Macrophage-Targeted Drug Delivery Depot for Obesity and Comorbid Type 2 Diabetes - 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.
