Document text
Principal Investigator: Andrew Michael Smith
Organization: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
Fiscal Year: 2024
Award: $587,866
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
More than 42% of adults in the United States live with obesity, a condition characterized by excess body fat
primarily within adipose tissue. Obesity is a risk factor for type 2 diabetes, cardiovascular diseases, cancer,
and severe COVID-19 disease and has few widely effective non-surgical interventions. Obesity comorbidities
are believed to be triggered by chronic inflammation in adipose tissue, in part caused by infiltration of
macrophage cells (MΦs) with adipogenic phenotypes in the obese state. However, the pathogenic role of MΦs
is complicated by their diverse and antagonistic roles in adipose metabolism and homeostasis as these cells
have the capacity to promote both lipogenesis and lipolysis and promote both tissue hypertrophy and atrophy.
Previously, we showed that polysaccharide-based nanocarriers could efficiently deliver drugs to adipose MΦs
after intraperitoneal injection. We found that certain classes of these therapies potently modulate MΦ
phenotype, induce rapid body weight loss, and reverse diabetic phenotype in obese rodents without changes in
food intake. We now propose to develop an extended-release drug depot to deliver these MΦ-targeted
nanocarrier drug conjugates to adipose tissue in a translational format designed for high patient adherence.
Two primary technological products will be (1) biodegradable composite depots constructed from materials that
are efficiently and safely eliminated from the body and (2) translational imaging techniques to longitudinally
monitor drug depots in vivo.
In Aim 1, we will tune the composition, size, and shape of the depots to generate implants with translational
form factors, steady release over 6 months, and minimal foreign body response. We will also validate methods
to image and monitor depots by magnetic resonance, ultrasound, and fluorescence modalities. In Aim 2, we
will maximize drug loading and redesign the backbone of our targeted nanocarrier and drug linkers for efficient
excretion and high solubility. In Aim 3, we will determine mechanisms by which regional depots elicit systemic
physiological changes. In Aim 4, we will measure the long-term impact of lead candidate depots on preventing
or reversing obesity and obesity-induced diabetes. We will study the dependence of efficacy on sex, hormonal
status reflecting menopause, and genetic or dietary obesity origins. If successful, the drug delivery system may
provide an urgently needed non-surgical high-adherence strategy to treat patients living with obesity to safely
enhance weight loss and prevent or reverse the progression of comorbidities.
Terms: <21+ years old><Address><Adherence><Adipocytes><Adipose Cell><Adipose tissue><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Animal Model><Animal Models and Related Studies><Animals><Apoplexy><Atrophic><Atrophy><Autoregulation><Biodegradation><Biological><Biology><Blinded><Blood Chemical Analyses><Blood Chemical Analysis><Body Tissues><Body Weight><Body Weight decreased><Body fat><Brain Vascular Accident><Cancers><Cardiac Diseases><Cardiac Disorders><Cardiovascular Diseases><Caring><Cell Body><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chemistry><Chronic><Clinic><Clinical><Clinical Evaluation><Clinical Testing><Conjugated Carrier><Dependence><Dextrans><Diabetes Mellitus><Diet><Disease><Disorder><Distal><Dose><Drug Carriers><Drug Delivery><Drug Delivery Systems><Drug Monitoring><Drug Precursors><Drug Targeting><Drug Therapy><Drugs><Eating><Endocrinology><Engineering><Excretory function><FDA approved><Fat Cells><Fatty Tissue><Fluorescence><Food Intake><Foreign Bodies><Formulation><Frequencies><Gastroenterologist><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Susceptibility><Genetic propensity><Glycans><Goals><Health Care Systems><Healthcare Systems><Heart Diseases><Hematology><Histopathology><Homeostasis><Hormonal><Human><Hydrolysis><Hypertrophy><IP injection><Illinois><Image><Imaging Device><Imaging Instrument><Imaging Procedures><Imaging Technics><Imaging Techniques><Imaging Tool><Immune><Immune Targeting><Immunes><Implant><Incidence><Individual><Infiltration><Inflammation><Inherited Predisposition><Inherited Susceptibility><Injectable><Intermediary Metabolism><Intervention><Intervention Strategies><Intraperitoneal Injections><Ketosis-Resistant Diabetes Mellitus><Lead><Lipocytes><Lipolysis><MR Imaging><MR Tomography><MRI><MRIs><Macrophage><Magnetic Resonance><Magnetic Resonance Imaging><Maintenance><Malignant Neoplasms><Malignant Tumor><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Menopause><Metabolic Processes><Metabolism><Metabolism and Endocrinology><Methods><Modality><Modern Man><Modification><Monitor><Mφ><NIDDM><NMR Imaging><NMR Tomography><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear Magnetic Resonance Imaging><Obesity><Obesity Epidemic><Out-patients><Outpatients><PPAR alpha><PPAR-α><PPARalpha><PPARα><Pathogenicity><Pathology><Patient Compliance><Patients><Pb element><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Pharmaceutical Preparations><Pharmacology><Pharmacotherapy><Phenotype><Physiologic><Physiological><Physiological Homeostasis><Play><Polysaccharides><Pro-Drugs><Process><Prodrugs><Public Health><Regimen><Risk Factors><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><Shapes><Slow-Onset Diabetes Mellitus><Solubility><Spatial Distribution><Specialist><Spinal Column><Spine><Stable Diabetes Mellitus><Stroke><System><T2 DM><T2D><T2DM><Technology><Testing><Therapeutic><Tissues><Toxic effect><Toxicities><Translating><Treatment Failure><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><United States><Universities><Vertebral column><Visceral><Visit><Weight><Weight Loss><Weight Reduction><Work><Zeugmatography><adipogenesis><adipose><adiposity><adult onset diabetes><adulthood><attenuation><backbone><biodegradable scaffold><biologic><blood chemistry><body weight loss><brain attack><cancer type><cardiovascular disorder><cerebral vascular accident><cerebrovascular accident><clinical care><clinical test><co-morbid><co-morbidity><cohort><comorbidity><corpulence><cytokine><design><designing><dextran><diabetes><diabetic><dietary><diets><drug treatment><drug/agent><excretion><exosome><extracellular><genetic etiology><genetic mechanism of disease><genetic vulnerability><genetically predisposed><glucose tolerance><heart disorder><heavy metal Pb><heavy metal lead><image translation><image-based method><imaging><imaging method><imaging modality><improved><in vivo><interventional strategy><ketosis resistant diabetes><lead candidate><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lipid biosynthesis><lipogenesis><malignancy><maturity onset diabetes><mechanical properties><mimetics><model of animal><mouse model><multidisciplinary><murine model><nanocarrier><nanomaterials><nanovessel><neoplasm/cancer><non-invasive imaging><noninvasive imaging><obesity intervention><obesity therapy><obesity treatment><patient adherence><patient cooperation><pre-clinical><preclinical><prevent><preventing><research clinical testing><response><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><sex><side effect><small molecule therapeutics><social role><stroked><strokes><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy failure><translational study><treatment adherence><treatment compliance><type 2 DM><type II DM><type two diabetes><ultrasound><weights><white adipose tissue><wt-loss><yellow adipose tissue>