Pub Date : 2024-08-08DOI: 10.3389/fddev.2024.1436842
M. Puccetti, Claudio Costantini, A. Schoubben, S. Giovagnoli, Maurizio Ricci
This review article explores the potential of engineering antigen-presenting cells (APCs) for the immunotherapy of autoimmune diseases. It discusses various strategies for modifying APCs to induce antigen-specific tolerance, thereby mitigating autoimmune responses. The review covers recent advancements in APC engineering techniques, including genetic modification and nanoparticle-based approaches, and evaluates their efficacy in preclinical models and clinical trials. Additionally, challenges and future directions for the development of APC-based immunotherapies for autoimmunity – and other forms of cell-based immunotherapy – are discussed. Along this direction, this review (i) describes various strategies for engineering APCs, including genetic modification, nanoparticle delivery systems, and ex vivo manipulation techniques; (ii) discusses the selection of target antigens and the design of APC-based immunotherapies, and (iii) reviews preclinical models used to evaluate the efficacy and safety of engineered APCs in inducing antigen-specific tolerance.
{"title":"Strategies and delivery systems for cell-based therapy in autoimmunity","authors":"M. Puccetti, Claudio Costantini, A. Schoubben, S. Giovagnoli, Maurizio Ricci","doi":"10.3389/fddev.2024.1436842","DOIUrl":"https://doi.org/10.3389/fddev.2024.1436842","url":null,"abstract":"This review article explores the potential of engineering antigen-presenting cells (APCs) for the immunotherapy of autoimmune diseases. It discusses various strategies for modifying APCs to induce antigen-specific tolerance, thereby mitigating autoimmune responses. The review covers recent advancements in APC engineering techniques, including genetic modification and nanoparticle-based approaches, and evaluates their efficacy in preclinical models and clinical trials. Additionally, challenges and future directions for the development of APC-based immunotherapies for autoimmunity – and other forms of cell-based immunotherapy – are discussed. Along this direction, this review (i) describes various strategies for engineering APCs, including genetic modification, nanoparticle delivery systems, and ex vivo manipulation techniques; (ii) discusses the selection of target antigens and the design of APC-based immunotherapies, and (iii) reviews preclinical models used to evaluate the efficacy and safety of engineered APCs in inducing antigen-specific tolerance.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Due to the inherent risk of a further pandemic influenza outbreak, there is a need and growing interest in investigating combinations of prophylactic vaccines and novel adjuvants, particularly to achieve antigen dose sparing and improved immunogenicity. Influenza is a highly variable virus, where the specific vaccine target is constantly changing, representing a major challenge to influenza vaccine development. Currently, commercial inactivated influenza vaccines have a poor CD8+ T response, which impacts cross-reactivity and the duration of response. Adjuvanted influenza vaccines can increase immune responses, thereby achieving better protection and cross-reactivity to help contain the spread of the disease. An early exploration of a hybrid cholesterol-PLGA nanoparticle delivery system containing the saponin tomatine and a NOD2 (nucleotide-binding oligomerization domain 2) agonist called SG101 was conducted. This combination was preliminarily evaluated for its ability to induce cellular immunity when combined with whole inactivated virus (WIV) influenza vaccine. After the adjuvants were manufactured using a single emulsion process, two formulations with different drug loadings were selected and physico-chemically characterized, showing sizes between 224 ± 32 and 309 ± 45 nm and different morphologies. After ensuring the lack of in vitro toxicity and hemolytic activity, a pilot in vivo assay evaluated the hybrid nanoparticle formulation for its ability to induce humoral and cellular immunity when combined with whole inactivated virus (WIV) H5N1 influenza vaccine by intramuscular administration in mice. Hemagglutinin inhibition (HAI) titers for adjuvanted groups showed no significant difference compared to the group vaccinated with the antigen alone. It was similar for CD4+ and CD8+ T cell responses, although the high drug loading formulation induced higher titers of IFNγ-positive CD8+ T cells. These proof-of-concept results encourage further investigations to develop the hybrid formulation with increased or different loading ratios, to investigate manufacturing optimization, and to evaluate the role of the individual immunostimulatory compounds in immune responses.
