Background: Liver fibrosis is a necessary pathological process in many chronic liver diseases. Studies have shown that the progression of chronic liver disease can be slowed by rational intervention in hepatic fibrosis. Berberine (BBR), a natural extract of Phellodendron amurense, inhibits the development of liver fibrosis through several mechanisms. However, the clinical application of BBR is limited due to its low solubility. Drug delivery systems have been developed to improve the solubility of hydrophobic drugs and increase their efficacy in treating the liver fibrosis.
Methods: In this study, a biocompatible nanomicelle was constructed by thin-film dispersion method using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG) as a carrier to encapsulate BBR (PVCL-PVA-PEG/BBR-MCs) to improve the solubility of BBR and reduce the systemic side effects. The ability to inhibit HSC-T6 cell activation of PVCL-PVA-PEG/BBR-MCs was evaluated in vitro. The anti-hepatic fibrosis effects of PVCL-PVA-PEG/BBR-MCs were investigated in vivo.
Results: PVCL-PVA-PEG/BBR-MCs have a uniform spherical shape with a mean particle size of 60.04 ± 0.027 nm and a potential of 1.49 ± 0.32 mV. It had an encapsulation efficiency of 98.52% ± 0.70 and drug loading content of 6.16% ± 0.04. Compared to free BBR, PVCL-PVA-PEG/BBR-MCs significantly inhibited HSC-T6 cell activation and TGF-β1-induced HSC-T6 cell migration in vitro. In vivo biodistribution experiments showed significantly improved hepatic distribution of PVCL-PVA-PEG/DiD-MCs compared to free DiD, suggesting that PVCL-PVA-PEG micelles enhance the ability of BBR to enter the liver and improve therapeutic efficacy. After treatment, PVCL-PVA-PEG/BBR-MCs significantly improved fibrotic liver structure and reduced collagen deposition in comparison to the CCl4-treated group; the treatment outcome was more effective than that of the free BBR group.
Conclusion: Our results demonstrate the advantages of encapsulating BBR in PVCL-PVA-PEG micelles and highlight the potential of PVCL-PVA-PEG/BBR-MCs as a therapeutic strategy for the treatment of liver fibrosis.
{"title":"Berberine-Loaded PVCL-PVA-PEG Self-Assembled Micelles for the Treatment of Liver Fibrosis.","authors":"Xiaozhu Zha, Yumei Hao, Yifan Ke, Yichun Wang, Yujia Zhang","doi":"10.2147/IJN.S465214","DOIUrl":"10.2147/IJN.S465214","url":null,"abstract":"<p><strong>Background: </strong>Liver fibrosis is a necessary pathological process in many chronic liver diseases. Studies have shown that the progression of chronic liver disease can be slowed by rational intervention in hepatic fibrosis. Berberine (BBR), a natural extract of Phellodendron amurense, inhibits the development of liver fibrosis through several mechanisms. However, the clinical application of BBR is limited due to its low solubility. Drug delivery systems have been developed to improve the solubility of hydrophobic drugs and increase their efficacy in treating the liver fibrosis.</p><p><strong>Methods: </strong>In this study, a biocompatible nanomicelle was constructed by thin-film dispersion method using polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG) as a carrier to encapsulate BBR (PVCL-PVA-PEG/BBR-MCs) to improve the solubility of BBR and reduce the systemic side effects. The ability to inhibit HSC-T6 cell activation of PVCL-PVA-PEG/BBR-MCs was evaluated in vitro. The anti-hepatic fibrosis effects of PVCL-PVA-PEG/BBR-MCs were investigated in vivo.</p><p><strong>Results: </strong>PVCL-PVA-PEG/BBR-MCs have a uniform spherical shape with a mean particle size of 60.04 ± 0.027 nm and a potential of 1.49 ± 0.32 mV. It had an encapsulation efficiency of 98.52% ± 0.70 and drug loading content of 6.16% ± 0.04. Compared to free BBR, PVCL-PVA-PEG/BBR-MCs significantly inhibited HSC-T6 cell activation and TGF-β1-induced HSC-T6 cell migration in vitro. In vivo biodistribution experiments showed significantly improved hepatic distribution of PVCL-PVA-PEG/DiD-MCs compared to free DiD, suggesting that PVCL-PVA-PEG micelles enhance the ability of BBR to enter the liver and improve therapeutic efficacy. After treatment, PVCL-PVA-PEG/BBR-MCs significantly improved fibrotic liver structure and reduced collagen deposition in comparison to the CCl<sub>4</sub>-treated group; the treatment outcome was more effective than that of the free BBR group.</p><p><strong>Conclusion: </strong>Our results demonstrate the advantages of encapsulating BBR in PVCL-PVA-PEG micelles and highlight the potential of PVCL-PVA-PEG/BBR-MCs as a therapeutic strategy for the treatment of liver fibrosis.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10857-10872"},"PeriodicalIF":6.6,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24eCollection Date: 2024-01-01DOI: 10.2147/IJN.S486868
Moises das Virgens Santana, Maria Beatriz S Magulas, Guilherme Castro Brito, Mariana Chaves Santos, Tainara Gomes de Oliveira, Wanderson Gabriel Gomes de Melo, Napoleao Martins Argolo Neto, Fernanda Roberta Marciano, Bartolomeu Cruz Viana, Anderson Oliveira Lobo
Purpose: Tissue engineering aims to recreate natural cellular environments to facilitate tissue regeneration. Gelatin methacrylate (GelMA) is widely utilized for its biocompatibility, ability to support cell adhesion and proliferation, and adjustable mechanical characteristics. This study developed a GelMA and graphene bioink platform at concentrations of 1, 1.5, and 2 mg/mL to enhance scaffold properties for tissue engineering applications.
