Oral delivery of insulin using ligand-directed nanoparticles that do not compete with physiological ligands

使用不与生理配体竞争的配体导向纳米颗粒口服胰岛素

• 批准号: 10373829
• 负责人: Raghu Ganugula
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF ALABAMA IN TUSCALOOSA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373829
• 关键词: Active Biological Transport; Address; Adoption; Affect; Affinity; Anxiety; Apical; Apoptosis; Beta Cell; Binding; Binding Sites; Bioavailable; Biodistribution; Biological; Biological Availability; Biological Models; Blood Glucose; Carbohydrates; Cell Line; Cell Surface Receptors; Cell physiology; Cell surface; Centers for Disease Control and Prevention (U.S.); Chemistry; Chronic; Clinical; Clinical Research; Communities; Complex; Coronary heart disease; Diabetes Mellitus; Dipeptidyl-Peptidase IV; Disease; Dosage Forms; Dose; Drug Carriers; Drug Delivery Systems; Drug Design; Drug Kinetics; Encapsulated; Epithelial; Excipients; Fasting; Food; Formulation; Foundations; Fright; Functional disorder; Gastrointestinal tract structure; Glucose; Glycosylated hemoglobin A; Goals; Grant; Health Professional; High Fat Diet; Hypoglycemia; In Vitro; Inflammation; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Intestinal Absorption; Intestines; Iron; Kidney; Kidney Diseases; Knowledge; Lead; Length; Ligands; Literature; Mammalian Cell; Mediating; Medicine; Microvascular Dysfunction; Modeling; Molecular Weight; Mucous body substance; Needles; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Nucleosome Core Particle; Oral; Oral Administration; Outcome; Pain; Pathogenicity; Patient Noncompliance; Patients; Peptide Hydrolases; Perception; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Physiological; Polyesters; Polymers; Rattus; Reporting; Resort; Retinal Diseases; Role; Schedule; Sodium; Stomach; Stroke; Surface; System; TFRC gene; Tablets; Technology; Testing; Therapeutic; Time; Toxic effect; Transferrin; United Kingdom; Weight Gain; Work; absorption; amphiphilicity; analog; capsule; cardiovascular disorder risk; compliance behavior; density; diabetic rat; drug disposition; drug efficacy; experience; gambogic acid; glucagon-like peptide 1; hepatic gluconeogenesis; improved; in vivo; in vivo Model; inhibitor/antagonist; insulin secretion; insulin sensitivity; intestinal barrier; macrovascular disease; nanoparticle; nanoscale; nanosystems; novel; prevent; prospective; psychologic; receptor; receptor binding; secretion process; side effect; stem; therapy outcome

Project Summary The primary focus of managing type 2 diabetes (T2D) has traditionally been the strict control of blood glucose using one or multiple orally administered medications. Drugs currently used to treat T2D range from pharmaceutical agents that increase insulin secretion or sensitivity, to those that decrease hepatic gluconeogenesis or intestinal carbohydrate absorption. Agents that are more recent include glucagon-like peptide-1 (GLP-1) analogues, which inhibit the breakdown of endogenous GLP-1 by dipeptidyl peptidase-IV (DPP-IV), and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, which block normal glucose reabsorption in the kidneys. According to the United Kingdom Prospective Diabetes Study (UKPDS 33), even though the efficacy of these drugs in preventing microvascular complications of T2D (e.g., retinopathy, neuropathy and nephropathy) has been partially established, their role in preventing macrovascular complications (e.g., coronary heart disease and stroke) remains elusive. Moreover, the same study points out that 50 percent of patients originally controlled with a single drug acquired tolerance and needed the addition of a second drug after three years, and by nine years, about 75 percent of patients needed multiple therapies to achieve the target HbA1c value. There is significant evidence that in some T2D patients, despite taking medications, the β-cell function undergoes continuous decline and eventually fails entirely, leaving these patients the only option of insulin therapy. Rather than being used as a treatment of last resort however, the clinical and research communities are recognizing that early initiation of insulin therapy in T2D patients will correct all of the underlying pathogenic mechanisms such as increased β-cell apoptosis, glucotoxicity, lipotoxicity, and inflammation. Major drawbacks of early insulin injections for T2D include risks of cardiovascular disease, weight gain and hypoglycemia, stemming from irregular or incorrect dosing, lack of time in the physician's schedule to manage insulin therapy, and most importantly, patient non-compliance. Successful oral delivery of insulin is therefore a therapeutic Holy Grail as its inherent ease of administration mimicking natural secretion process potentially obviates or minimizes many of the drawbacks, and should reduce much of the burden of managing T2D by health care professionals. However, gastric instability and lack of transport across tightly packed epithelium and overlying mucus are formidable challenges to successful intestinal absorption of insulin. The work enabled by previous findings, in which oral delivery of insulin using ligand-directed nanoparticles that do not compete with physiological ligands led to improved therapeutic outcomes compared to conventional nanoparticles. In this project, the technology is further developed by investigating, how fine-tuning the nanoparticle composition affect the drug disposition and therapeutic outcomes, under the influence of commonly experienced physiological and pathophysiology conditions. In doing so, the project will establish 1) optimal non-competitive nanoparticle chemistry, 2) active drug delivery under pertinent physiological conditions, and 3) the therapeutic window of oral insulin in T2D.

