Non-lamellar liquid crystal (NLLC) structures have gained increasing attention for the controlled release of entrapped drugs. In the present study, an in situ NLLC structure-forming depot formulation through contact with water was developed using a ternary mixture system of soya phosphatidyl choline (SPC), 1, 2-dioleoyl- sn -glycero-3-phosphoglycerol sodium salt (DOPG), and sorbitan trioleate (Span 85), and the long-term release of an entrapped model drug, leuprolide acetate (LA), was investigated using evaluation of in vitro release and in vivo blood concentration–time profiles. Polarized images and small angle X-ray scattering analysis were used to confirm the presence of NLLC structures by contacting the prepared formulation with water. In addition, LA release and blood concentration–time profiles were investigated using in vitro and in vivo experiments, respectively. In situ NLLC constructed formulations by contacting water were achieved using a ternary mixture of SPC, DOPG, and Span 85. In particular, negative curvature was increased with an increase in the amount of Span 85 in the formulation, and an Fd3m structure was obtained with a sustained release of LA. A maintained blood concentration of LA over 21 days was confirmed by subcutaneous ( s.c. ) administration of the formulation. No retained administered formulation at the injection site was confirmed 28 days after administration without any signs of irritation, inflammation, or other apparent toxicity confirmed by visual observation. This result may be helpful for the development of a lipid-based formulation of peptides and proteins with sustained drug release.
非层状液晶(NLLC)结构在控制包裹药物释放方面受到越来越多的关注。在本研究中，利用大豆磷脂酰胆碱(SPC)、1,2 -二油基- sn -甘油-3-磷酸甘油钠盐(DOPG)和三油酸山梨醇酯(Span 85)的三元混合物体系，通过与水接触，开发了一种原位NLLC结构形成库制剂，并通过体外释放和体内血药浓度-时间谱研究了包埋模型药物醋酸leuprolide (LA)的长期释放。通过极化图像和小角x射线散射分析，通过与水接触，证实了NLLC结构的存在。此外，分别通过体外和体内实验研究了LA的释放和血药浓度时间分布。使用SPC、DOPG和Span 85的三元混合物，通过接触水获得原位NLLC构建配方。特别是，随着配方中Span 85用量的增加，负曲率增加，LA缓释得到Fd3m结构。皮下注射(s.c。)证实血药浓度维持21天以上。制剂的管理。给药28天后，注射部位未发现残留给药制剂，没有任何刺激、炎症或其他明显毒性的迹象，目测证实。这一结果可能有助于开发具有持续药物释放的肽类和蛋白质的脂基制剂。
{"title":"Development of a depot formulation with an in situ non-lamellar liquid crystal-forming system with phospholipids","authors":"Hiroaki Todo, Rina Niki, Akie Okada, Ibuki Narita, Kazuya Inamura, Ayu Ito, Shoko Itakura, Ichiro Hijikuro, Kenji Sugibayashi","doi":"10.3389/fddev.2023.1270584","DOIUrl":"https://doi.org/10.3389/fddev.2023.1270584","url":null,"abstract":"Non-lamellar liquid crystal (NLLC) structures have gained increasing attention for the controlled release of entrapped drugs. In the present study, an in situ NLLC structure-forming depot formulation through contact with water was developed using a ternary mixture system of soya phosphatidyl choline (SPC), 1, 2-dioleoyl- sn -glycero-3-phosphoglycerol sodium salt (DOPG), and sorbitan trioleate (Span 85), and the long-term release of an entrapped model drug, leuprolide acetate (LA), was investigated using evaluation of in vitro release and in vivo blood concentration–time profiles. Polarized images and small angle X-ray scattering analysis were used to confirm the presence of NLLC structures by contacting the prepared formulation with water. In addition, LA release and blood concentration–time profiles were investigated using in vitro and in vivo experiments, respectively. In situ NLLC constructed formulations by contacting water were achieved using a ternary mixture of SPC, DOPG, and Span 85. In particular, negative curvature was increased with an increase in the amount of Span 85 in the formulation, and an Fd3m structure was obtained with a sustained release of LA. A maintained blood concentration of LA over 21 days was confirmed by subcutaneous ( s.c. ) administration of the formulation. No retained administered formulation at the injection site was confirmed 28 days after administration without any signs of irritation, inflammation, or other apparent toxicity confirmed by visual observation. This result may be helpful for the development of a lipid-based formulation of peptides and proteins with sustained drug release.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135731760","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 : 2023-08-24DOI: 10.3389/fddev.2023.1221628
D. Panou, S. Pedersen, M. Kristensen, H. M. Nielsen
