PhD.Diissertation Defense:Serap Sezen
pH-RESPONSIVE CYCLODEXTRIN NANOSPONGES FOR DRUG DELIVERY
Serap Sezen
Molecular Biology, Genetics and Bioengineering, PhD Thesis, 2024
Thesis Jury
Assoc. Prof. Feray Bakan Mısırlıoğlu (Thesis Advisor)
Assoc. Prof. Dr. Meral Yüce
Assoc. Prof. Murat Topuzoğulları
Asst. Prof. Nur Mustafaoğlu Varol
Assoc. Prof. Yasemin Budama Kılınç
Assoc Prof.Ali Zarrabi (Thesis Co-Advisor)
Date & Time: December 16th, 2024 – 09.30 AM
Place: FENS L048
Keywords: Cyclodextrin Nanosponges, Cancer Therapy, pH-Responsiveness, Doxorubicin, Targeted Drug Delivery.
Abstract
Smart drug delivery systems offer significant advantages in cancer treatment. The tumor microenvironment's acidified pH, caused by cancer cell metabolism, provides a unique opportunity to exploit pH-responsive therapies.
In this thesis, pH-responsive cyclodextrin nanosponges (CD NSs) were synthesized for the first time for drug delivery applications. β-cyclodextrin (β-CD) was oxidized and crosslinked with adipic acid dihydrazide (ADH) to produce NSs containing acid-sensitive hydrazone bonds, designed to cleave in acidic conditions. These NSs were used for doxorubicin delivery, with additional functionalization using folic acid to enhance selective uptake by cancer cells.
Comprehensive characterization techniques, including FTIR, ¹H-NMR, DLS, zeta potential measurements, UV-Vis, TGA, DSC, XRD, SEM, and TEM, confirmed successful β-CD oxidation, NS formation, drug loading, and folic acid conjugation. The NSs exhibited an amorphous structure, spherical morphology, uniform size distribution, and minimal surface charge. These NSs were thermally stable, having doxorubicin encapsulation efficiency (EE) of 58% and showed a 1.5-fold increase in drug release under acidic conditions compared to neutral pH.
Biological tests demonstrated that blank NSs were non-toxic to MCF-7 breast cancer cells and L929 fibroblast cells. Doxorubicin-loaded NSs (NS-Dox) induced selective cytotoxicity in MCF-7 cells while sparing L929 cells from the harmful effects. Folic acid conjugation significantly enhanced therapeutic efficacy by reducing the IC50 value of NS-Dox. Cellular uptake studies confirmed that doxorubicin encapsulation in NSs substantially improved internalization by MCF-7 cells.
These findings highlight the potential of the synthesized pH-responsive NSs as effective and targeted delivery vehicles for cancer therapy, offering a promising alternative to conventional treatments.