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Polymeric nanoparticles for target delivery of drugs to renal proximal tubules

Abstract

Type 2 diabetes mellitus is a chronic disease that results in dysfunctional regulation of blood glucose level and a multifactorial risk of other health problems, such as cardiovascular morbidity and mortality, and an important risk factor for chronic kidney disease. The constant increase in cases of diabetes mellitus 2 has encouraged innovative research on new drugs and treatment methods. A more recent type of treatment is based on the inhibition of sodium-glucose co-transporters (SGLT) which are intestinal cell and renal proximal tubule proteins responsible for the glucose absorption into the cell independently of insulin. While SGLT2 is only expressed in the kidney, SGLT1 is also expressed in the intestine. The encouraging results of clinical trials with the drug Sotaglioflozin, a dual SGLT1/SGLT2 inhibitor, were recently published. Despite the reduction in cardiovascular events in patients with type 2 diabetes mellitus, some adverse effects were reported, such as gastrointestinal discomfort, higher incidence of mycotic genital infections and a high occurrence of diarrhea, resulting in the rejection of the drugs by the patients. Motivated by the excellent results of clinical trials with Sotaglioflozin, this project will focus on the development of NPs for controlled release and specific delivery to the kidney, more specifically to the proximal tubules. The transport of Sotaglioflozin and its controlled release may increase the efficiency of renal inhibition of SGLT1/SGLT2 and reduce adverse effects, especially in the intestine, such as diarrhea. Three types of biopolymers were chosen, chitosan, polylactic-co-glycolic acid and pectin. Comparison of in vitro and in vivo biological responses, such as kidney targeting capacity, release kinetics, glycemic control, renal glucose excretion and toxicity will be performed by multicriteria decision-making methods to identify the most promising carrier for application in the treatment of type 2 diabetes mellitus. (AU)

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