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- Delivery of anti-HPV drugs to cervical cancer cellsPublication . Ferreira, Miguel Rodrigues; Sousa, Ângela Maria Almeida de; Costa, Diana Rita BarataHuman papillomavirus (HPV) is the main causative agent for the development of cervical cancer, the fourth most common cancer in women worldwide. Overexpression of HPV oncoproteins E6 and E7 are present on this type of cancer, disrupting the cell cycle regulation and proliferation through the involvement of tumor suppressor proteins p53 and pRb, respectively. Although preventive anti-HPV vaccines already exist, therapies for this type of cancer are still under development in order to find an effective cure for this type of cancer. Flavonoids have shown a high potential in such therapy, offering an effective and lowcost method that enables their use in less developed countries and where health care is poorer. Quercetin is the main flavonoid in therapeutic uses presenting high anticancer properties, showing particular prominence in cervical cancer therapy due to the fact that it potentiates E6 oncoprotein inhibition, thereby increasing p53 expression and thereby inducing apoptosis. However, quercetin use is limited due to its insolubility in aqueous medium and its low stability. Thus, quercetin low bioavailability limits its application in cancer therapies. Thus, this master thesis aims to develop quercetin-loaded delivery systems to enhance its bioavailability and effect in HPV positive cells. Three types of systems were formulated and characterized, one composed of sulfobutyl ether ß-Cyclodextrin (SBE-ß-CD) and the other two were chitosan-based, one conjugated with tripolyphosphate (TPP) and other with SBE-ß-CD. SBE-ßCD/Quercetin delivery systems had a size of 2468.33 nm, a polydispersity Index (PdI) of 0.123, a zeta potential of -21.03 mV and an encapsulation efficiency of approximately 100%. The Chitosan/TPP/Quercetin delivery systems showed a size of 325.1 nm, a PdI of 0.371, a zeta potential of +16.6 mV and an encapsulation efficiency of 10.80%. Finally, Chitosan/SBE-ß-CD/Quercetin delivery systems presented a size of 272.07 nm, a PdI of 0.287, a zeta potential of +38.0 mV and an encapsulation rate of approximately 100%. Scanning electron microscopy (SEM) was performed for all delivery systems, being possible to verify that Chitosan/TPP/Quercetin and Chitosan/SBE-ß-CD/Quercetin systems presented a regular and spherical morphology. Furthermore, fourier transform infrared spectroscopy (FTIR) and UV/vis spectra were also obtained and it was possible to verify the presence of all compounds and the interactions between them, and, for the systems composed by SBE-ß-CD it was also possible to verify that it was completely trapped inside the inclusion complexes. Cell viability assays were performed in HeLa cells (HPV positive) for each type of formulated system, with the most promising results being seen for the Chitosan/SBE-ßCD/Quercetin delivery systems. This type of delivery system showed a reduction in half inhibitory concentration (IC50) from 59.84 µM to 43.55 µM for 48 h of incubation when compared with free quercetin. In this manner, the results indicated that there is an increased therapeutic effect after encapsulation with Chitosan/SBE-ß-CD/Quercetin systems, thus representing a step forward in the design/development of flavonoids-based delivery systems for cervical cancer therapy applications.