Pub Date : 2025-02-10Epub Date: 2024-10-28DOI: 10.1021/acs.biomac.4c00936
Niannian Lv, Zhuo-Ran Yang, Jing-Wen Fan, Teng Ma, Kehan Du, Huimin Qin, Hao Jiang, Jintao Zhu
In situ polymerization on cell membranes can decrease cell mobility, which may inhibit tumor growth and invasion. However, the initiation of radical polymerization traditionally requires exogenous catalysts or free radical initiators, which might cause side effects in normal tissues. Herein, we synthesized a Y-type diacetylene-containing lipidated peptide amphiphile (TCDA-KFFFFK(GRGDS)-YIGSR, Y-DLPA) targeting integrins and laminin receptors on murine mammary carcinoma 4T1 cells, which underwent nanoparticle-to-nanofiber morphological transformation and in situ polymerization on cell membranes. Specifically, the polymerized Y-DLPA induced 4T1 cell apoptosis and disturbed the substance exchange and metabolism. In vitro assays demonstrated that the polymerized Y-DLPA nanofibers decreased the migration capacity of 4T1 cells, potentially suppressing tumor invasion and metastasis. When administered locally to 4T1 tumor-bearing mice, the Y-DLPA nanoparticles formed a biomimetic extracellular matrix that effectively suppressed tumor growth. This study provides an in situ polymerization strategy that can serve as an effective drug-free biomaterial with low side effects for antitumor therapy.
{"title":"Tumor Receptor-Mediated Morphological Transformation and <i>In Situ</i> Polymerization of Diacetylene-Containing Lipidated Peptide Amphiphile on Cell Membranes for Tumor Suppression.","authors":"Niannian Lv, Zhuo-Ran Yang, Jing-Wen Fan, Teng Ma, Kehan Du, Huimin Qin, Hao Jiang, Jintao Zhu","doi":"10.1021/acs.biomac.4c00936","DOIUrl":"10.1021/acs.biomac.4c00936","url":null,"abstract":"<p><p><i>In situ</i> polymerization on cell membranes can decrease cell mobility, which may inhibit tumor growth and invasion. However, the initiation of radical polymerization traditionally requires exogenous catalysts or free radical initiators, which might cause side effects in normal tissues. Herein, we synthesized a Y-type diacetylene-containing lipidated peptide amphiphile (TCDA-KFFFFK(GRGDS)-YIGSR, Y-DLPA) targeting integrins and laminin receptors on murine mammary carcinoma 4T1 cells, which underwent nanoparticle-to-nanofiber morphological transformation and <i>in situ</i> polymerization on cell membranes. Specifically, the polymerized Y-DLPA induced 4T1 cell apoptosis and disturbed the substance exchange and metabolism. <i>In vitro</i> assays demonstrated that the polymerized Y-DLPA nanofibers decreased the migration capacity of 4T1 cells, potentially suppressing tumor invasion and metastasis. When administered locally to 4T1 tumor-bearing mice, the Y-DLPA nanoparticles formed a biomimetic extracellular matrix that effectively suppressed tumor growth. This study provides an <i>in situ</i> polymerization strategy that can serve as an effective drug-free biomaterial with low side effects for antitumor therapy.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"825-834"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142491099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10Epub Date: 2025-01-29DOI: 10.1021/acs.biomac.4c01731
Qin-Fang Zhang, Rui-Mo Zhao, Yu Lei, Xiao-Li Tian, Yue Hu, Lan Zhang, Ji Zhang
Reactive oxygen species (ROS)-sensitive polymers are extensively used in cancer therapies. However, the ROS levels in the tumor microenvironment are often insufficient to trigger an adequate therapeutic response. Herein, we report a cinnamaldehyde (CA)-based ROS-responsive cationic polymer (PCA) and demonstrate its high efficiency in gene delivery and tumor cell growth inhibition. CA could be released from the polymer via a ROS-sensitive thioacetal bond by endogenous ROS. The released CA successively induced more ROS accumulation through GSH depletion, and the positive feedback helped PCA to achieve self-accelerating degradation. Results proved that PCA/p53 complexes were efficient in depleting GSH, upregulating ROS levels, and gene transfection. Besides, PCA was also shown to be effective in delivering the therapeutic gene p53. More importantly, PCA/p53 complexes could significantly induce tumor cell growth suppression by a synergistic effect of PCA and p53, providing valuable insights into the design of self-amplifying ROS-responsive polymeric gene vectors.
