Tammaro, Olimpia (2020) A microfluidic platform to design nanostructures with improved multi-modal imaging properties. [Tesi di dottorato]

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Nowadays, researchers are making many efforts in the medical field leading to new therapy and diagnosis methods exploiting opportunities given by nanotechnology innovation. For example, the combination of different imaging modalities can give the opportunity to obtain morphological and functional information simultaneously, providing a more accurate diagnosis. This advancement can be reached through the use of multimodal tracers and nanotechnology-based solutions allowing the simultaneous delivery of different diagnostic compounds and their safe administration for multimodal imaging acquisition. In this way is possible to protect the cargo molecules. Furthermore, a fundamental aspect is due to a proper design of the nanovectors used, correlating it with respect to the target purpose. Among different materials and processes available, nanoprecipitation is a consolidate method for polymeric nanoparticle production and its implementation in microfluidics can further improve the control over final product features accelerating its potential clinical translation. In this scenario, a Hydrodynamic Flow Focusing (HFF) approach is proposed and investigated as a production route to synthesis through a ONE-STEP process pegylated crosslinked Hyaluronic Acid NanoParticles (PEG-cHANPs). A feasibility study has been conducted to define the principal guidelines in terms of size and stability for the produced nanosystem. Based on the obtained results, a set of conditions has been elected as “gold conditions” and used in the following parts. To exploit the versatility of our microfluidic (µF) platform, the ONE-STEP process has been implemented to generate more complex structures with differents loaded agent. First, we have demonstrated that a homogeneous population of NPs with an average size of 140 nm is obtained and Gadolinium-based contrast agent (Gd-DTPA CA) and ATTO488 compounds are co-encapsulated simultaneously during the ONE-STEP process The results showed that the obtained architectures can be used as multimodal Magnetic Resonance Imaging (MRI)/Optical imaging probe. Furthermore, in accordance with the Hydrodenticity concept, a boosting of the T1 values is obtained with respect to the free Gd-DTPA. Thereafter, we have synthesized hybrid materials combining SiO2 and HA-PEG hydrogels loaded with Gd-DTPA as new MRI probes. Pre-synthetized SiO2 NPs have been added to the solvent phase during the ONE-STEP process. In this case, silica nanoparticles act as a templating agent, interfering with the nanoprecipitation step during the HFF. Resulting hybrid nanosystems have been characterized in terms of size, morphology and T1 values. Intending to develop new probes for combining MRI/Near-Infrared Fluorescence Imaging (NIRF), we explore the possibility to co-encapsulate Gd-DTPA and Indocyanine Green (ICG) in the ONE-STEP process for PEG-cHANPs production. ICG is the only NIRF dye approved by Food and Drug Administration, but its use is restricted by its low stability in biological media. Here we report a stability study of ICG regarding its interaction with the materials involved in PEG-cHANPs production and preliminary characterization of PEG-cHANPs loaded with ICG as Reactive Oxygen Species generators. Preliminary in-vitro tests with different cells lines have been conducted to evaluate the PEG-cHANPs-Gd-DTPA-ATTO488 behaviour for biological application.

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