Multivalent contrast agents based on Gd-DTPA-terminated poly (propylene imine) dendrimers for Magnetic Resonance Imaging

A convenient methodol. has been developed for the synthesis of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-terminated poly(propylene imine) dendrimers as contrast agents for magnetic resonance imaging (MRI). In our strategy, isocyanate-activated, tert-butyl-protected DTPA analogs were coupled to different generations of poly(propylene imine) dendrimers. Deprotection of the tert-Bu esters with trifluoroacetic acid in dichloromethane and extensive dialysis afforded gadolinium-chelating poly(propylene imine) dendrimers. The corresponding Gd-DTPA-based dendritic contrast agents were prepd. from GdCl3 in either water or citrate buffer. At. force microscopy and cryogenic transmission electron microscopy expts. of the fifth-generation Gd-DTPA based dendritic contrast agent in citrate buffer demonstrated the presence of well-defined spherical particles with nanoscopic dimensions (5-6 nm), and no self-aggregation of dendrimers was obsd. The efficiencies of these dendritic contrast agents in MRI, expressed in terms of longitudinal (r1) and transverse (r2) relaxivities, were detd. at 1.5 T at 20 °C. The r1 and r2 values increase considerably with increasing generation of Gd-DTPA-terminated dendrimer. The fifth-generation dendritic contrast agent displays the highest ionic relaxivities (per gadolinium), r1 = 19.7 mM-1 s-1 and r2 = 27.8 mM-1 s-1, which are substantially higher than the ionic relaxivities of parent Gd-DTPA. Moreover, a series of combined gadolinium and yttrium complexes of the fifth-generation dendrimer are prepd., resulting in well-defined dendritic contrast agents with tunable mol. relaxivitie

Multivalent contrast agents based on Gd-DTPA-terminated poly (propylene imine) dendrimers for Magnetic Resonance Imaging

A convenient methodol. has been developed for the synthesis of gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-terminated poly(propylene imine) dendrimers as contrast agents for magnetic resonance imaging (MRI). In our strategy, isocyanate-activated, tert-butyl-protected DTPA analogs were coupled to different generations of poly(propylene imine) dendrimers. Deprotection of the tert-Bu esters with trifluoroacetic acid in dichloromethane and extensive dialysis afforded gadolinium-chelating poly(propylene imine) dendrimers. The corresponding Gd-DTPA-based dendritic contrast agents were prepd. from GdCl3 in either water or citrate buffer. At. force microscopy and cryogenic transmission electron microscopy expts. of the fifth-generation Gd-DTPA based dendritic contrast agent in citrate buffer demonstrated the presence of well-defined spherical particles with nanoscopic dimensions (5-6 nm), and no self-aggregation of dendrimers was obsd. The efficiencies of these dendritic contrast agents in MRI, expressed in terms of longitudinal (r1) and transverse (r2) relaxivities, were detd. at 1.5 T at 20 °C. The r1 and r2 values increase considerably with increasing generation of Gd-DTPA-terminated dendrimer. The fifth-generation dendritic contrast agent displays the highest ionic relaxivities (per gadolinium), r1 = 19.7 mM-1 s-1 and r2 = 27.8 mM-1 s-1, which are substantially higher than the ionic relaxivities of parent Gd-DTPA. Moreover, a series of combined gadolinium and yttrium complexes of the fifth-generation dendrimer are prepd., resulting in well-defined dendritic contrast agents with tunable mol. relaxivitie

Design and synthesis of a bimodal target-specific contrast agent for angiogenesis

A bimodal target-specific contrast agent based on a cyclic peptide contg. the target-specific NGR sequence, gadolinium(III) diethylenetriaminepentaacetic acid (Gd(III)DTPA), and Oregon Green 488 (OG488) suitable for both MR imaging and optical imaging of angiogenesis is developed. The synthetic strategy for this target-specific contrast agent exploits the use of highly efficient, chemoselective reactions, such as native chem. ligation, and gives a straightforward approach for double labeling of peptides in general

Solid-phase synthesis of a cyclic NGR-functionalized GdIII-DTPA complex

A convenient methodology has been developed for the solid-phase synthesis of a cyclic NGR-functionalized GdIIIDTPA complex employing an isocyanate-functionalized DTPA pentaester. This methodology is an alternative strategy for the tagging of oligopeptides with GdIIIDTPA as an MRI label on the solid phase

Towards target-specific molecular imaging of angiogenesis with Gd-DTPA-based dendritic architectures

