Hasan Sahin, Ahu Arslan-Yildiz
Alginate forms a hydrogel via physical cross-linking with divalent cations. In literature, Ca2+ is mostly utilized due to strong interactions but additional procedures are required to disassociate Ca-alginate hydrogels. On the other hand, Mg-alginate hydrogels disassociate spontaneously, which might benefit certain applications. This study introduces Mg-alginate as the main component of a bio-ink for the first time to obtain 3D tumor models by magnetic bio-patterning technique. The bio-ink contains magnetic nanoparticles (MNPs) for magnetic manipulation, Mg-alginate hydrogel as a sacrificial material, and cells. The applicability of the methodology is tested for the formation of 3D tumor models using HeLa, SaOS-2, and SH-SY5Y cells. Long-term cultures are examined by Live/dead and MTT analysis and revealed high cell viability. Subsequently, Collagen and F-actin expressions are observed successfully in 3D tumor models. Finally, the anti-cancer drug Doxorubicin (DOX) effect is investigated on 3D tumor models, and IC50 values is calculated to assess the drug response. As a result, significantly higher drug resistance is observed for bio-patterned 3D tumor models up to tenfold compared to 2D control. Overall, Mg-alginate hydrogel is successfully used to form bio-patterned 3D tumor models, and the applicability of the model is shown effectively, especially as a drug screening platform.
{"title":"Development of Mg-Alginate Based Self Disassociative Bio-Ink for Magnetic Bio-Patterning of 3D Tumor Models.","authors":"Basak Coban, Mehmet Baskurt, Hasan Sahin, Ahu Arslan-Yildiz","doi":"10.1002/mabi.202400339","DOIUrl":"https://doi.org/10.1002/mabi.202400339","url":null,"abstract":"<p><p>Alginate forms a hydrogel via physical cross-linking with divalent cations. In literature, Ca<sup>2+</sup> is mostly utilized due to strong interactions but additional procedures are required to disassociate Ca-alginate hydrogels. On the other hand, Mg-alginate hydrogels disassociate spontaneously, which might benefit certain applications. This study introduces Mg-alginate as the main component of a bio-ink for the first time to obtain 3D tumor models by magnetic bio-patterning technique. The bio-ink contains magnetic nanoparticles (MNPs) for magnetic manipulation, Mg-alginate hydrogel as a sacrificial material, and cells. The applicability of the methodology is tested for the formation of 3D tumor models using HeLa, SaOS-2, and SH-SY5Y cells. Long-term cultures are examined by Live/dead and MTT analysis and revealed high cell viability. Subsequently, Collagen and F-actin expressions are observed successfully in 3D tumor models. Finally, the anti-cancer drug Doxorubicin (DOX) effect is investigated on 3D tumor models, and IC<sub>50</sub> values is calculated to assess the drug response. As a result, significantly higher drug resistance is observed for bio-patterned 3D tumor models up to tenfold compared to 2D control. Overall, Mg-alginate hydrogel is successfully used to form bio-patterned 3D tumor models, and the applicability of the model is shown effectively, especially as a drug screening platform.</p>","PeriodicalId":18103,"journal":{"name":"Macromolecular bioscience","volume":" ","pages":"e2400339"},"PeriodicalIF":4.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ayca Aydin, Songul Ulag, Sabereh Nouri, Elif Durasi, Pelin Pelit Arayıcı, Gülgün Bosgelmez Tinaz, Mehmet Mücahit Güncü, Rabia Cakir, Oguzhan Gunduz, Cem Bulent Ustundag
Periodontal diseases, if untreated, can cause gum recession and tooth root exposure, resulting in infection and irreversible damage. Traditional treatments using autologous grafts are painful and often result in postoperative complications. Scaffolds offer a less invasive alternative, promoting cell proliferation and healing without additional surgery, thus enhancing comfort for patients and doctors. This study developed Chitosan (Chit)/Collagen (Col) film surfaces and drug-loaded Polyvinyl Alcohol (PVA)/Amoxicillin (AMX) nanofibers using solvent casting and electrospinning methods, respectively. The surfaces are characterized by scanning electron microscopy (SEM), mechanical testing, Fourier Transform Infrared Spectroscopy (FTIR), and differential scanning calorimetry (DSC). Biocompatibility and antimicrobial properties are assessed using NIH/3T3 fibroblast cells and bacterial cultures. SEM images confirmed the structural integrity of AMX-loaded 13% PVA nanofibers, while FTIR analysis validated the compositional integrity of PVA/AMX nanofibers and Chit/Col film hybrid surfaces. Cell studies showed over 90% viability for Chit/Col film + PVA/AMX nanofiber hybrid bilayer membranes, confirming their biocompatibility. The antimicrobial assessment indicated that the Chit/Col film + PVA/AMX (0.2%) nanofiber hybrid bilayer membrane exhibited superior efficacy against Streptococcus mutans. These findings suggest that this hybrid bilayer membrane can enhance cell growth, promote proliferation, and enable controlled drug release, offering significant promise for regeneration of gingival tissues.
