Chemical Engineering / Kimya Mühendisliği
Permanent URI for this collectionhttps://hdl.handle.net/11147/14
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Conference Object Raft-Synthesis of Cholesterol Conjugated Polymers as Potential Therapeutic Carriers(American Chemical Society, 2011) Sevimli, Sema; İnci, Fatih; Bulmuş, Volga[No abstract available]Article Citation - WoS: 5Citation - Scopus: 6Efficient Synthesis of Crgd Functionalized Polymers as Building Blocks of Targeted Drug Delivery Systems(Elsevier Ltd., 2018) Thankappan, Hajeeth; Zelçak, Aykut; Taykoz, Damla; Bulmuş, VolgaSynthetic peptides with cyclic arginine-glycine-aspartate motif (cRGD) play an important role in cell recognition and cell adhesion. cRGD-decorated soluble polymers and polymeric nanoparticles have been increasingly used for cell-specific delivery of antitumor drugs. While the significance of cRGD modification for tumor cell-specific targeting of polymeric carriers is well-accepted, straightforward procedures ensuring the fidelity of cRGD modification of polymeric systems are still lacking. Herein, we have reported an in-situ polymerization approach for synthesis of cRGD-end-functionalized well-defined polymers as potential building blocks of targeted drug delivery systems. A new cRGD peptide functionalized RAFT agent was synthesized as confirmed by MALDI-TOF and 1H NMR spectroscopy. The ability of this RAFT agent to control polymerizations was then tested using two different monomers oligoethyleneglycol acrylate and t-butyl methacrylate. The RAFT-controlled character of polymerizations and the living characteristic of the synthesized polymers were investigated through a series of kinetic experiments. The cytotoxicity and targeting capability of cRGD-functionalized OEGA polymers were investigated using cell lines expressing αvβ3 integrins at varying extents.Article Citation - WoS: 65Citation - Scopus: 72Effect of Peg Grafting Density and Hydrodynamic Volume on Gold Nanoparticle-Cell Interactions: an Investigation on Cell Cycle, Apoptosis, and Dna Damage(American Chemical Society, 2016) Uz, Metin; Bulmuş, Volga; Alsoy Altınkaya, SacideIn this study, interactions of polyethylene glycol (PEG)-coated gold nanoparticles (AuNPs) with cells were investigated with particular focus on the relationship between the PEG layer properties (conformation, grafting density, and hydrodynamic volume) and cell cycle arrest, apoptosis, and DNA damage. Steric hindrance and PEG hydrodynamic volume controlled the protein adsorption, whereas the AuNP core size and PEG hydrodynamic volume were primary factors for cell uptake and viability. At all PEG grafting densities, the particles caused significant cell cycle arrest and DNA damage against CaCo2 and PC3 cells without apoptosis. However, at a particular PEG grafting density (∼0.65 chains/nm2), none of these severe damages were observed on 3T3 cells indicating discriminating behavior of the healthy (3T3) and cancer (PC3 and CaCo2) cells. It was concluded that the PEG grafting density and hydrodynamic volume, tuned with the PEG concentration and AuNP size, played an important role in particle-cell interactions.Article Citation - WoS: 31Citation - Scopus: 32Synthesis, Self-Assembly and Stimuli Responsive Properties of Cholesterol Conjugated Polymers(Royal Society of Chemistry, 2012) Sevimli, Sema; Sagnella, Sharon; Kavallaris, Maria; Bulmuş, Volga; Davis, Thomas P.Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to generate well-defined pH-responsive biofunctional polymers as potential 'smart' gene delivery systems. A series of five poly(dimethylamino ethyl methacrylate-co-cholesteryl methacrylate) P(DMAEMA-co-CMA) statistical copolymers, with similar molecular weights and varying cholesterol content, were prepared. The syntheses, compositions and molecular weight distributions for P(DMAEMA-co-CMA) were monitored by nuclear magnetic resonance (NMR), solid-state NMR and gel permeation chromatography (GPC) evidencing well-defined polymeric structures with narrow polydispersities. Aqueous solution properties of the copolymers were investigated using turbidimetry and light