由于流感大流行爆发的内在风险，人们需要研究预防性疫苗和新型佐剂的组合，特别是实现抗原剂量稀释和提高免疫原性，而且这种研究的兴趣日益浓厚。流感是一种高度易变的病毒，特定的疫苗靶点不断变化，这对流感疫苗的开发是一个重大挑战。目前，商用灭活流感疫苗的 CD8+ T 反应较差，影响交叉反应和反应持续时间。添加佐剂的流感疫苗可以提高免疫反应，从而获得更好的保护和交叉反应，有助于遏制疾病的传播。我们对含有皂素番茄碱和名为 SG101 的 NOD2（核苷酸结合寡聚化结构域 2）激动剂的胆固醇-PLGA 混合纳米颗粒递送系统进行了早期探索。初步评估了这种组合与全灭活病毒（WIV）流感疫苗结合使用时诱导细胞免疫的能力。在使用单一乳液工艺制造佐剂后，选择了两种不同药物载量的制剂，并对其进行了物理化学表征，结果显示这两种制剂的尺寸介于 224 ± 32 nm 和 309 ± 45 nm 之间，形态各异。在确保无体外毒性和溶血活性后，一项试验性体内试验评估了混合纳米颗粒配方与全灭活病毒（WIV）H5N1 流感疫苗结合后在小鼠体内肌肉注射诱导体液免疫和细胞免疫的能力。添加佐剂组的血凝素抑制滴度（HAI）与单独接种抗原组相比无显著差异。CD4+ 和 CD8+ T 细胞反应相似，但高药物载量配方诱导的 IFNγ 阳性 CD8+ T 细胞滴度更高。这些概念验证结果鼓励人们进一步研究开发增加或改变负载率的混合制剂，研究生产优化，并评估单个免疫刺激化合物在免疫反应中的作用。
{"title":"Preliminary results on novel adjuvant combinations suggest enhanced immunogenicity of whole inactivated pandemic influenza vaccines","authors":"Allegra Peletta, Aurélie Marmy, Samo Guzelj, Alcidia Ramos Barros, Ž. Jakopin, Gerrit Borchard","doi":"10.3389/fddev.2024.1382266","DOIUrl":"https://doi.org/10.3389/fddev.2024.1382266","url":null,"abstract":"Due to the inherent risk of a further pandemic influenza outbreak, there is a need and growing interest in investigating combinations of prophylactic vaccines and novel adjuvants, particularly to achieve antigen dose sparing and improved immunogenicity. Influenza is a highly variable virus, where the specific vaccine target is constantly changing, representing a major challenge to influenza vaccine development. Currently, commercial inactivated influenza vaccines have a poor CD8+ T response, which impacts cross-reactivity and the duration of response. Adjuvanted influenza vaccines can increase immune responses, thereby achieving better protection and cross-reactivity to help contain the spread of the disease. An early exploration of a hybrid cholesterol-PLGA nanoparticle delivery system containing the saponin tomatine and a NOD2 (nucleotide-binding oligomerization domain 2) agonist called SG101 was conducted. This combination was preliminarily evaluated for its ability to induce cellular immunity when combined with whole inactivated virus (WIV) influenza vaccine. After the adjuvants were manufactured using a single emulsion process, two formulations with different drug loadings were selected and physico-chemically characterized, showing sizes between 224 ± 32 and 309 ± 45 nm and different morphologies. After ensuring the lack of in vitro toxicity and hemolytic activity, a pilot in vivo assay evaluated the hybrid nanoparticle formulation for its ability to induce humoral and cellular immunity when combined with whole inactivated virus (WIV) H5N1 influenza vaccine by intramuscular administration in mice. Hemagglutinin inhibition (HAI) titers for adjuvanted groups showed no significant difference compared to the group vaccinated with the antigen alone. It was similar for CD4+ and CD8+ T cell responses, although the high drug loading formulation induced higher titers of IFNγ-positive CD8+ T cells. These proof-of-concept results encourage further investigations to develop the hybrid formulation with increased or different loading ratios, to investigate manufacturing optimization, and to evaluate the role of the individual immunostimulatory compounds in immune responses.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-05DOI: 10.3389/fddev.2024.1433453
Sarah F. Hathcock, Hallie E. Knight, Emma G. Tong, Alexandra E. Meyer, Henry D. Mauser, Nadine Vollmuth, Brandon J. Kim
The blood-brain barrier (BBB) is comprised of specialized brain endothelial cells (BECs) that contribute to maintaining central nervous system (CNS) homeostasis. BECs possess properties such as an array of multi-drug efflux transporters that eject various drugs and toxins, preventing their entry into the CNS. Together, it is estimated that these efflux transporters can eject up to 98% of known xenobiotic compounds. P-glycoprotein (P-gp) is a promiscuous efflux transporter at the BBB and can efflux up to 90 various substrates, representing a major hurdle in CNS drug delivery for therapeutic interventions. This necessitates the study of P-gp to discover drugs that are non-substrates of P-gp as well as to identify novel P-gp inhibitors. Here we report the generation of P-gp overexpressing BECs under the endogenous promoter control that could be used in the screening of P-gp substrates. These cells could provide utility in the design of drugs or identification of novel inhibitors.
