Abstract
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 T1 is observed since a T1 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.
Highlights
The Magnetic Resonance Imaging (MRI) represents the first-line diagnostic imaging modality for numerous indications
We have coupled a flow focused nanoprecipitation to an efficient crosslinking reaction based on Divinyl Sulfone (DVS) to entrap the relevant clinical gadolinium diethylenetriamine penta-acetic acid (Gd-diethylenetriaminepentaacetic acid (DTPA)) in crosslinked Hyaluronic Acid Nanoparticles able to increase its relaxometric properties without the chemical modification of the chelate (Fig. 1)
Crosslinked Hyaluronic Acid Nanoparticles to be applied in MRI field have been developed and loaded with a clinically relevant Gd-Contrast Agents (CAs), Gd-DTPA. crosslinked Hyaluronic Acid Nanoparticles (cHANPs) performances have been assessed in terms of longitudinal relaxation rates as a function of the crosslinking degree and loading conditions
Summary
The Magnetic Resonance Imaging (MRI) represents the first-line diagnostic imaging modality for numerous indications. 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, severely limiting the time window for MRI. 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]. Systems with nanometric and monodisperse size under 100 nm are likely to improve delivery functions[26] to the tissues, stability of the metal chelates, and provide enhanced relaxometric properties of the Gadolinium-based CAs
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