Rosa, Elisabetta (2023) Peptide based nanoformulations for biomedical applications. [Tesi di dottorato]

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Abstract

Self-assembling short and ultra-short peptides and lipopeptides can act as building blocks for the construction of nano-architectures that find a potential application in different biomedical fields. These new materials arise from noncovalent bonds within and between molecules, including hydrogen bonding, metal coordination, hydrophobic, van der Waals, electrostatic and π-π interactions. Some of these peptide sequences are able to form hydrogels (HGs) that can be defined as networks of interacting hydrophilic molecules able to absorb high amounts of water and biological fluids. Through a submicronization procedure, HGs can be turned into nanogels (NGs), which are particles in the nano-range preserving the inner structuration of the HG they arise from, defined core, covered by a shell of surfactants. Thanks to their dimensions, making them able to exploit the Enhanced Permeability and Retention (EPR) effect, they can be considered useful tools for the delivery of Active Pharmaceutical Ingredients (APIs) in lesion sites. In this thesis, new peptide-based matrices have been proposed for three different biomedical scopes: i) tissue engineering, ii) delivery of drugs and iii) contrast agents for Magnetic Resonance Imaging (MRI) applications. Several peptide derivatives have been punctually designed and synthesized in order to satisfy the specific requests, and fully characterized through a series of spectroscopic techniques. Different strategies were used to prompt the self-assembling behavior, to improve the rheological response of the obtained matrices and to promote the encapsulation of drugs and contrast agents. Aromatic groups or alkyl chains were used to allow the hydrogel formation, and mechanical properties were increased by combining together different building blocks or by inserting cross-linkable entities. Electrostatic interactions between the carrier and the delivered molecules were exploited to help the loading. New formulation methods were tested and standardized for the obtainment of stable and reproducible nanogel suspensions, which were used as reservoirs of drugs and contrast agents with the purpose of intravenous administration. The biocompatibility of the empty matrices was assessed in vitro and new insights were given on the internalization mechanism and cell specificity of peptide gelling nanoparticles. Tumor cell cytotoxicity assays were carried out to demonstrate the anticancer efficiency of Doxorubicin-loaded HGs and NGs and cell adhesion tests were used to detect the capability of the matrices to act as scaffolds for tissue engineering scopes. Also, in vivo studies were conducted to prove that peptide-based supramolecular contrast agents can be imaged by MRI technique.

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