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A rational design of multi-functional nanoplatform: Fluorescent-based “off-on” theranostic gold nanoparticles modified with D-?-Tocopherol succinate
(Elsevier B.V., 2021) Demiral, Ayşegül; Verimli, Nihan; Goralı, İrem; Yılmaz, Hülya; Çulha, Mustafa; Erdem, Sultan Sibel
It is crucial to develop nanocarrier systems to detect and treat drug-resistant micro tumors to prevent recurrence and/or metastasis of cancer. Due to their exceptional features such as biocompatibility, easy surface modification, serving as imaging and therapeutic agent, gold nanoparticles (AuNPs) draw attention as theranostic agents. It is beneficial to combine AuNPs with a second imaging and/or treatment modality such as photodynamic therapy (PDT). PDT is a non-mutagenic treatment approach in which photosensitizer is activated with light, generating reactive oxygen species and/or free radicals to destroy tumor cells. With the aim of developing “off-on” theranostic system, citrate stabilized spherical 13 nm AuNPs were densely coated with polyethylene glycol (PEG). To advance the theranostic feature of PEGylated AuNPs, they were further functionalized with FDA-Approved photosensitizer, Verteporfin (BPD-MA). Due to static quenching between BPD-MA and AuNPs as well as in between nearby BPD-MA molecules, the fluorescence of the ground state complex is quenched and the system is in “off” state. When BPD-MA molecules are cleaved from the AuNPs surface and diffuse away, fluorescence is recovered. Consequently, the system switches to the “on” state. Among the various mole ratios of BPD-MA carrying conjugates prepared, the most promising candidate was selected based on stability, quenching factor, and fluorescence recovery rate. The conjugate was further decorated with D-?-Tocopherol succinate (VitES) to increase the therapeutic efficacy of the theranostic agent via enhancing cellular uptake. Our results showed that it was possible to achieve as high as 80 times fluorescence quenching when the system was “off”. As the system switched from “off” to “on” state, 51% of the fluorescence was recovered. When BPD-MA was immobilized on the PEGylated AuNPs, the phototoxic effect of BPD-MA increased twice against the MCF-7 cell line. Moreover, the developed system showed four times more phototoxicity than BPD-MA alone after it was decorated with VitES. Since the developed system is capable of dual imaging (computed tomography and fluorescence) and dual treatment (PDT and hyperthermia), it potentially offers superior imaging and therapy options for various types of in vitro/in vivo applications.
Blood accessibility to fibrin in venous thrombosis is thrombus age-dependent and predicts fibrinolytic efficacy: An in vivo fibrin molecular imaging study
(Ivyspring International Publisher, 2015) Stein-Merlob, Ashley; Kessinger, Chase; Erdem, Sultan Sibel; Zelada, Henry; Hilderbrand, Scott; Lin, Charles; Jaff, Michael; Jaff, Michael; Reed, Guy; Henke, Peter; McCarthy, Jason; Jaffer, Farouc Amin
Fibrinolytic therapy of venous thromboembolism (VTE) is increasingly utilized, yet limited knowledge is available regarding in vivo mechanisms that govern fibrinolytic efficacy. In particular, it is unknown how age-dependent thrombus organization limits direct blood contact with fibrin, the target of blood-based fibrinolytic agents. Utilizing high-resolution in vivo optical molecular imaging with FTP11, a near-infrared fluorescence (NIRF) fibrin-specific reporter, here we investigated the in vivo interrelationships of blood accessibility to fibrin, thrombus age, thrombus neoendothelialization, and fibrinolysis in murine venous thrombosis (VT). In both stasis VT and non-stasis VT, NIRF microscopy showed that FTP11 fibrin binding was thrombus age-dependent. FTP11 localized to the luminal surface of early-stage VT, but only minimally to subacute VT (p<0.001). Transmission electron microscopy of early stage VT revealed direct blood cell contact with luminal fibrin-rich surfaces. In contrast, subacute VT exhibited an encasing CD31+ neoendothelial layer that limited blood cell contact with thrombus fibrin in both VT models. Next we developed a theranostic strategy to predict fibrinolytic efficacy based on the in vivo fibrin accessibility to blood NIRF signal. Mice with variably aged VT underwent FTP11 injection and intravital microscopy (IVM), followed by tissue plasminogen activator infusion to induce VT fibrinolysis. Fibrin molecular IVM revealed that early stage VT, but not subacute VT, bound FTP11 (p<0.05), and experienced higher rates of fibrinolysis and total fibrinolysis (p<0.05 vs. subacute VT). Before fibrinolysis, the baseline FTP11 NIRF signal predicted the net fibrinolysis at 60 minutes (p<0.001). Taken together, these data provide novel insights into the temporal evolution of VT and its susceptibility to therapeutic fibrinolysis. Fibrin molecular imaging may provide a theranostic strategy to identify venous thrombi amenable to fibrinolytic therapies.
