A Microfluidic Platform to design crosslinked Hyaluronic Acid Nanoparticles (cHANPs) for enhanced MRI (original) (raw)

Recent advancements in imaging diagnostics have focused on the use of nanostructures that entrap Magnetic Resonance Imaging (MRI) Contrast Agents (CAs), without the need to chemically modify the clinically approved compounds. Nevertheless, the exploitation of microfluidic platforms for their controlled and continuous production is still missing. Here, a microfluidic platform is used to synthesize crosslinked Hyaluronic Acid NanoParticles (cHANPs) in which a clinically relevant MRI-CAs, gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA), is entrapped. This microfluidic process facilitates a high degree of control over particle synthesis, enabling the production of monodisperse particles as small as 35 nm. Furthermore, the interference of Gd-DTPA during polymer precipitation is overcome by finely tuning process parameters and leveraging the use of hydrophilic-lipophilic balance (HLB) of surfactants and pH conditions. For both production strategies proposed to design Gd-loaded cHANPs, a boosting of the relaxation rate T 1 is observed since a T 1 of 1562 is achieved with a 10 μM of Gd-loaded cHANPs while a similar value is reached with 100 μM of the relevant clinical Gd-DTPA in solution. The advanced microfluidic platform to synthesize intravascularly-injectable and completely biocompatible hydrogel nanoparticles entrapping clinically approved CAs enables the implementation of straightforward and scalable strategies in diagnostics and therapy applications. The Magnetic Resonance Imaging (MRI) represents the first-line diagnostic imaging modality for numerous indications. It is a clinically well-established, non-invasive technique that leverages the magnetic properties of water protons present in the body to produce three-dimensional whole body anatomical and functional images 1,2. High magnetic fields (1.5 T and above) are clinically favoured because of their higher signal-to-noise ratio, capability for MR spectroscopy 3 and other forms of functional MRI, such as high-speed imaging and high-resolution imaging. MRI signal intensity is related to the relaxation rate of in vivo water protons and can be enhanced by the administration of a contrast agent (CA) prior to scanning. These CAs utilize paramagnetic metal ions to enhance the contrast in an MR image by positively influencing the relaxation rates of water protons in the immediate surroundings of the tissue in which they localize. The ability of CAs to effectively enhance image contrast depends on their relaxivity (longitudinal r 1 ; transversal r 2) and the level of accumulation at the target site 4. Among different CAs, Gadolinium-based ones, used in up to 30% of clinical MRI scans 5 , consist of polyamino carboxylate complexes of Gd ions, where Gd ions cytotoxicity is sequestered via chelation with ligands such as diethylenetriaminepentaacetic acid (DTPA) and tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) 6-8. However, despite its certain role, Gadolinium-based CAs, like most of other clinically relevant CAs, suffer from poor sensitivity 6 and rapid renal clearance, requiring long scan times, thus severely limiting the time window for MRI. In addition, they present low tissue specificity, leading to concerns in linking the use of these CAs with nephrogenic systemic fibrosis (NSF) 9 and progressive accumulation in various central nervous system (CNS) structures following repeated gadolinium administration 10 .