{"title":"Induction of P-glycoprotein overexpression in brain endothelial cells as a model to study blood-brain barrier efflux transport","authors":"Sarah F. Hathcock, Hallie E. Knight, Emma G. Tong, Alexandra E. Meyer, Henry D. Mauser, Nadine Vollmuth, Brandon J. Kim","doi":"10.3389/fddev.2024.1433453","DOIUrl":"https://doi.org/10.3389/fddev.2024.1433453","url":null,"abstract":"The blood-brain barrier (BBB) is comprised of specialized brain endothelial cells (BECs) that contribute to maintaining central nervous system (CNS) homeostasis. BECs possess properties such as an array of multi-drug efflux transporters that eject various drugs and toxins, preventing their entry into the CNS. Together, it is estimated that these efflux transporters can eject up to 98% of known xenobiotic compounds. P-glycoprotein (P-gp) is a promiscuous efflux transporter at the BBB and can efflux up to 90 various substrates, representing a major hurdle in CNS drug delivery for therapeutic interventions. This necessitates the study of P-gp to discover drugs that are non-substrates of P-gp as well as to identify novel P-gp inhibitors. Here we report the generation of P-gp overexpressing BECs under the endogenous promoter control that could be used in the screening of P-gp substrates. These cells could provide utility in the design of drugs or identification of novel inhibitors.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141677182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-05DOI: 10.3389/fddev.2024.1397153
Ana Paula Pereira Guimaraes, I. R. Calori, Hong Bi, Antonio Claudio Tedesco
The hanging drop method is a cost-effective approach for 3D spheroid culture. However, obtaining numerous spheroids in a limited area becomes challenging due to the risk of droplet coalescence, primarly during Petri dish handling. In this study, we describe a general method to fabricate a 3D printing-based support called SpheroMold that facilitates Petri dish handling and enhances spheroid production per unit area. As a proof-of-concept, we designed a digital negative mold which comprised 37 pegs within a 13.52 cm2 area, and then printed it using stereolithography; the density of pegs can be adjusted according to user requirements. The SpheroMold was created by pouring the base and curing agent (10:1) (Sylgard® 184 silicone) into the mold, curing it at 80°C, and then attaching it to the lid of a Petri dish. Our SpheroMold effectively prevented droplet coalescence during Petri dish inversion, enabling the production of numerous 3D spheroids while simplifying manipulation. Unlike conventional techniques, our design also facilitated a larger volume of culture medium per drop compared to a standard Petri dish, potentially decreasing the necessity for frequent medium exchange to sustain cellular health and reducing labor intensity.
