Pub Date : 2022-08-09DOI: 10.3389/fddev.2022.955569
Alyson Yamaguchi, J. van Dam, A. Dhalla, Kyle P. Horlen, M. Imran, April T. Vo, Mir Hashim
Biotherapeutics such as peptides and antibodies are highly efficacious clinically but, unlike conventional medications, cannot be administered orally as they get digested and inactivated. Thus, biotherapeutics require parenteral routes for delivery, such as intravenous, intramuscular or subcutaneous administration. However, these delivery methods have limitations such as poor patient compliance or may require clinical supervision compared to oral therapies. We explored whether a novel, orally administered transenteric delivery system (Robotic Pill) could provide equivalent bioavailability to parenterally administered drugs. Utilizing an awake canine model, we demonstrated that orally administered Robotic Pills containing either human IgG or an anti-cytokine monoclonal antibody directed against either TNFα or interleukin-17A yielded bioavailability equivalent to parenterally administered controls. The ability to achieve clinically relevant blood levels of biotherapeutics via any orally administered preparation represents an important advance in drug delivery.
{"title":"Transenteric delivery of antibodies via an orally ingestible robotic pill yields high bioavailability comparable to parenteral administration in awake canines","authors":"Alyson Yamaguchi, J. van Dam, A. Dhalla, Kyle P. Horlen, M. Imran, April T. Vo, Mir Hashim","doi":"10.3389/fddev.2022.955569","DOIUrl":"https://doi.org/10.3389/fddev.2022.955569","url":null,"abstract":"Biotherapeutics such as peptides and antibodies are highly efficacious clinically but, unlike conventional medications, cannot be administered orally as they get digested and inactivated. Thus, biotherapeutics require parenteral routes for delivery, such as intravenous, intramuscular or subcutaneous administration. However, these delivery methods have limitations such as poor patient compliance or may require clinical supervision compared to oral therapies. We explored whether a novel, orally administered transenteric delivery system (Robotic Pill) could provide equivalent bioavailability to parenterally administered drugs. Utilizing an awake canine model, we demonstrated that orally administered Robotic Pills containing either human IgG or an anti-cytokine monoclonal antibody directed against either TNFα or interleukin-17A yielded bioavailability equivalent to parenterally administered controls. The ability to achieve clinically relevant blood levels of biotherapeutics via any orally administered preparation represents an important advance in drug delivery.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48297874","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 : 2022-08-03DOI: 10.3389/fddev.2022.909958
Islam El Jaddaoui, Najib Al Idrissi, S. Hamdi, L. Wakrim, C. Nejjari, S. Amzazi, Abdelatif Elouahabi, Y. Bakri, H. Ghazal
During the unprecedented COVID-19 pandemic, the primary goal of many countries has been to achieve herd immunity through the organization of massive vaccination campaigns. Nevertheless, developing countries, including Africans, have been facing limited vaccine supply. Conventional inactivated or subunit vaccines are widely used across the world; however, their production is costly and could be limited by the supply chain during a pandemic such as COVID-19. Genetic vaccines, such as mRNA- or adenovirus-based vaccines, have been developed as alternatives but are still costly and require low-temperature storage. The plant-based vaccine concept has attracted increasing attention in recent years due to its potential advantages, such as low cost, high production volume, and thermostability. In this review, we propose plant-based vaccines as an attractive alternative for massive and rapid vaccination protocols against COVID-19 in African countries by exploiting local crops. In addition, we discuss the mechanisms of action, required standards, benefits, challenges, and prospects for the application of this novel biotechnological tool in the African continent.