Absorption of therapeutic peptides like glucagon-like peptide or insulin for diabetes therapy upon oral administration is highly restricted by the tight junction (TJ) proteins interconnecting the cells comprising the intestinal epithelium. An approach to improve transepithelial permeation of such biopharmaceuticals via the paracellular pathway is to use functional excipients, which transiently modulate the TJs. Here, we investigated the membrane-interacting peptide, penetramax, and the divalent cation chelator, ethylene glycol tetraacetic acid (EGTA) at different concentrations, to reveal and compare their cellular modes of action when increasing the transepithelial permeation of drug macromolecules. The epithelial integrity was studied in real time along with dextran permeation across differentiated epithelial Caco-2 cell monolayers. TJ protein expression and cytoskeleton organization were investigated during and after exposure to penetramax or EGTA. Based on orthogonal methods, we show that penetramax acts by a mechanism that immediately and transiently widens the paracellular space, resulting in size selective permeant passage and with subsequent reconstitution of the epithelium. At the same time, the expression and organization of different TJ proteins are modulated reversibly. In contrast, the effect of EGTA on modulating the paracellular space is slower and TJ protein unspecific, and without clear permeant size selectivity. Overall, these data provide in-depth insights for understanding intestinal barrier dynamics of importance when evaluating new or existing excipients for oral delivery of biopharmaceuticals, such as peptide therapeutics.
{"title":"Epithelium dynamics differ in time and space when exposed to the permeation enhancers penetramax and EGTA. A head-to-head mechanistic comparison","authors":"D. Panou, S. Pedersen, M. Kristensen, H. M. Nielsen","doi":"10.3389/fddev.2023.1221628","DOIUrl":"https://doi.org/10.3389/fddev.2023.1221628","url":null,"abstract":"Absorption of therapeutic peptides like glucagon-like peptide or insulin for diabetes therapy upon oral administration is highly restricted by the tight junction (TJ) proteins interconnecting the cells comprising the intestinal epithelium. An approach to improve transepithelial permeation of such biopharmaceuticals via the paracellular pathway is to use functional excipients, which transiently modulate the TJs. Here, we investigated the membrane-interacting peptide, penetramax, and the divalent cation chelator, ethylene glycol tetraacetic acid (EGTA) at different concentrations, to reveal and compare their cellular modes of action when increasing the transepithelial permeation of drug macromolecules. The epithelial integrity was studied in real time along with dextran permeation across differentiated epithelial Caco-2 cell monolayers. TJ protein expression and cytoskeleton organization were investigated during and after exposure to penetramax or EGTA. Based on orthogonal methods, we show that penetramax acts by a mechanism that immediately and transiently widens the paracellular space, resulting in size selective permeant passage and with subsequent reconstitution of the epithelium. At the same time, the expression and organization of different TJ proteins are modulated reversibly. In contrast, the effect of EGTA on modulating the paracellular space is slower and TJ protein unspecific, and without clear permeant size selectivity. Overall, these data provide in-depth insights for understanding intestinal barrier dynamics of importance when evaluating new or existing excipients for oral delivery of biopharmaceuticals, such as peptide therapeutics.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41878996","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 : 2023-08-24DOI: 10.3389/fddev.2023.1232012
P. Mohite, Sudarshan Singh, A. Pawar, Adinath Sangale, B. Prajapati
Poorly water-soluble drugs demonstrate significant challenge in pharmaceutical development, which is linked to their limited oral bioavailability and therapeutic efficacy. To overcome these limitations, lipid-based formulations have emerged as a promising approach to enhance the delivery of such drugs. Moreover, encapsulation within capsules to provide a convenient dosage form for oral administration. The encapsulation techniques are optimized to ensure uniform drug content and efficient encapsulation efficiency. Several investigations demonstrated that the lipid-based formulations in capsules significantly improved the solubility and dissolution rate of poorly water-soluble drugs compared to non-lipid formulations. Additionally, the encapsulation of lipid-based formulations protected the drug against degradation and improved its stability. Overall, incorporating lipid-based formulations in capsules represents a promising strategy for enhancing the delivery of poorly water-soluble drugs with improvement in solubility, dissolution, stability, and bioavailability, overcoming the challenges associated with these challenging drug molecules. The review focussed a brief on utilization of lipids in capsule form to improve therapeutic efficacy of poorly soluble, dissolution and bioavailability of drugs.