Compliance of medical biochemistry education in medical schools with national core education program 2014
(Walter De Gruyter Gmbh, 2019) Erdem, Sultan Sibel; Yiğitbaşı, Türkan; Yiğit, Pakize; Emekli, Nesrin
Background: Medical school curriculums are not standardized in Turkey and around the world, which results in great diversity in education. National Core Education Program (NCEP) has been prepared as a frame program and the aim of the program is to train medical doctors with basic abilities. Objective: The objective of this work is to compare biochemistry curriculum based on NCEP among medical schools in Turkey. Materials and methods: Twelve-question long survey was prepared. Sixty-nine out 84 medical schools were participated the study using 2017-2018 curriculum data. Biochemistry curriculums of medical schools are compared based on NCEP 2014. Results: Number of biochemistry hours and content of the lectures varies among medical schools. While biochemistry was intensely studied in the first and second years of the education program, biochemistry hours and number of universities offering biochemistry have dramatically decreased after the second year. Clinical biochemistry questions had lower positive response. Accredited medical schools include NCEP subjects in their curriculum in higher ratio than the unaccredited ones. Conclusion: Biochemistry curriculum shows variation among medical schools. Addition of clinical biochemistry beyond second year would improve NCEP adaptation. Multidisciplinary approach and vertical integration should be employed to improve quality of medical education.
Design of dense brush conformation bearing gold nanoparticles as theranostic agent for cancer
(Springer, 2019) Verimli, Nihan; Demiral, Ayşegül; Yılmaz, Hülya; Çulha, Mustafa; Erdem, Sultan Sibel
Dense brush conformation–bearing theranostic agents are emerging as drug delivery systems due to their higher ability to escape from reticuloendothelial system uptake which prolongs their in vivo circulation time. With the aim of developing dual therapy agent, 13-nm gold nanoparticles’ (AuNPs) surfaces were coated with different amounts of polyethylene glycol (PEG) (SH-PEG-NH2) to obtain dense brush conformation–bearing theranostic agents. Among the 14 different theranostic agent candidates prepared, the one hosting 1819 PEG per particle was selected as the most promising theranostic agent candidate based on structural conformation, stability, size, zeta potential, hemocompatibility, cell inhibition, and cell death pathway towards MCF-7 cell line. To test drug delivery efficiency of the developed PEGylated AuNP and to improve efficacy of the treatment, apoptotic peptide (AP) was covalently conjugated to NH2 terminus of the PEG in various ratios to yield AuNP-AP conjugate. Among the prepared conjugates, the one having 1 nmol of peptide per milliliter of AuNP yielded the most promising results based on the same criteria as employed for PEGylated AuNPs. Besides, incorporation of AP to AuNP returned in superior efficacy of AP since it was possible to achieve 50% cell death with 1000 times less amount of AP alone.
