Migren Tedavisinde Kullanılmak Üzere Geliştirilen Hibrit Nanopartiküllerin İn Vitro ve İn Vivo Etkinliklerinin Değerlendirilmesi

Abstract

Kaya MZ. Evaluation of In Vitro and In Vivo Activities of Hybrid Nanoparticles Developed for the Treatment of Migraine, PhD Thesis, Pharmaceutical Technology Program, Graduate School of Health Sciences, Hacettepe University, Ankara, 2023. In this thesis study, the development of PLGA nanoparticles conjugated with RZT-loaded CGRP (8-37) for intranasal administration for migraine treatment is aimed. The objective includes the in vitro characterization of the developed nanoparticles, cell culture experiments, determination of the amount of RZT reaching the brain in an in vivo mouse model, metabolic analyses, and evaluation of their effects on a cortical spreading depression migraine model created using optogenetic methods. Conjugation of CGRP (8-37) peptide to PLGA polymer was performed, and nanoparticle formulations were obtained using this conjugate. Cell culture studies revealed an increased receptor affinity of the nanoparticles through conjugation. Furthermore, it was demonstrated that the formulations were not cytotoxic at the concentrations to be used in in vivo experiments. Upon intranasal and intraperitoneal administration, the formulations facilitated higher transport of RZT to the brain compared to the RZT solution group, with the conjugated/targeted nanoparticle formulations showing even higher levels of RZT transport to the brain. Metabolomic studies indicated alterations in some metabolite levels in the brain after intranasal and intraperitoneal formulation application. The effectiveness of conjugated/targeted formulations was demonstrated in the in vivo mouse migraine model. Keywords: Migraine, Rizatriptan, CGRP (8-37), PLGA, Nanoparticle-Based Drug Delivery Systems Supporting Institutions: Scientific and Technological Research Council of Turkey (TÜBİTAK); The student received a scholarship under the TUBITAK 2244 (118C131) program during their doctoral education. Additionally, in vivo experiments were conducted in the USA with the support of the TUBITAK 2214 (1059B142100088) scholarship program.