pH-responsive i-motif-conjugated nanoparticles for MRI analysis

Abstract

Gadolinium (Gd)-based contrast agents (CA) are widely used to enhance anatomical details in magnetic resonance imaging (MRI). Significant research has expanded the field of CAs into bioresponsive CAs by modulating the signal to image and monitor biochemical processes, such as pH. In this work, we introduce the modular, dynamic actuation mechanism of DNA-based nanostructures as a new way to modulate the MRI signal based on rotational correlation time, τR. We combined a pH-responsive oligonucleotide (i-motif) and a clinical standard CA (Gd-DOTA), to develop a pH-responsive MRI CA. The i-motif folds into a quadruplex in acidic conditions and was incorporated onto gold nanoparticles (iM-GNP) to achieve increased relaxivity, r1, compared to unbound i-motif. In vitro, iM-GNP resulted in a significant increase in r1 over a decreasing pH range (7.5 - 4.5) with a calculated pKa = 5.88 ± 0.01 and a 16.7% change per 0.1 pH unit. In comparison, the control CA with a non-responsive DNA strand (T33-GNP) did not show a significant change in r1 over the same pH range. To demonstrate the potential for performance in tissue, CAs were evaluated in an ex vivo rat brain model. When compared to pre-contrast signal intensity (1/T1), the response to a simulated acidic microenvironment was over 5 times higher than the signal measured in a physiological pH. This approach paves a path for novel programmable, dynamic DNA-based complexes for τR-modulated bioresponsive MRI CAs.

Dynamic platform for magnetic resonance imaging of bioresponsive contrast agents

“…The decrease in acquisition time and potential for future translation towards clinical settings further emphasizes the importance of the development of these sequences at preclinical stages 76 . This platform would facilitate the analysis of sensors via in vitro MRI by reducing the impact of static field variations in the reproducibility of the measurements 110 , even at low volumes and concentrations 111 , therefore facilitating advancements in the field of MRI for chemical imaging 112,113 . Future studies can explore the use of more sophisticated phantoms as described by Keenan et al 95 , or directly image animal models.…”

“…Assessing these CAs (and their concentration) could then be useful to evaluate the fraction of tumor tissue with respect to the surrounding healthy tissues 121 . In a similar manner, DC-MRF could be especially useful when utilizing bioresponsive CAs, such as the pH-responsive CA described in Chapter 3, to identify relaxivity in the active and inactive form (in this case, in the folded and unfolded states), therefore facilitating the evaluation of biochemical signatures within the body 113,122,123 . In spite of the promising results in vitro, these sequences should be validated in vivo to fully comprehend the behavior of diverse MRI contrast agents (CA).…”