Development of light and pH-dual responsive self-quenching theranostic SPION to make EGFR overexpressing micro tumors glow and destroy
(Elsevier B.V., 2023) Verimli, Nihan; Goralı, Selen İrem; Abişoğlu, Beyza; Altan, Cem Levent; Sucu, Bilgesu Onur; Karataş, Ersin; Tülek, Ahmet; Bayraktaroğlu, Çiğdem; Beker, Mustafa Çağlar; Erdem, Sultan Sibel
Drug resistant and undetectable tumors easily escape treatment leading metastases and/or recurrence of the lethal disease. Therefore, it is vital to diagnose and destroy micro tumors using simple yet novel approaches. Here, we present fluorescence-based detection and light-based destruction of cancer cells that are known to be resistant to standard therapies. We developed a superparamagnetic iron oxide nanoparticle (SPION)-based theranostic agent that is composed of self-quenching light activated photosensitizer (BPD) and EGFR targeting ligand (Anti-EGFR ScFv or GE11 peptide). Photosensitizer (BPD) was immobilized to PEG-PEI modified SPION with acid-labile linker. Prior to stimulation of the theranostic system by light its accumulation within cancer cells is vital since BPD phototoxicity and fluorescence is activated by lysosomal proteolysis. As BPD is cleaved, the system switches from off to on position which triggers imaging and therapy. Targeting, therapeutic and diagnostic features of the theranostic system were evaluated in high and moderate level EGFR expressing pancreatic cancer cell lines. Our results indicate that the system distinguishes high and moderate EGFR expression levels and yields up to 4.3-fold increase in intracellular fluorescence intensity. Amplification of fluorescence signal was as low as 1.3-fold in the moderate or no EGFR expressing cell lines. Anti-EGFR ScFv targeted SPION caused nearly 2-fold higher cell death via apoptosis in high EGFR expressing Panc-1 cell line. The developed system, possessing advanced targeting, enhanced imaging and effective therapeutic features, is a promising candidate for multi-mode detection and destruction of residual drug-resistant cancer cells.
Evaluation of digoxin as anti-cancer agent in colon cancer cell line
(İstanbul Medipol Üniversitesi Sağlık Bilimleri Enstitüsü, 2017) Mohamud, Kalif Mohamed; Erdem, Sultan Sibel
Colorectal cancer is a common disease all over the world and the occurrence of colorectal cancer is increasing in developing countries. Generally the occurence and mortality of colorectal cancer are substantially advanced in men than women. Many factors play a significant role in the advancement of cancer. Genetics, diet, alcohol, smoking, and other environmental factors are among the main causes for colorectal cancer growth. The major goal of this study was to develop an in vitro cell culture based assay to investigate the effect of combination therapy of Digoxin and Irinotecan on chosen Human Colon Cancer Type (HCT 116) colon cancer cell line. Another objective was to examine the anticancer effect of Digoxin on HCT 116 cell line regarding to cell proliferation, apoptosis and inflammation. Digoxin, which is a commonly used cardiac glycoside, and chemotherapy agent called Irinotecan are chosen for the study. Initially, the colon carcinoma cell line HCT 116 was treated with varying concentrations of Digoxin to study its effect on cell survival and proliferation. Treatment of Digoxin not only inhibited the growth of HCT 116 cell line but also Digoxin induced apoptosis and disrupted cell membrane. IC50 values for Digoxin and Irinotecan were determined as 78 ?M and 330 ?M, respectively. When Digoxin is used in combination with Irinotecan, the findings clearly showed that two drugs had synergistic effects at all concentrations at certain ratios. The results showed that 55% of the cell death could be achieved if the Irinotecan is used at 94.99 µM in combination with 68.8 µM Digoxin. Our results showed that the system composed of Digoxin and Irinotecan has psitive outcome on the treatment of colon cancer. The results indicated that these two drugs can be used to generate more effective treatment for colorectal cancer as well as for other cancer types in near future.