{"title":"Plant-Based Vaccines Against COVID-19 for Massive Vaccination in Africa","authors":"Islam El Jaddaoui, Najib Al Idrissi, S. Hamdi, L. Wakrim, C. Nejjari, S. Amzazi, Abdelatif Elouahabi, Y. Bakri, H. Ghazal","doi":"10.3389/fddev.2022.909958","DOIUrl":"https://doi.org/10.3389/fddev.2022.909958","url":null,"abstract":"During the unprecedented COVID-19 pandemic, the primary goal of many countries has been to achieve herd immunity through the organization of massive vaccination campaigns. Nevertheless, developing countries, including Africans, have been facing limited vaccine supply. Conventional inactivated or subunit vaccines are widely used across the world; however, their production is costly and could be limited by the supply chain during a pandemic such as COVID-19. Genetic vaccines, such as mRNA- or adenovirus-based vaccines, have been developed as alternatives but are still costly and require low-temperature storage. The plant-based vaccine concept has attracted increasing attention in recent years due to its potential advantages, such as low cost, high production volume, and thermostability. In this review, we propose plant-based vaccines as an attractive alternative for massive and rapid vaccination protocols against COVID-19 in African countries by exploiting local crops. In addition, we discuss the mechanisms of action, required standards, benefits, challenges, and prospects for the application of this novel biotechnological tool in the African continent.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46145326","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 : 2022-07-25DOI: 10.3389/fddev.2022.931221
S. Amselem, S. Eyal
Astronauts have flown to space for decades, but the effects of spaceflight on human health have not been fully clarified yet. Several pathologies have only been detected after it has become customary for astronauts to spend months rather than days in space and with the advance of inflight monitoring. Examples include the neuro-ocular spaceflight associated syndrome, changes to the brain’s white matter, and, more recently, altered cerebral blood flow and related hypercoagulability. This review outlines spaceflight-induced brain disorders in astronauts and putative contributing factors. It next presents ongoing and upcoming studies of the BBB onboard space platforms. Finally, it describes how the space environment can be harnessed for improving drug-delivery across the BBB for humans both in space and on Earth.
{"title":"The Blood-Brain Barrier in Space: Implications for Space Travelers and for Human Health on Earth","authors":"S. Amselem, S. Eyal","doi":"10.3389/fddev.2022.931221","DOIUrl":"https://doi.org/10.3389/fddev.2022.931221","url":null,"abstract":"Astronauts have flown to space for decades, but the effects of spaceflight on human health have not been fully clarified yet. Several pathologies have only been detected after it has become customary for astronauts to spend months rather than days in space and with the advance of inflight monitoring. Examples include the neuro-ocular spaceflight associated syndrome, changes to the brain’s white matter, and, more recently, altered cerebral blood flow and related hypercoagulability. This review outlines spaceflight-induced brain disorders in astronauts and putative contributing factors. It next presents ongoing and upcoming studies of the BBB onboard space platforms. Finally, it describes how the space environment can be harnessed for improving drug-delivery across the BBB for humans both in space and on Earth.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48865335","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 : 2022-07-22DOI: 10.3389/fddev.2022.932576
A. Fujita, S. Noguchi, R. Hamada, Tsutomu Shimada, Satomi Katakura, T. Maruyama, Y. Sai, T. Nishimura, M. Tomi
Breast cancer resistance protein (BCRP) is expressed by brain capillary endothelial cells and at the interface between two placental syncytiotrophoblast layers in rodents and serves to suppress drug distribution to the brain and the fetus. The purpose of the present study is to determine and compare the apparent impact of a single BCRP molecule on drug transfer between the maternal blood-brain barrier and placental barrier in pregnant mice at different gestation ages. BCRP protein was quantified by liquid chromatography-tandem mass spectrometry. Genistein or dantrolene was continuously administered to pregnant Bcrp −/− or wild-type (WT) mice, and the brain-to-plasma concentration ratio in the mother (K p,brain) and the fetal-to-maternal ratio of plasma concentrations (K p,fp) were determined. At gestational day 15.5 (GD15.5), the protein amount of BCRP at the murine placental barrier was estimated to be approximately three times higher than at the maternal blood-brain barrier, but the levels were approximately the same at GD17.5 due to the decline of placental BCRP expression during gestation. On the other hand, the values of Bcrp −/−/WT ratio of K p,brain for genistein and dantrolene were 6.1 and 3.8, respectively, while the K p,fp ratios were all less than 2.0. These results indicate that the apparent impact of a single placental BCRP molecule on the restriction of drug distribution is much less than that of a single brain BCRP molecule, probably because the function of placental BCRP is attenuated by bypass transfer through the connexin26 gap junctions between adjacent syncytiotrophoblast layers. The present study also found that the expression amount of BCRP protein at the human placental barrier formed by the monolayer of syncytiotrophoblasts was lower than that in mice, but this species difference appears to be functionally compensated by the murine-specific bypass route through gap junctions, at least in part.
