Beyin Tümörü Tedavisinde Antikanser İlaçlarının Nazal Yolla Aktarımı İçin Lipit Temelli Taşıyıcıların Geliştirilmesi

Abstract

Treatment of brain tumor is a difficult obstacle to overcome due to the high selectivity and limited drug permeability of the blood-brain barrier. In recent years, as an alternative, drug transfer from the nose to the brain is an application that has come to the fore. By the nasal route, drug active substances can reach the brain by one of the direct routes (via olfactory and/or trigeminal nerves) or indirectly by being absorbed into the central circulation. However, there are some aspects that are open to improvement in trans-nasal method in terms of nose-to-brain drug delivery. It is known that agents administered intranasally lose their activity by enzymatic degradation on the surface of the nasal mucosa, and are cleaned from the body by the cilia in the nasal mucosa (mucociliary cleaning). For these reasons, delivery of agents in an appropriate drug delivery system that can significantly increase the process of delivery is necessary and very important to overcome these difficulties. The interaction of the particles with the mucus layer and the penetration through this layer depend not only on the size of particles but also their surface charge, surface morphology and elasticity. Hence, these critical parameters are vital in terms of drug delivery process via nose-to-brain administration. iv The aim of this thesis is to prepare hybrid particles in Janus structure (JNPs), which have the potential to be used effectively in drug delivery via nose-to-brain delivery and can simultaneously encapsulate more than one active agent with different solubilities, to study in vitro encapsulation and release, and to examine the interaction and penetration of the prepared janus structured hybrid particles with nasal mucus. For this purpose, in the first part of the study, it was aimed to design the size and other physicochemical properties of the JNPs for the targeted region and thus to prepare systems that can reach tumor cells. In the second part of the study, methylene blue (MM) and resveratrol (Res) were used as model drug molecules in order to evaluate the in vitro encapsulation/release capacities of JNPs designed for the targeted region. It has been determined that the particles can encapsulate molecules with different solubility individually and in pairs, and perform their simultaneous controlled release. Based on this, the anti-cancer agents Doxorubicin (Dox) and Curcumin (Cur) that are desired to be delivered to the brain were encapsulated and the encapsulation /release capacities were evaluated. Based on the results obtained, it has been observed that the agents can be simultaneously encapsulated into the polymer and lipid compartments of the JNP particles, and their simultaneous and sequential releases can occur. In the third part of the study, solid lipid nanoparticles (KLN) and polymer nanoparticles (polymer NP) which have similar size and zeta potential values below -25 mV with JNP9s, were interacted with mucus. It was observed that the particle type with the least interaction was JNP9s which can also provide effective penetration. In the fourth part of the study, penetration studies of JNP9 with nearly similar zeta potential values and sizes, KLN and polymer NPs were carried out with circular diffusion tubes. According to the results obtained, it has been observed that JNP9s, whose aspect ratio is determined as approximately 1.4, can diffuse better in mucin than KLN and polymer NP with spherical geometry, and thus they can clearly reveal the effect of their anisotropic structures. In the last part of the study, cytotoxicity analyzes of JNP9s (empty and dual-drug encapsulated) and free anti-cancer agents (Cur and Dox separately and together) were determined by the MTT (3-(4,5-dimethylthioazol-2-il)-2,5-diphenyltetrazolium v

bromide) method by using L-929 mouse fibroblast cell line. When the results of the analysis with empty and dual drug loaded JNP9s were examined, it was seen that the prepared particles showed low cytotoxicity to healthy cells, were biocompatible and could be used as a safe carrier system for the delivery of active drug agents. With this thesis, for the first time in the literature, lipid and polymer-based, biocompatible and multifunctional carriers with suitable size, special geometry and surface properties, a high potential to penetrate the nasal mucosa and ability to simultaneously encapsulate and release active pharmaceutical agents with different solubilities have been prepared fort he delivery of active pharmaceutical agents via nose-to-brain administration.