PH duyarlı çoklu ilaç salımı için metal organik çerçeve temelli mikro kapsüllerin hazırlanması ve karakterizasyonu
Preparation and characterization of metal organic framework based microcapsules for pH responsive multi-drug release
Yazar: EMİN UYSAL
Danışman: PROF. DR. NİHAL AYDOĞAN ; PROF. DR. HALİL KALIPÇILAR
Hacettepe Üniversitesi / Fen Bilimleri Enstitüsü / Kimya Mühendisliği Ana Bilim Dalı
Derece: Yüksek Lisans, 2023
Konu: Kimya Mühendisliği = Chemical Engineering

Özet:
İlaç taşınım sistemlerinin tasarımında ve hazırlanmasında üzerinde durulan en
önemli noktalardan bir tanesi, tedaviye yönelik birden fazla etkinin sinerjistik
olarak sağlanmasıdır. Özellikle kanser tedavisine yönelik çalışmalarda sinerjistik
etkinin sağlanması son yıllarda hızla önem kazanan ve üzerinde durulan bir
konudur. Bu sayede mono terapinin sınırlamalarını ortadan kaldırmak, tedaviyi
etkin kılmak ve en az ilaç/kimyasal dozu ile maksimum etkiyi sağlamak
amaçlanmaktadır. Veziküller bulundurdukları lipit ve sulu kompartmanlar,
biyouyumlulukları ve makromolekülleri dahi kapsülleme ve taşıyabilme
yetenekleri ile uzun yıllardır çalışılan yapılardır. İlaç taşıyıcı özelliklerinin yanı sıra
veziküller içerdikleri hidrofilik ve hidrofobik bileşenleri ile sinerjistik etki
sağlayabilecek şekilde tasarlanabilmektedir. Çalışmanın ilk kısmında bu amaç
doğrusunda, kemodinamik terapi yöntemlerinin önemli bir çeşidi olan fenton
reaksiyonlarını gerçekleştirebilecek, vezikülü oluşturan moleküllerden biri olarak
kullanılarak vezikülün çift tabakasında yer alacak ve sulu çekirdeği potansiyel bir

Abstract:
One of the most important points in the design and preparation of drug delivery
systems is the synergistic provision of multiple therapeutic effects. Providing
synergistic effects, especially in cancer treatment studies, is an issue that has
gained importance and focused on in recent years. In this way, it is aimed to
eliminate the limitations of monotherapy, to make the treatment effective and to
provide maximum effect with the least drug/chemical dose. Vesicles are
structures that have been studied for many years with their lipid and aqueous
compartments, their biocompatibility and ability to encapsulate and transport
even macromolecules. In addition to their drug carrier properties, vesicles can be
designed to provide synergistic effects with their hydrophilic and hydrophobic
components. In the first part of the study, a vesicle that can perform Fenton
reactions, which is an important type of chemodynamic therapy methods, was
synthesized. A surfactant, N,N-dimethylferrocenylmethylundecyl ammonium
bromide (Fc(C11)) has been used as the fenton agent. This surfactant has been
used as one of the vesicle forming molecules and is located in the bilayer of the
vesicle, allowing us to leave the aqueous core as a potential reservoir. Cationic Fc(C11) and anionic sodium dioctylsulfosuccinate (AOT) were used to obtain a
catanionic vesicle Characterization of vesicles was performed using dynamic
(DLS) and static light scattering (SLS).Monomeric Fc(C11) and vesicle Fc(C11)-
The performance of AOT fenton reaction was investigated by methylene blue
removal method. The data were analyzed by applying different kinetic models. As
a result of the experiments, chemodynamic therapy agent vesicles were obtained
that successfully carried out the fenton reactions. The second step of the study
was the synthesis and development of zeolitic imidazolate framework-8 (ZIF-8).
ZIF-8 is one of the main components of this drug delivery system. ZIF-8 is a type
of MOF that has been studied in many areas from gas separation to catalysis
processes since its discovery, with its advantages such as high porosity, chemical
and thermal stability. However, in the last decade, it has become a prominent
crystal structure in drug transport studies with its pH sensitive structure. Within
the scope of the study, ZIF-8 was synthesized as a potential chemotherapy agent
carrier that can make pH sensitive controlled release. The "one-pot" method was
used to load rhodamine-b (Rhb) into ZIF-8 as the model molecule. ZIF-8
synthesis was carried out in solvent environments such as methanol and water,
and the amount of zinc, imidazole and rhodamine-b was studied parametrically.
The release of rhodamine-b was carried out in phosphate buffer solutions with
different pH and the rhodamine uptake-release performance of ZIF-8 crystals was
investigated. Potential chemotherapy agent particles were obtained with the
ability of ZIF-8 crystals to successfully encapsulate and release (Rhb@ZIF-8) pH-
sensitive rhodamine-b, which is used as a model molecule. Then, in order to
increase the synergistic effect, polydopamine (PDA) with photothermal therapy
effect was coated on ZIF-8 crystals. The PDA coating was provided by the
polymerization of dopamine hydrochloride (DA-HCl) directly on the ZIF-8 surface
in alkaline medium. Tris buffer solution was used in the coating and a ratio of 1:1
by weight of DA-HCl:ZIF-8 was used. The photothermal effect of the obtained
particles (Rhb@ZIF-8/PDA) was followed by a thermal camera under a laser with
a wavelength of 808 nm. It has been observed that the particles provide the
necessary temperature increase for photothermal therapy even at low
concentrations. ZIF-8, Rhb@ZIF-8 and Rhb@ZIF-8/PDA particles were
characterized by DLS, AFM, TEM, XRD and FTIR and zeta potential
measurements. In the final stage of the study, chemodynamically effective vesicles and ZIF-8 crystals with photodynamic and chemotherapeutic effects
were combined by utilizing electrostatic interactions. Rhodamine-b release and
Fenton reaction performance of the obtained drug delivery system were
performed as mentioned above. As a result of the study, a multifunctional drug
delivery system with chemodynamic, photothermal and chemotherapeutic effects
was obtained with Rhb@ZIF-8/PDA coated on the outer surface of Fc(C11)-AOT
vesicles.