{"title":"SpheroMold: modernizing the hanging drop method for spheroid culture","authors":"Ana Paula Pereira Guimaraes, I. R. Calori, Hong Bi, Antonio Claudio Tedesco","doi":"10.3389/fddev.2024.1397153","DOIUrl":"https://doi.org/10.3389/fddev.2024.1397153","url":null,"abstract":"The hanging drop method is a cost-effective approach for 3D spheroid culture. However, obtaining numerous spheroids in a limited area becomes challenging due to the risk of droplet coalescence, primarly during Petri dish handling. In this study, we describe a general method to fabricate a 3D printing-based support called SpheroMold that facilitates Petri dish handling and enhances spheroid production per unit area. As a proof-of-concept, we designed a digital negative mold which comprised 37 pegs within a 13.52 cm2 area, and then printed it using stereolithography; the density of pegs can be adjusted according to user requirements. The SpheroMold was created by pouring the base and curing agent (10:1) (Sylgard® 184 silicone) into the mold, curing it at 80°C, and then attaching it to the lid of a Petri dish. Our SpheroMold effectively prevented droplet coalescence during Petri dish inversion, enabling the production of numerous 3D spheroids while simplifying manipulation. Unlike conventional techniques, our design also facilitated a larger volume of culture medium per drop compared to a standard Petri dish, potentially decreasing the necessity for frequent medium exchange to sustain cellular health and reducing labor intensity.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141384385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-22DOI: 10.3389/fddev.2024.1397056
Sara De Vincentiis, Francesca Merighi, Peter Blümler, Jose Gustavo De La Ossa Guerra, Mariachiara Di Caprio, Marco Onorati, Marco Mainardi, V. Raffa, Marina Carbone
This paper details the comprehensive design and prototyping of a 3D-printed wearable device tailored for mouse models which addresses the need for non-invasive applications in spinal cord studies and therapeutic treatments. Our work was prompted by the increasing demand for wearable devices in preclinical research on freely behaving rodent models of spinal cord injury. We present an innovative solution that employs compliant 3D-printed structures for stable device placement on the backs of both healthy and spinal cord-injured mice. In our trial, the device was represented by two magnets that applied passive magnetic stimulation to the injury site. This device was designed to be combined with the use of magnetic nanoparticles to render neurons or neural cells sensitive to an exogenous magnetic field, resulting in the stimulation of axon growth in response to a pulling force. We show different design iterations, emphasizing the challenges faced and the solutions proposed during the design process. The iterative design process involved multiple phases, from the magnet holder (MH) to the wearable device configurations. The latter included different approaches: a “Fitbit”, “Belt”, “Bib”, and ultimately a “Cape”. Each design iteration was accompanied by a testing protocol involving healthy and injured mice, with qualitative assessments focusing on animal wellbeing. Follow-up lasted for at least 21 consecutive days, thus allowing animal welfare to be accurately monitored. The final Cape design was our best compromise between the need for a thin structure that would not hinder movement and the resistance required to maintain the structure at the correct position while withstanding biting and mechanical stress. The detailed account of the iterative design process and testing procedures provides valuable insights for researchers and practitioners engaged in the development of wearable devices for mice, particularly in the context of spinal cord studies and therapeutic treatments. Finally, in addition to describing the design of a 3D-printed wearable holder, we also outline some general guidelines for the design of wearable devices.
本文详细介绍了为小鼠模型量身定制的 3D 打印可穿戴设备的综合设计和原型制作，该设备可满足脊髓研究和治疗中对无创应用的需求。在脊髓损伤自由行为啮齿动物模型的临床前研究中，对可穿戴设备的需求日益增长，这促使我们开展了这项工作。我们提出了一种创新的解决方案，利用顺应性 3D 打印结构将设备稳定地放置在健康小鼠和脊髓损伤小鼠的背部。在我们的试验中，该装置由两块磁铁组成，对损伤部位施加被动磁刺激。该装置的设计目的是结合使用磁性纳米粒子，使神经元或神经细胞对外源磁场敏感，从而在拉力作用下刺激轴突生长。我们展示了不同的设计迭代，强调了设计过程中面临的挑战和提出的解决方案。迭代设计过程涉及多个阶段，从磁铁支架（MH）到可穿戴设备配置。后者包括不同的方法："Fitbit"、"Belt"、"Bib "以及最终的 "Cape"。每次设计迭代都伴随着一个测试方案，测试对象包括健康和受伤的小鼠，定性评估侧重于动物的健康状况。随访至少连续 21 天，以便准确监测动物福利。Cape 的最终设计是我们在不妨碍运动的薄结构需求与保持结构正确位置所需的阻力（同时承受咬合和机械应力）之间的最佳折衷方案。对迭代设计过程和测试程序的详细介绍为从事小鼠可穿戴设备开发的研究人员和从业人员提供了宝贵的见解，特别是在脊髓研究和治疗方面。最后，除了介绍三维打印可穿戴支架的设计外，我们还概述了可穿戴设备设计的一些一般准则。
