HPV-İlişkili Servikal Kanserin Tedavisine Yönelik İlaç Yüklü Nanopartikül Formülasyonlarının Printing Teknolojisi ile Hazırlanması ve Karakterizasyonu
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Although clinical applications for the prevention and early detection of cervical cancer exist, the incidence and the mortality rate is especially high in women living in developing countries. One of the most important risk factors for cervical cancer, along with many risk factors, is the human papilloma virus (HPV). Chemotherapy of HPV-related cervical cancer is very limited. Chemotherapy drugs, which are known to be effective on this type of cancer, have solubility problems and solubility-related toxicity. It is needed to develop new drug delivery systems with the aim of preventing these problems, increasing cellular penetration, protecting drugs against enzymatic and physiological degradation, and keeping the drug in the application area for a long time. For this purpose, the development of polymeric nanoparticle based drug delivery systems is very important. On the other hand, to cervical cancer developing region can be reached directly by health personnel without the need of surgical methods and chemotherapy can be applied directly. Taking this into consideration, the preparation of drug loaded implantable film may increase the treatment success for cervical cancer and it may also reduce the side-effects seen during treatment. Disease history, age, sex, genetic and metabolic characteristics of each patient are different from each other. This leads to the need for appropriate medication and appropriate dose for the treatment of the patients. For this reason, research on the development of personalized medicines have been carried out in recent years. Thanks to printing technology, drug formulations can be prepared easily, quickly and economically in the desired dose and pattern. In this thesis, Paclitaxel, which is known to be effective on cervical cancer but has a solubility problem, was used as model anticancer drug and cidofovir, which is known to be effective against HPV was used as model antiviral drug. Using the nanoparticulate drug delivery systems and the cyclodextrin inclusion complex, the solubility problem of paclitaxel was abolished and controlled release of cidofovir was achieved. For the purpose of developing a local and personalized drug formulation, nanoparticulate formulations containing anticancer and antiviral drugs were printed on a bioadhesive film with adjustable dose and pattern by using ink-jet printers. In this way, a pharmaceutical formulation containing anticancer and antiviral drug for the treatment of cervical cancer has been prepared. In the first part of this thesis, inclusion complexes were formed by using 3 different cyclodextrin derivatives in order to increase the solubility of paclitaxel and characterization studies were realized. An encapsulation efficiency of 63% was achieved with the inclusion complexes prepared with hydroxypropyl-β-cyclodextrin and this inclusion complex was used to prepare the ink formulation containing paclitaxel. Likewise, cidofovir loaded nanoparticles based on polycaprolactone were prepared and characterization studies were carried out. The nanoparticle formulations prepared with poly (ethylene glycol)-b-poly (ε-caprolactone) methyl ether showed a particle size of 161 nm and an encapsulation efficiency of 76%. With the low particle size and high encapsulation efficiency, this nanoparticle formulation has been used to prepare ink formulations containing cidofovir. In the second part of the study, ink formulations suitable for printing technique were prepared and printed on the cellulose-based bioadhesive film with different doses and patterns by using inclusion complex and nanoparticles. At the end of the thesis, characterization studies of bioadhesive films printed with drugs, cell culture studies and ex vivo studies were performed. Cell culture studies showed that the paclitaxel cyclodextrin inclusion complex printed film reduced cell viability by 50% on HeLa cells and by 45% on C33a cells. In addition, characterization and ex vivo studies have shown that the printing process enhances the mechanical and bioadhesive properties of films. This thesis has taken an important step towards developing an effective, safety, and personalized drug formulation that carries antiviral and anticancer drugs for the local treatment of HPV-related cervical cancer.