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- 3D printed drug delivery system for cervical cancer treatmentPublication . Lopes, Guilherme Zoccal Rossignoli Lopes; Valente, Joana Filipa Abreu Pereira; Sousa, Ângela Maria Almeida de; Alves, Nuno Manuel FernandesCervical cancer (CC) is one of the leading causes of mortality among women worldwide and is strongly associated with persistent infection by the Human Papillomavirus (HPV). Despite advances in prevention through vaccination and screening, developing countries still have limited access to preventive healthcare, making CC a significant public health issue. The primary cause of this type of tumor is the oncogenic action of the E6 and E7 oncoproteins, encoded by the HPV genome. The viral E6 protein promotes the degradation of the tumor suppressor protein p53, essential for maintaining cellular integrity, thereby inhibiting apoptosis. Meanwhile, the E7 protein inactivates the retinoblastoma protein (pRb), leading to uncontrolled cell proliferation and tumor progression. Although advances have been made in prevention and treatment, innovative therapeutic approaches are still needed to enhance efficacy and mitigate the adverse effects of conventional treatments, such as surgery, chemotherapy, and radiotherapy. Concerning the above mentioned, this dissertation focuses on developing a 3D-printed (3DP) vaginal insert made of polycaprolactone (PCL) that will work as a platform for gene and drug delivery to treat HPV-induced CC. The dosage form (DF) presents an interconnected porous structure filled with alginate hydrogels, enabling the controlled release of therapeutic agents. Among the compounds incorporated into the template, there are the taxifolin (TAX), a flavonoid that exhibits selective cytotoxicity toward cells expressing the viral E6 protein, and the p53 encoding plasmid DNA (pDNA), intended to restore apoptotic pathways. The formulation was engineered to achieve a dual-release profile: TAX, embedded in 0.75% alginate, demonstrated a rapid release, whereas pDNA, embedded in 2% alginate, exhibited a sustained release over time. Characterisation studies, including thermal, chemical, mechanical, and morphological analyses were conducted to evaluate the system’s structural integrity and functional behaviour. Moreover, different alginate concentrations were studied to achieve different release profiles. This was an important step since it was important to guarantee that the drug has a quick effect on cancer cells while pDNA should have a prolonged therapeutic effect. Moreover, these experiments were performed under different pH conditions, simulating both the physiological environment (pH 7.4) and the tumor microenvironment (pH 5.8). To understand the drug release kinetics and compare the different sodium alginate concentrations used, several mathematical models were fitted to the experimental data. The obtained results of this dissertation demonstrate that additive manufacturing (AM) is a promising tool for developing personalised DF. The vaginal insert designed herein successfully exhibited a dual-release profile, combining the rapid release of TAX with the sustained release of pDNA, potentially enabling a more effective and localized treatment strategy for CC. Significant differences were observed in the release behaviour depending on both the alginate concentration and the pH of the surrounding medium. Overall, it was possible to achieve an ovule-shaped 3DP platform for vaginal administration, featuring an interconnected porous structure that was subsequently filled with alginate hydrogel. A dual-release effect with distinct profiles was achieved by modulating the hydrogel network density. Variations in alginate crosslinking enabled fine control over the release kinetics: TAX, incorporated into 0.75% alginate, exhibited a rapid release within the first 6 h, while pDNA, incorporated into 2% alginate, showed a prolonged and controlled release during the later stages of the study. Future research should focus on the biological validation of the system in cellular models to confirm its efficacy in the tumor microenvironment. Additionally, further studies could optimise the formulation and explore the incorporation of other therapeutic agents, broadening the applications of this technology for other gynecological diseases.