{"title":"3D-printed weight holders design and testing in mouse models of spinal cord injury","authors":"Sara De Vincentiis, Francesca Merighi, Peter Blümler, Jose Gustavo De La Ossa Guerra, Mariachiara Di Caprio, Marco Onorati, Marco Mainardi, V. Raffa, Marina Carbone","doi":"10.3389/fddev.2024.1397056","DOIUrl":"https://doi.org/10.3389/fddev.2024.1397056","url":null,"abstract":"This paper details the comprehensive design and prototyping of a 3D-printed wearable device tailored for mouse models which addresses the need for non-invasive applications in spinal cord studies and therapeutic treatments. Our work was prompted by the increasing demand for wearable devices in preclinical research on freely behaving rodent models of spinal cord injury. We present an innovative solution that employs compliant 3D-printed structures for stable device placement on the backs of both healthy and spinal cord-injured mice. In our trial, the device was represented by two magnets that applied passive magnetic stimulation to the injury site. This device was designed to be combined with the use of magnetic nanoparticles to render neurons or neural cells sensitive to an exogenous magnetic field, resulting in the stimulation of axon growth in response to a pulling force. We show different design iterations, emphasizing the challenges faced and the solutions proposed during the design process. The iterative design process involved multiple phases, from the magnet holder (MH) to the wearable device configurations. The latter included different approaches: a “Fitbit”, “Belt”, “Bib”, and ultimately a “Cape”. Each design iteration was accompanied by a testing protocol involving healthy and injured mice, with qualitative assessments focusing on animal wellbeing. Follow-up lasted for at least 21 consecutive days, thus allowing animal welfare to be accurately monitored. The final Cape design was our best compromise between the need for a thin structure that would not hinder movement and the resistance required to maintain the structure at the correct position while withstanding biting and mechanical stress. The detailed account of the iterative design process and testing procedures provides valuable insights for researchers and practitioners engaged in the development of wearable devices for mice, particularly in the context of spinal cord studies and therapeutic treatments. Finally, in addition to describing the design of a 3D-printed wearable holder, we also outline some general guidelines for the design of wearable devices.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141110098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-17DOI: 10.3389/fddev.2024.1407304
Clara Schweiker, Sergej Zankovic, Anna Baghnavi, Dirk Velten, Hagen Schmal, Ralf Thomann, Michael Seidenstuecker
The core/shell 3D printing process using CPC and alginate is intended to create biodegradable scaffolds that have a similar stability to bone tissue and also offer sufficient and continuous antibiotic release. In this way, a patient-specific and patient-friendly process will be established, which should optimally support the human organism in its regeneration. To generate the best possible strength values, the printed scaffolds underwent various post-treatments and were then tested in a material test. The test methods included self-setting, storage in a drying cabinet with a water-saturated atmosphere at 37°C, followed by incubation in PBS, freeze-drying, and coating the samples with alginate. Additionally, a degradation test at pH 7.4 and pH 5 was carried out to test stability under in vitro conditions. It was shown that the untreated and freeze-dried samples failed at a maximum load of 30–700 N, while the remaining scaffolds could withstand a load of at least 2,000 N. At this failure load, most of the test series showed an average deformation of 43.95%. All samples, therefore, remained below the strength of cancellous bone. However, based on a 20% load after surgery, the coated scaffolds represented the best possible alternative, with a Young’s modulus of around 1.71 MPa. We were able to demonstrate that self-setting occurs in core-shell printed CPC/alginate scaffolds after only 1 day, and that mass production is possible. By coating with alginate, the compressive strength could be increased without the need for additional post-treatment. The mechanical strength was sufficient to be available as a scaffold for bone regeneration and additionally as a drug delivery device for future applications and experiments.
