Browsing by Author "Bayram, Nazende Nur"

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Development of breast cancer targeted, multifunctional cross-linked micelle nanocarriers
(Abdullah Gül Üniversitesi, Fen Bilimleri Enstitüsü, 2023) Bayram, Nazende Nur; AGÜ, Fen Bilimleri Enstitüsü, Biyomühendislik Ana Bilim Dalı
In this thesis, we developed two different micelle-based nanocarriers, which are pH-responsive and core cross-linked micelle (CCMs), and specifically target HER2 receptor on breast cancer cells. Intracellularly degradable and stabilized micelles were prepared by core cross-linking and RAFT polymerization in the presence of an acid-sensitive cross-linker. Poly(OEGMA) and poly(SBMA) were used as shell parts of these micelles in order to compare the effect of hydrophilic coatings on nanocarrier characteristics. In the first design, we applied drug conjugation (Doxorubicin) with a cleavable linker while in the second design, we used the encapsulation method for drug loading. Targeted micelles were obtained by coupling of HER2-specific peptides (VSSTQDFP and LTVSPWY) and antibody (Herceptin) to POEGMA and poly (SBMA) based CCMs, respectively. These nanocarriers are designed to be stable in blood circulation but cleavable intracellulary to achieve controlled drug release. Nanocarriers were characterized structurally by FTIR and 1H-NMR spectroscopies for all synthesis and conjugation steps. Moreover, nanocarriers and drug-loaded formulations were investigated by Zetasizer, Nanosight, and TEM/SEM analysis. The results showed that designed nanocarriers have a very high potential for HER2-specific targeted drug release for the treatment of breast cancer. This thesis holds significant importance due to its successful demonstration of two distinct systems exhibiting high stability, pH sensitivity, and high selectivity for HER2-targeted therapy of breast cancer.
HER2-Specific Peptide (LTVSPWY) and Antibody (Herceptin) Targeted Core Cross-Linked Micelles for Breast Cancer: A Comparative Study
(MDPI, 2023) Bayram, Nazende Nur; Ulu, Gizem Tuğçe; Abdulhadi, Nusaibah Abdulsalam; Gürdap, Seda; İşoğlu, İsmail Alper; Baran, Yusuf; İşoğlu, Sevil Dinçer; 0000-0002-8697-1654; 0000-0001-6428-4207; 0000-0001-6582-4981; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Bayram, Nazende Nur; Gürdap, Seda; İşoğlu, İsmail Alper; İşoğlu, Sevil Dinçer
This study aims to prepare a novel breast cancer-targeted micelle-based nanocarrier, which is stable in circulation, allowing intracellular drug release, and to investigate its cytotoxicity, apoptosis, and cytostatic effects, in vitro. The shell part of the micelle is composed of zwitterionic sulfobetaine ((N-3-sulfopropyl-N,N-dimethylamonium)ethyl methacrylate), while the core part is formed by another block, consisting of AEMA (2-aminoethyl methacrylamide), DEGMA (di(ethylene glycol) methyl ether methacrylate), and a vinyl-functionalized, acid-sensitive cross-linker. Following this, a targeting agent (peptide (LTVSPWY) and antibody (Herceptin®)), in varying amounts, were coupled to the micelles, and they were characterized by 1H NMR, FTIR (Fourier-transform infrared spectroscopy), Zetasizer, BCA protein assay, and fluorescence spectrophotometer. The cytotoxic, cytostatic, apoptotic, and genotoxic effects of doxorubicin-loaded micelles were investigated on SKBR-3 (human epidermal growth factor receptor 2 (HER2)-positive) and MCF10-A (HER2-negative). According to the results, peptide-carrying micelles showed a higher targeting efficiency and better cytostatic, apoptotic, and genotoxic activities than antibody-carrying and non-targeted micelles. Also, micelles masked the toxicity of naked DOX on healthy cells. In conclusion, this nanocarrier system has great potential to be used in different drug-targeting strategies, by changing targeting agents and drugs.
HER2-Targeted, Degradable Core Cross-Linked Micelles for Specific and Dual pH-Sensitive DOX Release
(WILEY-V C H VERLAG GMBHPOSTFACH 101161, 69451 WEINHEIM, GERMANY, 2021) Bayram, Nazende Nur; Ulu, Gizem Tugce; Topuzogullari, Murat; Baran, Yusuf; Isoglu, Sevil Dincer; 0000-0002-8697-1654; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Bayram, Nazende Nur; Isoglu, Sevil Dincer
Here, a targeted, dual-pH responsive, and stable micelle nanocarrier is designed, which specifically selects an HER2 receptor on breast cancer cells. Intracellularly degradable and stabilized micelles are prepared by core cross-linking via reversible addition-fragmentation chain-transfer (RAFT) polymerization with an acid-sensitive cross-linker followed by the conjugation of maleimide-doxorubicin to the pyridyl disulfide-modified micelles. Multifunctional nanocarriers are obtained by coupling HER2-specific peptide. Formation of micelles, addition of peptide and doxorubicin (DOX) are confirmed structurally by spectroscopical techniques. Size and morphological characterization are performed by Zetasizer and transmission electron microscope (TEM). For the physicochemical verification of the synergistic acid-triggered degradation induced by acetal and hydrazone bond degradation, Infrared spectroscopy and particle size measurements are used. Drug release studies show that DOX release is accelerated at acidic pH. DOX-conjugated HER2-specific peptide-carrying nanocarriers significantly enhance cytotoxicity toward SKBR-3 cells. More importantly, no selectivity toward MCF-10A cells is observed compared to HER2(+) SKBR-3 cells. Formulations cause apoptosis depending on Bax and Caspase-3 and cell cycle arrest in G2 phase. This study shows a novel system for HER2-targeted therapy of breast cancer with a multifunctional nanocarrier, which has higher stability, dual pH-sensitivity, selectivity, and it can be an efficient way of targeted anticancer drug delivery.
