Pub Date : 2022-01-01Epub Date: 2022-05-09DOI: 10.3389/fddev.2022.838458
Ngoc B Pham, Nevil Abraham, Ketki Y Velankar, Nathan R Schueller, Errol J Philip, Yasmeen Jaber, Ellen S Gawalt, Yong Fan, Sumanta K Pal, Wilson S Meng
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.
{"title":"Localized PD-1 Blockade in a Mouse Model of Renal Cell Carcinoma.","authors":"Ngoc B Pham, Nevil Abraham, Ketki Y Velankar, Nathan R Schueller, Errol J Philip, Yasmeen Jaber, Ellen S Gawalt, Yong Fan, Sumanta K Pal, 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":null,"pages":null},"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}
Pub Date : 2022-01-01Epub Date: 2022-11-08DOI: 10.3389/fddev.2022.1043756
Timothy S Dutill, Michelle C Archer, Joseph McCollum, Chris Press, Lisa McNeill, Linda Hawkins, Tony Phan, Erik Laursen, Richard Cabullos, Lisa Bouchard, Regie J Castro, Mong-Wu Lin, Jeralyn Roco, Cecile Blois, Babatunde Adeagbo, Jeffrey A Guderian, Alana Gerhardt, Anna Marie Beckmann, Edward H Trappler, Ryan M Kramer, Christopher B Fox
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.
{"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, Michelle C Archer, Joseph McCollum, Chris Press, Lisa McNeill, Linda Hawkins, Tony Phan, Erik Laursen, Richard Cabullos, Lisa Bouchard, Regie J Castro, Mong-Wu Lin, Jeralyn Roco, Cecile Blois, Babatunde Adeagbo, Jeffrey A Guderian, Alana Gerhardt, Anna Marie Beckmann, Edward H Trappler, Ryan M Kramer, 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":null,"pages":null},"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}
Pub Date : 2022-01-01Epub Date: 2022-11-24DOI: 10.3389/fddev.2022.1062366
Sarah Pemberton, Demi C Galindo, Michael W Schwartz, William A Banks, Elizabeth M Rhea
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.
{"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":null,"pages":null},"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}
Pub Date : 2021-12-01DOI: 10.3389/fddev.2021.782635
David J Brayden
“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
“药物对不服药的病人不起作用，”C. Everett Coop，美国卫生局局长(1985)。这句话在讨论药物给药方案依从性差时被广泛使用。这尤其适用于儿童和老年人不坚持服药的情况，因为根据年龄分布确定生理差异的正确剂量是制定可接受的配方和给药装置的关键考虑因素。一般患者的概念是一个神话——没有一般的儿童或老年人，因此一种配方不一定对所有患者都安全有效。当一种新药提交监管机构审批时，临床试验通常在18岁以上和65岁以下的患者身上进行。针对“普通”患者的试验旨在确定一种药物是否安全有效，但对于非普通患者，包括儿科和老年人，也需要药物。很少有药物在儿科患者中进行临床试验，因此在缺乏特定配方的情况下，医生可以选择在标签外和/或以未经许可的方式使用这些药物(Chen et al.， 2021)。标签外使用是指在国家监管机构授予的许可证或标签的具体规定之外使用许可产品。对于儿科和老年人使用，这可能包括年龄范围、剂量水平或其在其他临床适应症中的使用。在儿科领域，一个常见的口头禅是“儿童不是小大人”。儿童期包括早产儿、足月婴儿(0-28天)、婴幼儿(28天- 23个月)、2-11岁的儿童和12 - 16/18岁的青少年。在没有许可药物的情况下，医生倾向于以mg/kg为基础调整成人许可药物的剂量，使用较低的剂量强度，或选择可能产生制备错误的复合制剂。在许多情况下，一种剂型在成人和儿童中的表现没有区别，安全性和有效性也不会受到损害。与给药有关的成人与儿童的差异包括体重、身高、身体含水量、代谢、胃pH值、胃排空、对药物和辅料的敏感性以及肝脏清除率。由于体内水分含量的差异会影响分布，儿科患者可能会出现药代动力学(PK)变化。转运蛋白、酶和载体的表达也可能发生改变，进而影响吸收、分布、代谢和排泄。儿科患者代谢酶表达的改变可能对PK参数产生深远影响，导致药物和赋形剂的安全性受损。同样，药物靶点的表达可能会减少，这可能会潜在地影响药效学(PD)结果。当涉及到配方时，操纵剂型以帮助吞咽或减少儿科剂量可能导致产品不稳定和与成人配方缺乏生物等效性，这进一步增加了该患者群体中不可预测的药物行为。近年来，欧洲药品管理局(2017年)起草了促进儿科医学发展的指南，并为治疗药物的儿科临床试验创造了更清晰的途径(EMA, 2020年)。它还要求申请人同意一份儿科实施计划(PIP)，如果由:Maria a . Deli，生物研究中心，匈牙利编辑和审查
{"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":null,"pages":null},"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}
Pub Date : 2021-10-25DOI: 10.3389/fddev.2021.784731
I. Cicha
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.
尽管侵入性心血管干预和药物治疗在过去25年中不断发展，但心血管疾病(CVD)仍然占全球所有死亡人数的31%。这相当于每年死亡1790万人，据世卫组织估计，到2030年，这一数字预计将增加到2360万人以上。根据《2017年欧洲心血管疾病统计》(Wilkins et al.， 2017)，仅在欧洲，心血管疾病就造成了390万人死亡。根据美国心脏协会2019年心脏病和中风统计报告(Benjamin et al.， 2019)，每40秒就有一名美国人患有心肌梗死(MI)。近年来，有效的药物可以更好地控制血液胆固醇水平，降低血压，最后减少炎症，这有助于改善心血管疾病患者的管理。然而，超过50%的CVD病例的第一个症状是急性心血管事件或心源性猝死。这一背景要求进行更可靠的风险评估，以便及早发现疾病并改进治疗方法。动脉粥样硬化和动脉血栓形成是心血管疾病的根本原因，可表现为急性冠状动脉综合征、中风或外周动脉疾病。药物输送系统，例如能够有针对性地应用药物，作为支持医生选择和实施推荐疗法的个性化工具，应该对受影响的患者产生巨大影响。新型药物输送系统和生物材料植入物的潜在治疗靶点包括易损的动脉粥样硬化斑块、缺血性心肌、大脑、视网膜和肾血管疾病，以及血栓形成。此外，心血管支架、假体和贴片可以作为局部给药工具，促进血管愈合，预防新动脉粥样硬化。然而，从雄心勃勃的实验想法到临床常规的道路仍然困难重重。为了克服开发改善心血管疾病患者预后的药物输送系统的障碍，必须解决几个重大挑战。除了最大的障碍是临床安全性和翻译之外，创新、个性化和按需给药也是主要的挑战。下面将详细讨论这些挑战。
{"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":null,"pages":null},"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}
Pub Date : 2021-09-15DOI: 10.3389/fddev.2021.726675
David J Brayden
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?
{"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":null,"pages":null},"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}
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