{"title":"Quantitative Comparison of Breast Cancer Resistance Protein (BCRP/ABCG2) Expression and Function Between Maternal Blood-Brain Barrier and Placental Barrier in Mice at Different Gestational Ages","authors":"A. Fujita, S. Noguchi, R. Hamada, Tsutomu Shimada, Satomi Katakura, T. Maruyama, Y. Sai, T. Nishimura, M. Tomi","doi":"10.3389/fddev.2022.932576","DOIUrl":"https://doi.org/10.3389/fddev.2022.932576","url":null,"abstract":"Breast cancer resistance protein (BCRP) is expressed by brain capillary endothelial cells and at the interface between two placental syncytiotrophoblast layers in rodents and serves to suppress drug distribution to the brain and the fetus. The purpose of the present study is to determine and compare the apparent impact of a single BCRP molecule on drug transfer between the maternal blood-brain barrier and placental barrier in pregnant mice at different gestation ages. BCRP protein was quantified by liquid chromatography-tandem mass spectrometry. Genistein or dantrolene was continuously administered to pregnant Bcrp −/− or wild-type (WT) mice, and the brain-to-plasma concentration ratio in the mother (K p,brain) and the fetal-to-maternal ratio of plasma concentrations (K p,fp) were determined. At gestational day 15.5 (GD15.5), the protein amount of BCRP at the murine placental barrier was estimated to be approximately three times higher than at the maternal blood-brain barrier, but the levels were approximately the same at GD17.5 due to the decline of placental BCRP expression during gestation. On the other hand, the values of Bcrp −/−/WT ratio of K p,brain for genistein and dantrolene were 6.1 and 3.8, respectively, while the K p,fp ratios were all less than 2.0. These results indicate that the apparent impact of a single placental BCRP molecule on the restriction of drug distribution is much less than that of a single brain BCRP molecule, probably because the function of placental BCRP is attenuated by bypass transfer through the connexin26 gap junctions between adjacent syncytiotrophoblast layers. The present study also found that the expression amount of BCRP protein at the human placental barrier formed by the monolayer of syncytiotrophoblasts was lower than that in mice, but this species difference appears to be functionally compensated by the murine-specific bypass route through gap junctions, at least in part.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41445083","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 : 2022-07-12DOI: 10.3389/fddev.2022.946045
Habib Baghirov
Biologics are at the frontier of CNS disease treatment. This applies both to therapeutic molecules such as peptides, antibodies and RNA interference agents, and to delivery vehicles of biological origin such as viral vectors and extracellular vesicles. Unlike small molecules, biologics are not likely to diffuse across cell membranes. To get into and across brain capillary endothelial cells (BCEC) forming the blood–brain barrier, they normally employ active, energy-dependent processes. They can initiate these processes non-specifically or trigger them by interaction with various receptor or transporter molecules at the luminal surface of BCEC. Designing biologics to use this specific engagement is more common in smaller formats, especially peptides and antibodies, but can also apply to targeted vehicles. This targeted design has employed a number of molecules expressed on BCEC – the transferrin receptor being the most common example, although there has been progress in identifying molecules that are even more specific to BCEC. In addition, the format of biologics and a multitude of their biophysical properties affect the way they interact with BCEC, and this diversity is even more salient between different classes of biologics. It affects the entire span of interaction with BCEC, from the initial engagement at the luminal surface to intracellular sorting, and eventually, entrapment or routing toward exocytosis into the brain parenchyma. In this article, I reviewed the progress in identifying novel targets that make the interactions between biologics and BCEC more specific, and in our understanding of the interplay between the properties of biologics and these interactions.
