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: 10580808
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580808
• 关键词: Active Biological Transport; Address; Adoption; Affect; Affinity; Anxiety; Apical; Apoptosis; Beta Cell; Binding; Binding Sites; 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; Communities; Complex; Coronary heart disease; Diabetes Mellitus; Dipeptidyl-Peptidase IV; Disease; Disease Progression; Dosage Forms; Dose; Drug Carriers; Drug Delivery Systems; Drug Kinetics; Encapsulated; Epithelium; Excipients; Fasting; Food; Formulation; Friends; 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; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Physiological; Polyesters; Polymers; Rattus; Reporting; Research; 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; conventional dosing; diabetic rat; drug disposition; drug efficacy; experience; gambogic acid; glucagon-like peptide 1; hepatic gluconeogenesis; improved; in vivo; in vivo Model; inhibitor; insulin secretion; insulin sensitivity; intestinal barrier; macrovascular disease; medication administration; nanoparticle; nanoscale; nanosystems; novel; prevent; prospective; psychologic; rational design; receptor; receptor binding; secretion process; side effect; stem; symporter; 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.

项目摘要 传统上，管理2型糖尿病（T2 D）的主要焦点是严格控制血糖 使用一种或多种口服药物。目前用于治疗T2 D的药物范围从 增加胰岛素分泌或敏感性的药剂，至降低肝胰岛素分泌或敏感性的药剂。 肠道碳水化合物的吸收。最近的药物包括胰高血糖素样 肽-1（GLP-1）类似物，其抑制内源性GLP-1被二肽基肽酶-IV分解 （DPP-IV）和钠-葡萄糖协同转运蛋白-2（SGLT-2）抑制剂，其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T2 D的微血管并发症中的作用（例如，视网膜病变、神经病变和肾病） 已经部分确定，它们在预防大血管并发症中的作用（例如，冠心病 和中风）仍然难以捉摸。此外，同一项研究指出，50%的患者最初控制 用一种药物获得耐受性，三年后需要添加第二种药物， 大约75%的患者需要多种治疗才能达到目标HbA 1c值。有 有重要证据表明，在一些T2 D患者中，尽管服用药物，β细胞功能仍发生了变化， 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。而 然而，临床和研究界都认识到， 在T2 D患者中早期开始胰岛素治疗将纠正所有潜在的致病机制 如β细胞凋亡增加、葡萄糖毒性、脂毒性和炎症。早期胰岛素的主要缺点 注射T2 D包括心血管疾病、体重增加和低血糖的风险， 不规则或不正确的剂量，医生的时间表中缺乏时间来管理胰岛素治疗，以及大多数 更重要的是，患者不服从。因此，胰岛素的成功口服递送是治疗的圣杯， 其模仿天然分泌过程固有的给药容易性潜在地消除或最小化了许多 的缺点，并应减少医疗保健专业人员管理T2 D的负担。 然而，胃的不稳定性和缺乏运输通过紧密包装的上皮和覆盖的粘液， 胰岛素的成功肠道吸收的巨大挑战。这项工作使以前的调查结果，在 所述口服递送使用不与生理配体竞争的配体导向的纳米颗粒 与传统的纳米颗粒相比，导致了改善的治疗效果。在这个项目中， 通过研究进一步开发，微调纳米颗粒组合物如何影响药物处置， 在常见生理和病理生理学影响下的治疗结局 条件在这样做的过程中，该项目将建立1）最佳的非竞争性纳米粒子化学，2）活性 在相关生理条件下的药物递送，和3）T2 D中口服胰岛素的治疗窗。

项目成果

Oral Nanocurcumin Alone or in Combination with Insulin Alleviates STZ-Induced Diabetic Neuropathy in Rats.

• DOI: 10.1021/acs.molpharmaceut.2c00465
• 发表时间: 2022-12-05
• 期刊: MOLECULAR PHARMACEUTICS
• 影响因子: 4.9
• 作者: Dwivedi, Subhash;Gottipati, Anuhya;Ganugula, Raghu;Arora, Meenakshi;Friend, Richard;Osburne, Robert;Rodrigues-Hoffman, Aline;Basu, Rita;Pan, Hui-Lin;Kumar, M. N. V. Ravi
• 通讯作者: Kumar, M. N. V. Ravi

Nanoparticles that do not compete with endogenous ligands - Molecular characterization in vitro, acute safety in canine, and interspecies pharmacokinetics modeling to humans.

• DOI: 10.1016/j.jconrel.2021.02.009
• 发表时间: 2021-04-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Zou D;Arora M;Ganugula R;Kumar M;Scott EM;Shah D;Kumar MNVR
• 通讯作者: Kumar MNVR

Urolithin A Nanoparticle Therapy for Cisplatin-Induced Acute Kidney Injury.

尿石素纳米颗粒治疗顺铂引起的急性肾损伤。

• DOI: 10.1159/000524509
• 发表时间: 2023
• 期刊: Nephron
• 影响因子: 2.5
• 作者: Kumar,MNVRavi