Frontiers in drug delivery最新文献

{"title":"Optimization and Characterization of a Liposomal Azithromycin Formulation for Alternative Macrophage Activation.","authors":"Abdullah A Masud,&nbsp;Fahd M Alsharif,&nbsp;Jarrod W Creameans,&nbsp;Jasmine Perdeh,&nbsp;David J Feola,&nbsp;Vincent J Venditto","doi":"10.3389/fddev.2022.908709","DOIUrl":"https://doi.org/10.3389/fddev.2022.908709","url":null,"abstract":"<p><p>Liposomal azithromycin (L-AZM) promotes macrophage polarization toward an M2-like phenotype in the context of myocardial infarction that results in improved cardiovascular outcomes in mice. To improve upon this formulation, we sought to identify optimized formulation, stability, and biological activity parameters necessary to enhance the immunomodulatory activity and efficacy of L-AZM. While our parent formulation contains a mixture of long-chain saturated phosphatidylcholine and phosphatidylglycerol lipids, we evaluated a series of formulations with different amounts of unsaturated lipids and cholesterol with the goal of improving the loading capacity and stability of the formulations. We also introduce fusogenic lipids to improve the cytosolic delivery to enhance the immune modulatory properties of the drug. To achieve these goals, we initially prepared a library of 24 formulations using thin film hydration and assessed the resultant liposomes for size and polydispersity. Five lead formulations were identified based on low polydispersity (<0.3) and stability over time. The lead formulations were then evaluated for stability in serum using dialysis and macrophage polarization activity <i>in vitro</i> as measured by decreased IL-12 expression. Collectively, our data indicate that the formulation components drive the balance between encapsulation efficiency and stability and that all the lead liposomal formulations improve <i>in vitro</i> alternative macrophage activation as compared to free AZM.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9670256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40699731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Localized PD-1 Blockade in a Mouse Model of Renal Cell Carcinoma.","authors":"Ngoc B Pham,&nbsp;Nevil Abraham,&nbsp;Ketki Y Velankar,&nbsp;Nathan R Schueller,&nbsp;Errol J Philip,&nbsp;Yasmeen Jaber,&nbsp;Ellen S Gawalt,&nbsp;Yong Fan,&nbsp;Sumanta K Pal,&nbsp;Wilson S Meng","doi":"10.3389/fddev.2022.838458","DOIUrl":"https://doi.org/10.3389/fddev.2022.838458","url":null,"abstract":"<p><p>Herein we report the impact of localized delivery of an anti-mouse PD-1-specific monoclonal antibody (aPD1) on Renca tumors in the resulting T cell responses and changes in broader immune gene expression profiles. Renca is a BALB/c mice syngeneic tumor that has been used to model human renal cell carcinoma In this study, T cell subsets were examined in tumors and draining lymph nodes of mice treated with localized PD-1 with and without the addition of adenosine deaminase (ADA), an enzyme that catabolizes adenosine (ADO), identified as an immune checkpoint in several types of human cancers. The biologics, aPD1, or aPD1 with adenosine deaminase (aPD1/ADA), were formulated with the self-assembling peptides Z15_EAK to enhance retention near the tumor inoculation site. We found that both aPD1 and aPD1/ADA skewed the local immune milieu towards an immune stimulatory phenotype by reducing Tregs, increasing CD8 T cell infiltration, and upregulating IFNɣ. Analysis of tumor specimens using bulk RNA-Seq confirmed the impact of the localized aPD1 treatment and revealed differential gene expressions elicited by the loco-regional treatment. The effects of ADA and Z15_EAK were limited to tumor growth delay and lymph node enlargement. These results support the notion of expanding the use of locoregional PD-1 blockade in solid tumors.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9486680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33466166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lyophilization Process Engineering and Thermostability of ID93 + GLA-SE, a Single-Vial Adjuvanted Subunit Tuberculosis Vaccine Candidate for Use in Clinical Studies.","authors":"Timothy S Dutill,&nbsp;Michelle C Archer,&nbsp;Joseph McCollum,&nbsp;Chris Press,&nbsp;Lisa McNeill,&nbsp;Linda Hawkins,&nbsp;Tony Phan,&nbsp;Erik Laursen,&nbsp;Richard Cabullos,&nbsp;Lisa Bouchard,&nbsp;Regie J Castro,&nbsp;Mong-Wu Lin,&nbsp;Jeralyn Roco,&nbsp;Cecile Blois,&nbsp;Babatunde Adeagbo,&nbsp;Jeffrey A Guderian,&nbsp;Alana Gerhardt,&nbsp;Anna Marie Beckmann,&nbsp;Edward H Trappler,&nbsp;Ryan M Kramer,&nbsp;Christopher B Fox","doi":"10.3389/fddev.2022.1043756","DOIUrl":"https://doi.org/10.3389/fddev.2022.1043756","url":null,"abstract":"<p><p>Promising clinical efficacy results have generated considerable enthusiasm for the potential impact of adjuvant-containing subunit tuberculosis vaccines. The development of a thermostable tuberculosis vaccine formulation could have significant benefits on both the