{"title":"Lipid-based oral formulation in capsules to improve the delivery of poorly water-soluble drugs","authors":"P. Mohite, Sudarshan Singh, A. Pawar, Adinath Sangale, B. Prajapati","doi":"10.3389/fddev.2023.1232012","DOIUrl":"https://doi.org/10.3389/fddev.2023.1232012","url":null,"abstract":"Poorly water-soluble drugs demonstrate significant challenge in pharmaceutical development, which is linked to their limited oral bioavailability and therapeutic efficacy. To overcome these limitations, lipid-based formulations have emerged as a promising approach to enhance the delivery of such drugs. Moreover, encapsulation within capsules to provide a convenient dosage form for oral administration. The encapsulation techniques are optimized to ensure uniform drug content and efficient encapsulation efficiency. Several investigations demonstrated that the lipid-based formulations in capsules significantly improved the solubility and dissolution rate of poorly water-soluble drugs compared to non-lipid formulations. Additionally, the encapsulation of lipid-based formulations protected the drug against degradation and improved its stability. Overall, incorporating lipid-based formulations in capsules represents a promising strategy for enhancing the delivery of poorly water-soluble drugs with improvement in solubility, dissolution, stability, and bioavailability, overcoming the challenges associated with these challenging drug molecules. The review focussed a brief on utilization of lipids in capsule form to improve therapeutic efficacy of poorly soluble, dissolution and bioavailability of drugs.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44556155","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 : 2023-08-11DOI: 10.3389/fddev.2023.1247162
Xu Zhang, Maohua Wang, Zhixian Liu, Ying Wang, Li Chen, Jiaqi Guo, Wentao Zhang, Yao Zhang, Chen Yu, T. Bie, Youjun Yu, Bing Guan
Neurodegenerative diseases (NDs) have become a serious global health problem as the population ages. Traditionally, treatment strategies for NDs have included oral and intravenous administration; however, the blood–brain barrier (BBB) can prevent drugs from reaching the brain, rendering the treatment incomplete and the effect unsatisfactory. Additionally, the prolonged or excessive use of drugs that can cross the BBB can damage liver and kidney function. Recent studies have shown that nose-to-brain drug delivery can noninvasively bypass the BBB, allowing drugs to enter the brain through the olfactory or trigeminal nerve pathways; additionally, nanoparticle carriers can enhance drug delivery. This review introduces drug carrier nanoparticles for nose-to-brain delivery systems, compares the advantages and disadvantages of different nanoparticles, and discusses the factors influencing nose-to-brain nanomedicine delivery and enhancement strategies. We also summarize nose-to-brain delivery and nanomedicines for treating NDs, the current challenges of this approach, and the future promise of nanomedicine-based ND treatment.