{"title":"Cinnamaldehyde-Based ROS-Responsive Polymeric Gene Vectors for Efficient Gene Delivery and Tumor Cell Growth Inhibition.","authors":"Qin-Fang Zhang, Rui-Mo Zhao, Yu Lei, Xiao-Li Tian, Yue Hu, Lan Zhang, Ji Zhang","doi":"10.1021/acs.biomac.4c01731","DOIUrl":"10.1021/acs.biomac.4c01731","url":null,"abstract":"<p><p>Reactive oxygen species (ROS)-sensitive polymers are extensively used in cancer therapies. However, the ROS levels in the tumor microenvironment are often insufficient to trigger an adequate therapeutic response. Herein, we report a cinnamaldehyde (<b>CA</b>)-based ROS-responsive cationic polymer (<b>PCA</b>) and demonstrate its high efficiency in gene delivery and tumor cell growth inhibition. <b>CA</b> could be released from the polymer via a ROS-sensitive thioacetal bond by endogenous ROS. The released <b>CA</b> successively induced more ROS accumulation through GSH depletion, and the positive feedback helped <b>PCA</b> to achieve self-accelerating degradation. Results proved that <b>PCA</b>/p53 complexes were efficient in depleting GSH, upregulating ROS levels, and gene transfection. Besides, <b>PCA</b> was also shown to be effective in delivering the therapeutic gene p53. More importantly, <b>PCA</b>/p53 complexes could significantly induce tumor cell growth suppression by a synergistic effect of <b>PCA</b> and p53, providing valuable insights into the design of self-amplifying ROS-responsive polymeric gene vectors.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"1362-1371"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10Epub Date: 2025-01-28DOI: 10.1021/acs.biomac.4c01215
György Hantal, Lennart Salmén, Barbara Hinterstoisser
To understand xylan-cellulose interactions in softwood, the adsorption behavior of hexameric softwood xylan proxies with various substitutions was analyzed on the three surfaces of a hexagonal cellulose microfibril. The study found that all surfaces could bind xylan motifs, showing equally high affinity for the hydrophilic (110) and hydrophobic (100) surfaces and significantly lower affinity for the hydrophilic (11̅0) surface. Unsubstituted xylose hexamers had the highest affinity and most ordered adsorption structures, while substitutions generally reduced the affinity and regularity. An exception was a motif with two glucuronic acids two residues apart, which displayed high affinity and increased tendency to adopt a 2-fold screw on hydrophilic surfaces. Surface affinity correlated with the tightness of xylan-cellulose associations and the ratio of the xylan-cellulose to xylan-water interaction energies. Novel methods to quantify backbone conformations were proposed. Future work should address differences in simulation models and explore the competition between xylan and glucomannan for cellulose surfaces.