scattering to determine hydrodynamic diameters and zeta potentials associated with the phase transition behaviour of P(DMAEMA-co-CMA) copolymers. UV-Visible spectroscopy was used to investigate the pH-responsive behaviour of copolymers. Hydrodynamic radii were measured in the range 10-30 nm (pH, temperature dependent) by dynamic light scattering (DLS). Charge studies indicated that P(DMAEMA-co-CMA) polymers have an overall cationic charge, mediated by pH. Potentiometric studies revealed that the buffering capacity and pK a values of polymers were dependent on cholesterol content as well as on cationic charge. The buffering capacity increased with increasing charge ratio, overall demonstrating transitions in the pH endosomal region for all five copolymeric structures. Cell viability assay showed that the copolymers displayed increasing cytotoxicity with decreasing number of cholesterol moieties. These preliminary results show the potential of these well-defined P(DMAEMA-co-CMA) polymers as in vitro siRNA delivery agents.Article Citation - WoS: 38Citation - Scopus: 38Ph- and Temperature-Responsive Amphiphilic Diblock Copolymers of 4-Vinylpyridine and Oligoethyleneglycol Methacrylate Synthesized by Raft Polymerization(Elsevier Ltd., 2014) Topuzogulları, Murat; Bulmuş Zareie, Volga; Bulmuş, Volga; Dalgakıran, Eray; Dinçer, SevilDiblock copolymers of 4-vinylpyridine (4VP) and oligoethyleneglycol methyl ether methacrylate (OEGMA) were synthesized for the first time using RAFT polymerization technique as potential drug delivery systems. Effects of the number of ethylene glycol units in OEGMA, chain length of hydrophobic P4VP block, pH, concentration and temperature on the solution behavior of the copolymers were investigated comprehensively. Copolymer chains formed micelles at pH values higher than 5 whereas unimeric polymers were observed to exist below pH 5, owing to the repulsion between positively charged P4VP blocks. The size of the micelles was dependent on the relative length of blocks, P4VP and POEGMA. Thermo-responsive properties of copolymers were investigated depending on the pH and length of P4VP block. The increase in the length of P4VP block decreased the LCST substantially at pH 7. At pH 3, LCST of copolymers shifted to higher temperatures due to the increased interaction of copolymers with water through positively charged P4VP block.Article Citation - WoS: 22Citation - Scopus: 25The Endocytic Pathway and Therapeutic Efficiency of Doxorubicin Conjugated Cholesterol-Derived Polymers(Royal Society of Chemistry, 2015) Sevimli, Sema; Sagnella, Sharon; Macmillan, Alexander; Whan, Renee; Kavallaris, Maria; Bulmuş, Volga; Davis, Thomas P.Previously synthesized poly(methacrylic acid-co-cholesteryl methacrylate) P(MAA-co-CMA) copolymers were examined as potential drug delivery vehicles. P(MAA-co-CMA) copolymers were fluorescently labelled and imaged in SHEP and HepG2 cells. To understand their cell internalization pathway endocytic inhibition studies were conducted. It was concluded that P(MAA-co-CMA) are taken up by the cells via clathrin-independent endocytosis (CIE) (both caveolae mediated and cholesterol dependent endocytosis) mechanisms. The formation and characterization of P(MAA-co-CMA)-doxorubicin (DOX) nanocomplexes was investigated by fluorescence lifetime imaging microscopy (FLIM), UV-Visible spectroscopy (UV-Vis) and dynamic light scattering (DLS) studies. The toxicity screening between P(MAA-co-CMA)-DOX nanocomplexes (at varying w/w ratios) and free DOX, revealed nanocomplexes to exhibit higher cytotoxicity towards cancer cells in comparison to normal cells. FLIM and confocal microscopy were employed for investigating the time-dependent release of DOX in SHEP cells and the cellular uptake profile of P(MAA-co-CMA)-DOX nanocomplexes in cancer and normal cell lines, respectively. The endocytic pathway of P(MAA-co-CMA)-DOX nanocomplexes were examined in SHEP and HepG2 cells via flow cytometry revealing the complexes to be internalized through both clathrin-dependent (CDE) and CIE mechanisms. The drug delivery profile, reported herein, illuminates the specific endocytic route and