{"title":"Transnasal-brain delivery of nanomedicines for neurodegenerative diseases","authors":"Xu Zhang, Maohua Wang, Zhixian Liu, Ying Wang, Li Chen, Jiaqi Guo, Wentao Zhang, Yao Zhang, Chen Yu, T. Bie, Youjun Yu, Bing Guan","doi":"10.3389/fddev.2023.1247162","DOIUrl":"https://doi.org/10.3389/fddev.2023.1247162","url":null,"abstract":"Neurodegenerative diseases (NDs) have become a serious global health problem as the population ages. Traditionally, treatment strategies for NDs have included oral and intravenous administration; however, the blood–brain barrier (BBB) can prevent drugs from reaching the brain, rendering the treatment incomplete and the effect unsatisfactory. Additionally, the prolonged or excessive use of drugs that can cross the BBB can damage liver and kidney function. Recent studies have shown that nose-to-brain drug delivery can noninvasively bypass the BBB, allowing drugs to enter the brain through the olfactory or trigeminal nerve pathways; additionally, nanoparticle carriers can enhance drug delivery. This review introduces drug carrier nanoparticles for nose-to-brain delivery systems, compares the advantages and disadvantages of different nanoparticles, and discusses the factors influencing nose-to-brain nanomedicine delivery and enhancement strategies. We also summarize nose-to-brain delivery and nanomedicines for treating NDs, the current challenges of this approach, and the future promise of nanomedicine-based ND treatment.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42743187","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 : 2023-07-24DOI: 10.3389/fddev.2023.1227776
Wiam El Kheir, Anaïs Dumais, Maude Beaudoin, B. Marcos, N. Virgilio, B. Paquette, N. Faucheux, Marc-Antoine Lauzon
Introduction: Extensive investigation has been undertaken regarding drug delivery systems for the management of glioblastoma multiforme (GBM). The infiltrative behavior of GBM cells within the brain tissue is primarily attributed to their heterogeneity, the movement of interstitial fluid (IFF), and the presence of chemokines. These factors contribute to the limited effectiveness of current conventional treatments. To address the dissemination of GBM cells, a proposed therapeutic approach involves utilizing a controlled release gradient of CXC-chemokine-ligand-12 (CXCL12). However, the impact of IFF on GBM cell migration within the brain underscores its critical importance as a significant parameter, which, surprisingly, has not been extensively studied in the context of localized drug delivery targeting the brain.Methods: Hydrogels are known for their inherent capacity to entrap various agents and exert precise control over their subsequent release. In the present investigation, we aimed to elucidate the release kinetics of CXCL12, whether in its free form or encapsulated within nanoparticles, from alginate-based hydrogels, both under static and dynamic conditions. To investigate the impact of convective forces mimicking the interstitial fluid flow (IFF) within the peritumoral environment of the brain, a three-dimensional in vitro model was developed. This model enabled the evaluation of CXCL12 release as a function of time and position, specifically accounting for the contribution of simulated IFF on the release behavior.Results: We first demonstrated that the release kinetic profiles under static culture conditions were independent of the initial mass loading and the predominant phenomenon occurring was diffusion. Subsequently, we investigated the release of CXCL12, which was loaded into Alginate/Chitosan-Nanoparticles (Alg/Chit-NPs) and embedded within an alginate hydrogel matrix. Mathematical modeling results also indicated the presence of electrostatic interactions between alginate and CXCL12. The Alg/Chit-NPs effectively slowed down the initial burst release, leading to a reduction in the diffusion coefficient of CXCL12. To further study the release behavior, we developed a perfusion bioreactor with a unique culture chamber designed to recapitulate the peritumoral environment and varied the fluid flow rates at 0.5 µL/min, 3 µL/min, 6.5 µL/min, and 10 µL/min. As the flow rate increased, the cumulative amount of released CXCL12 also increased for all three initial mass loadings. Beyond 3 µL/min, convection became the dominant mechanism governing CXCL12 release, whereas below this threshold, diffusion played a more prominent role.Conclusion: The indirect perfusion flow had a crucial impact on CXCL12 release and distribution inside the hydrogel in and against its direction. This system highlights the importance of considering the IFF in brain targeting delivery system and will be used in the future to study GBM cell behaviors in response to CXC