{"title":"Docking Structures Induced by Substitution Motifs of Softwood Xylan at Various Cellulose Surfaces.","authors":"György Hantal, Lennart Salmén, Barbara Hinterstoisser","doi":"10.1021/acs.biomac.4c01215","DOIUrl":"10.1021/acs.biomac.4c01215","url":null,"abstract":"<p><p>To understand xylan-cellulose interactions in softwood, the adsorption behavior of hexameric softwood xylan proxies with various substitutions was analyzed on the three surfaces of a hexagonal cellulose microfibril. The study found that all surfaces could bind xylan motifs, showing equally high affinity for the hydrophilic (110) and hydrophobic (100) surfaces and significantly lower affinity for the hydrophilic (11̅0) surface. Unsubstituted xylose hexamers had the highest affinity and most ordered adsorption structures, while substitutions generally reduced the affinity and regularity. An exception was a motif with two glucuronic acids two residues apart, which displayed high affinity and increased tendency to adopt a 2-fold screw on hydrophilic surfaces. Surface affinity correlated with the tightness of xylan-cellulose associations and the ratio of the xylan-cellulose to xylan-water interaction energies. Novel methods to quantify backbone conformations were proposed. Future work should address differences in simulation models and explore the competition between xylan and glucomannan for cellulose surfaces.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"929-942"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10Epub Date: 2025-01-30DOI: 10.1021/acs.biomac.4c01598
Milad Ghorbani, Nicholas P C Roxburgh, Mai P Tran, James P Blinco, Kristian Kempe
2,2,6,6-Tetramethylpiperidine-N-oxyl (TEMPO) structures possess potent antioxidant activities for biomedical applications. TEMPO immobilization on hydrophilic polymers is a powerful strategy to improve its properties; however, it is mostly limited to reversible-deactivation radical polymerizations or postpolymerization approaches. Here, we immobilized TEMPO units on a hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx) backbone through cationic ring-opening polymerization (CROP) of a new 2-oxazoline monomer bearing a methoxy-protected TEMPO 2-substituent with 2-ethyl-2-oxazoline (EtOx). The ratios of EtOx/TempOx were adjusted to optimize the nitroxide content while maintaining suitable water solubility of the resulting P(EtOxx-stat-TempOx-Oy•) copolymers upon deprotection. P(EtOx40-stat-TempOx-O10•) and P(EtOx33-stat-TempOx-O17•) showed a dual stimuli-responsive behavior and demonstrated significant radical-trapping activities in aqueous media. Particularly, a meaningful augmentation in the activity of TempOx-O• was observed when it was immobilized as P(EtOxx-stat-TempOx-Oy•). The P(EtOx40-stat-TempOx-O10•) system exhibited a longer-lasting activity in water, statistically comparable to that of the antioxidant ferrostatin-1 (Fer-1). Overall, this study introduces a biocompatible polymeric platform for TEMPO immobilization that augments its radical-trapping activity and offers controllable stimuli-responsive properties.
{"title":"Nitroxide-Containing Poly(2-oxazoline)s Show Dual-Stimuli-Responsive Behavior and Radical-Trapping Activity.","authors":"Milad Ghorbani, Nicholas P C Roxburgh, Mai P Tran, James P Blinco, Kristian Kempe","doi":"10.1021/acs.biomac.4c01598","DOIUrl":"10.1021/acs.biomac.4c01598","url":null,"abstract":"<p><p>2,2,6,6-Tetramethylpiperidine-<i>N</i>-oxyl (TEMPO) structures possess potent antioxidant activities for biomedical applications. TEMPO immobilization on hydrophilic polymers is a powerful strategy to improve its properties; however, it is mostly limited to reversible-deactivation radical polymerizations or postpolymerization approaches. Here, we immobilized TEMPO units on a hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx) backbone through cationic ring-opening polymerization (CROP) of a new 2-oxazoline monomer bearing a methoxy-protected TEMPO 2-substituent with 2-ethyl-2-oxazoline (EtOx). The ratios of EtOx/TempOx were adjusted to optimize the nitroxide content while maintaining suitable water solubility of the resulting P(EtOx<sub><i>x</i></sub><i>-stat-</i>TempOx-O<sub><i>y</i></sub><sup>•</sup>) copolymers upon deprotection. P(EtOx<sub>40</sub><i>-stat-</i>TempOx-O<sub>10</sub><sup>•</sup>) and P(EtOx<sub>33</sub><i>-stat-</i>TempOx-O<sub>17</sub><sup>•</sup>) showed a dual stimuli-responsive behavior and demonstrated significant radical-trapping activities in aqueous media. Particularly, a meaningful augmentation in the activity of TempOx-O<sup>•</sup> was observed when it was immobilized as P(EtOx<sub><i>x</i></sub><i>-stat-</i>TempOx-O<sub><i>y</i></sub><sup>•</sup>). The P(EtOx<sub>40</sub><i>-stat-</i>TempOx-O<sub>10</sub><sup>•</sup>) system exhibited a longer-lasting activity in water, statistically comparable to that of the antioxidant ferrostatin-1 (Fer-1). Overall, this study introduces a biocompatible polymeric platform for TEMPO immobilization that augments its radical-trapping activity and offers controllable stimuli-responsive properties.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"1260-1273"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chitosan (CHT) is a known piezoelectric biomacromolecule; however, its usage is limited due to rapid degradation in an aqueous system. Herein, we prepared CHT film via a solvent casting method and cross-linked in an alkaline solution. Sodium hydroxide facilitated deprotonation, leading to increased intramolecular hydrogen bonding and mechanical properties. The CHT film remained intact for 30 days in aqueous environments. A systematic study revealed a gradual increase in the output voltage from 0.9 to 1.8 V under external force (1-16 N). In addition, the CHT film showed remarkable antibacterial and anti-inflammatory activities under ultrasound stimulation and inhibition of inflammatory cytokines. The CHT films also displayed enhanced cellular proliferation and ∼5-fold faster migration of NIH3T3 cells under US stimulation. Overall, this work presents a robust, biocompatible, and wearable CHT device that can transform biomechanical energy into electrical pulses for the modulation of cell fate processes and other bioactivities.
