cRGD Peptide-Conjugated Icosahedral closo-B₁₂^2- Core Carrying Multiple Gd³⁺-DOTA Chelates for α_vβ₃ Integrin-Targeted Tumor Imaging (MRI)

Abstract

A vertex-differentiated icosahedral closo-B122− core was utilized to construct a αvβ3 integrin receptor-targeted (via cRGD peptide) high payload MRI contrast agent (CA-12) carrying 11 copies of Gd3+-DOTA chelates attached to the closo-B122− surface via suitable linkers. The resulting polyfunctional MRI contrast agent possessed a higher relaxivity value per-Gd compared to Omniscan, a small molecular contrast agent commonly used in clinical settings. The αvβ3 integrin receptor specificity of CA-12 was confirmed via in vitro cellular binding experiments and in vivo MRI of mice bearing human PC-3 prostate cancer xenografts. Integrin αvβ3-positive MDA-MB-231 cells exhibited 300% higher uptake of CA-12 than αvβ3-negative T47D cells. Serial T1-weighted MRI showed superior contrast enhancement of tumors by CA-12 compared to both a non-targeted 12-fold Gd3+-DOTA closomer control (CA-7) and Omniscan. Contrast enhancement by CA-12 persisted for 4 h post-injection, and subsequent enhancement of kidney tissue indicated a renal elimination route similar to Omniscan. No toxic effects of CA-12 were apparent in any mice for up to 24 h post-injection. Post-mortem ICP-OES analysis at 24 hours detected no residual Gd in any of the tissue samples analyzed.

Lanthanide Probes for Bioresponsive Imaging

“…211 While the per Gd(III) relaxivity of the scaffold containing macrocyclic Gd(III)-DO3A chelates ( q = 1) was notably lower (6.2 mM −1 s −1 ), this still represents a significant improvement over the monomeric complexes. 210 …”

Closomers: Versatile Monodisperse Molecular Nanoparticles

“…After the successful development of the synthetic pathway and preparation of heterofunctional closomers, a number of articles were dedicated to the creation of complex systems bearing therapeutic or diagnostic, as well as tracking or directing, functions. The first example of such closomers contained eleven Gd 3+ ‐DOTA‐based CA molecules and a directing moiety – a cyclic derivative of the RGD peptide cyclo‐RGDfK . Previously, it was demonstrated that the attachment of contrast agent moieties to the closomer core significantly increases the MRI contrast , .…”

“…For closomer 99 , the increase in relaxivity was not as dramatic (4.7 m m –1 s –1 ); however, both closomers 98 and 99 showed very low toxicity and extended circulation times , . The possibility of carrying a targeting unit has made closomer‐based contrast reagents very attractive diagnostic tools for certain types of tumors . Closomer 113 not only demonstrated an increased relaxivity compared to Omniscan (5.9 m m –1 s –1 vs. 4.2 m m –1 s –1 ) but also high affinity to implanted tumors and longer contrast enhancement times.…”

In vitro assessment of the dual-targeting behavior of a peptide-based magnetic resonance imaging contrast agent

“…In tumor cells expressing both α v β 3 and CD 13 , the two motifs of RGD and NGR can simultaneously bind to the target tissue, which enhances the incorporation of the contrast agent; the higher concentration of the contrast agent in the tumor area will improve imaging visibility. In this study, the targeting behavior of the contrast agent that we designed was examined using MDA-MB-231 human breast cancer cells (which overexpress α v β 3 ) (19,20) and PC-3 human prostate cancer cells (which overexpress CD 13 ) (21). 4,7,10- 3 ].…”