{"title":"Impact of simulated brain interstitial fluid flow on the chemokine CXCL12 release from an alginate-based hydrogel in a new 3D in vitro model","authors":"Wiam El Kheir, Anaïs Dumais, Maude Beaudoin, B. Marcos, N. Virgilio, B. Paquette, N. Faucheux, Marc-Antoine Lauzon","doi":"10.3389/fddev.2023.1227776","DOIUrl":"https://doi.org/10.3389/fddev.2023.1227776","url":null,"abstract":"Introduction: Extensive investigation has been undertaken regarding drug delivery systems for the management of glioblastoma multiforme (GBM). The infiltrative behavior of GBM cells within the brain tissue is primarily attributed to their heterogeneity, the movement of interstitial fluid (IFF), and the presence of chemokines. These factors contribute to the limited effectiveness of current conventional treatments. To address the dissemination of GBM cells, a proposed therapeutic approach involves utilizing a controlled release gradient of CXC-chemokine-ligand-12 (CXCL12). However, the impact of IFF on GBM cell migration within the brain underscores its critical importance as a significant parameter, which, surprisingly, has not been extensively studied in the context of localized drug delivery targeting the brain.Methods: Hydrogels are known for their inherent capacity to entrap various agents and exert precise control over their subsequent release. In the present investigation, we aimed to elucidate the release kinetics of CXCL12, whether in its free form or encapsulated within nanoparticles, from alginate-based hydrogels, both under static and dynamic conditions. To investigate the impact of convective forces mimicking the interstitial fluid flow (IFF) within the peritumoral environment of the brain, a three-dimensional in vitro model was developed. This model enabled the evaluation of CXCL12 release as a function of time and position, specifically accounting for the contribution of simulated IFF on the release behavior.Results: We first demonstrated that the release kinetic profiles under static culture conditions were independent of the initial mass loading and the predominant phenomenon occurring was diffusion. Subsequently, we investigated the release of CXCL12, which was loaded into Alginate/Chitosan-Nanoparticles (Alg/Chit-NPs) and embedded within an alginate hydrogel matrix. Mathematical modeling results also indicated the presence of electrostatic interactions between alginate and CXCL12. The Alg/Chit-NPs effectively slowed down the initial burst release, leading to a reduction in the diffusion coefficient of CXCL12. To further study the release behavior, we developed a perfusion bioreactor with a unique culture chamber designed to recapitulate the peritumoral environment and varied the fluid flow rates at 0.5 µL/min, 3 µL/min, 6.5 µL/min, and 10 µL/min. As the flow rate increased, the cumulative amount of released CXCL12 also increased for all three initial mass loadings. Beyond 3 µL/min, convection became the dominant mechanism governing CXCL12 release, whereas below this threshold, diffusion played a more prominent role.Conclusion: The indirect perfusion flow had a crucial impact on CXCL12 release and distribution inside the hydrogel in and against its direction. This system highlights the importance of considering the IFF in brain targeting delivery system and will be used in the future to study GBM cell behaviors in response to CXC","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46252690","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}
Osteoarthritis (OA) is a chronic inflammatory disease that causes synovial hyperplasia, cartilage destruction, and the formation of bone spurs. Macrophages play an indispensable role in the pathogenesis of OA by producing proinflammatory cytokines. To achieve the effect of arthritis, hormones can effectively inhibit the progression of inflammation by inhibiting the secretion of inflammatory cytokines by macrophages in traditional therapy. However, the drug is quickly cleared from the joint space, and the high injection site infection rate and low local drug concentration make the clinical efficacy of corticosteroids greatly reduced. We described the design and preparation of Polyethylene Glycol-grafted Poly Alpha-lipoic Acid-dexamethasone Nanoparticles (NPDXM/PPLA), elucidated the mechanism of action of NPDXM/PPLA in the treatment of OA in mice, and provided an experimental basis for investigating the treatment of OA with polymer nanoparticles loaded with dexamethasone. Flow cytometry and confocal laser scanning microscopy were used to confirm that NPDXM/PPLA was well absorbed and released by macrophages, and it was discovered that NPDXM/PPLA could efficiently reduce the proliferation of activated macrophages (RAW 264.7 cells). Enzyme-linked immunosorbent assay revealed that NPDXM/PPLA could efficiently reduce the expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α. The knee bone structure of OA mice was investigated by MicroCT, and it was discovered that intraarticular injection of NPDXM/PPLA effectively alleviated the bone damage of the articular cartilage. Therefore, NPDXM/PPLA is a potential therapeutic nanomedicine for the treatment of OA.
