Nintedanib İçeren Hedeflendirilmiş Hibrit Nanopartikül Formülasyonlarının Tasarlanması ve Multipl Skleroz Tedavisindeki Etkinliğinin Değerlendirilmesi

Abstract

Within the scope of this thesis study, the effect of Nintedanib, which is used in the clinic for its antifibrotic and anti-inflammatory effects, in mice with in vivo experimental autoimmune encephalomyelitis (EAE) model was evaluated by comparing it with methyl prednisolone, which is widely used in multiple sclerosis (MS) treatment. For this purpose, ND, which is known to cross the blood-brain barrier (BBB) in very low amounts, was loaded into a hybrid nanoparticle (HNP) drug carrier system with a polymeric inner core lipid outer shell structure, which is one of the frequently preferred carrier systems to overcome the BBB. In addition, the designed HNPs were conjugated with a type I collagen-specific peptide to selectively target type I collagen, which was found to accumulate in the spinal cord due to MS. HNPs with suitable properties (particle size <200 nm, etc.) were designed to overcome KBE and the HNP formulation was conjugated with an appropriate proportion of peptides. Drug loading efficiency and release kinetics of the formulations were calculated. The cytotoxicity of ND and HNP formulations were evaluated on L929 cells. Clinical scoring in mice showed that peptide-conjugated, ND-loaded HNP was effective in the treatment of MS, and changes in myelin basic protein and type I collagen were observed. In addition, brain and spinal cord tissues obtained from animals. Metabolomic studies carried out in brain and spinal cord tissues obtained from animals revealed changes in the amounts of substances associated with MS. It has been shown that peptide conjugation to HNP provides more drug transport to the disease site. With these studies for HNP formulations designed for the treatment of MS, it has been found that the formulations are safe and as effective as the market preparation.