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

Abstract

Pancreatic adenocarcinoma has a 5 year survival of approximately 3% and median survival of 6 months and is among the most dismal of prognoses in all of medicine. This poor prognosis is largely due to delayed diagnosis where patients remain asymptomatic until advanced disease is present. Therefore, techniques to allow early detection of pancreatic adenocarcinoma are desperately needed. Imaging of pancreatic tissue is notoriously difficult, and the development of new imaging techniques would impact our understanding of organ physiology and pathology with applications in disease diagnosis, staging, and longitudinal response to therapy in vivo. Magnetic resonance imaging (MRI) provides numerous advantages for these types of investigations; however, it is unable to delineate the pancreas due to low inherent contrast within this tissue type. To overcome this limitation, we have prepared a new Gd(III) contrast agent that accumulates in the pancreas and provides significant contrast enhancement by MR imaging. We describe the synthesis and characterization of a new dithiolane-Gd(III) complex and a straightforward and scalable approach for conjugation to a gold nanoparticle. We present data that show the nanoconjugates exhibit very high per particle values of r1 relaxivity at both low and high magnetic field strengths due to the high Gd(III) payload. We provide evidence of pancreatic tissue labeling that includes MR images, post-mortem biodistribution analysis, and pancreatic tissue evaluation of particle localization. Significant contrast enhancement was observed allowing clear identification of the pancreas with contrast-to-noise ratios exceeding 35:1.

Gd(III)-Gold Nanoconjugates Provide Remarkable Cell Labeling for High Field Magnetic Resonance Imaging

“…25,26 The DTPA complex is negatively charged, while the DO3A complexes are neutral. The four different chelates were peptide-coupled to lipoic acid-NHS ester in 1:1 DMSO:pH 8.5 carbonate buffer, and purified by reverse-phase high performance liquid chromatography (HPLC) at approximately 60% yield generating 1a–4a , respectively (Figure S1).…”

“…25 Lip-Gd@AuNPs were the first T 1 -weighted CAs to accumulate in the pancreas and provide enhanced image contrast. Although this system was designed for pancreatic localization, the DNA-free strategy is ideal for developing cell tracking agents for T 1 -weighted MRI.…”

Combined Magnetic Resonance Imaging and Photodynamic Therapy Using Polyfunctionalised Nanoparticles Bearing Robust Gadolinium Surface Units

“…Most clinically used contrast agents are based on paramagnetic (4f 7 ) gadolinium(III) ions, which interact with water molecules to improve the relaxation rates of the protons, enhancing the image contrast . The immobilisation of trivalent gadolinium units on the surface of gold nanoparticles dramatically increases the relaxation rate experienced by the protons of the water molecules in their vicinity . This can be partly traced to the effect on the rotational correlation time, which increases when the assembly rotates slowly, leading to greatly increased relaxivity per Gd 3+ ion.…”

A Markedly Improved Synthetic Approach for the Preparation of Multifunctional Au-DNA Nanoparticle Conjugates Modified with Optical and MR Imaging Probes

“…The new class of particles exhibits increased r 1 relaxivity, improved Gd(III) loading/particle, increased cellular uptake at lower incubations concentrations, with comparable conjugate stability relative to the previous generations of our multimodal nanoparticles. 41–43 The observed increase in low-field magnetic relaxivity, improved Gd(III) loading, and significantly higher cellular uptake of the particles will allow the use of far less contrast agent per cell labeling experiments. Over the last two decades we have routinely discovered that there is no “one imaging probe fits” for different cell types.…”