Nowadays, magnetic resonance imaging (MRI) is the first diagnostic imaging modality for numerous indications able to provide anatomical information with high spatial resolution through the use of magnetic fields and gradients. Indeed, thanks to the characteristic relaxation time of each tissue, it is possible to distinguish between healthy and pathological ones. However, the need to have brighter images to increase differences and catch important diagnostic details has led to the use of contrast agents (CAs). Among them, Gadolinium-based CAs (Gd-CAs) are routinely used in clinical MRI practice. During these last years, FDA highlighted many risks related to the use of Gd-CAs such as nephrotoxicity, heavy allergic effects, and, recently, about the deposition within the brain. These alerts opened a debate about the opportunity to formulate Gd-CAs in a different way but also to the use of alternative and safer compounds to be administered, such as manganese- (Mn-) based agents. In this review, the physical principle behind the role of relaxivity and the T1 boosting will be described in terms of characteristic correlation times and inner and outer spheres. Then, the recent advances in the entrapment of Gd-CAs within nanostructures will be analyzed in terms of relaxivity boosting obtained without the chemical modification of CAs as approved in the chemical practice. Finally, a critical evaluation of the use of manganese-based CAs will be illustrated as an alternative ion to Gd due to its excellent properties and endogenous elimination pathway.

Microfluidics is emerging as a promising tool to control physicochemical properties of nanoparticles and to accelerate clinical translation. Indeed, microfluidic-based techniques offer more advantages in nanomedicine over batch processes, allowing fine-tuning of process parameters. In particular, the use of microfluidics to produce nanoparticles has paved the way for the development of nano-scaled structures for improved detection and treatment of several diseases. Here, ionotropic gelation is implemented in a custom-designed microfluidic chip to produce different nanoarchitectures based on chitosan-hyaluronic acid polymers. The selected biomaterials provide biocompatibility, biodegradability and non-toxic properties to the formulation, making it promising for nanomedicine applications. Furthermore, results show that morphological structures can be tuned through microfluidics by controlling the flow rates. Aside from the nanostructures, the ability to encapsulate gadolinium contrast agent for magnetic resonance imaging and a dye for optical imaging is demonstrated. In conclusion, the polymer nanoparticles here designed revealed the dual capability of enhancing the relaxometric properties of gadolinium by attaining Hydrodenticity and serving as a promising nanocarrier for multimodal imaging applications.