cost and feasibility of global vaccine distribution. The tuberculosis vaccine candidate ID93 + GLA-SE has reached Phase 2 clinical testing, demonstrating safety and immunogenicity as a two-vial point-of-care mixture. Earlier publications have detailed efforts to develop a lead candidate single-vial lyophilized thermostable ID93 + GLA-SE vaccine formulation. The present report describes the lyophilization process development and scale-up of the lead candidate thermostable ID93 + GLA-SE composition. The manufacture of three full-scale engineering batches was followed by one batch made and released under current Good Manufacturing Practices (cGMP). Up to 4.5 years of stability data were collected. The cGMP lyophilized ID93 + GLA-SE passed all manufacturing release test criteria and maintained stability for at least 3 months when stored at 37°C and up to 24 months when stored at 5°C. This work represents the first advancement of a thermostable adjuvant-containing subunit tuberculosis vaccine to clinical testing readiness.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10538572/pdf/nihms-1890761.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41175944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endocytosis of insulin at the blood-brain barrier.","authors":"Sarah Pemberton, Demi C Galindo, Michael W Schwartz, William A Banks, Elizabeth M Rhea","doi":"10.3389/fddev.2022.1062366","DOIUrl":"10.3389/fddev.2022.1062366","url":null,"abstract":"<p><p>For insulin to act within the brain, it is primarily transported from the blood across the blood-brain barrier (BBB). However, the endocytic machinery necessary for delivering insulin to the brain remains unknown. Additionally, there are processes within the brain endothelial cell that are designed to respond to insulin binding and elicit intracellular signaling. Using pharmacological inhibitors of different types of endocytosis (clathrin-vs. caveolin-mediated), we investigated molecular mediators of both insulin BBB binding in isolated mouse brain microvessels and BBB insulin transport in mice studied by brain perfusion. We found clathrin-mediated mechanisms responsible for insulin surface binding in isolated brain microvessels while caveolin-mediated endocytosis may mediate BBB insulin transport specifically in the hypothalamus. These results further define the molecular machinery necessary for transporting insulin into the CNS and highlight the distinction between insulin internalization for transendothelial transport vs. intracellular signaling.</p>","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46449992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug Delivery Formulations and Devices Tailored for Paediatric and Older Patients","authors":"David J Brayden","doi":"10.3389/fddev.2021.782635","DOIUrl":"https://doi.org/10.3389/fddev.2021.782635","url":null,"abstract":"“Drugs don’t work in patients who don’t take them,” C. Everett Coop, US Surgeon General (1985). This is a quote widely used in discussions of poor compliance with drug dosing regimens. It is particularly apt in relation to the non-adherence to medications by children and older persons, where ascertaining correct doses in the context of physiological differences according to age profiles is a key consideration in making acceptable formulations and devices for delivery. The concept of the average patient is a myth—there is no average child or older person, hence one formulation will not necessarily be safe and effective for all patients. When a new medicine is submitted to regulatory agencies for approval, clinical trials are generally carried out on patients over the age of 18 and under the age of 65. Trials in “average” patients aim to determine if a medicine will be safe and efficacious, but drugs are also required for patients that lie outside of the average, including paediatrics and older persons. Few drugs have undergone clinical trials in paediatric patients, so in the absence of specific formulations, physicians can opt to use such drugs off-label and/or in an unlicensed fashion (Chen et al., 2021). Off-label use is one when a licenced product is used outside the specifics of the license or label granted by the national regulator. For use in paediatrics and older persons, this might include the age range, the dose level, or its use in other clinical indications. A common mantra in the field of paediatrics is that “children are not small adults”. Childhood spans pre-term infants, full term infants (0–28 days), infants and toddlers (28 days–23 months), children from 2–11 years old, and adolescents from 12 to 16/18 years old. In the absence of a licenced drug, physicians tend to adjust the dose of a drug licenced in adults on a mg/kg basis, use a lower dose strength, or opt for a compounded formulation where preparation errors can be made. In many cases there will be no difference between how a dosage form performs in adults and children and safety and efficacy will not be compromised. The