Browsing by Subject "Antineoplastic agents."

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Open Access
Characterization of chemosensitivity profiles of breast cancer cell lınes, with and without stem cell like features = Kök-hücre özelliği olan ve olmayan meme kanseri hücre hatlarının ilaç hassasiyet profillerinin tanımlanması
(2014) Akbar, Muhammad Waqas
Breast cancer is the second most common cause of death worldwide from cancer due to complications with its diagnosis and resistance to therapy. Recent studies have shown that breast tumors when compared with other solid tumors also contain a subpopulation termed as cancer stem cells (CSCs). CSCs are hard to kill due to their therapy resistant capacities. These unharmed cells then result into relapse of tumor after treatment. Some established breast cancer cell lines also behave in similar fashion to CSCs in overall manner thus termed as CSC like cell lines. This study primarily focuses on characterizing CSC like cell lines from non CSC like cell lines based upon their gene expression and prediction of drugs which can target these groups separately. In this study two databases, Cancer Cell Line Encyclopedia (CCLE) and Cancer Genome Project (CGP), were used which contain gene expression data and drugs cytotoxicity data for most of the established cancer cell lines. Breast cancer cell lines gene expression data was used to predict two gene lists which can separate breast cancer cell lines into CSC like and non CSC like cell lines by in silico analysis. These gene lists were named as Patentable and Non Patentable. Additionally four drugs were predicted which can target CSC like group (Midostaurin and Elesclomol) and non CSC like group (Panobinostat and Lapatinib) separately. Later these findings were validated in vitro. Non Patentable gene list could not be validated due to low concordance with microarray data. On the other hand, Patentable gene list was validated and was found concordant with microarray data. Out of four selected drugs, Panobinostat and Lapatinib showed increased toxicity to non CSC like cell lines while only Midostaurin showed toxicity to CSC like cell lines. To investigate further that cell lines were grown in 3D cell culture conditions, to increase their stem cell like properties (stemness). But only one cell line MDA-MB-157 which was found as CSC like, showed expected behavior. Additionally this cell line increased resistance to Lapatinib and Panobinostat and became more sensitive to Midostaurin. Correlation analysis showed some genes as potential biomarkers for selected drugs. In conclusion, in this study various genes are proposed to differentiate CSC like cell lines from non CSC like cell lines. And Midostaurin can be potential drug to treat CSC like cells while Lapatinib and Panobinostat showed increased activity against non CSC like cell lines.
Open Access
Conjugated polymer nanoparticles for biomedical applications including bioimaging and drug delivery
(2013) Ünal, Özlem
Open Access
Multifunctional conjugated polymer nanoparticles as an anticancer drug carrier and a fluorescent probe for cell imaging
(2012) Gezici, Özlem
The main motivation of this study is to develop multifunctional nanoparticles which can perform simultaneously the drug delivery and cell imaging tasks. To this end, firstly nanoparticles (Nps) with an average diameter of about 25 nm and based on a green emitting, hydrophobic conjugated polymer, poly[(9,9-bis{propenyl}fluorenyl-2,7- diyl))-co-(1,4-benzo-{2,1,3}-thiodiazole)] (PPFBT) and Nps with an average diameter of about 150 nm and based on a red emitting, hydrophobic conjugated polymer, poly[(9,9-bis{3-azido-propyl}fluorenyl-2,7-divinylene)-co-(1,4-benzo- {2,1,3}-thiodiazole)] (PAPFVBT) were prepared, characterized and their convenience as a fluorescent probe for cell imaging was evaluated via in vitro cell assays. Then, drug loaded nanocapsules in which PPFBT or PAPFVBT acts both as a fluorescent reporter and the main matrix of the nanocapsules accommodating an anticancer drug, camptothecin (CPT), were synthesized through a facile, single step reprecipitation method. CPT is a hydrophobic, water-insoluble drug but the encapsulation improved its water-solubility. The CPT loading efficiency in the nanoparticles has been determined to be 100% when a drug to polymer ratio of 1:25 (w/w) was used. Cell viability of Human hepatocellular carcinoma cell line (Huh7) was investigated in the absence and presence of CPT using Sulforhodamine B (SRB) assay. SRB assay results supported further by the fluorescence microscope cell images clearly confirmed that blank and CPT-loaded PPFBT Nps have been taken up by the cells very efficiently and these nanoparticles were accumulated in the cytoplasm. Time and dose dependent SRB assay results indicate that the blank PPFBT Nps are not toxic to the Huh7 cells up to 25 µM. However, even a very low dose of CPT was found to be sufficient to induce the apoptosis of the cells when it was delivered through nanoparticles. Thus, at the end of 48 h, the half maximal inhibitory concentration (IC50) of free CPT and CPT-loaded PPFBT Nps were calculated to be 0.9 µM and 0.1 µM respectively, corresponding to that CPT-loaded PPFBT Nps are 9 times more effective than free CPT. However, at the end of 72 h, the IC50 of free CPT and CPT-loaded PPFBT Nps decreased to 0.1 µM and 0.008 µM, respectively. In this case, CPT-loaded PPFBT Nps are 12.5 times more effective than free CPT in inducing the apoptosis of Huh7 cells. Although the free drug (CPT) reaches IC50 of 0.1 µM after 72 h, it is possible to achieve this value with CPT-loaded Nps at the end of 48 h. On the other hand, dose dependent SRB assay results indicate that the blank PAPFVBT Nps are not toxic to the Huh7 cells up to 16 µM. At the end of 72 h, IC50 of free CPT and CPTloaded PAPFVBT Nps were calculated to be 0.03 µM and 0.1 µM respectively, corresponding to that CPT-loaded PAPFVBT Nps are 3.3 times less effective than free CPT. Having bigger size (~150 nm) of PAPFVBT Nps is the main reason of not being effective as PPFBT Nps (~25 nm).
Open Access
Slow release and delivery of antisense oligonucleotide drug by self-assembled peptide amphiphile nanofibers
(2012) Bulut, Selma
Antisense oligonucleotides are short single stranded DNA sequences and they are suggested to be used for treatment of several disorders including cancer. They could enter the cell and specifically inhibit the target gene, however chemical stability, controlled release and intracellular delivery are areas that has to be focused on to increase their efficacy. Gels composed of nanofibrous peptide network have been previously suggested as carriers for controlled delivery of drugs to improve stability and to provide controlled release, but have not been used for oligonucleotide delivery. In this work, a self-assembled peptide nanofibrous system is formed by mixing a cationic peptide amphiphile (PA) with Bcl-2 antisense oligodeoxynucleotide (ODN), G3139, through electrostatic interactions. The self-assembly of PA-ODN gel was characterized by circular dichroism, rheology, atomic force microscopy (AFM) and scanning electron microscopy (SEM). AFM and SEM images revealed establishment of the nanofibrous PA-ODN network. Due to the electrostatic interactions between PA and ODN, ODN release can be controlled by changing PA and ODN concentrations in the PA-ODN gel. Cellular delivery of the ODN by PA-ODN nanofiber complex was observed by fluorescently labeled ODN molecule. Cells incubated with PA-ODN complex had enhanced cellular uptake compared to cells incubated with naked ODN. Furthermore, Bcl-2 mRNA amounts were lower in MCF-7 human breast cancer cells in the presence of PA-ODN complex compared to naked ODN and mismatch ODN evidenced by quantitative RT-PCR studies. These results suggest that PA molecules can control ODN release, enhance cellular uptake and present a novel efficient approach for gene therapy studies and oligonucleotide based drug delivery. In follow-up studies, increase in the internalization efficacy of ODN by incorporation of bioactive sequences, RGDS, to peptide sequence was also shown.