An Optimal Synthetic Strategy for Conjugating Folic Acid with Manganese-Doped Silica Nanoparticles to Enhance Their Colloidal Stability

The inadequate biosafety of MRI contrast agents (CAs) remains a challenging issue. Both increasing the magnetic relaxivity of CAs and targeting them through conjugation with folates are promising approaches to addressing this issue. Silica nanoparticles (SNs) with Mn2+ ions specifically localized in the outer layer were selected as the target for further surface modification for the covalent attachment of folates. It was shown that when Mn-containing SNs are conjugated with folates via preliminary amino modification of the surface silanol groups, the folate-conjugated SNs suffer from colloidal instability. Thus, precoating Mn-containing SNs with unfolded BSA exposes surface amino groups that successfully conjugate with folates without loss of colloidal stability. Partial washout of surface-localized Mn2+ follows folate conjugation of Mn-containing SNs, although residual Mn2+ ions provide r1(2) relaxivities of 62.1 (160.4) mM−1s−1 at 0.47 T.