therapeutic efficiency of P(MAA-co-CMA)-DOX nanocomplexes strongly suggesting these particles to be promising candidates for in vivo applications.Article Citation - WoS: 20Citation - Scopus: 22A New Proton Sponge Polymer Synthesized by Raft Polymerization for Intracellular Delivery of Biotherapeutics(Royal Society of Chemistry, 2014) Kurtuluş, Işıl; Yılmaz, Gökhan; Üçüncü, Muhammed; Emrullahoğlu, Mustafa; Becer, C. Remzi; Bulmuş, VolgaA spermine-like polymer was synthesized via reversible addition- fragmentation chain transfer polymerization as a potential endosomal escaping agent. A new methacrylate monomer, 2-((tert-butoxycarbonyl)(2-((tert- butoxycarbonyl)amino)ethyl)amino)ethylmethacrylate (BocAEAEMA), was prepared and then polymerized via RAFT polymerization at constant monomer or initiator concentration at varying [M]/[R]/[I] ratios. In all polymerizations, ln[M] 0/[M] increased linearly with time. The linear increase in M n with monomer conversion was also observed. P(BocAEAEMA)s with controlled molecular weights and narrow molecular weight distributions were obtained. The in vitro cytotoxicity and proton sponge capacity of deprotected polymers P(AEAEMA) were investigated in comparison with a widely used endosomal-disruptive polymer, PEI. P(AEAEMA)s were found to possess proton sponge capacity comparable with PEI. More importantly, P(AEAEMA)s were not toxic on NIH 3T3 cells at concentrations where PEI (25 kDa) was highly toxic (0.4 μM and above). P(AEAEMA) was able to fully condense a DNA fragment at nitrogen/phosphate (N/P) ratios of 10 and above, as evidenced by gel electrophoresis. P(BocAEAEMA) was then chain-extended with a model sugar monomer, mannose-acrylate (ManAc), to yield P(AEAEMA)-b-P(ManAc) block copolymers, to potentially provide cell-recognition ability to the polyplex particles. Although the presence of the P(ManAc) block partially inhibited the interaction of P(AEAEMA) with DNA, P(AEAEMA)13-b-P(ManAc)7 was able to form polyplexes with DNA at N/P ratios ranging between 20/1 and 2/1. Dynamic light scattering measurements showed that while P(AEAEMA) (M n = 5.5 kDa) and DNA formed polyplex particles having a hydrodynamic diameter (Dh) of 125 ± 51 nm, P(AEAEMA)13-b- P(ManAc)7 and DNA formed particles with a smaller Dh of 38 ± 10 nm.Article Citation - WoS: 79Citation - Scopus: 90Hydrophobically-Associating Cationic Polymers as Micro-Bubble Surface Modifiers in Dissolved Air Flotation for Cyanobacteria Cell Separation(Elsevier Ltd., 2014) Yap, R.K.L.; Whittaker, M.; Diao, M.; Stuetz, R. M.; Jefferson, B.; Bulmuş, Volga; Peirson, W. L.; Nguyen, A. V.; Henderson, R. K.Dissolved air flotation (DAF), an effective treatment method for clarifying algae/cyanobacteria-laden water, is highly dependent on coagulation-flocculation. Treatment of algae can be problematic due to unpredictable coagulant demand during blooms. To eliminate the need for coagulation-flocculation, the use of commercial polymers or surfactants to alter bubble charge in DAF has shown potential, termed the PosiDAF process. When using surfactants, poor removal was obtained but good bubble adherence was observed. Conversely, when using polymers, effective cell removal was obtained, attributed to polymer bridging, but polymers did not adhere well to the bubble surface, resulting in a cationic clarified effluent that was indicative of high polymer concentrations. In order to combine the attributes of both polymers (bridging ability) and surfactants (hydrophobicity), in this study, a commercially-available cationic polymer, poly(dimethylaminoethyl methacrylate) (polyDMAEMA), was functionalised with hydrophobic pendant groups of various carbon chain lengths to improve adherence of polymer to a bubble surface. Its performance in PosiDAF was contrasted against commercially-available poly(diallyl dimethyl ammonium chloride) (polyDADMAC). All synthesised polymers used for bubble surface modification were found to produce positively charged bubbles. When applying these cationic micro-bubbles in PosiDAF, in the absence of coagulation-flocculation, cell removals in excess of 90% were obtained, reaching a maximum of 