Patients and methods: Graphene was incorporated into GelMA matrices to improve mechanical strength and electrical conductivity of the bioinks. The compressive strength and thermal stability of the resulting GelMA/graphene scaffolds were assessed through DSC analysis and mechanical testing. Cytotoxicity assays were conducted to determine cell survival rates. Cryoprinting at -30°C was employed to preserve scaffold structure and function. The chorioallantoic membrane (CAM) assay was used to evaluate biocompatibility and angiogenic potential.
Results: The integration of graphene significantly amplified the compressive strength and thermal stability of GelMA scaffolds. Cytotoxicity assays indicated robust cell survival rates of 90%, confirming the biocompatibility of the developed materials. Cryoprinting effectively preserved scaffold integrity and functionality. The CAM assay validated the biocompatibility and angiogenic potential, demonstrating substantial vascularization upon scaffold implantation onto chick embryo CAM.
Conclusion: Integrating graphene into GelMA hydrogels, coupled with low-temperature 3D printing, represents a potent strategy for enhancing scaffold fabrication. The resultant GelMA/graphene scaffolds exhibit superior mechanical properties, biocompatibility, and pro-vascularization capabilities, making them highly suitable for diverse tissue engineering and regenerative medicine applications.
{"title":"Cryogenic 3D Printing of GelMA/Graphene Bioinks: Improved Mechanical Strength and Structural Properties for Tissue Engineering.","authors":"Moises das Virgens Santana, Maria Beatriz S Magulas, Guilherme Castro Brito, Mariana Chaves Santos, Tainara Gomes de Oliveira, Wanderson Gabriel Gomes de Melo, Napoleao Martins Argolo Neto, Fernanda Roberta Marciano, Bartolomeu Cruz Viana, Anderson Oliveira Lobo","doi":"10.2147/IJN.S486868","DOIUrl":"10.2147/IJN.S486868","url":null,"abstract":"<p><strong>Purpose: </strong>Tissue engineering aims to recreate natural cellular environments to facilitate tissue regeneration. Gelatin methacrylate (GelMA) is widely utilized for its biocompatibility, ability to support cell adhesion and proliferation, and adjustable mechanical characteristics. This study developed a GelMA and graphene bioink platform at concentrations of 1, 1.5, and 2 mg/mL to enhance scaffold properties for tissue engineering applications.</p><p><strong>Patients and methods: </strong>Graphene was incorporated into GelMA matrices to improve mechanical strength and electrical conductivity of the bioinks. The compressive strength and thermal stability of the resulting GelMA/graphene scaffolds were assessed through DSC analysis and mechanical testing. Cytotoxicity assays were conducted to determine cell survival rates. Cryoprinting at -30°C was employed to preserve scaffold structure and function. The chorioallantoic membrane (CAM) assay was used to evaluate biocompatibility and angiogenic potential.</p><p><strong>Results: </strong>The integration of graphene significantly amplified the compressive strength and thermal stability of GelMA scaffolds. Cytotoxicity assays indicated robust cell survival rates of 90%, confirming the biocompatibility of the developed materials. Cryoprinting effectively preserved scaffold integrity and functionality. The CAM assay validated the biocompatibility and angiogenic potential, demonstrating substantial vascularization upon scaffold implantation onto chick embryo CAM.</p><p><strong>Conclusion: </strong>Integrating graphene into GelMA hydrogels, coupled with low-temperature 3D printing, represents a potent strategy for enhancing scaffold fabrication. The resultant GelMA/graphene scaffolds exhibit superior mechanical properties, biocompatibility, and pro-vascularization capabilities, making them highly suitable for diverse tissue engineering and regenerative medicine applications.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10745-10765"},"PeriodicalIF":6.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24eCollection Date: 2024-01-01DOI: 10.2147/IJN.S475234
Yameng Song, Caiyun Yin, Ning Kong
Diabetic retinopathy is one of the complications of diabetes mellitus that occurs in the early stages. It is a disease that has a serious impact, and may lead to blindness when the disease progresses to advanced stages. Currently, treatments for diabetic retinopathy are mainly limited to its advanced stages of the disease, being restricted to a single therapeutic mechanism. Stem cells hold the promise of regenerative therapy and have the potential to comprehensively improve diabetic retinopathy. However, direct stem cell therapy carries some risk of carcinogenesis. Exosomes secreted by stem cells have shown a similar overall improvement in disease as stem cells. Exosomes can carry a number of biologically active materials from donor cells to recipient cells or distant organs, regulating intercellular signaling. Exosomes have shown remarkable efficacy in alleviating oxidative stress, inhibiting inflammatory responses, suppressing angiogenesis, reducing apoptosis and protecting neural tissues. Currently, the experimental literature using stem cell exosomes in the treatment of diabetic retinopathy tends to converge on the above experimental results. With this in mind, we have chosen to explore exosomes in depth from a subtle molecular perspective. We will elaborate on this perspective in this paper and propose to advocate exosome therapy as one promising approach for the treatment of diabetic retinopathy to ameliorate the lesions through multiple mechanisms.
