Physicochemical Properties of Mixed Micellar Aggregates Containing CCK Peptides and Gd Complexes Designed as Tumor Specific Contrast Agents in MRI

Abstract

New amphiphilic molecules containing a bioactive peptide or a claw moiety have been prepared in order to obtain mixed micelles as target-specific contrast agents in magnetic resonance imaging. The first molecule, C(18)H(37)CONH(AdOO)(2)-G-CCK8 (C18CCK8), contains a C18 hydrophobic moiety bound to the C-terminal cholecystokinin octapeptide amide (CCK 26-33 or CCK8). The second amphiphilic compound, C(18)H(37)CONHLys(DTPAGlu)CONH(2) (C18DTPAGlu) or its gadolinium complex, (C18DTPAGlu(Gd)), contains the same C18 hydrophobic moiety bound, through a lysine residue, to the DTPAGlu chelating agent. The mixed aggregates as well as the pure C18DTPAGlu aggregate, in the presence and absence of Gd, have been fully characterized by surface tension measurements, FT-PGSE-NMR, fluorescence quenching, and small-angle neutron scattering measurements. The structural characterization of the mixed aggregates C18DTPAGlu(Gd)-C18CCK8 indicates a spherical arrangement of the micelles with an external shell of approximately 21 A and an inner core of approximately 20 A. Both the DTPAGlu(Gd) complexes and the CCK8 peptides point toward the external surface. The measured values for relaxivity in saline medium at 20 MHz proton Larmor frequency and 25 degrees C are 18.7 mM(-)(1) s(-)(1). These values show a large enhancement in comparison with the isolated DTPAGlu(Gd) complex.

Molecular Determinants in the Transport of a Bile Acid-Derived Diagnostic Agent in Tumoral and Nontumoral Cell Lines of Human Liver

“…CCK-8 was prepared by peptide synthesis as reported previously (Accardo et al, 2004) and kindly supplied by Department of Chemistry IFM, University of Torino (Torino, Italy). All other chemicals were of the highest commercially available purity.…”

Peptide‐labeled supramolecular aggregates as selective doxorubicin carriers for delivery to tumor cells

“…19 Finally, the gadolinium complexes of this new class of supramolecular aggregates have been proposed as high relaxivity and target selective contrast agents in MRI. 15,17 In this article, we report on new liposomal aggregates obtained by combining together, in a 90:10 molar ratio, the two monomers schematized in Figure 1. Monomer (a), (C18) 2 DOTA, contains two hydrocarbon chains in the hydrophobic region and the anionic DOTA chelating agent as hydrophilic moiety.…”

“…The strategy adopted for the preparation of such class of supramolecular aggregates is based on the coaggregation of two amphiphilic monomers, the first containing an hydrophobic moiety and a branched chelating agent, the second containing the same hydrophobic moiety based on one or two C18 hydrocarbon chains, and a bioactive reporter peptide, such as the well-known peptides CCK8 or octreotide. [15][16][17][18][19] CCK8 is the C-terminal sequence of the cholecystokinin hormone and provides the binding sequence for the cholecystokinin receptor subtypes CCK 1 -R and CCK 2 -R, 20,21 whereas octreotide is a somatostatin analog and has high affinity for the somatostatin receptors sstr2 and sstr5. 22 An alternative strategy in which the chelating agent, the reporter peptide and the hydrophobic hydrocarbon moiety are placed together on the same amphiphilc moiety, has been also successfully used.…”

Rotational Dynamics Account for pH‐Dependent Relaxivities of PAMAM Dendrimeric, Gd‐Based Potential MRI Contrast Agents

“…[15] For example, macromolecular agents tend to be retained in the vascular space by virtue of their size, hence they are useful for blood-pool imaging by magnetic resonance angiography [16][17][18] or for evaluation of the microvasculature in tumour tissues. [19,20] The conjugation of low-molecularweight chelates to macromolecules can be achieved through different ways, involving linear polymers, [21][22][23][24][25] dendrimers, [26][27][28][29][30] micelles [31][32][33][34][35] or protein-bound complexes. [36][37][38][39] In the past, the non-optimal water exchange rate has been a critical issue for macromolecular, Gd III -based MRI contrast agents, since low exchange rates often limit proton relaxivity.…”