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Berberine-Loaded PVCL-PVA-PEG Self-Assembled Micelles for the Treatment of Liver Fibrosis. 用于治疗肝纤维化的小檗碱负载 PVCL-PVA-PEG 自组装胶束
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-25 eCollection Date: 2024-01-01 DOI: 10.2147/IJN.S465214
Xiaozhu Zha, Yumei Hao, Yifan Ke, Yichun Wang, Yujia Zhang

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.

背景:肝纤维化是许多慢性肝病的必要病理过程。研究表明,对肝纤维化进行合理干预可延缓慢性肝病的进展。小檗碱(BBR)是黄柏的天然提取物,可通过多种机制抑制肝纤维化的发展。然而,由于小檗碱的溶解度较低,其临床应用受到了限制。为了改善疏水性药物的溶解度,提高其治疗肝纤维化的疗效,人们开发了药物输送系统:方法:本研究以聚乙烯醇-己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物(PVCL-PVA-PEG)为载体,采用薄膜分散法构建了生物相容性纳米胶束,用于包封BBR(PVCL-PVA-PEG/BBR-MCs),以提高BBR的溶解度并减少其全身副作用。在体外评估了 PVCL-PVA-PEG/BBR-MCs 抑制 HSC-T6 细胞活化的能力。在体内研究了 PVCL-PVA-PEG/BBR-MCs 的抗肝纤维化作用:PVCL-PVA-PEG/BBR-MCs呈均匀球形,平均粒径为60.04 ± 0.027 nm,电位为1.49 ± 0.32 mV。它的封装效率为 98.52% ± 0.70,药物装载量为 6.16% ± 0.04。与游离 BBR 相比,PVCL-PVA-PEG/BBR-MCs 能显著抑制体外 HSC-T6 细胞活化和 TGF-β1 诱导的 HSC-T6 细胞迁移。体内生物分布实验显示,与游离 DiD 相比,PVCL-PVA-PEG/DiD-MCs 的肝脏分布明显改善,这表明 PVCL-PVA-PEG 胶束增强了 BBR 进入肝脏的能力,提高了疗效。治疗后,与CCl4治疗组相比,PVCL-PVA-PEG/BBR-MCs能明显改善纤维化肝脏结构,减少胶原沉积;治疗效果优于游离BBR组:我们的研究结果证明了将BBR包裹在PVCL-PVA-PEG胶束中的优势,并突出了PVCL-PVA-PEG/BBR-MCs作为治疗肝纤维化的一种治疗策略的潜力。
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引用次数: 0
Cryogenic 3D Printing of GelMA/Graphene Bioinks: Improved Mechanical Strength and Structural Properties for Tissue Engineering. GelMA/Graphene 生物链接的低温三维打印:提高组织工程的机械强度和结构特性
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-24 eCollection Date: 2024-01-01 DOI: 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.

目的:组织工程旨在重建自然细胞环境,促进组织再生。甲基丙烯酸明胶(Gelatin methacrylate,GelMA)因其生物相容性、支持细胞粘附和增殖的能力以及可调节的机械特性而被广泛使用。本研究开发了一种浓度为 1、1.5 和 2 mg/mL 的 GelMA 和石墨烯生物墨水平台,以增强组织工程应用的支架特性:在 GelMA 基质中加入石墨烯,以提高生物墨水的机械强度和导电性。通过 DSC 分析和机械测试评估了 GelMA/ 石墨烯支架的抗压强度和热稳定性。细胞毒性试验用于确定细胞存活率。为了保持支架的结构和功能,采用了-30°C低温打印技术。绒毛膜(CAM)试验用于评估生物相容性和血管生成潜力:结果:石墨烯的加入大大提高了 GelMA 支架的抗压强度和热稳定性。细胞毒性实验表明细胞存活率高达 90%,证实了所开发材料的生物相容性。低温打印可有效保持支架的完整性和功能性。CAM试验验证了这种材料的生物相容性和血管生成潜力,表明支架植入小鸡胚胎CAM后血管大量生成:结论:将石墨烯整合到 GelMA 水凝胶中,再加上低温三维打印技术,是提高支架制造能力的有效策略。由此产生的 GelMA/ 石墨烯支架具有优异的机械性能、生物相容性和促进血管生成的能力,非常适合各种组织工程和再生医学应用。
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引用次数: 0
Stem Cell-Derived Exosomes: Natural Intercellular Messengers with Versatile Mechanisms for the Treatment of Diabetic Retinopathy. 干细胞衍生的外泌体:治疗糖尿病视网膜病变的多种机制的天然细胞间信使。
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-24 eCollection Date: 2024-01-01 DOI: 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.