{"title":"Stem Cell-Derived Exosomes: Natural Intercellular Messengers with Versatile Mechanisms for the Treatment of Diabetic Retinopathy.","authors":"Yameng Song, Caiyun Yin, Ning Kong","doi":"10.2147/IJN.S475234","DOIUrl":"10.2147/IJN.S475234","url":null,"abstract":"<p><p>Diabetic retinopathy is one of the complications of diabetes mellitus that occurs in the early stages. It is a disease that has a serious impact, and may lead to blindness when the disease progresses to advanced stages. Currently, treatments for diabetic retinopathy are mainly limited to its advanced stages of the disease, being restricted to a single therapeutic mechanism. Stem cells hold the promise of regenerative therapy and have the potential to comprehensively improve diabetic retinopathy. However, direct stem cell therapy carries some risk of carcinogenesis. Exosomes secreted by stem cells have shown a similar overall improvement in disease as stem cells. Exosomes can carry a number of biologically active materials from donor cells to recipient cells or distant organs, regulating intercellular signaling. Exosomes have shown remarkable efficacy in alleviating oxidative stress, inhibiting inflammatory responses, suppressing angiogenesis, reducing apoptosis and protecting neural tissues. Currently, the experimental literature using stem cell exosomes in the treatment of diabetic retinopathy tends to converge on the above experimental results. With this in mind, we have chosen to explore exosomes in depth from a subtle molecular perspective. We will elaborate on this perspective in this paper and propose to advocate exosome therapy as one promising approach for the treatment of diabetic retinopathy to ameliorate the lesions through multiple mechanisms.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10767-10784"},"PeriodicalIF":6.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-24eCollection Date: 2024-01-01DOI: 10.2147/IJN.S477159
Héctor M Ramos-Zaldívar, Iva Polakovicova, Edison Salas-Huenuleo, Claudia P Yefi, David Silva-Ancahuail, Pedro Jara-Guajardo, Juan Esteban Oyarzún, Álvaro Neira-Troncoso, Patricia V Burgos, Viviana A Cavieres, Eloísa Arias-Muñoz, Carlos Martínez, Ana L Riveros, Alejandro H Corvalán, Marcelo J Kogan, Marcelo E Andia
Introduction: The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain.
Methods: We employed superparamagnetic iron oxide nanoparticles (SPIONs), exosomes loaded with SPIONs, gold nanorods, and Chinese ink nanoparticles. SPIONs were prepared via chemical coprecipitation, while exosomes were isolated from the B16F10 melanoma cell line through the Exo-Spin column protocol and loaded with SPIONs through electroporation. Gold nanorods were functionalized with polyethylene glycol. We utilized C57BL/6 mice for post-mortem and in vivo procedures. To evaluate the retrograde directional flow, we injected each nanoparticle solution in the deep cervical lymph node. The head and neck were fixed for magnetic resonance imaging and histological analysis.
Results: Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within the deep cervical lymph nodes post-mortem and in vivo, exclusively through lymphatic structures.
Discussion: The functional anatomy of dural lymphatics has been found to be conserved between mice and humans, suggesting that our findings may have significant implications for advancing targeted drug delivery systems using nanoparticles. Understanding the retrograde transport of nanoparticles through the meningeal lymphatic network could lead to novel therapeutic approaches in nanomedicine, offering new insights into fluid dynamics in both physiological and neuropathological contexts. Further research into this pathway may unlock new strategies for treating neurological diseases or enhancing drug delivery to the brain.
{"title":"The Cervical and Meningeal Lymphatic Network as a Pathway for Retrograde Nanoparticle Transport to the Brain.","authors":"Héctor M Ramos-Zaldívar, Iva Polakovicova, Edison Salas-Huenuleo, Claudia P Yefi, David Silva-Ancahuail, Pedro Jara-Guajardo, Juan Esteban Oyarzún, Álvaro Neira-Troncoso, Patricia V Burgos, Viviana A Cavieres, Eloísa Arias-Muñoz, Carlos Martínez, Ana L Riveros, Alejandro H Corvalán, Marcelo J Kogan, Marcelo E Andia","doi":"10.2147/IJN.S477159","DOIUrl":"10.2147/IJN.S477159","url":null,"abstract":"<p><strong>Introduction: </strong>The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain.</p><p><strong>Methods: </strong>We employed superparamagnetic iron oxide nanoparticles (SPIONs), exosomes loaded with SPIONs, gold nanorods, and Chinese ink nanoparticles. SPIONs were prepared via chemical coprecipitation, while exosomes were isolated from the B16F10 melanoma cell line through the Exo-Spin column protocol and loaded with SPIONs through electroporation. Gold nanorods were functionalized with polyethylene glycol. We utilized C57BL/6 mice for <i>post-mortem</i> and in vivo procedures. To evaluate the retrograde directional flow, we injected each nanoparticle solution in the deep cervical lymph node. The head and neck were fixed for magnetic resonance imaging and histological analysis.</p><p><strong>Results: </strong>Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within the deep cervical lymph nodes <i>post-mortem</i> and in vivo, exclusively through lymphatic structures.</p><p><strong>Discussion: </strong>The functional anatomy of dural lymphatics has been found to be conserved between mice and humans, suggesting that our findings may have significant implications for advancing targeted drug delivery systems using nanoparticles. Understanding the retrograde transport of nanoparticles through the meningeal lymphatic network could lead to novel therapeutic approaches in nanomedicine, offering new insights into fluid dynamics in both physiological and neuropathological contexts. Further research into this pathway may unlock new strategies for treating neurological diseases or enhancing drug delivery to the brain.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10725-10743"},"PeriodicalIF":6.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Acute lung injury (ALI) leads to diffuse pulmonary interstitial and alveolar edema, further developing into acute respiratory distress syndrome (ARDS). The present therapeutic approaches showed limited effects with poor clinical efficacy or severe side effects. This study aims to develop novel pharmaceutical agents to reduce lung damage with acceptable side effects for ALI.