{"title":"The Roads We Take: Cellular Targets and Pathways Leading Biologics Across the Blood–Brain Barrier","authors":"Habib Baghirov","doi":"10.3389/fddev.2022.946045","DOIUrl":"https://doi.org/10.3389/fddev.2022.946045","url":null,"abstract":"Biologics are at the frontier of CNS disease treatment. This applies both to therapeutic molecules such as peptides, antibodies and RNA interference agents, and to delivery vehicles of biological origin such as viral vectors and extracellular vesicles. Unlike small molecules, biologics are not likely to diffuse across cell membranes. To get into and across brain capillary endothelial cells (BCEC) forming the blood–brain barrier, they normally employ active, energy-dependent processes. They can initiate these processes non-specifically or trigger them by interaction with various receptor or transporter molecules at the luminal surface of BCEC. Designing biologics to use this specific engagement is more common in smaller formats, especially peptides and antibodies, but can also apply to targeted vehicles. This targeted design has employed a number of molecules expressed on BCEC – the transferrin receptor being the most common example, although there has been progress in identifying molecules that are even more specific to BCEC. In addition, the format of biologics and a multitude of their biophysical properties affect the way they interact with BCEC, and this diversity is even more salient between different classes of biologics. It affects the entire span of interaction with BCEC, from the initial engagement at the luminal surface to intracellular sorting, and eventually, entrapment or routing toward exocytosis into the brain parenchyma. In this article, I reviewed the progress in identifying novel targets that make the interactions between biologics and BCEC more specific, and in our understanding of the interplay between the properties of biologics and these interactions.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41518409","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 : 2022-07-11DOI: 10.3389/fddev.2022.964298
C. Foged
The worldwide pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has come at immense social and economic costs, both to individuals and societies. For vaccine research, the COVID-19 pandemic has been a scienti fi cally highly exciting period with remarkable collaborative achievements, which have been referred to as the medical parallel to the moon landing, and it has underlined that vaccines are as important as ever for global public health care. It is indisputable that vaccines have contributed to reducing deaths and severe illness. The pandemic has provided a unique opportunity for testing and comparing different COVID-19 vaccine platforms which were developed and approved at an unprecedented pace. Although the COVID-19 pandemic is not over yet, we are moving beyond the emergency response and are adapting to live alongside with the virus, while strategies are being developed for handling the lasting threat of SARS-CoV-2. It is time for re fl ection on what we have learned from the COVID-19 vaccine rollout, and what grand challenges that must be addressed in the vaccine delivery fi eld. Some of the most important challenges are presented below.Inthe
{"title":"Grand Challenges in Vaccine Delivery: Lessons Learned From the COVID-19 Vaccine Rollout","authors":"C. Foged","doi":"10.3389/fddev.2022.964298","DOIUrl":"https://doi.org/10.3389/fddev.2022.964298","url":null,"abstract":"The worldwide pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has come at immense social and economic costs, both to individuals and societies. For vaccine research, the COVID-19 pandemic has been a scienti fi cally highly exciting period with remarkable collaborative achievements, which have been referred to as the medical parallel to the moon landing, and it has underlined that vaccines are as important as ever for global public health care. It is indisputable that vaccines have contributed to reducing deaths and severe illness. The pandemic has provided a unique opportunity for testing and comparing different COVID-19 vaccine platforms which were developed and approved at an unprecedented pace. Although the COVID-19 pandemic is not over yet, we are moving beyond the emergency response and are adapting to live alongside with the virus, while strategies are being developed for handling the lasting threat of SARS-CoV-2. It is time for re fl ection on what we have learned from the COVID-19 vaccine rollout, and what grand challenges that must be addressed in the vaccine delivery fi eld. Some of the most important challenges are presented below.Inthe","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42635494","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 : 2022-07-11DOI: 10.3389/fddev.2022.945459
You Xu, Enise Tugba Turan, Z. Shi, H. Franzyk, Aneesh Thakur, C. Foged