{"title":"Flexible and Robust Piezoelectric Chitosan Films with Enhanced Bioactivity.","authors":"Srishti Chakraborty, Souvik Debnath, Kailas Mahipal Malappuram, Sampath Parasuram, Huan-Tsung Chang, Kaushik Chatterjee, Amit Nain","doi":"10.1021/acs.biomac.4c01464","DOIUrl":"10.1021/acs.biomac.4c01464","url":null,"abstract":"<p><p>Chitosan (CHT) is a known piezoelectric biomacromolecule; however, its usage is limited due to rapid degradation in an aqueous system. Herein, we prepared CHT film via a solvent casting method and cross-linked in an alkaline solution. Sodium hydroxide facilitated deprotonation, leading to increased intramolecular hydrogen bonding and mechanical properties. The CHT film remained intact for 30 days in aqueous environments. A systematic study revealed a gradual increase in the output voltage from 0.9 to 1.8 V under external force (1-16 N). In addition, the CHT film showed remarkable antibacterial and anti-inflammatory activities under ultrasound stimulation and inhibition of inflammatory cytokines. The CHT films also displayed enhanced cellular proliferation and ∼5-fold faster migration of NIH3T3 cells under US stimulation. Overall, this work presents a robust, biocompatible, and wearable CHT device that can transform biomechanical energy into electrical pulses for the modulation of cell fate processes and other bioactivities.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"1128-1140"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142968657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10Epub Date: 2025-01-11DOI: 10.1021/acs.biomac.4c01264
Yusuf Olatunji Waidi, Vasudev S Wagh, Shivangi Mishra, Siddharth Jhunjhunwala, Syed G Dastager, Kaushik Chatterjee
Emerging techniques of additive manufacturing, such as vat-based three-dimensional (3D) bioprinting, offer novel routes to prepare personalized scaffolds of complex geometries. However, there is a need to develop bioinks suitable for clinical translation. This study explored the potential of bacterial-sourced methacrylate levan (LeMA) as a bioink for the digital light processing (DLP) 3D bioprinting of bone tissue scaffolds. LeMA was successfully synthesized, characterized, and used to fabricate 3D-bioprinted scaffolds with excellent printability and physicochemical properties. In vitro studies demonstrated superior cytocompatibility of 15% w/v LeMA gels compared to 20% gels. 15% LeMA gels supported osteogenic differentiation , as evidenced by alkaline phosphatase activity and mineral deposition by MC3T3 pre-osteoblasts. Importantly, the LeMA hydrogels positively modulated the macrophage phenotype, promoting the expression of the anti-inflammatory marker CD206. These findings suggest that 3D-printed LeMA scaffolds can create a favorable microenvironment for bone regeneration, highlighting their potential for tissue repair and regeneration applications.