Methods: Naked gene delivery system based on epigallocatechin 3-gallate (EGCG) was synthesized to deliver plasmid expressing DNA damage regulated autophagy modulator 1 (DRAM1), designated as EGCG/DRAM1 (ED). ED was characterized by dynamic light scattering analysis and transmission electron microscope. The biodistribution of ED in mice was measured by an in vivo small animal imaging system. The therapeutic potentials of ED were evaluated in MLE12 cells and LPS-induced ALI mice.
Results: Our results showed that ED was nearly spherical with a diameter of ~100 nm and increased the stability of DRAM1 plasmid that encapsulated. The synthesized ED showed negligible toxicity at the selected experimental concentration in MLE12 cells. ED could be taken up by MLE12 cells with high efficiency and escape from the lysosome. In ALI mice, ED facilitated the accumulation and retention of DRAM1 plasmid in lung, and attenuated pulmonary edema and pulmonary vascular permeability. The therapeutic effects of ED on ALI were associated with increased autophagy and reduced oxidative stress in lung.
Conclusion: In summary, ED attenuated pulmonary edema and pulmonary vascular permeability, and improved pulmonary dysfunction in ALI mice. This naked gene delivery system for autophagy enhancement may serve as a potential therapeutic strategy to attenuate ALI.
背景:急性肺损伤(ALI)导致弥漫性肺间质和肺泡水肿,并进一步发展为急性呼吸窘迫综合征(ARDS)。目前的治疗方法效果有限,临床疗效不佳或副作用严重。本研究旨在开发新型药物,以减轻 ALI 对肺部的损伤,同时减少可接受的副作用:方法:合成了基于表没食子儿茶素-3-没食子酸酯(EGCG)的裸基因递送系统,用于递送表达 DNA 损伤调控自噬调节因子 1(DRAM1)的质粒,命名为 EGCG/DRAM1 (ED)。通过动态光散射分析和透射电子显微镜对 ED 进行了表征。通过体内小动物成像系统测量了 ED 在小鼠体内的生物分布。在 MLE12 细胞和 LPS 诱导的 ALI 小鼠中评估了 ED 的治疗潜力:结果:我们的研究结果表明,ED 接近球形,直径约为 100 nm,并能提高包被 DRAM1 质粒的稳定性。在选定的实验浓度下,合成的 ED 在 MLE12 细胞中的毒性可忽略不计。ED 可被 MLE12 细胞高效吸收并从溶酶体中逸出。在 ALI 小鼠中,ED 可促进 DRAM1 质粒在肺中的积累和保留,减轻肺水肿和肺血管通透性。ED对ALI的治疗效果与自噬增加和肺氧化应激减少有关:总之,ED 减轻了 ALI 小鼠的肺水肿和肺血管通透性,改善了肺功能障碍。这种增强自噬的裸基因递送系统可作为减轻 ALI 的一种潜在治疗策略。
{"title":"Naked Gene Delivery Induces Autophagy for Effective Treatment of Acute Lung Injury in a Mouse Model.","authors":"Yu-Yan Qin, Hui Yu, Yong Huang, Xiaoyi Yang, Songpei Li, Ao Shen, Yinshan Lin, Mei Zhang, Qiulian Zhu, Jingwei Zhang, Lingmin Zhang, Xi-Yong Yu","doi":"10.2147/IJN.S477947","DOIUrl":"10.2147/IJN.S477947","url":null,"abstract":"<p><strong>Background: </strong>Acute lung injury (ALI) leads to diffuse pulmonary interstitial and alveolar edema, further developing into acute respiratory distress syndrome (ARDS). The present therapeutic approaches showed limited effects with poor clinical efficacy or severe side effects. This study aims to develop novel pharmaceutical agents to reduce lung damage with acceptable side effects for ALI.</p><p><strong>Methods: </strong>Naked gene delivery system based on epigallocatechin 3-gallate (EGCG) was synthesized to deliver plasmid expressing DNA damage regulated autophagy modulator 1 (DRAM1), designated as EGCG/DRAM1 (ED). ED was characterized by dynamic light scattering analysis and transmission electron microscope. The biodistribution of ED in mice was measured by an in vivo small animal imaging system. The therapeutic potentials of ED were evaluated in MLE12 cells and LPS-induced ALI mice.</p><p><strong>Results: </strong>Our results showed that ED was nearly spherical with a diameter of ~100 nm and increased the stability of DRAM1 plasmid that encapsulated. The synthesized ED showed negligible toxicity at the selected experimental concentration in MLE12 cells. ED could be taken up by MLE12 cells with high efficiency and escape from the lysosome. In ALI mice, ED facilitated the accumulation and retention of DRAM1 plasmid in lung, and attenuated pulmonary edema and pulmonary vascular permeability. The therapeutic effects of ED on ALI were associated with increased autophagy and reduced oxidative stress in lung.</p><p><strong>Conclusion: </strong>In summary, ED attenuated pulmonary edema and pulmonary vascular permeability, and improved pulmonary dysfunction in ALI mice. This naked gene delivery system for autophagy enhancement may serve as a potential therapeutic strategy to attenuate ALI.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10801-10818"},"PeriodicalIF":6.6,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23eCollection Date: 2024-01-01DOI: 10.2147/IJN.S479306
Wei Xu, Keren Wang, Ke Wang, Ye Zhao, Zhaoying Yang, Xiuying Li