Glow in the dark tumor: enhanced near-ir visualization and destruction of cancer with a self-quenched theranostic
(2025) Güler, Selen İrem; Altan, Cem Levent; Demircioğlu, Emine Esma; Verimli, Nihan; Abisoğlu, Beyza; Bayraktaroğlu, Çiğdem; Erdem, Sultan Sibel
Late diagnosis is one of the major obstacles for the treatment of breast cancer which can be overcome with a system offering sensitive imaging and selective therapeutic effect. In this study, we developed a “dark-bright” multifunctional drug delivery system bringing real-time imaging and non-invasive therapy together. Theranostic ability of the system was delivered by Verteporfin (VP), serving as a fluorescence probe and a photosensitizer. To create a “dark state” system via self-quenching ability of VP, it was immobilized onto the superparamagnetic iron oxide nanoparticle (SPION) surface. Upon cellular uptake of the “dark state” system, release of VP led to fluorescence regain, switching the system to “bright state” after which photodynamic therapy (PDT) was initiated to lead to cell death. Theranostic feature of the system was evaluated in MCF-7 and MDA-MB-231 cell lines. Following internalization, fluorescence signal was increased up to ∼56-fold in MCF-7 cells. The IC50 value decreased ∼20-fold and ∼117-fold in MCF-7 and MDA-MB-231 cell lines, respectively. Moreover, the system significantly inhibited migration in the highly aggressive MDA-MB-231 cell line and induced apoptosis by caspase-3 activation. The developed “dark-bright” system is a promising multifunctional drug delivery vehicle with extraordinary theranostic features for the detection and destruction of micro tumors.
Guiding empiric treatment for serious bacterial infections via point of care beta-lactamase characterization
(Ieee-Inst Electrical Electronics Engineers Inc, 2016) Palanisami, Akilan; Khan, Shazia; Erdem, Sultan Sibel; Hasan, Tayyaba
Fever is one of the most common symptoms of illness in infants and represents a clinical challenge due to the potential for serious bacterial infection. As delayed treatment for these infections has been correlated with increased morbidity and mortality, broad-spectrum beta-lactam antibiotics are often prescribed while waiting for microbiological lab results (1-3 days). However, the spread of antibiotic resistance via the beta-lactamase enzyme, which can destroy beta-lactam antibiotics, has confounded this paradigm; empiric antibiotic regimens are increasingly unable to cover all potential bacterial pathogens, leaving some infants effectively untreated until the pathogen is characterized. This can lead to lifelong sequela or death. Here, we introduce a fluorescent, microfluidic assay that can characterize beta-lactamase derived antibiotic susceptibility in 20 min with a sensitivity suitable for direct human specimens. The protocol is extensible, and the antibiotic spectrum investigated can be feasibly adapted for the pathogens of regional relevance. This new assay fills an important need by providing the clinician with hitherto unavailable point of care information for treatment guidance in an inexpensive and simple diagnostic format.
Imaging Granzyme B activity assesses immune-mediated myocarditis
(Lippincott Williams and Wilkins, 2015) Konishi, Masanori; Erdem, Sultan Sibel; Weissleder, Ralph; Lichtman, Andrew; McCarthy, Jason; Libby, Peter
Rationale: The development of molecular imaging approaches that assess specific immunopathologic mechanisms can advance the study of myocarditis. Objective: This study validates a novel molecular imaging tool that enables the in vivo visualization of granzyme B activity, a major effector of cytotoxic CD8(+) T lymphocytes. Methods and Results: We synthesized and optimized a fluorogenic substrate capable of reporting on granzyme B activity and examined its specificity ex vivo in mice hearts with experimental cytotoxic CD8(+) T lymphocyte-mediated myocarditis using fluorescence reflectance imaging, validated by histological examination. In vivo experiments localized granzyme B activity in hearts with acute myocarditis monitored by fluorescent molecular tomography in conjunction with coregistered computed tomography imaging. A model anti-inflammatory intervention (dexamethasone administration) in vivo reduced granzyme B activity (vehicle versus dexamethasone: 504263 versus 194 +/- 77 fluorescence intensities in hearts; P=0.002). Conclusions: Molecular imaging of granzyme B activity can visualize T cell-mediated myocardial injury and monitor the response to an anti-inflammatory intervention.