{"title":"Vat-Based 3D-Bioprinted Scaffolds from Photocurable Bacterial Levan for Osteogenesis and Immunomodulation.","authors":"Yusuf Olatunji Waidi, Vasudev S Wagh, Shivangi Mishra, Siddharth Jhunjhunwala, Syed G Dastager, Kaushik Chatterjee","doi":"10.1021/acs.biomac.4c01264","DOIUrl":"10.1021/acs.biomac.4c01264","url":null,"abstract":"<p><p>Emerging techniques of additive manufacturing, such as vat-based three-dimensional (3D) bioprinting, offer novel routes to prepare personalized scaffolds of complex geometries. However, there is a need to develop bioinks suitable for clinical translation. This study explored the potential of bacterial-sourced methacrylate levan (LeMA) as a bioink for the digital light processing (DLP) 3D bioprinting of bone tissue scaffolds. LeMA was successfully synthesized, characterized, and used to fabricate 3D-bioprinted scaffolds with excellent printability and physicochemical properties. In vitro studies demonstrated superior cytocompatibility of 15% w/v LeMA gels compared to 20% gels. 15% LeMA gels supported osteogenic differentiation , as evidenced by alkaline phosphatase activity and mineral deposition by MC3T3 pre-osteoblasts. Importantly, the LeMA hydrogels positively modulated the macrophage phenotype, promoting the expression of the anti-inflammatory marker CD206. These findings suggest that 3D-printed LeMA scaffolds can create a favorable microenvironment for bone regeneration, highlighting their potential for tissue repair and regeneration applications.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"954-966"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10Epub Date: 2025-01-15DOI: 10.1021/acs.biomac.4c01571
Suzhen Wang, Zhezhe Li, Lili Zhao, Yuerong Lin, Hailong Che
Polymer-based photosensitizers have found various applications in photodynamic therapy (PDT). However, the absence of targeting ability commonly results in a substantial reduction in photosensitizer accumulation at the tumor site, significantly limiting the therapeutic efficacy of the system. In addition, the development of biodegradable polymeric photosensitizers is of critical importance for biological applications. In this work, we present the development of guanidine-functionalized biodegradable photosensitizers based on poly(trimethylene carbonate) (PTMC) block copolymers, which can self-assemble into polymersomes. The presence of guanidine groups on the surface of polymersomes can significantly enhance the cellular uptake efficiency of photosensitizers, thereby improving the intracellular production of reactive oxygen species (ROS). The in vitro study demonstrates that the guanidinylated polymersome photosensitizers can promote the killing of cancer cells compared to unfunctionalized polymersomes in the presence of light irradiation. The guanidine-functionalized PTMC-based polymersome photosensitizers, with the integration of cell-targeting ability and biodegradability, are anticipated to provide a novel strategy for developing advanced biomedical polymer systems for PDT.
{"title":"Polycarbonate-Based Polymersome Photosensitizers with Cell-Penetrating Properties for Improved Killing of Cancer Cells.","authors":"Suzhen Wang, Zhezhe Li, Lili Zhao, Yuerong Lin, Hailong Che","doi":"10.1021/acs.biomac.4c01571","DOIUrl":"10.1021/acs.biomac.4c01571","url":null,"abstract":"<p><p>Polymer-based photosensitizers have found various applications in photodynamic therapy (PDT). However, the absence of targeting ability commonly results in a substantial reduction in photosensitizer accumulation at the tumor site, significantly limiting the therapeutic efficacy of the system. In addition, the development of biodegradable polymeric photosensitizers is of critical importance for biological applications. In this work, we present the development of guanidine-functionalized biodegradable photosensitizers based on poly(trimethylene carbonate) (PTMC) block copolymers, which can self-assemble into polymersomes. The presence of guanidine groups on the surface of polymersomes can significantly enhance the cellular uptake efficiency of photosensitizers, thereby improving the intracellular production of reactive oxygen species (ROS). The in vitro study demonstrates that the guanidinylated polymersome photosensitizers can promote the killing of cancer cells compared to unfunctionalized polymersomes in the presence of light irradiation. The guanidine-functionalized PTMC-based polymersome photosensitizers, with the integration of cell-targeting ability and biodegradability, are anticipated to provide a novel strategy for developing advanced biomedical polymer systems for PDT.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"1251-1259"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10Epub Date: 2025-01-22DOI: 10.1021/acs.biomac.4c01441