{"title":"Core-shell 3D printed biodegradable calcium phosphate cement—Alginate scaffolds for possible bone regeneration applications","authors":"Clara Schweiker, Sergej Zankovic, Anna Baghnavi, Dirk Velten, Hagen Schmal, Ralf Thomann, Michael Seidenstuecker","doi":"10.3389/fddev.2024.1407304","DOIUrl":"https://doi.org/10.3389/fddev.2024.1407304","url":null,"abstract":"The core/shell 3D printing process using CPC and alginate is intended to create biodegradable scaffolds that have a similar stability to bone tissue and also offer sufficient and continuous antibiotic release. In this way, a patient-specific and patient-friendly process will be established, which should optimally support the human organism in its regeneration. To generate the best possible strength values, the printed scaffolds underwent various post-treatments and were then tested in a material test. The test methods included self-setting, storage in a drying cabinet with a water-saturated atmosphere at 37°C, followed by incubation in PBS, freeze-drying, and coating the samples with alginate. Additionally, a degradation test at pH 7.4 and pH 5 was carried out to test stability under in vitro conditions. It was shown that the untreated and freeze-dried samples failed at a maximum load of 30–700 N, while the remaining scaffolds could withstand a load of at least 2,000 N. At this failure load, most of the test series showed an average deformation of 43.95%. All samples, therefore, remained below the strength of cancellous bone. However, based on a 20% load after surgery, the coated scaffolds represented the best possible alternative, with a Young’s modulus of around 1.71 MPa. We were able to demonstrate that self-setting occurs in core-shell printed CPC/alginate scaffolds after only 1 day, and that mass production is possible. By coating with alginate, the compressive strength could be increased without the need for additional post-treatment. The mechanical strength was sufficient to be available as a scaffold for bone regeneration and additionally as a drug delivery device for future applications and experiments.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140966247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-06DOI: 10.3389/fddev.2024.1415104
Michelle A. Erickson, Morten S. Nielsen
{"title":"Editorial: Endo- and transcytotic pathways at the brain barriers","authors":"Michelle A. Erickson, Morten S. Nielsen","doi":"10.3389/fddev.2024.1415104","DOIUrl":"https://doi.org/10.3389/fddev.2024.1415104","url":null,"abstract":"","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141011102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-19DOI: 10.3389/fddev.2024.1337686
Madhuri Dandamudi, Peter Mcloughlin, G. Behl, Lee Coffey, Anuj Chauhan, David Kent, Sweta Rani, Laurence Fitzhenry
Age-related macular degeneration (AMD) is a multifactorial degenerative disease characterised by the gradual loss of central vision in individuals aged more than 50 years. There is currently no cure for this disease, but treatment can delay its progression. Consequently, there is an urgent need for the development of both new and cost-effective therapeutics. In this study, a novel combination of a corticosteroid and flavonoid was investigated on human retinal pigment epithelial cell lines to explore its potential pharmacological effect on AMD. Combination therapies, such as anti-VEGF (vascular endothelial growth factor) agents combined with photodynamic therapy and anti-VEGF agents in conjunction with corticosteroids, have been utilized previously and are known to be effective. However anti-VEGF injections are associated with serious side effects and are costly. Various disease conditions associated with AMD were stimulated on human retinal cells, which were then exposed to different concentrations of triamcinolone acetonide (TA) and quercetin (QCN) individually and in combination. This investigation aimed to assess their potential for the treatment of AMD. The combination of TA and QCN demonstrated a superior anti-inflammatory effect, as TA and QCN primarily act on different inflammatory signaling pathways. Furthermore, in terms of anti-VEGF activity, both drugs exert their effects through different mechanisms: QCN inhibits kinase pathways leading to the deactivation of VEGF receptors, whereas TA destabilises VEGF mRNA, resulting in increased suppression of VEGF-C with combination treatments. The anti-oxidant assay yielded similar outcomes, demonstrating a synergetic effect when treated with combination drugs. These findings collectively suggest TA and QCN as a promising combination therapy for targeting AMD with multiple pathological conditions.
