Frontiers in drug delivery最新文献

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"title":"In Vitro Estimation of Tracheobronchial and Alveolar Doses Using Filters","authors":"W. Finlay, D. Farina, S. Tavernini, Andrew R. Martin","doi":"10.3389/fddev.2022.901289","DOIUrl":"https://doi.org/10.3389/fddev.2022.901289","url":null,"abstract":"To date, in vitro estimation of doses delivered by an inhaler to the different major regions of the lung has required combining particle size measurements of the inhaled aerosol with in silico deposition models. Such a two step process is labor and time intensive. Here, we describe instead the development of an apparatus that allows direct estimation of regional lung deposition by measurement of doses collected on purpose-built metal grid filters that mimic tracheobronchial deposition efficiency. Placing these filters downstream of the Alberta Idealized Throat and upstream of a final filter allows collection of doses depositing in the extrathoracic, tracheobronchial and alveolar regions. Artificial electrostatic deposition on the metal tracheobronchial filters is prevented by a custom inline electrostatic neutralizer. We use the resulting apparatus to estimate regional deposition with a variety of dry powder inhalers during realistic, time-varying inhalation maneuvers and three pMDIs with a constant flow rate of 30 l/min. These results are compared to those obtained with the traditional two step approach that combines cascade impaction with a regional deposition model. Good agreement is found between the two approaches, indicating that the present direct method may be an efficient, time-saving alternative method for in vitro estimation of regional lung doses.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42114652","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}

{"title":"Regulatory Considerations Specific to Liposome Drug Development as Complex Drug Products","authors":"Yuwei Wang, D. Grainger","doi":"10.3389/fddev.2022.901281","DOIUrl":"https://doi.org/10.3389/fddev.2022.901281","url":null,"abstract":"Nearly a half-century after original liposome discovery as a prospective lipid pharmaceutical carrier, the global liposomal drug delivery market has increased dramatically, with an annual market growth rate of 13.2%, valued at ∼$6,993 million by 2027. As an intrinsically complex delivery system, liposomal formulations face much greater characterization and regulatory review challenges than traditional small molecule drugs and biologics. Due to rapid liposomal drug development, both European Medicines Agency (EMA) and US Food and Drug Administration (FDA) now provide regulatory guidance for new liposomal drug application reviews. The expanding global liposome drug market and associated driving forces for increased research and development (R&D) in novel liposomal products are key factors propelling liposomal drug interests. We review and compare EU and US regulations on liposomal drug submissions, and provide insights into regulatory strategies throughout the entire liposomal drug development process. This addresses current gaps noted between liposome-based drug development in research labs and current regulatory guidance for liposomal drug approvals in order to facilitate more efficient, less costly, and less risky complex drug development.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48152722","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}

{"title":"Effects of Nicotine Exposure From Tobacco Products and Electronic Cigarettes on the Pathogenesis of Neurological Diseases: Impact on CNS Drug Delivery","authors":"Sejal Sharma, Sabrina Rahman Archie, Vrajesh Kanchanwala, Kyle Mimun, Md. Ashrafur Rahman, Yong Zhang, T. Abbruscato","doi":"10.3389/fddev.2022.886099","DOIUrl":"https://doi.org/10.3389/fddev.2022.886099","url":null,"abstract":"Nicotine, the major component of tobacco smoke (TS) and electronic cigarette (e-cig) vape, has been reported in some cases to be prodromal to cerebrovascular toxicity as well as a promoting factor for the onset of various neurological diseases. In some conditions, pre-exposure to nicotine can lead to a state of compromised blood-brain barrier (BBB) integrity, including altered BBB-related protein expression, BBB leakage, and defective ion and glucose homeostasis within the brain. Moreover, drugs used to treat central nervous system disorders (CNS) have been reported to interact with nicotine and other components of TS/e-cig through both transporter and enzyme-based mechanisms. Herein we discuss nicotine’s potential toxicity at the brain cerebrovasculature and explain how nicotine (from smoking/vaping) may interfere with the uptake of CNS drugs through a CNS drug interaction perspective.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48882072","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}

{"title":"Half a Century of Technological Advances in Pulmonary Drug Delivery: A Personal Perspective","authors":"A. Clark","doi":"10.3389/fddev.2022.871147","DOIUrl":"https://doi.org/10.3389/fddev.2022.871147","url":null,"abstract":"The last half century of pulmonary product development is reviewed in the context of the main drivers of innovation, technology development, and the advancement of science. A perspective on development timeframes, patent lifetimes, and the odds of success of developing of new inhaler technologies is presented.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43076108","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}