Han Nguyen, Ngoc Ha Luong, Jacqueline K Peil, Yan Tong, Dana K Mitchell, Melissa L Fishel, Chien-Chi Lin
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) exhibiting high stiffness and fast stress relaxation. In this work, gelatin-based viscoelastic hydrogels were developed to mimic the compositions, stiffness, and fast stress relaxation of PDAC tissues. The hydrogels were cross-linked by gelatin-norbornene-boronic acid (GelNB-BA), thiolated macromers, and a 1,2-diol-containing linear synthetic polymer PHD. Controlling the thiol-norbornene cross-linking afforded tunable stiffness, whereas increasing PHD content led to hydrogels with PDAC-mimicking fast stress relaxation. In vitro studies, including proliferation, morphology, and mRNA-sequencing, showed that fast-relaxing hydrogels supported PDAC cell proliferation, epithelial-mesenchymal transition (EMT), and integrin β1 activation. Blocking integrin β1 in vitro led to upregulating EMT markers in both slow and fast-relaxing hydrogels. However, this strategy profoundly impacted tumor growth rate and reduced tumor size but did not alter metastasis patterns in an orthotopic mouse model. This suggests a need to further evaluate the antitumor effect of integrin β1 blockade.
{"title":"Fast-Relaxing Hydrogels Promote Pancreatic Adenocarcinoma Cell Aggressiveness through Integrin β1 Signaling.","authors":"Han Nguyen, Ngoc Ha Luong, Jacqueline K Peil, Yan Tong, Dana K Mitchell, Melissa L Fishel, Chien-Chi Lin","doi":"10.1021/acs.biomac.4c01441","DOIUrl":"10.1021/acs.biomac.4c01441","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) exhibiting high stiffness and fast stress relaxation. In this work, gelatin-based viscoelastic hydrogels were developed to mimic the compositions, stiffness, and fast stress relaxation of PDAC tissues. The hydrogels were cross-linked by gelatin-norbornene-boronic acid (GelNB-BA), thiolated macromers, and a 1,2-diol-containing linear synthetic polymer PHD. Controlling the thiol-norbornene cross-linking afforded tunable stiffness, whereas increasing PHD content led to hydrogels with PDAC-mimicking fast stress relaxation. <i>In vitro</i> studies, including proliferation, morphology, and mRNA-sequencing, showed that fast-relaxing hydrogels supported PDAC cell proliferation, epithelial-mesenchymal transition (EMT), and integrin β1 activation. Blocking integrin β1 <i>in vitro</i> led to upregulating EMT markers in both slow and fast-relaxing hydrogels. However, this strategy profoundly impacted tumor growth rate and reduced tumor size but did not alter metastasis patterns in an orthotopic mouse model. This suggests a need to further evaluate the antitumor effect of integrin β1 blockade.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"1098-1110"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10Epub Date: 2025-01-31DOI: 10.1021/acs.biomac.4c01696
Billy Deng, Stuart Alexander McNelles, Jingyu Sun, Joaquin Ortega, Alex Adronov
Decoration of proteins and enzymes with well-defined polymeric structures allows precise decoration of protein surfaces, enabling controlled modulation of activity. Here, the impact of dendronization on the interaction between avidin and biotin was investigated. A series of generation 3-7 bis(2,2-hydroxymethyl)propionic acid (bis-MPA) dendrons were coupled to either biotin or avidin to yield a library of dendronized avidin and biotin structures. The thermodynamics of binding each biotinylated generation to a library of avidin conjugates was probed with isothermal titration calorimetry (ITC). Dissociation constants of high-generation biotin-dendrons (G5 and G6) with higher-generation avidin-dendron conjugates (Av-G6) increased from ∼10-15 M (for the native structures) to ∼10-6 M, and binding was found to be weaker than that of the Avidin-HABA complex. Avidin-G5 and Avidin-G6 were highly size-selective for biotinylated ligands; both prevented the binding of aprotinin (6.9 kDa), bovine serum albumin (BSA), and PEG3400 while forming fractional complexes with smaller biotinylated dendrons.