99% cell removal and thus demonstrating process viability. Of the synthesised polymers, the polymer containing the largest hydrophobic functionality resulted in highly anionic treated effluent, suggesting stronger adherence of polymers to bubble surfaces and reduced residual polymer concentrations.Article Citation - WoS: 42Citation - Scopus: 43Well-Defined Cholesterol Polymers With Ph-Controlled Membrane Switching Activity(American Chemical Society, 2012) Sevimli, Sema; İnci, Fatih; Zareie, Hadi M.; Bulmuş, VolgaCholesterol has been used as an effective component of therapeutic delivery systems because of its ability to cross cellular membranes. Considering this, well-defined copolymers of methacrylic acid and cholesteryl methacrylate, poly(methacrylic acid-co-cholesteryl methacrylate) P(MAA-co-CMA), were generated as potential delivery system components for pH-controlled intracellular delivery of therapeutics. Statistical copolymers with varying cholesterol contents (2, 4, and 8 mol %) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Dynamic light scattering (DLS) analysis showed that the hydrodynamic diameters of the copolymers in aqueous solutions ranged from 5 ± 0.3 to 7 ± 0.4 nm for the copolymers having 2 and 4 mol % CMA and 8 ± 1.1 to 13 ± 1.9 nm for the copolymer having 8 mol % CMA with increasing pH (pH 4.5-7.4). Atomic force microscopy (AFM) analysis revealed that the copolymer having 8 mol % CMA formed supramolecular assemblies while the copolymers having 2 and 4 mol % CMA existed as unimers in aqueous solution. The pH-responsive behavior of the copolymers was investigated via UV-visible spectroscopy revealing phase transitions at pH 3.9 for 2 mol % CMA, pH 4.7 for 4 mol % CMA, and pH 5.4 for 8 mol % CMA. Lipid bilayers and liposomes as models for cellular membranes were generated to probe their interactions with the synthesized copolymers. The interactions were determined in a pH-dependent manner (at pH 5.0 and 7.4) using surface plasmon resonance (SPR) spectroscopy and liposome leakage assay. Both the SPR analyses and liposome leakage assays indicated that the copolymer containing 2 mol % CMA displayed the greatest polymer-lipid interactions at pH 5.0, presenting the highest binding ability to the lipid bilayer surfaces, and also demonstrating the highest membrane destabilization activity. CellTiter-Blue assay showed that the copolymers did not affect the cell viability up to 30 μM over a period of 72 h. © 2012 American Chemical Society.Article Citation - WoS: 17Citation - Scopus: 16Ph-Labile Sheddable Block Copolymers by Raft Polymerization: Synthesis and Potential Use as Sirna Conjugates(Elsevier Ltd., 2013) Huang, Xin; Sevimli, Sema İlknur; Bulmuş, VolgaWell-defined amphiphilic block copolymers composed of hydrophilic and hydrophobic blocks linked through an acid-labile acetal bond were synthesized directly by RAFT polymerization using a new poly(ethylene glycol) (PEG) macroRAFT agent modified with an acid-labile group at its R-terminal. The new macroRAFT agent was used for polymerization of poly(t-butyl methacrylate) (PtBMA) or poly(cholesterol-methacrylate) (PCMA) to synthesize well-defined block copolymers with a PEG block sheddable under acidic conditions. The chain extension polymerization kinetics showed known traits of RAFT polymerization. The molecular weight distributions of the copolymers prepared using the new macroRAFT agent remained below 1.2 during the polymerizations and the molecular weight of the copolymers was linearly proportional to monomer conversions. The acid-catalyzed hydrolysis behavior of the PEG-macroRAFT agent and the PEG-b-PtBMA (Mn = 13,600 by GPC, PDI = 1.10) was studied by GPC, 1H NMR and UV-vis spectroscopy. The half-life of acid-hydrolysis was 70 min at pH 2.2 and 92 h at pH 4.0. The potential use of the pH-labile shedding behavior of the copolymers was demonstrated by conjugating a thiol-modified siRNA to ω-pyridyldisulfide modified PEG-b-PCMA. The resultant PEG-b-PCMA-b-siRNA triblock modular polymer released PCMA-b-siRNA segment in acidic and siRNA segment in reductive conditions, as confirmed by polyacrylamide gel electrophoresis.