Gallo, Enrico (2024) Development of pharmaceutical tools for enhanced bioimaging. [Tesi di dottorato]

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Abstract

Nanomedicine has recently gained substantial attention due to its potential to revolutionize both diagnostic and therapeutic approaches for a wide range of human diseases. Among the various nanosystems being investigated in nanomedicine, self-assembled peptide-based nanomaterials have emerged as highly promising candidates. Peptides offer the advantage of being engineered to form a variety of micro- and nanostructures, each with significant potential in the biomedical field. Indeed, once assembled into such structures, peptides can be utilized in a wide range of applications, including tissue regeneration, enhanced drug delivery, as fluorescent probes, and as improved bioimaging agents. For instance, in tissue regeneration, biocompatible and biodegradable peptide-based hydrogels have been proposed as suitable three-dimensional scaffolds capable of supporting cell growth, differentiation, and migration, thereby making them ideal for applications in wound healing, bone regeneration, and the engineering of complex tissues such as cartilage and muscle. Their bioactivity can be further enhanced through the incorporation of growth factors, cytokines, or other biomolecules that promote tissue repair and regeneration. Instead, in drug delivery, peptide-based nanostructures can encapsulate both hydrophilic and hydrophobic therapeutic agents, thereby protecting them from degradation while enabling controlled and localized release at the target site. This targeted approach can significantly enhance the efficacy of drugs, such as chemotherapeutics, by reducing systemic toxicity and minimizing side effects. Furthermore, peptide nanostructures can be functionalized with ligands to selectively target specific tissues or cell receptors, making them particularly advantageous in cancer therapy and regenerative medicine. Self-assembling peptide materials are also being explored as agents for advanced bioimaging techniques, such as Fluorescence Imaging (FI), and Magnetic Resonance Imaging (MRI). By incorporating imaging-enhancing moieties, these peptide-based systems can enhance the sensitivity and specificity of imaging methods, enabling earlier detection and more accurate monitoring of disease progression, particularly in cancer and neurodegenerative diseases. In this context, the present PhD project has been focused on the development of peptide-based matrices for four distinct biomedical applications: i) tissue engineering, ii) drug delivery, iii) as probes for FI, and iv) as contrast agents for MRI. Several peptide derivatives were specifically designed and synthesized to meet the unique requirements of each application and were thoroughly characterized using a range of spectroscopic techniques. To achieve the final materials with the desired characteristics, the self-assembly process was induced and controlled using various strategies. Aromatic groups or alkyl chains were introduced to promote hydrogel formation, while mechanical properties were improved by combining different building blocks or incorporating cross-linkable components. Various loading strategies were employed to maximize the encapsulation of drugs or contrast agents within the structures. Additionally, to create a supramolecular system capable of simultaneously interacting with both hydrophobic and hydrophilic drugs, or with structurally different contrast agents, we explored the possibility of co-encapsulating two or more functional groups within the same sequence. The autofluorescence properties of self-assembling amyloid-like peptides were also investigated. The in vitro biocompatibility of both empty and drug-loaded matrices was assessed, providing new insights into the internalization mechanisms and cell specificity of peptide-based nanogels. Tumor cell cytotoxicity assays were conducted on various cell lines to confirm the anticancer efficacy of drug-loaded supramolecular structures, while cell adhesion tests were performed to evaluate the matrices' potential as scaffolds for tissue engineering. Furthermore, in vivo studies were conducted to verify that peptide-based supramolecular contrast agents can be visualized using MRI and CEST-MRI techniques.

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