RAFT-synthesized POEGMA-b-P4VP block copolymers: preparation of nanosized micelles for anticancer drug release
(SPRINGERONE NEW YORK PLAZA, SUITE 4600 , NEW YORK, NY 10004, UNITED STATES, 2021) Bayram, Nazende Nur; Topuzogullari, Murat; Isoglu, Ismail Alper; Isoglu, Sevil Dincer; 0000-0002-8697-1654; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Bayram, Nazende Nur; Isoglu, Ismail Alper; Isoglu, Sevil Dincer
To achieve high stability and biocompatibility in physiological environment, oligoethyleneglycol methacrylate (OEGMA) and 4-vinylpyridine (4VP)-based amphiphilic block copolymers were prepared as micellar carriers to deliver doxorubicin into tumor cells. First, macroinitiator of OEGMA was synthesized by RAFT polymerization at [M](0)/[CTA](0)/[I](0) ratio of 100/1/0.2 in dimethylformamide (DMF) at 70 degrees C, in the presence of 4,4'-azobis(4-cyanovaleric acid) (ACVA) as initiator and 4-cyano-4-(thiobenzoylthio)pentanoic acid (CTA) as chain transfer agent, respectively. It was followed by copolymerization with 4-VP at similar conditions. The formation of RAFT-mediated polymers was approved by FTIR, H-1-NMR and GPC. For the preparation of drug-loaded micelles, a dialysis method was applied and hydrophobic doxorubicin, as a model drug, was entrapped into the micelles. Size distributions and morphologies of drug-loaded micelles were investigated by light scattering and scanning electron microscopy, respectively. Critical micelle concentration was estimated as 0.0019 mg/mL by measuring light scattering intensity in different polymer concentrations. Also, drug loading and entrapment efficiencies were calculated as 4.41% and 17.65% by measuring the DOX amount in the micelles, spectrophotometrically. At last, the drug-loaded micelles were applied to SKBR-3 breast cancer cell lines and revealed up to %40 cell inhibition at 48 and 72 h. As a result, these nanosized and biocompatible micelles can be used for the delivery of hydrophobic drugs, and they can also be modified for further targeting and imaging applications toward specific cancer cells.
Sulfobetaine-Based Homo- and Copolymers by RAFT: Cross-Linked Micelles and Aqueous Solution Properties
(AMER CHEMICAL SOC, 2022) Gurdap, Seda; Bayram, Nazende Nur; Isoglu, Ismail Alper; Isoglu Dincer, Sevil; 0000-0002-6887-6549; 0000-0001-6428-4207; 0000-0001-6582-4981; 0000-0002-8697-1654; AGÜ, Yaşam ve Doğa Bilimleri Fakültesi, Biyomühendislik Bölümü; Gürdap, Seda; Bayram, Nazende Nur; İsoğlu, İsmail Alper; İsoğlu Dinçer, Sevil
In this study, we describe the synthesis and aqueous solution behavior of temperature-sensitive N-(3-sulfopropyl)-N-methacroyloxyethyl-N,N-dimethylammonium betaine (SBMA) homopolymers and core cross-linked micelles (CCMs) with an SBMA shell. Reversible addition–fragmentation chain transfer polymerization has been utilized to synthesize sulfobetaine homopolymers, followed by CCM formation during copolymerization in the presence of an acid-degradable cross-linker. First, SBMA homopolymers of varying chain lengths were synthesized, and it has been demonstrated that an increase in the chain length and concentration of the homopolymer resulted in an increase in the upper critical solution temperature (UCST). Besides, micelles showed concentration-dependent dual temperature-sensitive behavior with UCST and LCST transitions. Also, homopolymers and CCMs were characterized by FTIR, 1H-NMR, GPC, and TEM. Micelle formation and temperature sensitivity were also investigated by DLS. As a result, stabilized micelles were successfully prepared with the motivation of preventing premature drug release and achieving a pH- and temperature-controlled system. Due to their dual-responsive characteristics, the CCMs show promising potential to be used as smart drug carriers for controlled delivery.