Remote Loading of Melanocortin and GLP-1 Peptides in Polymers for Treatment of Obesity

About This Grant

ABSTRACT Rates of obesity have steadily increased in the US, with about 50% of Americans projected to be obese by 2030. Recent advances include GLP-1 peptides, such as semaglutide, approved in 2021 for adult obesity, and setmelanotide, approved in 2020 for early-onset syndromic obesity due to POMC and leptin receptor deficiency. However, setmelanotide is not sufficiently effective for MC4R haploinsufficiency or common dietary obesity, causes hyperpigmentation, and requires daily injections. GLP-1 therapies also show variable efficacy, with 23% of patients losing less than 5% of body weight after two years and up to 30% experiencing nausea. To improve the potency and specificity of MC4R peptide agonists like setmelanotide, we performed extensive structure-activity relationship work involving the synthesis and characterization of 426 new melanocortin peptides (MCs). This work led to discovery of MCs with 4X increased potency relative to setmelanotide, and with reduced hyperpigmentation. Also exciting, we recently discovered that MCs increase the dose-sensitivity to GLP-1s without increasing malaise or activity in the brain’s emesis center. This finding could help reduce well-known toxicity of GLP-1s, allowing more patients to benefit from GLP-1s. To realize cost-effective and facile PLGA microsphere encapsulation and delivery of the MCs and GLP-1s, we recently discovered an extremely simple, efficient, and generalizable water-based remote encapsulation method for peptides, involving short-term mixing of aqueous peptides and empty poly(lactic-co-glycolic acid) (PLGA) microspheres. In this R56 grant our team will further develop and optimize the remote-loading method for GLP-1s, while further advancing the mechanism of the rapid and spontaneous remote peptide loading based on peptide-polymer binding with or without additional excipients at physiological temperature. The new encapsulation method will allow for the combination of multiple formulations of sterile empty PLGA microspheres that encapsulate the peptide drugs to achieve constant drug release. We will determine the dosing of both single MC and MC/GLP-1 combinations in acute and chronic animal models of both genetic (MC4R+/-) and dietary obesity. For MCs we will use remote-loaded setmelanotide formulations already developed in the lab. We will evaluate pharmacokinetics of the remote-loaded GLP-1s to facilitate microsphere combination for constant peptide release and to test their release performance in vivo. Hence, this new drug delivery approach using MCs and their GLP-1 combinations could be useful for future treatments of a wide variety of forms of obesity.