Thermostable dry powder formulations with high aerosol performance are attractive inhalable solid dosage forms for local treatment of lung diseases. However, preserved long-term physical stability of dry powder inhaler (DPI) formulations is critical to ensure efficient and reproducible delivery to the airways during the shelf life of the drug product. Here, we show that ternary excipient mixtures of the disaccharide trehalose (Tre), the polysaccharide dextran (Dex), and the shell-forming dispersion enhancer leucine (Leu) stabilize siRNA-loaded lipid-polymer hybrid nanoparticles (LPNs) during spray drying into nanocomposite microparticles, and result in inhalable solid dosage forms with high aerosol performance and long-term stability. The stabilizing roles of Tre and Dex were also studied separately by investigating DPI formulations containing binary mixtures of Leu/Tre and Leu/Dex, respectively. DPI formulations containing binary Leu/Dex mixtures were amorphous and displayed preserved long-term physical stability of LPNs and chemical stability of siRNA in accelerated stability studies under exaggerated storage conditions (ambient temperature and relative humidity). In contrast, powders containing binary Leu/Tre mixtures were amorphous, and hence metastable, and were recrystallized after six months of storage. Ternary mixtures of Tre, Leu, and Dex provided the most efficient protection of the LPNs during the spray drying process and prevented recrystallization of amorphous Tre. Hence, in ternary mixtures, Leu, Tre, and Dex have the following functions: the shell-forming Leu functions as a dispersion enhancer and is essential for high aerosol performance, the disaccharide Tre provides LPN protection during manufacturing and storage due to efficient coverage of the LPN surface, and the polysaccharide Dex promotes the formation of porous particles and prevents recrystallization of Tre during long-term storage. Therefore, the use of ternary excipient mixtures composed of Leu, Tre, and Dex, may prevent instability problems of DPI formulations and preserve the aerosol performance during long-term storage, which is essential for effective pulmonary drug delivery.
{"title":"Inhalable Composite Microparticles Containing siRNA-Loaded Lipid-Polymer Hybrid Nanoparticles: Saccharides and Leucine Preserve Aerosol Performance and Long-Term Physical Stability","authors":"You Xu, Enise Tugba Turan, Z. Shi, H. Franzyk, Aneesh Thakur, C. Foged","doi":"10.3389/fddev.2022.945459","DOIUrl":"https://doi.org/10.3389/fddev.2022.945459","url":null,"abstract":"Thermostable dry powder formulations with high aerosol performance are attractive inhalable solid dosage forms for local treatment of lung diseases. However, preserved long-term physical stability of dry powder inhaler (DPI) formulations is critical to ensure efficient and reproducible delivery to the airways during the shelf life of the drug product. Here, we show that ternary excipient mixtures of the disaccharide trehalose (Tre), the polysaccharide dextran (Dex), and the shell-forming dispersion enhancer leucine (Leu) stabilize siRNA-loaded lipid-polymer hybrid nanoparticles (LPNs) during spray drying into nanocomposite microparticles, and result in inhalable solid dosage forms with high aerosol performance and long-term stability. The stabilizing roles of Tre and Dex were also studied separately by investigating DPI formulations containing binary mixtures of Leu/Tre and Leu/Dex, respectively. DPI formulations containing binary Leu/Dex mixtures were amorphous and displayed preserved long-term physical stability of LPNs and chemical stability of siRNA in accelerated stability studies under exaggerated storage conditions (ambient temperature and relative humidity). In contrast, powders containing binary Leu/Tre mixtures were amorphous, and hence metastable, and were recrystallized after six months of storage. Ternary mixtures of Tre, Leu, and Dex provided the most efficient protection of the LPNs during the spray drying process and prevented recrystallization of amorphous Tre. Hence, in ternary mixtures, Leu, Tre, and Dex have the following functions: the shell-forming Leu functions as a dispersion enhancer and is essential for high aerosol performance, the disaccharide Tre provides LPN protection during manufacturing and storage due to efficient coverage of the LPN surface, and the polysaccharide Dex promotes the formation of porous particles and prevents recrystallization of Tre during long-term storage. Therefore, the use of ternary excipient mixtures composed of Leu, Tre, and Dex, may prevent instability problems of DPI formulations and preserve the aerosol performance during long-term storage, which is essential for effective pulmonary drug delivery.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"52 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41301997","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 : 2022-06-06DOI: 10.3389/fddev.2022.913225
H. Genç, E. Efthimiadou, I. Cicha
Cardiovascular diseases (CVD), including life-threatening atherosclerosis and arterial thrombosis, account for almost 50% of all deaths in Europe and around 30% of all deaths worldwide. Despite the ongoing improvement and accessibility of invasive cardiovascular interventions and pharmacological therapies, pathological processes often progress asymptomatically, before manifesting themselves as unstable angina pectoris, myocardial infarction, sudden cardiac death or stroke. Since atherosclerosis and thrombosis represent localized disease processes, insufficient response to systemically-administered drugs is a common problem. The available pharmacological therapies are often burdened by poor tolerability, limited efficacy and/or bioavailability. Although encapsulating drugs in a nanoscale shell increases their circulation time and availability, it does not guarantee disease-specific targeting, or the proper control of the drug release. In contrast, on-demand drug delivery has the advantage of localized treatment and allows reducing off-target effects by a stimuli-controlled drug release in the affected region. Such “smart” systems are expected to have a great therapeutic potential in CVD. This mini-review article highlights recent advances in stimuli-responsive drug delivery approaches to CVD, with specific drug release triggered either internally or externally.