{"title":"Dendrimer-Mediated Molecular Sieving on Avidin.","authors":"Billy Deng, Stuart Alexander McNelles, Jingyu Sun, Joaquin Ortega, Alex Adronov","doi":"10.1021/acs.biomac.4c01696","DOIUrl":"10.1021/acs.biomac.4c01696","url":null,"abstract":"<p><p>Decoration of proteins and enzymes with well-defined polymeric structures allows precise decoration of protein surfaces, enabling controlled modulation of activity. Here, the impact of dendronization on the interaction between avidin and biotin was investigated. A series of generation 3-7 bis(2,2-hydroxymethyl)propionic acid (bis-MPA) dendrons were coupled to either biotin or avidin to yield a library of dendronized avidin and biotin structures. The thermodynamics of binding each biotinylated generation to a library of avidin conjugates was probed with isothermal titration calorimetry (ITC). Dissociation constants of high-generation biotin-dendrons (G5 and G6) with higher-generation avidin-dendron conjugates (Av-G6) increased from ∼10<sup>-15</sup> M (for the native structures) to ∼10<sup>-6</sup> M, and binding was found to be weaker than that of the Avidin-HABA complex. Avidin-G5 and Avidin-G6 were highly size-selective for biotinylated ligands; both prevented the binding of aprotinin (6.9 kDa), bovine serum albumin (BSA), and PEG<sub>3400</sub> while forming fractional complexes with smaller biotinylated dendrons.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"1320-1334"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10Epub Date: 2025-01-26DOI: 10.1021/acs.biomac.4c01410
Hyo Jae Jeon, Joo Hyung Lee, Ae Ji Park, Jeong-Mo Choi, Kyungtae Kang
This study proposes fluorenylmethoxycarbonyl (Fmoc)-protected single amino acids (Fmoc-AAs) as a minimalistic model system to investigate liquid-liquid phase separation (LLPS) and the elusive liquid-to-solid transition of condensates. We demonstrated that Fmoc-AAs exhibit LLPS depending on the pH and ionic strength, primarily driven by hydrophobic interactions. Systematic examination of the conditions under which each Fmoc-AA undergoes LLPS revealed distinct residue-dependent trends in the critical concentrations and phase behavior. Importantly, we elucidated the liquid-to-solid transition process, suggesting that it may be driven by a molecular mechanism different from that of LLPS. Fmoc-AA condensates showed promise for biomolecular enrichment and catalytic applications. This work provides significant insights into the molecular mechanisms of LLPS and the subsequent liquid-to-solid transition, offering a robust platform for future studies related to protocells and protein aggregation diseases.
{"title":"A Single Amino Acid Model for Hydrophobically Driven Liquid-Liquid Phase Separation.","authors":"Hyo Jae Jeon, Joo Hyung Lee, Ae Ji Park, Jeong-Mo Choi, Kyungtae Kang","doi":"10.1021/acs.biomac.4c01410","DOIUrl":"10.1021/acs.biomac.4c01410","url":null,"abstract":"<p><p>This study proposes fluorenylmethoxycarbonyl (Fmoc)-protected single amino acids (Fmoc-AAs) as a minimalistic model system to investigate liquid-liquid phase separation (LLPS) and the elusive liquid-to-solid transition of condensates. We demonstrated that Fmoc-AAs exhibit LLPS depending on the pH and ionic strength, primarily driven by hydrophobic interactions. Systematic examination of the conditions under which each Fmoc-AA undergoes LLPS revealed distinct residue-dependent trends in the critical concentrations and phase behavior. Importantly, we elucidated the liquid-to-solid transition process, suggesting that it may be driven by a molecular mechanism different from that of LLPS. Fmoc-AA condensates showed promise for biomolecular enrichment and catalytic applications. This work provides significant insights into the molecular mechanisms of LLPS and the subsequent liquid-to-solid transition, offering a robust platform for future studies related to protocells and protein aggregation diseases.</p>","PeriodicalId":30,"journal":{"name":"Biomacromolecules","volume":" ","pages":"1075-1085"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}