Intravascular fibrin molecular imaging improves the detection of unhealed stents assessed by optical coherence tomography in vivo
(Oxford University Press, 2017) Hara, Tetsuya; Ughi, Giovanni J.; McCarthy, Jason R.; Erdem, Sultan Sibel; Mauskapf, Adam; Lyon, Samantha C.; Fard, Ali M.; Edelman, Elazer R.; Tearney, Guillermo J.; Jaffer, Farouc A.
Aims Fibrin deposition and absent endothelium characterize unhealed stents that are at heightened risk of stent thrombosis. Optical coherence tomography (OCT) is increasingly used for assessing stent tissue coverage as a measure of healed stents, but cannot precisely identify whether overlying tissue represents physiological neointima. Here we assessed and compared fibrin deposition and persistence on bare metal stent (BMS) and drug-eluting stent (DES) using near-infrared fluorescence (NIRF) molecular imaging in vivo, in combination with simultaneous OCT stent coverage. Methods and results Rabbits underwent implantation of one BMS and one DES without overlap in the infrarenal aorta (N = 20 3.5 x 12 mm). At Days 7 and/or 28, intravascular NIRF-OCT was performed following the injection of fibrin-targeted NIRF molecular imaging agent FTP11-CyAm7. Intravascular NIRF-OCT enabled high-resolution imaging of fibrin overlying stent struts in vivo, as validated by histopathology. Compared with BMS, DES showed greater fibrin deposition and fibrin persistence at Days 7 and 28 (P < 0.01 vs. BMS). Notably, for edge stent struts identified as covered by OCT on Day 7, 92.8 +/- 9.5% of DES and 55.8 +/- 23.6% of BMS struts were NIRF fibrin positive (P < 0.001). At Day 28, 18.6 +/- 10.6% (DES) and 5.1 +/- 8.7% (BMS) of OCT-covered struts remained fibrin positive (P < 0.001). Conclusion Intravascular NIRF fibrin molecular imaging improves the detection of unhealed stents, using clinically translatable technology that complements OCT. A sizeable percentage of struts deemed covered by OCT are actually covered by fibrin, particularly in DES, and therefore such stents might remain prothrombotic. These findings have implications for the specificity of standalone clinical OCT assessments of stent healing.
Manyetik nanoparçacıkların pankreas kanser hücre hattına özgü DNA nanoparçacıkları ile modifikasyonu yoluyla hücreye hedeflendirilmesi
(İstanbul Medipol Üniversitesi Sağlık Bilimleri Enstitüsü, 2020) Keçeloğlu, Gizem; Erdem, Sultan Sibel; Üçışık, Mehmet Hikmet
Kanser türüne özel geliştirilmeye çalışılan kişiselleştirilmiş tıp uygulamaları, aptamer, ligand ve antikor gibi ajanların afiniteye bağlı olarak aktif hedeflemede kullanılmasını içerir. Bu yaklaşım, spesifik bir hücre biyobelirtecine yönelik molekül-molekül etkileşimini içermekte, tedavideki başarı da ilacı kanser hücrelerine yönlendirebilme yeterliliğine bağlı olarak sınırlı kalmaktadır. Alternatif bir hedefleme yöntemi olarak çalışmamız, birden fazla etkileşim ile hücre hedefleme yetisine sahip DNA nanoparçacığın manyetik nanoparçacık ile birleştirilerek kanserli hücrelere hedeflendirilmesini konu alır. Çalışmanın amacı, hipertermide kullanılmak üzere manyetik nanoparçacıkların DNA nanoparçacık sistemi ile konjuge edilerek Panc02 pankreas kanser hücre hattına hedeflendirilmesidir. Bu