{"title":"Investigation of novel combination therapy for age-related macular degeneration on ARPE-19 cells","authors":"Madhuri Dandamudi, Peter Mcloughlin, G. Behl, Lee Coffey, Anuj Chauhan, David Kent, Sweta Rani, Laurence Fitzhenry","doi":"10.3389/fddev.2024.1337686","DOIUrl":"https://doi.org/10.3389/fddev.2024.1337686","url":null,"abstract":"Age-related macular degeneration (AMD) is a multifactorial degenerative disease characterised by the gradual loss of central vision in individuals aged more than 50 years. There is currently no cure for this disease, but treatment can delay its progression. Consequently, there is an urgent need for the development of both new and cost-effective therapeutics. In this study, a novel combination of a corticosteroid and flavonoid was investigated on human retinal pigment epithelial cell lines to explore its potential pharmacological effect on AMD. Combination therapies, such as anti-VEGF (vascular endothelial growth factor) agents combined with photodynamic therapy and anti-VEGF agents in conjunction with corticosteroids, have been utilized previously and are known to be effective. However anti-VEGF injections are associated with serious side effects and are costly. Various disease conditions associated with AMD were stimulated on human retinal cells, which were then exposed to different concentrations of triamcinolone acetonide (TA) and quercetin (QCN) individually and in combination. This investigation aimed to assess their potential for the treatment of AMD. The combination of TA and QCN demonstrated a superior anti-inflammatory effect, as TA and QCN primarily act on different inflammatory signaling pathways. Furthermore, in terms of anti-VEGF activity, both drugs exert their effects through different mechanisms: QCN inhibits kinase pathways leading to the deactivation of VEGF receptors, whereas TA destabilises VEGF mRNA, resulting in increased suppression of VEGF-C with combination treatments. The anti-oxidant assay yielded similar outcomes, demonstrating a synergetic effect when treated with combination drugs. These findings collectively suggest TA and QCN as a promising combination therapy for targeting AMD with multiple pathological conditions.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140685201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-12DOI: 10.3389/fddev.2024.1360302
A. Haqqani, Kasandra Bélanger, Danica B. Stanimirovic
The delivery of therapeutics into the brain is highly limited by the blood-brain barrier (BBB). Although this is essential to protect the brain from potentially harmful material found in the blood, it poses a great challenge for the treatment of diseases affecting the central nervous system (CNS). Substances from the periphery that are required for the function of the brain must rely on active mechanisms of entry. One such physiological pathway is called receptor-mediated transcytosis (RMT). In this process, ligands bind to specific receptors expressed at the luminal membrane of endothelial cells composing the BBB leading to the internalization of the receptor-ligand complex into intracellular vesicles, their trafficking through various intracellular compartments and finally their fusion with the abluminal membrane to release the cargo into the brain. Targeting such RMT receptors for BBB crossing represents an emerging and clinically validated strategy to increase the brain permeability of biologicals. However, the choice of an appropriate receptor is critical to achieve the best selectivity and efficacy of the delivery method. Whereas the majority of work has been focused on transferrin (Tf) receptor (TfR), the search for novel receptors expressed in brain endothelial cells (BECs) that can deliver protein or viral vector cargos across the BBB has yielded several novel targets with diverse molecular/structural properties and biological functions, and mechanisms of transcytosis. In this review, we summarize well-studied RMT pathways, and explore mechanisms engaged in BBB transport by various RMT receptors. We then discuss key criteria that would be desired for an optimal RMT target, based on lessons-learned from studies on TfR and accumulating experimental evidence on emerging RMT receptors and their ligands.
{"title":"Receptor-mediated transcytosis for brain delivery of therapeutics: receptor classes and criteria","authors":"A. Haqqani, Kasandra Bélanger, Danica B. Stanimirovic","doi":"10.3389/fddev.2024.1360302","DOIUrl":"https://doi.org/10.3389/fddev.2024.1360302","url":null,"abstract":"The delivery of therapeutics into the brain is highly limited by the blood-brain barrier (BBB). Although this is essential to protect the brain from potentially harmful material found in the blood, it poses a great challenge for the treatment of diseases affecting the central nervous system (CNS). Substances from the periphery that are required for the function of the brain must rely on active mechanisms of entry. One such physiological pathway is called receptor-mediated transcytosis (RMT). In this process, ligands bind to specific receptors expressed at the luminal membrane of endothelial cells composing the BBB leading to the internalization of the receptor-ligand complex into intracellular vesicles, their trafficking