{"title":"On-Demand Drug Delivery: Recent Advances in Cardiovascular Applications","authors":"H. Genç, E. Efthimiadou, I. Cicha","doi":"10.3389/fddev.2022.913225","DOIUrl":"https://doi.org/10.3389/fddev.2022.913225","url":null,"abstract":"Cardiovascular diseases (CVD), including life-threatening atherosclerosis and arterial thrombosis, account for almost 50% of all deaths in Europe and around 30% of all deaths worldwide. Despite the ongoing improvement and accessibility of invasive cardiovascular interventions and pharmacological therapies, pathological processes often progress asymptomatically, before manifesting themselves as unstable angina pectoris, myocardial infarction, sudden cardiac death or stroke. Since atherosclerosis and thrombosis represent localized disease processes, insufficient response to systemically-administered drugs is a common problem. The available pharmacological therapies are often burdened by poor tolerability, limited efficacy and/or bioavailability. Although encapsulating drugs in a nanoscale shell increases their circulation time and availability, it does not guarantee disease-specific targeting, or the proper control of the drug release. In contrast, on-demand drug delivery has the advantage of localized treatment and allows reducing off-target effects by a stimuli-controlled drug release in the affected region. Such “smart” systems are expected to have a great therapeutic potential in CVD. This mini-review article highlights recent advances in stimuli-responsive drug delivery approaches to CVD, with specific drug release triggered either internally or externally.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42434119","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 : 2022-05-23DOI: 10.3389/fddev.2022.896342
I. Gonda
It is easy to forget that just a few decades ago, delivery of drugs by inhalation was at the periphery of medicine, even for the treatment of respiratory diseases. Today, it would be almost unthinkable that a patient with asthma, chronic obstructive pulmonary disease (COPD), or cystic fibrosis would not be taking some form of inhaled medication and, indeed, typically more than one daily (Anderson et al., 2022). While the dominant inhalation technology invented in mid-1950s for decades were metered dose inhalers (MDIs), due to concerns over the environmental impact of propellants that provide the energy for the production of the aerosols, the pharmaceutical industry put a massive effort into reformulating drugs as dry powder inhalers (DPIs), particularly since the Montreal agreement signed in 1987 (Stein and Thiel, 2016). Instead of propellants, “passive” DPIs utilize the energy of the patients’ inspiratory effort to pull the drug powder formulation out of the inhaler and disperse it into respirable particles. In addition to the inspiratory effort, some considerable “mental” effort is needed to use any inhalation treatment correctly. The non-adherence to the instructions for use, including incorrect technique, is about 50%, and it has not improved much with time (Gonda, 2019 and refs. therein). Additionally, in their ground-breaking publication that influencedmuch subsequent debate, Clark and Hollingworth (1993) pointed out that a fundamental attribute of each DPI was its flow resistance and that the inspiratory flow rate achieved through an inhaler depended on the patient’s inspiratory effort and the device resistance. They also highlighted the subtle opposing impact of an increased inspiratory flow rate by a patient: while it will likely lead to better powder dispersion into smaller physical (and aerodynamic) size, the increased velocity of the drug-carrying particles will enhance deposition higher up in the respiratory tract. That suggested that with the right design, the regional dose delivery