amaçla, öncelikle Panc02 mürin pankreas kanseri hücre hattına özgü DNA nanoparçacık yuvarlanan halka çoğaltması (RCA) yöntemiyle sentezlenmiştir. DNA nanoparçacığın sekansına komplementer bir bağlayıcı sekans, amit bağı oluşumuyla manyetik demir oksit nanoparçacıklarının yüzeyine bağlanmıştır. Bağlayıcı sekans manyetik nanoparçacığın, DNA nanoparçacık ile konjugasonunu mümkün kılmıştır. Yapılan karakterizasyon çalışmaları sonucunda DNA nanoparçacığın morfolojisinde (büyüklük ve yapısal) değişiklikler olmasına rağmen Panc02 hücre hattına seçici olarak bağlanma özelliğini koruduğu kontrollü hücre kültürü çalışmaları neticesinde belirlenmiştir. Elde edilen veriler, DNA nanoparçacığın antikor, aptamer ve ligandlara alternatif olarak manyetik nanoparçacık başta olmak üzere birçok farklı ilaç taşıma sistemini hücrelere hedeflemede kullanılabileceğini göstermiştir. Ayrıca kendi başına taşıma sistemi olarak kullanıldığında DNA nanoparçacığın çeşitli terapi ajanlarını istenilen hücreye taşıyarak klasik tedavi yöntemlerine seçicilik kazandırabileceği öngörülmektedir.
Near-infrared dyes and their use in medical science
(2016) Erdem, Sultan Sibel
Targeted imaging (diagnosis) and therapy using near-infrared (NIR) dyes can be accomplished with the help of the data obtained from fluorescence emission of the fluorophores and play an important role particularly in deep tissue imaging. The area NIR dyes absorb and emit light is defined as NIR spectroscopy (NIRS, 650–850 nm). Although NIR dyes are widely used for imagining purposes, they also find application in photodynamic therapy. In preclinical studies, phthalocyanine (Pc), chlorine, porphyrin, bacteriochlorin, cyanine, Alexa-fluor, and various BODIPY dye series are used as NIR fluorescent dyes/agents. When compared to other dyes, one of the most promising NIR dye is Pc because of their photophysical and chemical properties particularly for the imaging applications. Although NIR dyes have several advantages, their toxicity limits their usage in clinics. Indocyanine green, having negligible side effects, is the only FDA approved NIR dye used in clinics. It is used for controlling of cardiac function, liver output, and retinal angiography. In conclusion, the development of new generation NIR dyes with improved chemical, photophysical, and photochemical properties that are more appropriate for the aforementioned applications is inevitable. Nevertheless, the NIR dyes that have been developed and will be developed should be combined with the nanoparticular systems and/or targeting moieties to make them more advantageous for NIRS and therapy.
Over kanseri?ne yöneli?k fotodi?nami?k terapi? temelli? kombi?nasyon terapi? uygulaması
(Zeynep Kamil Kadın ve Çocuk Hastalıkları Eğitim ve Araştırma Hastanesi, 2018) Erdem, Sultan Sibel; Akgül Obeidin, Vildan; Parlar, Rabia Edibe; Şahin, Ubeydullah