Introduction: Exosomes (Exos) are promising drug delivery systems due to their low immunogenicity, minimal toxicity, high biocompatibility, and effective delivery capabilities. However, addressing the cardiotoxicity and other toxic side effects associated with anthracyclines has proven challenging.
Methods: In this study, we loaded doxorubicin (Dox) into Exos derived from human placental mesenchymal stem cells (MSCs) and modified them with carboxylated Fe3O4 nanoparticles (NPs) to create an Exo-Dox-NP delivery system. Using an external magnetic force (MF), we regulated the distribution of Exos for targeted Dox delivery in breast cancer treatment. We characterized and determined the drug-loading efficiency of Exo-Dox-NPs, their uptake by tumor cells, and the modulation of drug release. The therapeutic efficacy of Exo-Dox-NPs was evaluated through both in vitro and in vivo anti-tumor experiments.
Results: Our results indicated that Exo-Dox-NPs remain stable in the bloodstream while releasing the drug in the acidic environment of tumor cells and their lysosomes. As a drug delivery system, Exo-Dox-NPs enhanced Dox absorption by tumor cells, demonstrating high targeting specificity. Moreover, Exo-Dox-NPs inhibited the migration of breast cancer cells, as confirmed by scratch migration and Transwell Matrigel invasion assays. In vivo experiments confirmed the effective targeting and delivery of Dox to malignant tumors using Exo-Dox-NPs/MFs, with the Exo-Dox-NP/MF formulation exhibiting the most potent anti-tumor activity.
Conclusion: The utilization of Exos as carriers for Dox showed promising efficacy in breast cancer management. Carboxylated Fe3O4 NPs demonstrated to be suitable targeting agents, potentially advancing the development of natural nanocarriers for combination cancer therapy.
{"title":"Key Magnetized Exosomes for Effective Targeted Delivery of Doxorubicin Against Breast Cancer Cell Types in Mice Model.","authors":"Wei Xu, Keren Wang, Ke Wang, Ye Zhao, Zhaoying Yang, Xiuying Li","doi":"10.2147/IJN.S479306","DOIUrl":"10.2147/IJN.S479306","url":null,"abstract":"<p><strong>Introduction: </strong>Exosomes (Exos) are promising drug delivery systems due to their low immunogenicity, minimal toxicity, high biocompatibility, and effective delivery capabilities. However, addressing the cardiotoxicity and other toxic side effects associated with anthracyclines has proven challenging.</p><p><strong>Methods: </strong>In this study, we loaded doxorubicin (Dox) into Exos derived from human placental mesenchymal stem cells (MSCs) and modified them with carboxylated Fe<sub>3</sub>O<sub>4</sub> nanoparticles (NPs) to create an Exo-Dox-NP delivery system. Using an external magnetic force (MF), we regulated the distribution of Exos for targeted Dox delivery in breast cancer treatment. We characterized and determined the drug-loading efficiency of Exo-Dox-NPs, their uptake by tumor cells, and the modulation of drug release. The therapeutic efficacy of Exo-Dox-NPs was evaluated through both in vitro and in vivo anti-tumor experiments.</p><p><strong>Results: </strong>Our results indicated that Exo-Dox-NPs remain stable in the bloodstream while releasing the drug in the acidic environment of tumor cells and their lysosomes. As a drug delivery system, Exo-Dox-NPs enhanced Dox absorption by tumor cells, demonstrating high targeting specificity. Moreover, Exo-Dox-NPs inhibited the migration of breast cancer cells, as confirmed by scratch migration and Transwell Matrigel invasion assays. In vivo experiments confirmed the effective targeting and delivery of Dox to malignant tumors using Exo-Dox-NPs/MFs, with the Exo-Dox-NP/MF formulation exhibiting the most potent anti-tumor activity.</p><p><strong>Conclusion: </strong>The utilization of Exos as carriers for Dox showed promising efficacy in breast cancer management. Carboxylated Fe<sub>3</sub>O<sub>4</sub> NPs demonstrated to be suitable targeting agents, potentially advancing the development of natural nanocarriers for combination cancer therapy.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10711-10724"},"PeriodicalIF":6.6,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22eCollection Date: 2024-01-01DOI: 10.2147/IJN.S477320
Ana R S Ribeiro, Theresa Neuper, Jutta Horejs-Hoeck