糖尿病视网膜病变是糖尿病早期并发症之一。这种疾病影响严重,发展到晚期可能导致失明。目前,糖尿病视网膜病变的治疗方法主要局限于晚期,治疗机制单一。干细胞是再生疗法的希望所在,具有全面改善糖尿病视网膜病变的潜力。然而,干细胞直接疗法存在一定的致癌风险。干细胞分泌的外泌体对疾病的整体改善效果与干细胞相似。外泌体可将一些具有生物活性的物质从供体细胞携带到受体细胞或远处器官,调节细胞间的信号传递。外泌体在减轻氧化应激、抑制炎症反应、抑制血管生成、减少细胞凋亡和保护神经组织等方面显示出显著功效。目前,利用干细胞外泌体治疗糖尿病视网膜病变的实验文献与上述实验结果趋于一致。有鉴于此,我们选择从微妙的分子角度深入探讨外泌体。我们将在本文中详细阐述这一观点,并建议将外泌体疗法作为治疗糖尿病视网膜病变的一种有前景的方法,通过多种机制改善病变。
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引用次数: 0
The Cervical and Meningeal Lymphatic Network as a Pathway for Retrograde Nanoparticle Transport to the Brain. 颈部和脑膜淋巴管网是纳米粒子逆行运输到大脑的通道
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-24 eCollection Date: 2024-01-01 DOI: 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.

导言脑膜淋巴管被描述为一条将脑脊液和间质单向输送到颈深淋巴结的通道。然而,这些血管表现出典型的初始淋巴管的解剖和分子特征,周围没有平滑肌,瓣膜很少或没有。鉴于其结构,理论上这种网络可以实现双向运动。尽管如此,我们尚未将其作为纳米粒子从外周组织进入大脑的潜在途径进行评估:方法:我们采用了超顺磁性氧化铁纳米颗粒(SPIONs)、装载有 SPIONs、金纳米棒和中国墨水纳米颗粒的外泌体。SPIONs是通过化学共沉淀法制备的,而外泌体则是通过Exo-Spin柱方案从B16F10黑色素瘤细胞系中分离出来的,并通过电穿孔载入SPIONs。金纳米棒由聚乙二醇功能化。我们利用 C57BL/6 小鼠进行尸检和体内操作。为了评估逆行定向流动,我们将每种纳米粒子溶液注入深颈部淋巴结。头颈部固定后进行磁共振成像和组织学分析:结果:我们在此表明,从 B16F10 黑色素瘤细胞系提取的细胞外囊泡以及超顺磁性氧化铁纳米粒子、金纳米棒和中国墨水纳米粒子在死后和体内颈深淋巴结内给药后,可以完全通过淋巴结构到达 C57BL/6 小鼠的脑膜淋巴管和大脑:讨论:硬脑膜淋巴管的功能解剖在小鼠和人类之间是一致的,这表明我们的研究结果可能对推进使用纳米颗粒的靶向给药系统具有重要意义。了解纳米粒子通过脑膜淋巴管网的逆向运输可能会为纳米医学带来新的治疗方法,为生理和神经病理学背景下的流体动力学提供新的见解。对这一途径的进一步研究可能会为治疗神经系统疾病或加强向大脑的药物输送提供新的策略。
{"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}
引用次数: 0
Naked Gene Delivery Induces Autophagy for Effective Treatment of Acute Lung Injury in a Mouse Model. 裸基因递送诱导自噬,有效治疗小鼠模型的急性肺损伤
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-24 eCollection Date: 2024-01-01 DOI: 10.2147/IJN.S477947
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

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。
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引用次数: 0
Key Magnetized Exosomes for Effective Targeted Delivery of Doxorubicin Against Breast Cancer Cell Types in Mice Model. 关键磁化外泌体在小鼠模型中有效靶向递送多柔比星治疗乳腺癌细胞类型。
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-23 eCollection Date: 2024-01-01 DOI: 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.