Kanser, tüm dünyada olduğu gibi ülkemizde de en ölümcül hastalıkların başında gelmektedir. Kanserin, lokal, minimum yan etkiyle ve hedefe yönelik olarak tedavisi hasta için büyük önem taşımaktadır. Fotodinamik Terapi (FDT), lokal, fotokimyaya dayalı ve yan etkisi minimum olan bir tedavi yöntemidir. Özetle FDT, ışıkla aktive olan ilaç (fotosensitizer), ışık ve oksijenin birleşmesi sonucu ortaya çıkan serbest radikallerin ve/veya tekil (singlet) oksijenin hücrede bir dizi zincir reaksiyon başlatarak hücre ölümüne sebep olması prensibine dayanır. Oksijen, ışık ve fotosensitizer tek başına herhangi bir toksik etki göstermeyip, ancak bir araya geldiklerinde başlayan fotokimyasal reaksiyonlar sonucu oluşan sitotoksisite sebebiyle hedeflenen hücrenin ölümü gerçekleşir. FDT’nin en önemli bileşeni hücre içinde, ışık enerjisini kimyasal enerjiye dönüştüren araç olan fotosensitizerdir. FDT’nin etkinliği farklı terapi modelleri ile birleştirilerek arttırılabilir. Kanser gibi dejeneratif hastalıkların genellikle birden fazla patolojik mekanizma içerdiklerini ve bu hastalıklarla tek tedavi yöntemiyle savaşmanın yeterli olmayacağını akılda tutmak gerekir. Bu nedenle iki ya da daha fazla tedavi yönteminin eş zamanlı olarak kullanılması başarıyı arttırmaktadır. Kombinasyon terapinin amacı kullanılan tedavi yöntemleri ve/veya ilaç ile hücredeki farklı sinyal yolaklarını dolayısı ile farklı hücre hasarı yollarını hedef alarak birden fazla mekanizmayı aktive ederek kanser hücresinin yok edilmesi ihtimalini arttırmaktır. Bu bilgilerin ışığında FDT ve kemoterapiden oluşan yeni kombinasyon terapinin SKOV-3 over kanser hücre hattında etkisi araştırıldı. Özgün, suda çözünürlüğü yüksek fotosensitizer ile klinikte sıklıkla kemoterapi ilacı olarak kullanılan İrinotekan kullanıldı. FDT ve kemoterapiden oluşan kombinasyon terapinin uygulanan tedavinin sırasına bağlı olarak çok büyük değişiklik gösterdiği görüldü. Örneğin, FDT’nin önce uygulandığı durumda belirli ilaç dozlarında güçlü antagonist etki görüldü. Öte yandan, aynı ilaç konsantrasyonlarında yalnızca uygulama sırası değiştirilerek sinerjik etkinin elde edilebileceği görüldü.
Skov-3 over kanseri hücre hattında fotodinamik terapi uygulaması
(2017) Erdem, Sultan Sibel; Parlar, Rabia Edibe; Akgül Obeidin, Vildan; Şahin, Ubeydullah
Sürdürülen sayısız araştırmaya ve geliştirilen ilaçlara rağmen günümüzde kanser hala milyonlarca insanın ölümüne neden olan hastalıkların başında gelmektedir. Over kanseri en ölümcül kanserlerden biri olup kadınlarda en çok görülen beşinci kanser türüdür. Uygulanan tedavi yöntemleri arasından kemoterapiye nispeten daha iyi yanıt alınmasına rağmen over kanseri halen tam olarak tedavi edilememektedir. Bu nedenle geleneksel tedavi yöntemlerinin ağır yan etkilerinden sıyrılmış, kanser hücresine karşı seçicilik gösteren etkili yöntemlerin geliştirilmesi ve/veya var olan yöntemlerin birleştirilerek özgün tedavilerin geliştirilmesi gerekmektedir. Fotodinamik terapi (FDT), ışıkla aktive olan molekül (fotosensitizer), oksijen ve uygun dalga boyundaki ışığın birleşmesi sonucu ortaya çıkan bir dizi fotokimyasal/fotofiziksel reaksiyonlar sonucu hücrenin ölümü prensibine dayanır. Özgün, suda çözünürlüğü yüksek fotosensitizerin SKOV-3 over kanser hattında FDT çalışmaları yapıldı. 100 µM konsantrasyona kadar karanlık toksisite görülmezken, aynı değerde ışıkla aktivasyonu sonucu fotosensitizerin reaktif oksijen türleri üreterek yüksek fototoksisiteye sebep olduğu görüldü. SKOV-3 over kanseri hücre hattında IC50 değeri 79 µM olarak belirlendi.
