Preparation of lhrh receptor targeted cisplatin containing peg-plga-pga triblock polymeric micelles for use in ovarian cancer and investigation the possibilities in oral administration with in vitro/ex vivo/in vivo studies

Cancer, today, is one of the most threatening diseases to society. World statistics on the number of cancer patients in 2020 will be more than 15 million was stated. World statistics stated that the number of cancer patients will be more than 15 million in 2020. Ovarian cancer is the ninth most common cancer in women and the most lethal gynecologic cancer. Based on the cancer statics in 2014, ovarian cancer is the seventh most common cancer in women with 6,1% in Turkey. Depending on the location and stage, many types of cancer may be treated with surgery, radiotherapy and chemotherapy. Chemotherapy has an important role in ovarian cancer and EMA (European Medicines Agency) and FDA (Food and Drug Administration) approved drugs for the treatment are Melphalan, Doxorubicin, Cisplatin, Carboplatin, Altretamine, Paclitaxel, Topotocan, Gemcitabine, Trabestedine and Bevacizumab. Cisplatin is most commonly used chemotherapeutic agent and it is chosen as first stage drug in ovarian cancer. Cisplatin is indicated in primary, advanced stage and refractory ovarian cancer. In treatment with Cisplatin, gastrointestinal side effects as well as urinary, hematologic, otologic, physhoneurologic side effects and side effects in cardiovascular system may be observed. When using Cisplatin with other anticancer drugs and radiotherapy, it is stated that it can cause bone marrow inhibition. Classical drug application routes in chemotherapy are intravenous and oral. There are some disadvantages of these methods. Absorption of the drugs used for the oral route is not complete. Hence, it should be applied in higher dosage and this situation causes an increase in toxicity. It is known that there is a problem in intravenously applied drug because of the low specifity and harmful effects in healthy tissues. In order to eliminate or minimize the observed negativity in treatment, increasing the delivery to cellular levels, optimization of concentration in circulatory system or other biological fluids and release kinetics of drugs, changing the pharmacokinetic and pharmacodynamic properties of drugs, ensuring the efficient and safety usage in low and high doses, eliminating or minimazing the toxic and immunogenic properties, increasing the stability of drugs and obtaining the pharmacological response in the desired level at target site without causing any undesired interactions with ohter parts of the body, nowadays targeting studies are carried out. In the scope of the proposed thesis, the use of LHRH (Luteinizing Hormone Releasing Hormone) receptors in drug targeting are planned. LHRH is a decapeptide produced by the hypothalamus and the hormonal effect on reproduction. LHRH binds with high affinity to LHRH receptor to start luteinizing hormone and follicile-stimulating hormone release. Some of 11 aminoacids in the LHRH (GnRH) polypeptide sequence, is induced in only receptor binding and others in both activation and binding. LHRH receptor is a rhodopsin-like G-protein linked protein which is localized in gonadotropic cell membrane in pituatary gland and containes an extracellular domain with 7 transmembrane domain. LHRH ligant bearing structures are taken into cell with receptor-mediated endocytosis when bind to the LHRH receptor. LHRH receptor is expressed in undetectable small amount in other normal tissues except pituatary gland. In addition to this, it is known that this receptor is synthesized in 52% of breast cancers, 80% of ovarian and endometrial cancer species and 86% of prostate cancer species. In the scope of the thesis, fot the purpose of oral chemotherapy, it is planned to prepare LHRH targeted Cisplatin containing PEG-PLGA-PGA (Polyethyleneglycol-Polylactid-co-glycolyde-Polyglutamicacid) triblock polymeric micelle, characterize the prepared polymeric micelles and investigate the activity in ovarian cancer with in vitro/ex vivo/in vivo studies. When literature data and clinical research web site was scanned, LHRH receptor targeted drug containing Cisplatin or different PEG-PLGA-PGA triblock oral drug delivery systems consisting of polymeric micelles has not been found. Keywords: PEG-PLGA-PGA micelle; LHRH; oral; ovarian; Cisplatin