The signaling pathway that comprises cyclic guanosine monophosphate-adenosine monophosphate (cGAMP or GMP-AMP) synthase (cGAS) and Stimulator of Interferon Genes (STING) is emerging as a druggable target for immunotherapy, with tumor-resident dendritic cells (DC) playing a critical role in mediating its effects. The STING receptor is part of the DNA-sensing cellular machinery, that can trigger the secretion of pro-inflammatory mediators, priming effector T cells and initiating specific antitumor responses. Yet, recent studies have highlighted the dual role of STING activation in the context of cancer: STING can either promote antitumor responses or enhance tumor progression. This dichotomy often depends on the cell type in which cGAS-STING signaling is induced and the activation mode, namely acute versus chronic. Of note, STING activation at the DC level appears to be particularly important for tumor eradication. This review outlines the contribution of the different conventional and plasmacytoid DC subsets and describes the mechanisms underlying STING-mediated activation of DCs in cancer. We further highlight how the STING pathway plays an intricate role in modulating the function of DCs embedded in tumor tissue. Additionally, we discuss the strategies being employed to harness STING activation for cancer treatment, such as the development of synthetic agonists and nano-based delivery systems, spotlighting the current techniques used to prompt STING engagement specifically in DCs.
由环鸟苷单磷酸-腺苷单磷酸(cGAMP 或 GMP-AMP)合成酶(cGAS)和干扰素基因刺激器(STING)组成的信号通路正逐渐成为免疫疗法的药物靶点,肿瘤驻留的树突状细胞(DC)在介导其效应方面发挥着关键作用。STING 受体是 DNA 传感细胞机制的一部分,它能触发促炎介质的分泌,激发效应 T 细胞并启动特异性抗肿瘤反应。然而,最近的研究强调了 STING 激活在癌症中的双重作用:STING 既能促进抗肿瘤反应,也能增强肿瘤进展。这种二分法通常取决于诱导 cGAS-STING 信号的细胞类型和激活模式,即急性还是慢性。值得注意的是,直流电水平的 STING 激活似乎对根除肿瘤尤为重要。本综述概述了不同的常规和浆细胞直流亚群的贡献,并描述了 STING 介导的直流细胞在癌症中的激活机制。我们进一步强调了 STING 通路如何在调节肿瘤组织中的 DC 功能方面发挥着错综复杂的作用。此外,我们还讨论了利用 STING 激活治疗癌症的策略,如开发合成激动剂和基于纳米的递送系统,并重点介绍了目前用于促使 STING 特异性参与直流细胞的技术。
{"title":"The Role of STING-Mediated Activation of Dendritic Cells in Cancer Immunotherapy.","authors":"Ana R S Ribeiro, Theresa Neuper, Jutta Horejs-Hoeck","doi":"10.2147/IJN.S477320","DOIUrl":"10.2147/IJN.S477320","url":null,"abstract":"<p><p>The signaling pathway that comprises cyclic guanosine monophosphate-adenosine monophosphate (cGAMP or GMP-AMP) synthase (cGAS) and Stimulator of Interferon Genes (STING) is emerging as a druggable target for immunotherapy, with tumor-resident dendritic cells (DC) playing a critical role in mediating its effects. The STING receptor is part of the DNA-sensing cellular machinery, that can trigger the secretion of pro-inflammatory mediators, priming effector T cells and initiating specific antitumor responses. Yet, recent studies have highlighted the dual role of STING activation in the context of cancer: STING can either promote antitumor responses or enhance tumor progression. This dichotomy often depends on the cell type in which cGAS-STING signaling is induced and the activation mode, namely acute versus chronic. Of note, STING activation at the DC level appears to be particularly important for tumor eradication. This review outlines the contribution of the different conventional and plasmacytoid DC subsets and describes the mechanisms underlying STING-mediated activation of DCs in cancer. We further highlight how the STING pathway plays an intricate role in modulating the function of DCs embedded in tumor tissue. Additionally, we discuss the strategies being employed to harness STING activation for cancer treatment, such as the development of synthetic agonists and nano-based delivery systems, spotlighting the current techniques used to prompt STING engagement specifically in DCs.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10685-10697"},"PeriodicalIF":6.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Large-diameter titanium dioxide nanotubes (TNTs) have shown promise in preserving osteoblast function under oxidative stress (OS) in vitro. However, their ability to enhance osteogenesis in vivo under OS conditions and the underlying mechanisms remain unclear.
Purpose: This study aimed to evaluate the osteogenic potential of 110 nm TNTs (TNT110) compared to 30 nm TNTs (TNT30) in an aging rat model exhibiting OS, and to investigate the mechanisms involved.
