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
基本信息
- 批准号:10373829
- 负责人:
- 金额:$ 37.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Active Biological TransportAddressAdoptionAffectAffinityAnxietyApicalApoptosisBeta CellBindingBinding SitesBioavailableBiodistributionBiologicalBiological AvailabilityBiological ModelsBlood GlucoseCarbohydratesCell LineCell Surface ReceptorsCell physiologyCell surfaceCenters for Disease Control and Prevention (U.S.)ChemistryChronicClinicalClinical ResearchCommunitiesComplexCoronary heart diseaseDiabetes MellitusDipeptidyl-Peptidase IVDiseaseDosage FormsDoseDrug CarriersDrug Delivery SystemsDrug DesignDrug KineticsEncapsulatedEpithelialExcipientsFastingFoodFormulationFoundationsFrightFunctional disorderGastrointestinal tract structureGlucoseGlycosylated hemoglobin AGoalsGrantHealth ProfessionalHigh Fat DietHypoglycemiaIn VitroInflammationInjectionsInsulinInsulin-Dependent Diabetes MellitusInterventionIntestinal AbsorptionIntestinesIronKidneyKidney DiseasesKnowledgeLeadLengthLigandsLiteratureMammalian CellMediatingMedicineMicrovascular DysfunctionModelingMolecular WeightMucous body substanceNeedlesNeuropathyNon-Insulin-Dependent Diabetes MellitusNucleosome Core ParticleOralOral AdministrationOutcomePainPathogenicityPatient NoncompliancePatientsPeptide HydrolasesPerceptionPerformancePharmaceutical PreparationsPharmacologic SubstancePhysiciansPhysiologicalPolyestersPolymersRattusReportingResortRetinal DiseasesRoleScheduleSodiumStomachStrokeSurfaceSystemTFRC geneTabletsTechnologyTestingTherapeuticTimeToxic effectTransferrinUnited KingdomWeight GainWorkabsorptionamphiphilicityanalogcapsulecardiovascular disorder riskcompliance behaviordensitydiabetic ratdrug dispositiondrug efficacyexperiencegambogic acidglucagon-like peptide 1hepatic gluconeogenesisimprovedin vivoin vivo Modelinhibitor/antagonistinsulin secretioninsulin sensitivityintestinal barriermacrovascular diseasenanoparticlenanoscalenanosystemsnovelpreventprospectivepsychologicreceptorreceptor bindingsecretion processside effectstemtherapy outcome
项目摘要
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.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Raghu Ganugula其他文献
Raghu Ganugula的其他文献
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{{ truncateString('Raghu Ganugula', 18)}}的其他基金
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:
10399664 - 财政年份:2020
- 资助金额:
$ 37.25万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 37.25万 - 项目类别:
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:
10027854 - 财政年份:2020
- 资助金额:
$ 37.25万 - 项目类别:
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