导言:外泌体(Exos)具有免疫原性低、毒性小、生物相容性高和有效的给药能力等特点,是一种前景广阔的给药系统。然而,解决与蒽环类药物相关的心脏毒性和其他毒副作用已被证明具有挑战性:在这项研究中,我们将多柔比星(Dox)装入源自人胎盘间充质干细胞(MSCs)的Exos中,并用羧化的Fe3O4纳米颗粒(NPs)对其进行修饰,从而创建了Exo-Dox-NP递送系统。我们利用外部磁力(MF)来调节 Exos 的分布,从而在乳腺癌治疗中实现 Dox 的靶向递送。我们对 Exo-Dox-NPs 的药物负载效率、肿瘤细胞对其的吸收以及药物释放的调控进行了表征和测定。我们通过体外和体内抗肿瘤实验评估了 Exo-Dox-NPs 的疗效:结果:我们的研究结果表明,Exo-Dox-NPs 在血液中保持稳定,同时在肿瘤细胞及其溶酶体的酸性环境中释放药物。作为一种给药系统,Exo-Dox-NPs 能增强肿瘤细胞对 Dox 的吸收,表现出高度的靶向特异性。此外,Exo-Dox-NPs 还能抑制乳腺癌细胞的迁移,划痕迁移和 Transwell Matrigel 侵袭实验证实了这一点。体内实验证实,Exo-Dox-NPs/MFs 能有效靶向恶性肿瘤输送 Dox,其中 Exo-Dox-NP/MF 配方的抗肿瘤活性最强:结论:利用 Exos 作为 Dox 的载体在乳腺癌治疗中具有良好的疗效。羧基化的 Fe3O4 NPs 被证明是合适的靶向药物,有可能推动用于癌症综合治疗的天然纳米载体的发展。
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引用次数: 0
The Role of STING-Mediated Activation of Dendritic Cells in Cancer Immunotherapy. STING 介导的树突状细胞激活在癌症免疫疗法中的作用
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-22 eCollection Date: 2024-01-01 DOI: 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。
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引用次数: 0
Elucidating the Mechanism of Large-Diameter Titanium Dioxide Nanotubes in Protecting Osteoblasts Under Oxidative Stress Environment: The Role of Fibronectin and Albumin Adsorption. 阐明大直径二氧化钛纳米管在氧化应激环境下保护成骨细胞的机制:纤连蛋白和白蛋白吸附的作用
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-22 eCollection Date: 2024-01-01 DOI: 10.2147/IJN.S488154
Yun Xiang, Dini Lin, Qiang Zhou, Hongyu Luo, Zixin Zhou, Shuyi Wu, Keyuan Xu, Xiaoting Tang, Pingping Ma, Chunyuan Cai, Xinkun Shen

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.

