A Microfluidic Platform to design Multimodal PEG - crosslinked Hyaluronic Acid Nanoparticles (PEG-cHANPs) for diagnostic applications

Abstract

The combination of different imaging modalities can allow obtaining simultaneously morphological and functional information providing a more accurate diagnosis. This advancement can be reached through the use of multimodal tracers, and nanotechnology-based solutions allow the simultaneous delivery of different diagnostic compounds moving a step towards their safe administration for multimodal imaging acquisition. Among different processes, nanoprecipitation is a consolidate method for the production of nanoparticles and its implementation in microfluidics can further improve the control over final product features accelerating its potential clinical translation. A Hydrodynamic Flow Focusing (HFF) approach is proposed to produce through a ONE-STEP process Multimodal Pegylated crosslinked Hyaluronic Acid NanoParticles (PEG-cHANPs). A monodisperse population of NPs with an average size of 140 nm is produced and Gd-DTPA and ATTO488 compounds are co-encapsulated, simultaneously. The results showed that the obtained multimodal nanoparticle could work as MRI/Optical imaging probe. Furthermore, under the Hydrodenticity effect, a boosting of the T1 values with respect to free Gd-DTPA is preserved. Multimodal Imaging is a promising approach that allows the combination of different imaging techniques, overcoming limitations proper of every single modality 1,2. For example, recently, Magnetic Resonance Imaging (MRI) and Optical imaging (OI) have been used in combination to obtain the excellent sensitivity of the OI with the high spatial resolution of the MRI 3-5. Image acquisition can occur at different times (asynchronously) requiring post-processing analyses performed through digital image manipulation techniques; however, the best consistency both in time and space is achieved when images are simultaneously acquired (synchronously) 6. Despite the great advantages in the Hardware developments, probes able to support simultaneous acquisitions are still missing. Indeed, in current clinical practice, a cocktail of diagnostic compounds is injected with extremely high risk for the patient. In this scenario, the possibility to efficiently co-deliver through a single vector, different diagnostic compounds for different imaging modalities represents a key point. This challenge can be adequately tackled by applying nanotechnologies to the medical field 7-9. Indeed, nanosystems can be used as vectors of active agents and their composition, size, shape, and surface chemistry can be finely modulated to obtain the simultaneous delivery of multiple diagnostic compounds with a significant impact on an early and accurate diagnosis 10-12. Nanovectors can provide simultaneous visualization of the diseased site through different innovative imaging techniques, enhanced-circulation time for the diagnostic compounds, controlled release kinetics, and superior dose scheduling for improved patient compliance 13. However, when systemically injected, nanoparticles are immediately sequestered by macrophages

Nanoparticle Surface Functionalization: How to Improve Biocompatibility and Cellular Internalization

“…NPs can be applied to cancer for two main purposes: diagnosis and therapy (Borkowska et al, 2020;Tammaro et al, 2020). The usage of nanoplatforms for diagnosis can be classified by two different approaches: biomolecule detection and imaging techniques.…”

Theranostic Design of Angiopep-2 Conjugated Hyaluronic Acid Nanoparticles (Thera-ANG-cHANPs) for Dual Targeting and Boosted Imaging of Glioma Cells

“…The ability of hydrogel matrices to boost the relaxivity of Gd-chelates has been widely described by the hydrodenticity theory [ 29 , 30 , 31 , 32 , 33 , 47 ].…”

“…In addition, this natural interaction can be useful to provide an early and more accurate MRI and, in this perspective, it has already been reported that hydrogels, in particular HA, boost relaxometry properties of MRI CAs [ 28 , 29 ]. In detail, Russo et al, demonstrated that HA matrices are able to boost the relaxivity of Gd-based CAs for MRI by a hydrodenticity effect [ 30 , 31 , 32 , 33 ]. Indeed, hydrodenticity effect arises from the establishment of a complex equilibrium between the elastodynamics of polymer chains of the hydrogel and water molecules which are packed around Gd-chelates forming gado-meshes that, improving the hydration degree of the CA, boost its relaxivity.…”

Natural Polymers in Micro- and Nanoencapsulation for Therapeutic and Diagnostic Applications: Part I: Lipids and Fabrication Techniques

“…Diagnostics are also gaining from the merits of encapsulation. This was demonstrated in the simultaneous co-encapsulation of MRI contrast agent Gd-DTPA and fluorescent label ATTO488 in multimodal PEG -crosslinked hyaluronic acid nanoparticles (PEG-cHANPs) to formulate a probe for diagnostic purposes [14]. The PEG-cHANPs were observed to improve MR signals while concurrently magnifying the relaxation time, T 1 5 times due to the presence of the ATTO 488 in the human glioma U87 MG cell line.…”

“…The PEG-cHANPs were observed to improve MR signals while concurrently magnifying the relaxation time, T 1 5 times due to the presence of the ATTO 488 in the human glioma U87 MG cell line. Tammaro et al, [14] implied that this could lead to the decrease in the administered dose of the probe, thereby resulting in a better resolution and higher quality images.…”