from a DPI can be quite inspiratory flow independent if these opposing factors are exquisitely balanced. However, it does not appear that the development of the majority of currently approved DPIs that use mostly technologies from several decades ago made a deliberate attempt to achieve such “flow independence.”Does it matter? In a recent publication in this journal, Weers (2022) presents his perspective that the concerns of certain physicians treating COPD patients with inhaled bronchodilators may be unwarranted regarding the inability of some patients to exert adequate flow rates through their devices. He provides a summary of clinical data with this class of drugs, showing that the safety and efficacy of the approved bronchodilator DPIs are adequate for the majority of the patients, despite the fact that in the “standard” in vitro tests, the DPIs appear to show “flow-dependent” performance. Edited by: Philip Chi Lip Kwok, The University of Sydney, Aus
人们很容易忘记，就在几十年前，通过吸入给药还处于医学的边缘，甚至用于治疗呼吸道疾病。如今，几乎不可想象的是，哮喘、慢性阻塞性肺病（COPD）或囊性纤维化患者不会服用某种形式的吸入药物，事实上，通常每天不止一次（Anderson等人，2022）。尽管20世纪50年代中期发明的几十年来占主导地位的吸入技术是计量吸入器，但由于担心为生产气溶胶提供能量的推进剂对环境的影响，制药行业投入了大量精力将药物重新配方为干粉吸入器，特别是自1987年签署蒙特利尔协定以来（Stein和Thiel，2016）。“被动”DPI不是推进剂，而是利用患者吸气的能量将药物粉末配方从吸入器中取出，并将其分散成可呼吸的颗粒。除了吸气的努力，还需要一些相当大的“精神”努力才能正确使用任何吸气治疗。不遵守使用说明的情况，包括不正确的技术，约占50%，而且随着时间的推移，情况没有太大改善（Gonda，2019和其中的参考文献）。此外，Clark和Hollingworth（1993）在他们的开创性出版物中指出，每个DPI的一个基本属性是其流动阻力，通过吸入器实现的吸气流速取决于患者的吸气努力和设备阻力。他们还强调了患者吸气流速增加的微妙相反影响：虽然这可能会使粉末更好地分散到更小的物理（和空气动力学）尺寸中，但携带药物的颗粒速度的增加将增强在呼吸道中的沉积。这表明，在正确的设计下，如果这些相反的因素得到巧妙的平衡，DPI的区域剂量输送可以完全独立于吸气流量。然而，目前批准的大多数主要使用几十年前技术的DPI的开发似乎并没有刻意尝试实现这种“流量独立性”。这有关系吗？在本杂志最近发表的一篇文章中，Weers（2022）提出了他的观点，即某些医生用吸入性支气管扩张剂治疗COPD患者的担忧可能是没有根据的，因为一些患者无法通过他们的设备施加足够的流速。他提供了这类药物的临床数据摘要，表明批准的支气管扩张剂DPI的安全性和有效性对大多数患者来说是足够的，尽管在“标准”体外测试中，DPI似乎显示出“流量依赖性”性能。编辑：Philip Chi Lip Kwok，澳大利亚悉尼大学
{"title":"Commentary: Suboptimal Inspiratory Flow Rates With Passive Dry Powder Inhalers: Big Issue or Overstated Problem?","authors":"I. Gonda","doi":"10.3389/fddev.2022.896342","DOIUrl":"https://doi.org/10.3389/fddev.2022.896342","url":null,"abstract":"It is easy to forget that just a few decades ago, delivery of drugs by inhalation was at the periphery of medicine, even for the treatment of respiratory diseases. Today, it would be almost unthinkable that a patient with asthma, chronic obstructive pulmonary disease (COPD), or cystic fibrosis would not be taking some form of inhaled medication and, indeed, typically more than one daily (Anderson et al., 2022). While the dominant inhalation technology invented in mid-1950s for decades were metered dose inhalers (MDIs), due to concerns over the environmental impact of propellants that provide the energy for the production of the aerosols, the pharmaceutical industry put a massive effort into reformulating drugs as dry powder inhalers (DPIs), particularly since the Montreal agreement signed in 1987 (Stein and Thiel, 2016). Instead of propellants, “passive” DPIs utilize the energy of the patients’ inspiratory effort to pull the drug powder formulation out of the inhaler and disperse it into respirable particles. In addition to the inspiratory effort, some considerable “mental” effort is needed to use any inhalation treatment correctly. The non-adherence to the instructions for use, including incorrect technique, is about 50%, and it has not improved much with time (Gonda, 2019 and refs. therein). Additionally, in their ground-breaking publication that influencedmuch subsequent debate, Clark and Hollingworth (1993) pointed out that a fundamental attribute of each DPI was its flow resistance and that the inspiratory flow rate achieved through an inhaler depended on the patient’s inspiratory effort and the device resistance. They also highlighted the subtle opposing impact of an increased