背景:大直径二氧化钛纳米管(TNTs)在体外氧化应激(OS)条件下有望保护成骨细胞的功能。目的:本研究旨在评估 110 nm TNTs(TNT110)与 30 nm TNTs(TNT30)相比在老龄大鼠模型中的成骨潜力,并研究其中的机制:方法:表征了TNTs的表面特性,并进行了体外和体内实验,以评估其在OS条件下的骨诱导效应。通过转录组学、蛋白质组学分析和 Western 印迹法研究 TNT110 对成骨细胞的保护机制。蛋白质吸附研究的重点是纤维连接蛋白(FN)和白蛋白(BSA)在调节成骨细胞对 TNT110 的行为中的作用:在体外和体内实验中,TNT110都能显著改善新骨形成,并支持成骨细胞在OS条件下存活。随后的核糖核酸测序结果表明,TNT110往往会减轻炎症反应和活性氧(ROS)的表达,同时促进内质网(ER)应激和细胞外基质受体的相互作用,所有这些对成骨细胞的存活和功能至关重要。进一步证实表明,TNT110 组成骨细胞的细胞行为变化只有在血清存在的情况下才能发生。此外,OS条件下的蛋白质组分析表明,FN和BSA在增强TNT110对OS的抵抗力方面起着关键作用。仅用 FN/BSA 对 TNT110 进行表面预处理可有益地影响成骨细胞的早期粘附、扩散、ER 活性和 ROS 表达,而 TNT30 则没有观察到这一趋势:结论:TNT110通过调节蛋白质吸附有效地保护了OS微环境中的成骨细胞功能,FN和BSA可协同促进成骨。这些发现表明 TNT110 有潜力用于老年患者的植入物。
{"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}
引用次数: 0
Photodynamic Therapy for Oral Squamous Cell Carcinoma: Current Status, Challenges, and Prospects. 口腔鳞状细胞癌的光动力疗法:现状、挑战与前景。
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-22 eCollection Date: 2024-01-01 DOI: 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.

口腔鳞状细胞癌(OSCC)是头颈部最常见、最致命的恶性肿瘤。OSCC的标准治疗方法是手术、放疗和化学放疗,这些方法会对口腔造成严重的外观和功能损伤,影响患者的生活质量。光动力疗法(PDT)是一种很有前景的替代疗法,它使用光激活的光敏剂诱导靶组织产生选择性光毒性和坏死。与传统治疗方法相比,PDT 具有多种优势,如微创、副作用小、选择性高以及可保留口腔功能和外观。本综述探讨了光动力疗法治疗 OSCC 的原理、机制和当前应用。我们探讨了光穿透深度和组织缺氧等挑战,并强调了在光敏剂增强、纳米技术集成和精准治疗方面的逐步创新。此外,我们还探讨了生物标志物,以完善患者选择和定制个性化治疗方案。光动力疗法有望成为治疗 OSCC 的一种安全有效的方法。然而,要完善治疗方案并验证持续的治疗效果,还必须进行更多的研究。
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引用次数: 0
Revolutionizing Intervertebral Disc Regeneration: Advances and Future Directions in Three-Dimensional Bioprinting of Hydrogel Scaffolds. 椎间盘再生的革命性变革:水凝胶支架三维生物打印的进展和未来方向。
IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY Pub Date : 2024-10-21 eCollection Date: 2024-01-01 DOI: 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.

水凝胶是一种多功能平台。通过合理的结构和功能设计,它们利用材料工程学调整其物理和化学特性,如孔径、微结构、可降解性、刺激响应特性等,具有多种生物医学应用。水凝胶三维(3D)打印已成为一种很有前途的技术,可精确沉积含有细胞的生物材料,从而制造出复杂的三维结构,如人工椎骨和椎间盘(IVD)。尽管还处于早期阶段,但三维打印技术已在再生医学领域显示出巨大的潜力,可在人体内制造各种可移植组织。目前,利用工程水凝胶作为载体或支架治疗椎间盘变性(IVDD)面临着诸多挑战。然而,水凝胶仍然是一种不可或缺的多功能制造技术,对于解决日益严重的椎间盘退变问题至关重要。此外,它还具有作为微米级平台进行各种应用的潜力。本综述主要关注 IVDD 的新兴治疗策略,深入分析了这些策略的优缺点以及需要应对的挑战。此外,它还广泛探讨了水凝胶和各种纳米级生物材料墨水的生物特性,比较了三维打印中使用的不同流行制造工艺,并深入研究了将三维打印技术与水凝胶相结合的潜在临床应用和前景。
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引用次数: 0
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International Journal of Nanomedicine
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