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    MESOPOROUS SILICA NANOPARTICLES FOR THE SELECTIVE DELIVERY OF DOXORUBICIN TO FOLATE RECEPTOR- EXPRESSING CANCER CELLS
    (Università della Calabria, 2025-05-29) Longobucco, Camilla; Sisci, Diego; Catalano, Stefania
    Breast and cervical cancers significantly impact women's health globally, with breast cancer accounting for approximately 2.3 million new cases annually. This highlights the urgent need for targeted therapeutic strategies that effectively eliminate tumor cells while preserving normal tissues. In this study, we developed a mesoporous silica-based nanodevice, FOL-MSN-DOXO, designed for the localized delivery of the chemotherapeutic agent doxorubicin (DOXO). This nanodevice utilizes the acidic tumor microenvironment for drug release via an acid-labile bond and incorporates folic acid (FOL) to enhance uptake by folate receptor-expressing cancer cells (FR+). The efficacy of FOL-MSN-DOXO was evaluated through various in vitro assays, including fluorescence-activated cell sorting (FACS), growth assays, and ROS measurements, as well as immunostaining of dorsal root ganglia (DRG) cells from neonatal rats. Our results demonstrate that FOL-MSN-DOXO effectively induces apoptosis in FR+ cancer cells (e.g., HeLa and T-47D), while exhibiting minimal toxicity towards FR3 normal cells (3T3-L1 and BJhTERT). Conversely, free DOXO exhibited significant toxicity across all tested cell lines. Notably, FOL-MSN-DOXO reduced neuronal toxicity compared to free DOXO, underscoring its neuroprotective potential. In summary, FOL-MSN-DOXO offers a promising targeted drug delivery system that selectively induces cytotoxicity in FR+ cancer cells while sparing normal tissues. This approach mitigates the neurotoxic effects associated with doxorubicin, highlighting the efficacy and safety of folic acid-functionalized mesoporous silica nanoparticles in cancer treatment.
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    Methods and strategies for the synthesis of biologically active oligopeptides and small molecules for potential applications in the field of drug delivery
    (Università della Calabria, 2025-01-21) Cavallaro, Palmira Alessia; Catalano, Stefania; Leggio, Antonella
    My PhD research activity focused on the development of novel methods and strategies for synthesizing biologically active short-chain peptides and piperazine-based small molecules, as well as designing mesoporous silica-based nanocarriers capable of incorporating and transporting these compounds, with the aim of enhancing their therapeutic potential. The main activities carried out during my PhD research were as follows: • Development of a novel peptide synthesis method for the production of small peptides in the solution phase. This approach combines TiCl4 as a condensing agent with microwave heating, enabling the rapid and efficient formation of dipeptide systems with urethane protecting groups on the N-terminal amino group. • Design and synthesis of a new cyclic somatostatin analog, c(-FWKTE-), using microwave-assisted solid-phase peptide synthesis (SPPS) and Fmoc chemistry. This cyclic pentapeptide includes the biologically active 7-10 sequence of somatostatin and glutamic acid at the C-terminus. Preliminary in vitro tests were carried out to explore its antiproliferative activity against breast cancer cell lines. • Design and synthesis of a novel class of piperazine-based molecules as potential inhibitors of the NS2B/NS3 protease in Flaviviridae viruses, including Zika and Dengue. These compounds, incorporating urea, sulfonamide, and acyl functional groups, were evaluated for antiviral activity through live-virus assays in human hepatoma cells. Furthermore, the anticancer potential of these piperazine derivatives was investigated in breast cancer cell lines. • Development of mesoporous silica-based (MSN) nanodevices with a dual architecture. featuring targeting molecules on their external surface and linkers within the pores for subsequent drug anchoring via covalent and non-covalent interactions. These nanocarriers are designed to enhance the therapeutic efficacy of the synthesized compounds by improving their delivery and bioavailability. The surface properties of these systems were analyzed to assess the impact of different modifications on the nanoparticle surface structure and their potential for novel applications. This thesis includes published works, studies ready for submission, and ongoing research that requires further investigation before completion and publication.
