Polymeric nanoparticles for inductive browning of white adipose tissue

Global epidemics of obesity and its associated comorbidities pose formidable challenges to human healthCurrent few medications available for obesity treatment only produce modest effects and are usually accompanied with unpleasantpotentially harmful side effectsThere is accumulating evidence that significant metabolic differences that distinguish beige brown adipocytes from white adipocytes can potentially be exploited to establish new therapeutic strategies for treatment and prevention of obesityIt has been recently demonstrated that inhibition of Notch signaling through intraperitoneal injection of dibenzazepineDBZasecretase inhibitorresults in profound transformation of white adipocytes into beige adipocytesbrowningand consequently reduces obesity and improves glucose balance in obese miceHowevertranslation of this discovery into clinical practice is challenged by potential off target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesisThusthere is a critical need for the development of new drug delivery systems that will allow selective spatio temporal delivery of Notch inhibitor DBZ to adipose tissuesThe goal of this proposal is to develop a biodegradable polymeric nanoparticulate system designed to deliver DBZ in a controlled manner to white adipose tissuesWATto achieve browning of white adipocytes and thereby reduce obesity in obese miceThe collaborative research work by DrMeng Deng and DrShihuan Kuang has recently demonstrated the promise of DBZ loaded poly lactide co glycolidePLGAnanoparticlesDBZ NPsfor direct intracellular delivery of DBZ to the adipocytes within specific subcutaneous WAT depotsThis has resulted in the formation of Adipo Therapeutics to explore commercial opportunities linked to these findingsPLGA has been selected as the delivery system because it is an FDA approved biodegradable and biocompatible materialThe goal of this project will be achieved by performing the followingAimOptimize a DBZ NP system for intracellular delivery of DBZ to promote browning of white adipocytesAimEstablish the efficacy of the optimized DBZ NPs to reduce obesity in miceThe overall hypothesis is that DBZ NPs can be optimized to provide sustained intracellular release of biologically active DBZ both in culture and in vivoand will suppress Notch signalingthereby inducing browning of white adipocytes and reducing obesity in a mouse modelAt the end of Phase IAdipo Therapeutics expects to have optimized a novel technology platform composed of polymer based nanoparticles to induce beige adipocyte biogenesisDuring Phase IIAdipo Therapeutics plans to explore clinical translation of the polymer based technology platformIt is also expected that application of this engineered nanoparticulate system will improve fundamental understanding of the role of Notch signaling in browning and regulating body energy homeostasisSuccessful completion of the project will have an impact in development of safe and effective therapeutic strategies for the treatment for obesity Transformation of white adipocytes into beige adipocytesbrowninghas great potential for development of new therapeutics for treatment and prevention of obesityCurrent strategies for enhancement of beige adipocyte biogenesis and function involve genetic and systemic pharmacological manipulationswhich are associated with significant translational challenges due to off target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesisThe proposed study seeks to develop a clinically translatable polymeric nanoparticulate system that induces browning of white adipocytes to reduce obesity in a spatio temporally controlled manner