through various intracellular compartments and finally their fusion with the abluminal membrane to release the cargo into the brain. Targeting such RMT receptors for BBB crossing represents an emerging and clinically validated strategy to increase the brain permeability of biologicals. However, the choice of an appropriate receptor is critical to achieve the best selectivity and efficacy of the delivery method. Whereas the majority of work has been focused on transferrin (Tf) receptor (TfR), the search for novel receptors expressed in brain endothelial cells (BECs) that can deliver protein or viral vector cargos across the BBB has yielded several novel targets with diverse molecular/structural properties and biological functions, and mechanisms of transcytosis. In this review, we summarize well-studied RMT pathways, and explore mechanisms engaged in BBB transport by various RMT receptors. We then discuss key criteria that would be desired for an optimal RMT target, based on lessons-learned from studies on TfR and accumulating experimental evidence on emerging RMT receptors and their ligands.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140250468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-05DOI: 10.3389/fddev.2024.1359700
Hyun-Bum Kim, Quentin Brosseau, Julia Radzio, Jinhui Wang, Hiromi Muramatsu, Da Kuang, M. S. Grady, H. Isaac Chen, John A. Wolf, A. V. Ulyanova, Tamas Bartfai, Junhyong Kim, N. Pardi, J. Sul, Paulo Arratia, James Eberwine, Kuo-Ching Mei, Po-Yu Chou, Grady MS Kuang D, HI Chen
Multi-RNA co-transfection is starting to be employed to stimulate immune responses to SARS-CoV-2 viral infection. While there are good reasons to utilize such an approach, there is little background on whether there are synergistic RNA-dependent cellular effects. To address this issue, we use transcriptome-induced phenotype remodeling (TIPeR) via phototransfection to assess whether mRNAs encoding the Spike and Nucleocapsid proteins of SARS-CoV-2 virus into single human astrocytes (an endogenous human cell host for the virus) and mouse 3T3 cells (often used in high-throughput therapeutic screens) synergistically impact host cell biologies. An RNA concentration-dependent expression was observed where an increase of RNA by less than 2-fold results in reduced expression of each individual RNAs. Further, a dominant inhibitory effect of Nucleocapsid RNA upon Spike RNA translation was detected that is distinct from codon-mediated epistasis. Knowledge of the cellular consequences of multi-RNA transfection will aid in selecting RNA concentrations that will maximize antigen presentation on host cell surface with the goal of eliciting a robust immune response. Further, application of this single cell stoichiometrically tunable RNA functional genomics approach to the study of SARS-CoV-2 biology promises to provide details of the cellular sequalae that arise upon infection in anticipation of providing novel targets for inhibition of viral replication and propagation for therapeutic intervention.
{"title":"Single cell phototransfection of mRNAs encoding SARS-CoV2 spike and nucleocapsid into human astrocytes results in RNA dependent translation interference","authors":"Hyun-Bum Kim, Quentin Brosseau, Julia Radzio, Jinhui Wang, Hiromi Muramatsu, Da Kuang, M. S. Grady, H. Isaac Chen, John A. Wolf, A. V. Ulyanova, Tamas Bartfai, Junhyong Kim, N. Pardi, J. Sul, Paulo Arratia, James Eberwine, Kuo-Ching Mei, Po-Yu Chou, Grady MS Kuang D, HI Chen","doi":"10.3389/fddev.2024.1359700","DOIUrl":"https://doi.org/10.3389/fddev.2024.1359700","url":null,"abstract":"Multi-RNA co-transfection is starting to be employed to stimulate immune responses to SARS-CoV-2 viral infection. While there are good reasons to utilize such an approach, there is little background on whether there are synergistic RNA-dependent cellular effects. To address this issue, we use transcriptome-induced phenotype remodeling (TIPeR) via phototransfection to assess whether mRNAs encoding the Spike and Nucleocapsid proteins of SARS-CoV-2 virus into single human astrocytes (an endogenous human cell host for the virus) and mouse 3T3 cells (often used in high-throughput therapeutic screens) synergistically impact host cell biologies. An RNA concentration-dependent expression was observed where an increase of RNA by less than 2-fold results in reduced expression of each individual RNAs. Further, a dominant inhibitory effect of Nucleocapsid RNA upon Spike RNA translation was detected that is distinct from codon-mediated epistasis. Knowledge of the cellular consequences of multi-RNA transfection will aid in selecting RNA concentrations that will maximize antigen presentation on host cell surface with the goal of eliciting a robust immune response. Further, application of this single cell stoichiometrically tunable RNA functional genomics approach to the study of SARS-CoV-2 biology promises to provide details of the cellular sequalae that arise upon infection in anticipation of providing novel targets for inhibition of viral replication and propagation for therapeutic intervention.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140264241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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