inspiratory flow rate by a patient: while it will likely lead to better powder dispersion into smaller physical (and aerodynamic) size, the increased velocity of the drug-carrying particles will enhance deposition higher up in the respiratory tract. That suggested that with the right design, the regional dose delivery from a DPI can be quite inspiratory flow independent if these opposing factors are exquisitely balanced. However, it does not appear that the development of the majority of currently approved DPIs that use mostly technologies from several decades ago made a deliberate attempt to achieve such “flow independence.”Does it matter? In a recent publication in this journal, Weers (2022) presents his perspective that the concerns of certain physicians treating COPD patients with inhaled bronchodilators may be unwarranted regarding the inability of some patients to exert adequate flow rates through their devices. He provides a summary of clinical data with this class of drugs, showing that the safety and efficacy of the approved bronchodilator DPIs are adequate for the majority of the patients, despite the fact that in the “standard” in vitro tests, the DPIs appear to show “flow-dependent” performance. Edited by: Philip Chi Lip Kwok, The University of Sydney, Aus","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46543651","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 : 2022-05-13DOI: 10.3389/fddev.2022.899260
D. Bitoque, Cláudia F. Fernandes, Alexandra M. L. Oliveira, G. A. Silva
Retinal diseases lead to severe vision loss and are currently a major cause of vision impairment in industrialized countries. The significant number of genetic defects of the retina underlying these disorders, coupled to the absence of effective treatments, require new therapeutic solutions. Recent gene therapy developments in the field of ophthalmic research reveal the great potential of this approach. In recent years, non-viral vectors have been extensively studied due to their properties such as large gene packaging capacity and low immunogenicity. Hitherto, their development and optimisation for retinal gene therapy have been hindered by their inability to directly target retinal cells. The goal of this review is to summarize the most promising strategies to direct non-viral vectors for retinal cells to avoid off-target effects and promote their specific uptake, gene expression and overall efficiency.
{"title":"Strategies to Improve the Targeting of Retinal Cells by Non-Viral Gene Therapy Vectors","authors":"D. Bitoque, Cláudia F. Fernandes, Alexandra M. L. Oliveira, G. A. Silva","doi":"10.3389/fddev.2022.899260","DOIUrl":"https://doi.org/10.3389/fddev.2022.899260","url":null,"abstract":"Retinal diseases lead to severe vision loss and are currently a major cause of vision impairment in industrialized countries. The significant number of genetic defects of the retina underlying these disorders, coupled to the absence of effective treatments, require new therapeutic solutions. Recent gene therapy developments in the field of ophthalmic research reveal the great potential of this approach. In recent years, non-viral vectors have been extensively studied due to their properties such as large gene packaging capacity and low immunogenicity. Hitherto, their development and optimisation for retinal gene therapy have been hindered by their inability to directly target retinal cells. The goal of this review is to summarize the most promising strategies to direct non-viral vectors for retinal cells to avoid off-target effects and promote their specific uptake, gene expression and overall efficiency.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43136174","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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