Stimuli-responsive theranostic system: A promising approach for augmented multimodal imaging and efficient drug release
(Elsevier B.V., 2022) Demiral, Ayşegül; Goralı, S. İrem; Yılmaz, Hülya; Verimli, Nihan; Çulha, Mustafa; Erdem, Sultan Sibel
Destruction of drug resistant and invisible micro-tumors requires innovative screening and treatment modalities. Theranostic nanosystems offering multimodal imaging and therapy are attractive platforms with potential to make micro-tumors visible to clinicians. Gold nanoparticles (AuNPs) are intrinsic theranostic agents and act as fluorescence quenchers. They can be easily transformed to multimodal imaging and combination therapy agents by combining them with various adjuvant therapies such as photodynamic therapy. In this study, we developed a highly specific, hybrid theranostic agent that is only activated when it meets with its stimuli at the site of interest. Surface-coated AuNPs were modified with Cathepsin B cleavable peptide (stimuli responsive linker) and Verteporfin (photosensitizer and fluorescence imaging agent). Unless the theranostic system meets with the internal stimuli in tumor cells, fluorescence is quenched due to AuNP-Verteporfin and Verteporfin-Verteporfin interactions. Following cellular internalization of the theranostic agent, fluorescence is gained by Cathepsin B cleavage and phototoxicity is initiated by light. The system was efficiently internalized by SKOV-3 cells and demonstrated high specificity towards its stimuli. In comparison to Verteporfin, ?14-fold fluorescence increase, 81% fluorescence recovery and comparable toxicity were achieved. The system is a promising candidate for multimodal imaging and dual treatment to destroy the micro-tumors.
Verteporfin mediated sequence dependent combination therapy against ovarian cancer cell line
(Elsevier Science Sa, 2018) Erdem, Sultan Sibel; Akgül Obeidin, Vildan; Yiğitbaşı, Türkan; Tümer, S. Serranur; Yiğit, Pakize
Ovarian Cancer is one of the deadliest gynecological cancer showing high resistance to chemotherapy. Non overlapping and synergistic combination therapies are the best option to overcome this multi-pathological silent disease. Cationic peptides (CPs) with high targeting feature and ability to pass through cell membrane induce apoptosis via disruption of cancer cell membrane. Photodynamic Therapy (PDT) is a noninvasive clinically approved treatment modality combining light activated photosensitizer, light and oxygen. In this study we present, combination therapy composed of 9-mer +4 charge bearing CP and Benzoporphyrin derivative monoacid, (BPD-MA, Verteporfin) mediated PDT. In order to evaluate the effect of sequence on the outcome of the therapy, CP and BPD-MA mediated PDT was applied in two different sequence: 'CP first' BPD-MA first'. Treatment efficacy of combination therapy in SKOV-3 ovarian cancer cell line has been evaluated based on cell inhibition, cell death pathway, Combination index (CI), and Dose Reduction Index (DRI) values. When SKOV-3 ovarian cancer cell line treated with BPD-MA mediated PDT (5 J/cm (2)) and CP individually, IC30 values for each drug were determined as 1.1 mu M and 240 mu M respectively and apoptosis was the major death cell pathway for both of the drugs. In the case of combination therapy, SKOV-3 cell line treated with drugs in constant ratio yet on different sequence. Drugs were used in constant ratio so that one of them would not deemphasize the effect of other in any concentration point. Our theoretical and experimental results were in agreement and showed that the treatment outcome significantly depends on the order of the treatment. For instance, while BPD-MA mediated PDT was applied prior to CP, cell inhibition at IC30 value of BPD-MA was roughly 28% with CI = 3.3 suggesting antagonistic interaction between each therapy. When the sequence of treatment was changed to CP first, cell inhibition at IC30 concentration of CP was determined as 98% with CI = 0.3 creating substantial synergism between the drugs. Moreover, synergistic interactions were observed at all concentration points at CP first scenario. DRI value for CP first treatment option was much higher compared to BPD-MA first treatment making the former treatment sequence more attractive option for clinically relevant combination therapies. Based on our results, we strongly believe that 9-mer CP and BPD-MA-PDT based combination therapy, offering synergistic therapeutic outcome, may increase chances of treatment of ovarian cancer in comparison to 9-mer CP and/or BPD-MA alone case.

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