differences between adults and children relevant to dosing include weight, height, body water content, metabolism, gastric pH, gastric emptying, sensitivity to drugs and excipients, and hepatic clearance. Pharmacokinetic (PK) changes may arise in paediatric patients due to differences in body water content that can influence distribution. There may also be altered expression of transporters, enzymes, and carriers that in turn impact absorption, distribution, metabolism, and excretion. Altered expression of metabolising enzymes in paediatric patients can have a profound effect on PK parameters leading to compromised drug and excipient safety. Similarly, the expression of drug targets may be reduced, and this may potentially affect the pharmacodynamic (PD) outcome. When it comes to the formulation, manipulating a dosage form to aide swallowing or to reduce th","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"122 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41280779","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":"The Grand Challenges in Cardiovascular Drug Delivery","authors":"I. Cicha","doi":"10.3389/fddev.2021.784731","DOIUrl":"https://doi.org/10.3389/fddev.2021.784731","url":null,"abstract":"Despite the ongoing development in invasive cardiovascular interventions and pharmacological therapies over the past 25 years, cardiovascular diseases (CVD) continue to account for 31% of all deaths worldwide. This amounts to 17.9 million deaths per year, a number that is expected to grow to more than 23.6 million by 2030, according to WHO estimates. According to the European Cardiovascular Disease Statistics 2017 (Wilkins et al., 2017), CVD caused 3.9 million deaths in Europe alone. As reported by the 2019 Heart Disease and Stroke Statistics of the American Heart Association (Benjamin et al., 2019), every 40 s, an American will suffer from a myocardial infarction (MI). In the recent years, effective medicines allowed to better control blood cholesterol levels, to lower blood pressure and, finally, to reduce inflammation, which contributed to improved management of patients with CVD. However, the first symptom of CVD in more than 50% cases is acute cardiovascular event or sudden cardiac death. This background calls for more reliable risk assessment allowing earlier disease detection and for improved therapeutic approaches. Atherosclerosis and arterial thrombosis, the underlying causes of cardiovascular morality, can manifest as acute coronary syndromes, stroke or peripheral arterial disease. Drug delivery systems, which enable for example targeted application of medicines should have an enormous impact for the affected patients, as personalized tools to support the physicians in both the choice and the administration of recommended therapies. Among the potential therapeutic targets of novel drug delivery systems and biomaterial implants are vulnerable atherosclerotic plaques, ischemic myocardium, cerebro-, retino-, and renovascular disorders, but also thrombosis. Besides, cardiovascular stents, prostheses and patches can serve as tools for local drug delivery to enhance vascular healing and prevent neoatherosclerosis. The road from the ambitious experimental ideas to the clinical routine remains difficult, however. There are several Grand Challenges that must be addressed to overcome the hurdles for the development of drug delivery systems that will improve the outcomes of patients with CVD. Besides the biggest obstacle, which is the clinical safety and translation, also innovation, personalization and drug delivery on-demand represent major challenges. These challenges are discussed in detail below.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41808820","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":"The Centenary of the Discovery of Insulin: An Update on the Quest for Oral Delivery","authors":"David J Brayden","doi":"10.3389/fddev.2021.726675","DOIUrl":"https://doi.org/10.3389/fddev.2021.726675","url":null,"abstract":"Not many topics in drug delivery science have exercised so many pharmaceutical, formulation, and bioengineering minds than the oral delivery of macromolecules, especially when insulin is the focus. The year 2021 marks a hundred years since the discovery of insulin by Banting and Best to treat Type 1 diabetes. Repeated efforts to deliver it orally since then have met with failure, with particular disappointment resulting from encouraging preclinical studies in the 1980s. Here, the barriers to synthesizing successful oral inulin formulations are discussed. It is apparent that this peptide has chemistry and pharmacology features that make its oral delivery one of the toughest challenges in delivery science. At this seminal point in its history, the question is whether oral delivery of insulin will ever be possible, or even if this quest is still desirable?","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43279275","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}