Dendritic MRI contrast agents are attractive candidates for mol. imaging of angiogenesis, since the multivalent dendritic architecture is an ideal mol. scaffold for constructing multiple MRI labels and target-specific markers on a single mol. Recently, different generation of the poly(propylene imine) dendrimers were functionalized with Gd-DTPA. The higher generations of these dendritic contrast agents display a pronounced enhancement of both the longitudinal and the transverse relaxivity compared to the parent Gd-DTPA complex. The kinetic physiol. properties of different generations dendritic contrast agents were investigated in mice at 1.5 T. Dynamic Contrast Enhanced Magnetic Resonance Angiog. expts. showed that the first generation dendritic MRI contrast agent was rapidly cleared by the renal system, while the fifth generation was cleared at significantly slower rate. Moreover, a Gd-DTPA complex functionalized with a target-specific oligopeptide for angiogenesis, the cyclic NGR motif, is prepd. and will be tested in vivo for MR imaging of angiogenesis. Conjugation of both target-specific peptides and MRI contrast agents on dendritic mols. may lead to an even larger improvement, both in binding as a result of multivalency and in terms of signal amplification

Dynamic contrast-enhanced MR Imaging kinetic parameters and molecular weight of dentritic contrast agents in tumor angiogenesis in mice

To evaluate the relationship between dynamic contrast agent–enhanced magnetic resonance (MR) imaging–derived kinetic parameters and contrast agents of equal chemical composition and configuration but with different molecular weights in a tumor angiogenesis model. This study was approved by the ethical review committee. Maintenance and care of animals was in compliance with guidelines set by the institutional animal care committee. Dynamic contrast-enhanced MR imaging was performed with dendritic contrast agents in 16 mice with tumor xenografts; mice were placed in groups of four for each molecular weight of the contrast agent. The magnitude and spatial distribution of kinetic parameters (transfer coefficient [KPS] and plasma fraction [fPV]) were compared with molecular weight of the contrast agent by determining the Spearman correlation coefficient (r) and the quantitative relationship between the endothelial KPS and molecular weight. Inverse relationships between molecular weight of contrast agent and KPS and fPV of tumor rim (r = –0.8, P <.001 and r = –0.5, P = .04, respectively) and core (r = –0.7, P = .004 and r = –0.6, P = .01, respectively) were observed. The quantitative relationship between KPS and molecular weight (MW) was KPS = 0.4/MW0.44. A decreasing stepwise pattern in fPV was noted between contrast agents with low (0.7- and 3.0-kDa) molecular weight and those with high (12- and 51-kDa) molecular weight. Macromolecular permeability is best measured with high-molecular-weight contrast agents; endothelial KPS values measured with low-molecular-weight contrast agents incorporate tissue perfusion and permeability and demonstrate heterogeneous microcirculatory flow

Dynamic contrast-enhanced magnetic resonance imaging at 1.5 Tesla with gadopentetate dimeglumine to assess the angiostatic effects of anginex in mice.

The purpose of this study was to evaluate the effects of anginex on tumour angiogenesis assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) on a clinical 1.5 Tesla MR system and with the clinically available contrast agent gadopentetate dimeglumine. C57BL/6 mice carrying B16F10 melanomas were treated with anginex, TNP-470 or saline. Tumour growth curves and microvessel density (MVD) were recorded to establish the effects of treatment. DCE-MRI was performed on day 16 after tumour inoculation, and the endothelial transfer coefficients of the microvessel permeability surface-area product (KPS) were calculated using a two-compartment model. Both anginex and TNP-470 resulted in smaller tumour volumes (

The designer anti-angiogenic peptide anginex targets tumor endothelial cells and inhibits tumor growth in animal models

The de novo designed angiogenesis inhibitor anginex was tested in vitro and in vivo for its mechanism of action and antitumor activity. The data presented here demonstrate that anginex is a powerful antiangiogenic agent with significant antitumor activity. The mechanism of action of anginex was found to be the induction of anoikis leading to apoptosis in angiogenically activated endothelial cells, resulting in an up to 90% inhibition of migration in the wound assay. Anginex inhibited angiogenesis as demonstrated in the in vitro mouse aortic ring assay. In addition, tumor-induced angiogenesis in the chick chorioallantoic membrane was markedly inhibited. Anginex showed profound antitumor activity in the syngeneic mouse B16F10 melanoma model and in a xenograft human tumor model. Microvessel density determination as well as magnetic resonance imaging showed that the antitumor activity in these tumor models resulted from the antiangiogenic activity of anginex. A complete absence of toxicity was observed in these models. The data presented here demonstrate that anginex is a promising agent for further clinical development