项目概要 传统上，管理 2 型糖尿病 (T2D) 的首要重点是严格控制血糖 使用一种或多种口服药物。目前用于治疗 T2D 的药物包括 增加胰岛素分泌或敏感性的药物，以及降低肝功能的药物 糖异生或肠道碳水化合物吸收。最近的药物包括胰高血糖素样药物 肽-1 (GLP-1) 类似物，可抑制二肽基肽酶-IV 分解内源性 GLP-1 (DPP-IV) 和钠-葡萄糖协同转运蛋白-2 (SGLT-2) 抑制剂，可阻断正常的葡萄糖重吸收 肾脏。根据英国前瞻性糖尿病研究 (UKPDS 33)，即使疗效 这些药物在预防 T2D 微血管并发症（例如视网膜病变、神经病变和肾病）方面的作用 已经部分确定，它们在预防大血管并发症（例如冠心病）中的作用 和中风）仍然难以捉摸。此外，同一项研究还指出，50% 的患者最初控制 单一药物获得耐受性，三年后需要添加第二种药物，九年后 多年来，约 75% 的患者需要多种治疗才能达到目标 HbA1c 值。有 重要证据表明，在一些 T2D 患者中，尽管服用药物，β 细胞功能仍会发生变化 持续下降并最终完全失败，使这些患者成为胰岛素治疗的唯一选择。相当 然而，临床和研究界正在认识到，这并不是作为最后的治疗手段 T2D 患者及早开始胰岛素治疗将纠正所有潜在的致病机制 例如增加 β 细胞凋亡、糖毒性、脂毒性和炎症。早期胰岛素的主要缺点 T2D 注射包括心血管疾病、体重增加和低血糖的风险，这些风险源于 不规则或不正确的剂量、医生日程安排中缺乏时间来管理胰岛素治疗，以及大多数 重要的是，患者不依从。因此，成功的口服胰岛素是治疗的圣杯 其固有的易于管理模仿自然分泌过程可能消除或最大限度地减少许多 缺点，并且应该减轻医疗保健专业人员管理 T2D 的大部分负担。 然而，胃的不稳定性以及缺乏穿过紧密堆积的上皮和上覆粘液的运输是 肠道成功吸收胰岛素面临着巨大的挑战。之前的研究结果促成了这项工作， 使用不与生理配体竞争的配体定向纳米颗粒口服胰岛素 与传统纳米颗粒相比，治疗效果得到改善。在这个项目中，技术是 通过研究微调纳米颗粒成分如何影响药物处置和 在常见的生理和病理生理学影响下的治疗结果 状况。在此过程中，该项目将建立 1) 最佳的非竞争性纳米颗粒化学，2) 活性 相关生理条件下的药物输送，以及 3) T2D 口服胰岛素的治疗窗。