{"title":"Production of Polyvinyl Alcohol/Amoxicillin - Chitosan/Collagen Hybrid Bilayer Membranes for Regeneration of Gingival Tissues.","authors":"Ayca Aydin, Songul Ulag, Sabereh Nouri, Elif Durasi, Pelin Pelit Arayıcı, Gülgün Bosgelmez Tinaz, Mehmet Mücahit Güncü, Rabia Cakir, Oguzhan Gunduz, Cem Bulent Ustundag","doi":"10.1002/mabi.202400331","DOIUrl":"https://doi.org/10.1002/mabi.202400331","url":null,"abstract":"<p><p>Periodontal diseases, if untreated, can cause gum recession and tooth root exposure, resulting in infection and irreversible damage. Traditional treatments using autologous grafts are painful and often result in postoperative complications. Scaffolds offer a less invasive alternative, promoting cell proliferation and healing without additional surgery, thus enhancing comfort for patients and doctors. This study developed Chitosan (Chit)/Collagen (Col) film surfaces and drug-loaded Polyvinyl Alcohol (PVA)/Amoxicillin (AMX) nanofibers using solvent casting and electrospinning methods, respectively. The surfaces are characterized by scanning electron microscopy (SEM), mechanical testing, Fourier Transform Infrared Spectroscopy (FTIR), and differential scanning calorimetry (DSC). Biocompatibility and antimicrobial properties are assessed using NIH/3T3 fibroblast cells and bacterial cultures. SEM images confirmed the structural integrity of AMX-loaded 13% PVA nanofibers, while FTIR analysis validated the compositional integrity of PVA/AMX nanofibers and Chit/Col film hybrid surfaces. Cell studies showed over 90% viability for Chit/Col film + PVA/AMX nanofiber hybrid bilayer membranes, confirming their biocompatibility. The antimicrobial assessment indicated that the Chit/Col film + PVA/AMX (0.2%) nanofiber hybrid bilayer membrane exhibited superior efficacy against Streptococcus mutans. These findings suggest that this hybrid bilayer membrane can enhance cell growth, promote proliferation, and enable controlled drug release, offering significant promise for regeneration of gingival tissues.</p>","PeriodicalId":18103,"journal":{"name":"Macromolecular bioscience","volume":" ","pages":"e2400331"},"PeriodicalIF":4.4,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cells coordinate their activity and regulate biological processes in response to chemical signals. Mimicking natural processes, control over the formation of artificial supramolecular materials is of high interest for their application in biology and medicine. Supramolecular material that can form in response to chemical signals is important for the development of autonomously responsive materials. Herein, a supramolecular hydrogel system is reported enabling in situ generation of hydrogelators in response to a specific chemical signal. Using self-immolative chemistry, spatial control over the formation of supramolecular hydrogel material and structured free-standing hydrogel objects via providing H2O2 locally is demonstrated. In addition, a hybrid system is developed enabling in situ generation of the H2O2 by the action of an enzyme and glucose, providing an extra handle for the development of an intelligent soft material. This generic design should enable the use of various (chemical)stimuli that can be obtained via coupling different stimuli and various chemical and/or biological markers and appears a versatile approach for the design of smart artificial soft materials that can find application in theranostic purposes.
{"title":"Biochemical Signal-Induced Supramolecular Hydrogelation for Structured Free-Standing Soft Material Formation.","authors":"Dineshkumar Bharathidasan, Akshay Sunil Salvi, Suryasarathi Bose, Chandan Maity","doi":"10.1002/mabi.202400419","DOIUrl":"https://doi.org/10.1002/mabi.202400419","url":null,"abstract":"<p><p>Cells coordinate their activity and regulate biological processes in response to chemical signals. Mimicking natural processes, control over the formation of artificial supramolecular materials is of high interest for their application in biology and medicine. Supramolecular material that can form in response to chemical signals is important for the development of autonomously responsive materials. Herein, a supramolecular hydrogel system is reported enabling in situ generation of hydrogelators in response to a specific chemical signal. Using self-immolative chemistry, spatial control over the formation of supramolecular hydrogel material and structured free-standing hydrogel objects via providing H<sub>2</sub>O<sub>2</sub> locally is demonstrated. In addition, a hybrid system is developed enabling in situ generation of the H<sub>2</sub>O<sub>2</sub> by the action of an enzyme and glucose, providing an extra handle for the development of an intelligent soft material. This generic design should enable the use of various (chemical)stimuli that can be obtained via coupling different stimuli and various chemical and/or biological markers and appears a versatile approach for the design of smart artificial soft materials that can find application in theranostic purposes.</p>","PeriodicalId":18103,"journal":{"name":"Macromolecular bioscience","volume":" ","pages":"e2400419"},"PeriodicalIF":4.4,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rong Mu, Ling Yang, Xinyue Wang, Binrui Yang, Jia Li, Aijun Wang, Guorui Zhang, Chufeng Sun, Yang Wu, Bo Yu, Bin Li
Front Cover: Polymer brushes are grafted to the substrate through surface-initiated atom transfer radical polymerization (SI-ATRP) to form a durable polymeric layer, which enhances surface lubrication, reduces bacterial adhesion, and improves biocompatibility and anti-inflammatory properties. The polymer brush coating shows potential application in dental materials. More details can be found in article 2400194 by Jia Li, Guorui Zhang, Bin Li, and co-workers.