{"title":"Polyethylene Glycol-grafted poly alpha-lipoic acid-dexamethasone nanoparticles for osteoarthritis","authors":"Yuanqiang Cheng, Zheng Jing, Yan-wei Xu, Lihui Sun, Dongbo Li, Jianguo Liu, Dongsong Li","doi":"10.3389/fddev.2023.1168287","DOIUrl":"https://doi.org/10.3389/fddev.2023.1168287","url":null,"abstract":"Osteoarthritis (OA) is a chronic inflammatory disease that causes synovial hyperplasia, cartilage destruction, and the formation of bone spurs. Macrophages play an indispensable role in the pathogenesis of OA by producing proinflammatory cytokines. To achieve the effect of arthritis, hormones can effectively inhibit the progression of inflammation by inhibiting the secretion of inflammatory cytokines by macrophages in traditional therapy. However, the drug is quickly cleared from the joint space, and the high injection site infection rate and low local drug concentration make the clinical efficacy of corticosteroids greatly reduced. We described the design and preparation of Polyethylene Glycol-grafted Poly Alpha-lipoic Acid-dexamethasone Nanoparticles (NPDXM/PPLA), elucidated the mechanism of action of NPDXM/PPLA in the treatment of OA in mice, and provided an experimental basis for investigating the treatment of OA with polymer nanoparticles loaded with dexamethasone. Flow cytometry and confocal laser scanning microscopy were used to confirm that NPDXM/PPLA was well absorbed and released by macrophages, and it was discovered that NPDXM/PPLA could efficiently reduce the proliferation of activated macrophages (RAW 264.7 cells). Enzyme-linked immunosorbent assay revealed that NPDXM/PPLA could efficiently reduce the expression of proinflammatory cytokines IL-1β, IL-6, and TNF-α. The knee bone structure of OA mice was investigated by MicroCT, and it was discovered that intraarticular injection of NPDXM/PPLA effectively alleviated the bone damage of the articular cartilage. Therefore, NPDXM/PPLA is a potential therapeutic nanomedicine for the treatment of OA.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47476855","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 : 2023-07-19DOI: 10.3389/fddev.2023.1253709
P. Kwok, M. Momin, Basanth Babu Eedara, S. F. Chow
{"title":"Editorial: Strategies to overcome the barriers to effective inhaled treatments","authors":"P. Kwok, M. Momin, Basanth Babu Eedara, S. F. Chow","doi":"10.3389/fddev.2023.1253709","DOIUrl":"https://doi.org/10.3389/fddev.2023.1253709","url":null,"abstract":"","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45235751","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 : 2023-07-13DOI: 10.3389/fddev.2023.1223177
Mona Purcell, Sahab Babaee, Michael Galluppi, J. Cline, Guangli Hu, I. Petrescu, Jennifer Hughes, M. Allen, Eric Messina, Steven C. Persak, Y. Krishnamachari, Ashley Lay-Fortenbery, Corin O. Miller
Many commercially available biologics, previously delivered only intravenously, are being re-formulated for subcutaneous delivery to improve patient access and compliance. However, due to inherent solubility limitations, large volume injections (more than 2 mL) are typically required. Different strategies are being explored to improve the tolerability of such injections, including the co-formulation with hyaluronidase and/or implementing different needle designs. While there have been separate reports of measuring injection forces and using imaging to track injection delivery and tissue response, there is no current set of methods to simultaneously characterize the injection delivery (bleb) and measure injection pressures. In this study we describe the development of Computed Tomography imaging methods in minipigs to characterize the morphology of the bleb following injection, along with inline pressure measurements to assess subcutaneous pressure during injection using two different injection volumes, 4.5 mL and 9 mL. We show that these parameters change with injection volume, and that inclusion of hyaluronidase in the injection increases bleb dispersion and reduces skin distention while also lowering the injection pressure. This method will likely be a valuable tool for assessing and comparing different injection delivery methods and formulations.
