High Relaxivity Gd(III)–DNA Gold Nanostars: Investigation of Shape Effects on Proton Relaxation

Abstract

Gadolinium(III) nanoconjugate contrast agents (CAs) have distinct advantages over their small-molecule counterparts in magnetic resonance imaging. In addition to increased Gd(III) payload, a significant improvement in proton relaxation efficiency, or relaxivity (r1), is often observed. In this work, we describe the synthesis and characterization of a nanoconjugate CA created by covalent attachment of Gd(III) to thiolated DNA (Gd(III)–DNA), followed by surface conjugation onto gold nanostars (DNA–Gd@stars). These conjugates exhibit remarkable r1 with values up to 98 mM−1 s−1. Additionally, DNA–Gd@stars show efficient Gd(III) delivery and biocompatibility in vitro and generate significant contrast enhancement when imaged at 7 T. Using nuclear magnetic relaxation dispersion analysis, we attribute the high performance of the DNA–Gd@stars to an increased contribution of second-sphere relaxivity compared to that of spherical CA equivalents (DNA–Gd@spheres). Importantly, the surface of the gold nanostar contains Gd(III)–DNA in regions of positive, negative, and neutral curvature. We hypothesize that the proton relaxation enhancement observed results from the presence of a unique hydrophilic environment produced by Gd(III)–DNA in these regions, which allows second-sphere water molecules to remain adjacent to Gd(III) ions for up to 10 times longer than diffusion. These results establish that particle shape and second-sphere relaxivity are important considerations in the design of Gd(III) nanoconjugate CAs.

Gd(III)-Dithiolane Gold Nanoparticles for T1-Weighted Magnetic Resonance Imaging of the Pancreas

“…The loading of Lip-DO3A@AuNP and Lip-DTPA@AuNP represents greater than a 3- and 2-fold increase in Gd(III) payload and packing density, respectively, relative to previously reported DNA-Gd@AuNP (564 Gd(III)/AuNP and 0.8 Gd(III)/nm 2 of AuNP). 12 This phenomenon is attributed to the efficient packing of small molecular Gd(III) chelates relative to polyvalent DNA-Gd(III) conjugates on the surface of the AuNP.…”

Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents

“…132 Recently, Rotz et al . described the surface conjugation of DNA–Gd onto gold nanostars and nanospheres 95 and found that DNA–Gd@stars exhibited remarkable r 1 values up to 98 mM −1 s −1 , much higher than those of DNA–Gd@spheres, where r 1 values were 25 times larger than FDA-approved Gd chelates at 25 °C (Fig. 14a and b).…”

Enhancing T 1 magnetic resonance imaging contrast with internalized gadolinium(III) in a multilayer nanoparticle

“…Furthermore, these nanostructured Gd(III) agents present enhanced relaxivity compared with free Gd(III) chelates due to both cumulative effect of the high number of Gd(III) ions per nanocarrier and the reduced global tumbling motion that enhance the r 1 of each nanocomplex (10,(15)(16)(17)(18)(19).…”

“…We can infer from this increased relaxivity that the presence of PEG molecules on the surface of the nanoparticles facilitates the approach of water protons to the NM surface, closer to the internally encapsulated Gd(III) ions, and reduces the mobility of the nanocomplex. The diffusion of water in the proximity of the Gd(III) is known to play an important role in the enhancement of proton relaxivity (19,29,(41)(42)(43). Besides Gd(III) concentration and surface functionalization, temperature can also affect the relaxivity, which can have a major impact in vivo (33).…”