Methods: Surface properties of TNTs were characterized, and in vitro and in vivo experiments were conducted to assess their osteoinductive effects under OS. Transcriptomic, proteomic analyses, and Western blotting were performed to investigate the protective mechanisms of TNT110 on osteoblasts. Protein adsorption studies focused on the roles of fibronectin (FN) and albumin (BSA) in modulating osteoblast behavior on TNT110.
Results: In both in vitro and in vivo experiments, TNT110 significantly improved new bone formation and supported osteoblast survival under OS conditions. Subsequent ribonucleic acid sequencing results indicated that TNT110 tended to attenuate inflammatory responses and reactive oxygen species (ROS) expression while promoting endoplasmic reticulum (ER) stress and extracellular matrix receptor interactions, all of which are crucial for osteoblast survival and functionality. Further confirmation indicated that the cellular behavior changes of osteoblasts in the TNT110 group could only occur in the presence of serum. Moreover, proteomic analysis under OS conditions revealed the pivotal roles of FN and BSA in augmenting TNT110's resistance to OS. Surface pretreatment of TNT110 with FN/BSA alone could beneficially influence the early adhesion, spreading, ER activity, and ROS expression of osteoblasts, a trend not observed with TNT30.
Conclusion: TNT110 effectively protects osteoblast function in the OS microenvironment by modulating protein adsorption, with FN and BSA synergistically enhancing osteogenesis. These findings suggest TNT110's potential for use in implants for elderly patients.
{"title":"Elucidating the Mechanism of Large-Diameter Titanium Dioxide Nanotubes in Protecting Osteoblasts Under Oxidative Stress Environment: The Role of Fibronectin and Albumin Adsorption.","authors":"Yun Xiang, Dini Lin, Qiang Zhou, Hongyu Luo, Zixin Zhou, Shuyi Wu, Keyuan Xu, Xiaoting Tang, Pingping Ma, Chunyuan Cai, Xinkun Shen","doi":"10.2147/IJN.S488154","DOIUrl":"10.2147/IJN.S488154","url":null,"abstract":"<p><strong>Background: </strong>Large-diameter titanium dioxide nanotubes (TNTs) have shown promise in preserving osteoblast function under oxidative stress (OS) in vitro. However, their ability to enhance osteogenesis in vivo under OS conditions and the underlying mechanisms remain unclear.</p><p><strong>Purpose: </strong>This study aimed to evaluate the osteogenic potential of 110 nm TNTs (TNT110) compared to 30 nm TNTs (TNT30) in an aging rat model exhibiting OS, and to investigate the mechanisms involved.</p><p><strong>Methods: </strong>Surface properties of TNTs were characterized, and in vitro and in vivo experiments were conducted to assess their osteoinductive effects under OS. Transcriptomic, proteomic analyses, and Western blotting were performed to investigate the protective mechanisms of TNT110 on osteoblasts. Protein adsorption studies focused on the roles of fibronectin (FN) and albumin (BSA) in modulating osteoblast behavior on TNT110.</p><p><strong>Results: </strong>In both in vitro and in vivo experiments, TNT110 significantly improved new bone formation and supported osteoblast survival under OS conditions. Subsequent ribonucleic acid sequencing results indicated that TNT110 tended to attenuate inflammatory responses and reactive oxygen species (ROS) expression while promoting endoplasmic reticulum (ER) stress and extracellular matrix receptor interactions, all of which are crucial for osteoblast survival and functionality. Further confirmation indicated that the cellular behavior changes of osteoblasts in the TNT110 group could only occur in the presence of serum. Moreover, proteomic analysis under OS conditions revealed the pivotal roles of FN and BSA in augmenting TNT110's resistance to OS. Surface pretreatment of TNT110 with FN/BSA alone could beneficially influence the early adhesion, spreading, ER activity, and ROS expression of osteoblasts, a trend not observed with TNT30.</p><p><strong>Conclusion: </strong>TNT110 effectively protects osteoblast function in the OS microenvironment by modulating protein adsorption, with FN and BSA synergistically enhancing osteogenesis. These findings suggest TNT110's potential for use in implants for elderly patients.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10639-10659"},"PeriodicalIF":6.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-22eCollection Date: 2024-01-01DOI: 10.2147/IJN.S481901
Weiqian Zhang, Shuiying Chen, Zhongyu Bai, Menglai Gan, Mingwei Chen, Ying Zhang, Sai Liu, Dongjuan Liu
Oral squamous cell carcinoma (OSCC) is the most prevalent and deadly malignancy of the head and neck. The standard treatments for OSCC are surgery, radiotherapy, and chemoradiotherapy, which can cause severe cosmetic and functional damage to the oral cavity and impair the patients' quality of life. Photodynamic therapy (PDT) is a promising alternative that uses light-activated photosensitizers to induce selective phototoxicity and necrosis in the target tissues. PDT has several advantages over conventional treatments, such as minimal invasion, low side effects, high selectivity and preservation of the oral function and appearance. This review explores the principles, mechanisms, and current applications of PDT for OSCC. We address the challenges, such as the depth of light penetration and tissue hypoxia, and underscore the progressive innovations in photosensitizer enhancement, nanotechnological integration, and precision therapy. The exploration of biomarkers for refining patient selection and tailoring individualized treatment regimens is also undertaken. PDT holds promise as a secure and efficacious modality for OSCC management. Nonetheless, additional investigation is imperative to refine treatment protocols and validate sustained therapeutic success.