{"title":"Characterization of large volume subcutaneous injections using computed tomography imaging and simultaneous pressure measurements","authors":"Mona Purcell, Sahab Babaee, Michael Galluppi, J. Cline, Guangli Hu, I. Petrescu, Jennifer Hughes, M. Allen, Eric Messina, Steven C. Persak, Y. Krishnamachari, Ashley Lay-Fortenbery, Corin O. Miller","doi":"10.3389/fddev.2023.1223177","DOIUrl":"https://doi.org/10.3389/fddev.2023.1223177","url":null,"abstract":"Many commercially available biologics, previously delivered only intravenously, are being re-formulated for subcutaneous delivery to improve patient access and compliance. However, due to inherent solubility limitations, large volume injections (more than 2 mL) are typically required. Different strategies are being explored to improve the tolerability of such injections, including the co-formulation with hyaluronidase and/or implementing different needle designs. While there have been separate reports of measuring injection forces and using imaging to track injection delivery and tissue response, there is no current set of methods to simultaneously characterize the injection delivery (bleb) and measure injection pressures. In this study we describe the development of Computed Tomography imaging methods in minipigs to characterize the morphology of the bleb following injection, along with inline pressure measurements to assess subcutaneous pressure during injection using two different injection volumes, 4.5 mL and 9 mL. We show that these parameters change with injection volume, and that inclusion of hyaluronidase in the injection increases bleb dispersion and reduces skin distention while also lowering the injection pressure. This method will likely be a valuable tool for assessing and comparing different injection delivery methods and formulations.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"69813363","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 : 2023-07-12DOI: 10.3389/fddev.2023.1148795
Sanna Koponen, Emmi Kokki, Toni Tamminen, S. Ylä-Herttuala
Introduction: The eye is an excellent target for gene therapy because of its anatomical features. Gene therapy to treat ocular disorders relies on efficient gene delivery and transgene expression in the target cells. The aim of this study was to compare the biodistribution and safety of two different AAV serotypes after intravitreal (IVT) and subretinal injections.Methods: AAV2 (1 × 1012 vg/mL) and AAV9 (5 × 1012 vg/mL) vectors expressing an enhanced green fluorescent protein (EGFP) and an AAV9-empty (6 × 1011 vg/mL) vector were injected intravitreally or subretinally into both eyes of adult C57Bl/OlaHsd mice. The biodistribution of the viral vectors in the eye and off-target tissues was studied using qPCR. GFP expression was studied from cryosections, and GFP transduction efficacy was verified using immunohistostaining for GFP. In addition, electroretinography (ERG) was used to assess the effect of vectors on retinal function.Results: In addition to the eyes, viral vector copies were found in distant off-target tissues such as the liver, especially after AAV9-EGFP IVT and subretinal injections. AAV9-EGFP injections showed more GFP expression throughout the retina compared to AAV2-EGFP. AAV2-EGFP IVT showed transgene expression mainly in the ganglion cell layer, whereas subretinal injection showed GFP expression in the retinal pigment epithelium. In addition, GFP was expressed at a moderate level in the liver after both injection routes of AAV9 and in parts of the brain after all injection groups except AAV9-empty. Lowered a- and b-amplitude values were seen in ERG in both scotopic and photopic experiments after AAV9-EGFP subretinal injection compared to all other groups.Discussion: This study shows that intraocular injection of AAV2 and AAV9 transduces retinal cells. Although the more efficient transduction of the retina, negative effect on the retinal function, and off-target transgene expression of AAV9 makes AAV2 a more suitable gene delivery vector to treat ocular disorders.
