Dual-controlled delivery of furosemide and atenolol using a biodegradable nanosystem for antihypertensive therapy

The fundamental objective of this work was to develop double-layered nanosystems based on biodegradable polymers for combination therapy of arterial hypertension (AH). These nanosystems were designed and characterised with furosemide (FUR) and atenolol (ATN) as model antihypertensive drugs. Biodegradable copolymeric carriers were synthesized by the ring-opening polymerization (ROP) of glycolide (GA), epsilon-caprolactone (CL), and L,L-lactide (LLA) with rutin as a natural initiator. The obtained materials were utilized to generate macromolecular conjugates of FUR. Simultaneously, poly(L,Lactide) (PLLA) was synthesized by ROP of the LLA monomer. The double-layered nanosystems were then developed with a non-solvent additionphase separation method. FUR was ester bonded to the copolymeric matrices that comprised the nanosystem's core, whereas ATN was physically bound to PLLA to form the nanosystem shell. According to first-order kinetics, nanosystems released FUR in the range of 69.9-79.4% and ATN in the range of 86.1-91.9% after 85 h of incubation. For ATN release, it was discovered that the diffusion mechanism was dominant. The simultaneous release of FUR was assessed by hydrolysis of the ester bond in the synthesized conjugates as well as diffusion through the copolymeric shell. Cytotoxicity experiments on human embryonic kidney cells, including the neutral red uptake (NRU), MTT, and Lactate Dehydrogenase Activity (LDH) assays, revealed that the produced materials were non-toxic at the concentrations used.