{"title":"Photodynamic Therapy for Oral Squamous Cell Carcinoma: Current Status, Challenges, and Prospects.","authors":"Weiqian Zhang, Shuiying Chen, Zhongyu Bai, Menglai Gan, Mingwei Chen, Ying Zhang, Sai Liu, Dongjuan Liu","doi":"10.2147/IJN.S481901","DOIUrl":"10.2147/IJN.S481901","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is the most prevalent and deadly malignancy of the head and neck. The standard treatments for OSCC are surgery, radiotherapy, and chemoradiotherapy, which can cause severe cosmetic and functional damage to the oral cavity and impair the patients' quality of life. Photodynamic therapy (PDT) is a promising alternative that uses light-activated photosensitizers to induce selective phototoxicity and necrosis in the target tissues. PDT has several advantages over conventional treatments, such as minimal invasion, low side effects, high selectivity and preservation of the oral function and appearance. This review explores the principles, mechanisms, and current applications of PDT for OSCC. We address the challenges, such as the depth of light penetration and tissue hypoxia, and underscore the progressive innovations in photosensitizer enhancement, nanotechnological integration, and precision therapy. The exploration of biomarkers for refining patient selection and tailoring individualized treatment regimens is also undertaken. PDT holds promise as a secure and efficacious modality for OSCC management. Nonetheless, additional investigation is imperative to refine treatment protocols and validate sustained therapeutic success.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10699-10710"},"PeriodicalIF":6.6,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11512526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-21eCollection Date: 2024-01-01DOI: 10.2147/IJN.S469302
Xiaobo Zhang, Xidan Gao, Xuefang Zhang, Xin Yao, Xin Kang
Hydrogels are multifunctional platforms. Through reasonable structure and function design, they use material engineering to adjust their physical and chemical properties, such as pore size, microstructure, degradability, stimulus-response characteristics, etc. and have a variety of biomedical applications. Hydrogel three-dimensional (3D) printing has emerged as a promising technique for the precise deposition of cell-laden biomaterials, enabling the fabrication of intricate 3D structures such as artificial vertebrae and intervertebral discs (IVDs). Despite being in the early stages, 3D printing techniques have shown great potential in the field of regenerative medicine for the fabrication of various transplantable tissues within the human body. Currently, the utilization of engineered hydrogels as carriers or scaffolds for treating intervertebral disc degeneration (IVDD) presents numerous challenges. However, it remains an indispensable multifunctional manufacturing technology that is imperative in addressing the escalating issue of IVDD. Moreover, it holds the potential to serve as a micron-scale platform for a diverse range of applications. This review primarily concentrates on emerging treatment strategies for IVDD, providing an in-depth analysis of their merits and drawbacks, as well as the challenges that need to be addressed. Furthermore, it extensively explores the biological properties of hydrogels and various nanoscale biomaterial inks, compares different prevalent manufacturing processes utilized in 3D printing, and thoroughly examines the potential clinical applications and prospects of integrating 3D printing technology with hydrogels.
{"title":"Revolutionizing Intervertebral Disc Regeneration: Advances and Future Directions in Three-Dimensional Bioprinting of Hydrogel Scaffolds.","authors":"Xiaobo Zhang, Xidan Gao, Xuefang Zhang, Xin Yao, Xin Kang","doi":"10.2147/IJN.S469302","DOIUrl":"10.2147/IJN.S469302","url":null,"abstract":"<p><p>Hydrogels are multifunctional platforms. Through reasonable structure and function design, they use material engineering to adjust their physical and chemical properties, such as pore size, microstructure, degradability, stimulus-response characteristics, etc. and have a variety of biomedical applications. Hydrogel three-dimensional (3D) printing has emerged as a promising technique for the precise deposition of cell-laden biomaterials, enabling the fabrication of intricate 3D structures such as artificial vertebrae and intervertebral discs (IVDs). Despite being in the early stages, 3D printing techniques have shown great potential in the field of regenerative medicine for the fabrication of various transplantable tissues within the human body. Currently, the utilization of engineered hydrogels as carriers or scaffolds for treating intervertebral disc degeneration (IVDD) presents numerous challenges. However, it remains an indispensable multifunctional manufacturing technology that is imperative in addressing the escalating issue of IVDD. Moreover, it holds the potential to serve as a micron-scale platform for a diverse range of applications. This review primarily concentrates on emerging treatment strategies for IVDD, providing an in-depth analysis of their merits and drawbacks, as well as the challenges that need to be addressed. Furthermore, it extensively explores the biological properties of hydrogels and various nanoscale biomaterial inks, compares different prevalent manufacturing processes utilized in 3D printing, and thoroughly examines the potential clinical applications and prospects of integrating 3D printing technology with hydrogels.</p>","PeriodicalId":14084,"journal":{"name":"International Journal of Nanomedicine","volume":"19 ","pages":"10661-10684"},"PeriodicalIF":6.6,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11505483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}