{"title":"AAV2 and AAV9 tropism and transgene expression in the mouse eye and major tissues after intravitreal and subretinal delivery","authors":"Sanna Koponen, Emmi Kokki, Toni Tamminen, S. Ylä-Herttuala","doi":"10.3389/fddev.2023.1148795","DOIUrl":"https://doi.org/10.3389/fddev.2023.1148795","url":null,"abstract":"Introduction: The eye is an excellent target for gene therapy because of its anatomical features. Gene therapy to treat ocular disorders relies on efficient gene delivery and transgene expression in the target cells. The aim of this study was to compare the biodistribution and safety of two different AAV serotypes after intravitreal (IVT) and subretinal injections.Methods: AAV2 (1 × 1012 vg/mL) and AAV9 (5 × 1012 vg/mL) vectors expressing an enhanced green fluorescent protein (EGFP) and an AAV9-empty (6 × 1011 vg/mL) vector were injected intravitreally or subretinally into both eyes of adult C57Bl/OlaHsd mice. The biodistribution of the viral vectors in the eye and off-target tissues was studied using qPCR. GFP expression was studied from cryosections, and GFP transduction efficacy was verified using immunohistostaining for GFP. In addition, electroretinography (ERG) was used to assess the effect of vectors on retinal function.Results: In addition to the eyes, viral vector copies were found in distant off-target tissues such as the liver, especially after AAV9-EGFP IVT and subretinal injections. AAV9-EGFP injections showed more GFP expression throughout the retina compared to AAV2-EGFP. AAV2-EGFP IVT showed transgene expression mainly in the ganglion cell layer, whereas subretinal injection showed GFP expression in the retinal pigment epithelium. In addition, GFP was expressed at a moderate level in the liver after both injection routes of AAV9 and in parts of the brain after all injection groups except AAV9-empty. Lowered a- and b-amplitude values were seen in ERG in both scotopic and photopic experiments after AAV9-EGFP subretinal injection compared to all other groups.Discussion: This study shows that intraocular injection of AAV2 and AAV9 transduces retinal cells. Although the more efficient transduction of the retina, negative effect on the retinal function, and off-target transgene expression of AAV9 makes AAV2 a more suitable gene delivery vector to treat ocular disorders.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45602483","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}
Pabinafusp alfa, which is an anti-mucopolysaccharidosis II drug, consists of iduronate-2-sulfatase (IDS) genetically fused with an anti-transferrin receptor (TfR) antibody. While IDS is known to enter cells via mannose-6-phosphate receptor (M6PR)-mediated endocytosis, the anti-TfR antibody moiety of pabinafusp alfa is supposed to trigger the TfR-mediated transcytosis involved in its blood-brain barrier (BBB) penetration to deliver IDS into the brain, which thus makes it effective for treatment of brain symptoms of the disease. However, since these uptake processes remain unexamined in vitro, this study aims at elucidating how human brain cells manipulate these receptors to facilitate pabinafusp alfa uptake. The results of pabinafusp alfa uptake assays showed that the TfR played an primary role in its uptake by brain microvascular endothelial cells. The TfR contribution was also found in neuronal cells at levels comparable to M6PR. Interestingly, the predominant roles of TfR over M6PR in pabinafusp alfa uptake were also observed in astrocytes and pericytes. To summarize, our results support the TfR-targeting strategy of pabinafusp alfa for facilitating its BBB penetration while simultaneously identifying previously unnoticed TfR roles in its uptake into human neuronal and non-neuronal brain cells. These findings are certain to provide important insights into the mechanisms behind clinical actions of pabinafusp alfa.
{"title":"Transferrin receptor-targeting property of pabinafusp alfa facilitates its uptake by various types of human brain-derived cells in vitro","authors":"Tomoki Fukatsu, Hanae Morio, Tomomi Furihata, Hiroyuki Sonoda","doi":"10.3389/fddev.2023.1082672","DOIUrl":"https://doi.org/10.3389/fddev.2023.1082672","url":null,"abstract":"Pabinafusp alfa, which is an anti-mucopolysaccharidosis II drug, consists of iduronate-2-sulfatase (IDS) genetically fused with an anti-transferrin receptor (TfR) antibody. While IDS is known to enter cells via mannose-6-phosphate receptor (M6PR)-mediated endocytosis, the anti-TfR antibody moiety of pabinafusp alfa is supposed to trigger the TfR-mediated transcytosis involved in its blood-brain barrier (BBB) penetration to deliver IDS into the brain, which thus makes it effective for treatment of brain symptoms of the disease. However, since these uptake processes remain unexamined in vitro, this study aims at elucidating how human brain cells manipulate these receptors to facilitate pabinafusp alfa uptake. The results of pabinafusp alfa uptake assays showed that the TfR played an primary role in its uptake by brain microvascular endothelial cells. The TfR contribution was also found in neuronal cells at levels comparable to M6PR. Interestingly, the predominant roles of TfR over M6PR in pabinafusp alfa uptake were also observed in astrocytes and pericytes. To summarize, our results support the TfR-targeting strategy of pabinafusp alfa for facilitating its BBB penetration while simultaneously identifying previously unnoticed TfR roles in its uptake into human neuronal and non-neuronal brain cells. These findings are certain to provide important insights into the mechanisms behind clinical actions of pabinafusp alfa.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44905517","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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