Costagliola di Polidoro, Angela (2021) Understanding the mechanisms of crossing delivery and targeting of nanostructures for brain theranostics. [Tesi di dottorato]

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The review of the state of the art in the study of nano-bio-interactions reveals that the scientific community is still in an embryonal stage of comprehension of the mechanisms involved in the interaction of nanomaterial with the biological environment at all different levels, with most of the studies involving scarcely reliable NPs and biological models. This translates directly in the development of poorly effective nanoformulations and consequently in their poor clinical translation. In this framework, my thesis work aimed to the study, characterization, and deep understanding of the connection existing between the synthetic and biological identity of Hyaluronic Acid (HA) - based NPs, as a clinically relevant NP model. Starting from a patented, microfluidic-based nanoprecipitation process to produce crosslinked Hyaluronic Acid Nanoparticles (cHANPs), a library of HA-based nanovectors with different synthetic identities was produced with tight control over production process leading to highly homogeneous population of NPs with well-defined features. The choice of HA at different MW, the introduction of another polymer (polyethylene glycol – PEG) and the encapsulation of different active agents allowed to characterize the impact that these variables have on the thermodynamic of the processes of nucleation and growth, the crosslinking of the hydrogel matrix and encapsulation efficiencies, as presented in our work “A Microfluidic Platform to design Multimodal PEG - crosslinked Hyaluronic Acid Nanoparticles (PEG-cHANPs) for diagnostic applications” 51. Secondly, the biological identity of these nanovectors was investigated in different biological sera assessing their colloidal stability, their antifouling ability and changes in surface properties due to protein absorption, as well as the impact that these changes have on the uptake and the uptake kinetic of NPs by cells. Moving further, Glioblastoma Multiforme was chosen as a case study to identify disease-specific biological barriers and investigate the potentialities of theranostic cHANPs (Thera-cHANPs) as well as specifically engineered theranostic cHANPs (Thera-ANG-cHANPs) to overcome these biological barriers, preserving the Hydrodenticity effect and keeping unmodified their functionality, validating their efficacy against tumor cells, as presented in our publication “Theranostic design of Angiopep-2 conjugated Hyaluronic Acid Nanoparticles (Thera-ANG-cHANPs) for dual targeting and boosted imaging of glioma cells”. In addition, the ability of cHANPs of preserving structural stability was confirmed in an extremely complex biological environment, such as human atherosclerotic plaques (AP). After a specific surface functionalization (Ab-cHANPs), the ability of Ab-cHANPs in preserving the Hydrodenticity effect upon injection in this human complex tissue was assessed in a clinical 1.5 T MRI as described in our work “Targeting Nanostrategies for Imaging of Atherosclerosis”.

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