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    APPLICATIONS OF ANSWER SET PROGRAMMING TO LINEAR TEMPORAL LOGIC OVER FINITE TRACES
    (Università della Calabria, 2025-01-08) Ielo, Antonio; Terracina, Gorgio; Ricca, Francesco; Dodaro, Carmine
    Linear Temporal Logic over Finite Traces (LTLf) is a popular logic to express high level specifications that require reasoning about time. It was introduced in the seminal work of De Giacomo and Vardi, motivated by the fact that many Artificial Intelligence applications that require temporal reasoning are more intuitively described as finite execution sequences, rather than infinite execution sequences as in Linear Temporal Logic. Due to the high complexity that characterizes LTLf-related problems, efficienty systems are required. Reasoning tasks in LTLf are usually tackled by automata theoretic techniques or by SAT-based approaches. This thesis proposes an alternative approach to LTLf-related reasoning problems that is based on Answer Set Programming (ASP). Answer Set Programming is a declarative logic programming paradigm that stems from research in stable model semantics for logic programs and knowledge representation and reasoning. ASP is more expressive than SAT, thus, the solutions we obtain are more compact, intuitive and readable than SAT counterparts; moreover the usage of ASP does not result in a compromise on efficiency and effectiveness. Indeed, the approach presented in this thesis often obtains better performance with respect to existing SAT-based solutions; also, ASP enabled the development of novel solutions for unsatisfiable core enumeration and query checking in declarative process mining contexts.
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    NLPbasedapproachesformodelinginASP
    (Università della Calabria, 2025-10-01) Kareem, Irfan; Terracina, Giorgio; Ricca, Francesco; BorrotoSantana, ManuelAlejandro
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    Qualitative and regularity properties of solutions to quasilinear elliptic problems
    (Università della Calabria, 2025-01-20) Vuono, Domenico; Terracina, Giorgio; Sciunzi, Bernardino; Montoro, Luigi
    The thesis focuses on the study of the regularity and qualitative properties of solutions to quasilinear elliptic problems. The thesis is divided into two main parts. The first part (chapters 1–5) focuses on problems involving anisotropic functionals, where the main operator is governed by a norm that is generally non-Euclidean, leading to the p-Finsler Laplace operator. The second part (chapters 6–7) examines the regularity properties of solutions to equations involving both the scalar and vectorial Euclidean p-Laplacian operator. • In Chapter 1, we introduce a suitable anisotropic Kelvin-type transformation applied to the Finsler Laplace operator for specific types of anisotropy, particularly the Riemannian case. This transformation leads to a solution that satisfies an anisotropic equation involving the dual norm. • In Chapter 2, we prove Liouville-type theorems for stable solutions (and solutions stable outside a compact set) of quasilinear anisotropic elliptic equations. Specifically, for some general p-Finsler equations, we show that the only stable solutions to suitable nonlinear problems in RN under certain conditions on the dimension of the space and the nonlinearity of the zero-order term of the equation, are identically zero. • In Chapter 3, we establish rigidity results for Finsler p-Laplacian-type equations, including Liouville-type theorems and one-dimensional symmetry results. The proofs are based on a Poincar´e-type inequality and an extension of a formula by Sternberg and Zumbrun, which relates the second derivatives of a weak solution to the principal curvatures of the associated level set, within the anisotropic framework. • In Chapter 4, an asymptotic analysis of solutions to anisotropic doubly critical equations in RN is provided, with particular focus on the behavior of the solutions and their gradients. Specifically, we examine these solutions both near the origin and at infinity, establishing that they exhibit properties analogous to their Euclidean counterparts. • In Chapter 5, we analyze solutions to degenerate anisotropic elliptic equations with a focus on their regularity. Specifically, we derive second-order estimates and establish regularity results for the associated stress field. • Chapter 6 concerns regularity and symmetry properties for the p-Laplacian system. More specifically, we focus on second-order estimates for the stress field. As a consequence of our regularity results, we deduce a weighted Sobolev inequality, which leads to weak comparison principles. Additionally, we apply the moving plane technique to derive symmetry and monotonicity results for the solutions, under suitable assumptions. • Chapter 7 is devoted to the study of solutions to p-Laplace equations as p approaches the semilinear limiting case p = 2. Our focus is on the integrability of the third derivatives of the solutions. As a corollary, the obtained estimates enable us to deduce regularity results for the stress field of the solution. The results presented in this thesis were obtained during my three-year doctoral program. They stem from various scientific collaborations and are included in the following research papers: [15, 16, 77, 78, 91, 92, 128].