Comparison of MRI properties between multimeric DOTAGA and DO3A gadolinium-dendron conjugates

The inherent lack of sensitivity of MRI needs the development of new Gd contrast agents in order to extend 20Hz,37%, the application of this technique to cellular imaging. For this purpose, two multimeric MR contrast agents obtained by peptidic coupling between an amido amine dendron and GdDOTAGA chelates (premetalation strategy, G1-4GdDOTAGA) or DO3A derivatives which then were postmetalated (G1-4GdDO-3A) have been prepared. By comparison to the monomers, an increase of longitudinal relaxivity has been observed for both structures. Especially for G1-4GdDO-3A, a marked increase is observed between 20 and 60 MHz. This structure differs from G1-4GdDOTAGA by an increased rigidity due to the aromatic linker between each chelate and the organic framework. This has the effect of limiting local rotational movements, which has a positive impact on relaxivity

Physicochemical and MRI characterization of Gd3+-loaded polyamidoamine and hyperbranched dendrimers

Generation 4 polyamidoamine (PAMAM) and, for the first time, hyperbranched poly(ethylene imine) or polyglycerol dendrimers have been loaded with Gd3+ chelates, and the macromolecular adducts have been studied in vitro and in vivo with regard to MRI contrast agent applications. The Gd3+ chelator was either a tetraazatetracarboxylate DOTA-pBn4− or a tetraazatricarboxylate monoamide DO3A-MA3− unit. The water exchange rate was determined from a 17O NMR and 1H Nuclear Magnetic Relaxation Dispersion study for the corresponding monomer analogues [Gd(DO3A-AEM)(H2O)] and [Gd(DOTA-pBn-NH2)(H2O)]− (k ex 298 =3.4 and 6.6×106s−1, respectively), where H3DO3A-AEM is {4-[(2-acetylaminoethylcarbamoyl)methyl]-7,10-bis(carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl)}-acetic acid and H4DOTA-pBn-NH2 is 2-(4-aminobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. For the macromolecular complexes, variable-field proton relaxivities have been measured and analyzed in terms of local and global motional dynamics by using the Lipari-Szabo approach. At frequencies below 100MHz, the proton relaxivities are twice as high for the dendrimers loaded with the negatively charged Gd(DOTA-pBn)− in comparison with the analogous molecule bearing the neutral Gd(DO3A-MA). We explained this difference by the different rotational dynamics: the much slower motion of Gd(DOTA-pBn)−-loaded dendrimers is likely related to the negative charge of the chelate which creates more rigidity and increases the overall size of the macromolecule compared with dendrimers loaded with the neutral Gd(DO3A-MA). Attachment of poly(ethylene glycol) chains to the dendrimers does not influence relaxivity. Both hyperbranched structures were found to be as good scaffolds as regular PAMAM dendrimers in terms of the proton relaxivity of the Gd3+ complexes. The in vivo MRI studies on tumor-bearing mice at 4.7T proved that all dendrimeric complexes are suitable for angiography and for the study of vasculature parameters like blood volume and permeability of tumor vessel

Supramolecular assembly of an amphiphilic GdIII chelate: tuning the reorientational correlation time and the water exchange rate

In this paper we report the synthesis and the characterization of the novel ligand H5EPTPA-C16 ((hydroxymethylhexadecanoyl ester)ethylenepropylenetriaminepentaacetic acid). This ligand was designed to chelate the GdIII ion in a kinetically and thermodynamically stable way while ensuring an increased water exchange rate (kex) on the GdIII complex due to steric compression around the water binding site. The attachment of a palmitic ester unit to the pendant hydroxymethyl group on the ethylenediamine bridge yields an amphiphilic conjugate that forms micelles in aqueous solution with a long tumbling time (R). The critical micelle concentration (CMC = 0.34 mM) of the amphiphilic [Gd(EPTPA-C16)(H2O)]2- chelate was determined by variable concentration proton relaxivity measurements. A global analysis of the data obtained in variable temperature and multiple field 17O NMR, and 1H NMRD measurements allowed the determination of parameters governing relaxivity for [Gd(EPTPA-C16)(H2O)]2-; this is the first time that paramagnetic micelles with optimized water exchange are investigated. The water exchange rate was found to be kex298 = 1.7×108 s-1, very similar to that previously reported for the nitrobenzyl derivative [Gd(EPTPA-bz-NO2)(H2O)]2- (kex298 = 1.5×108 s-1). The rotational dynamics of the micelles was analysed using the Lipari-Szabo approach. The micelles formed in aqueous solution show a considerable flexibility, with a local rotational correlation time of the GdIII segments, lO298 = 330 ps, being much shorter than the global rotational correlation time of the supramolecular aggregates, gO298 = 2100 ps. This internal flexibility of the micelles is responsible for the only limited increase of the proton relaxivity observed on micelle formation (r1 = 22.59 mM-1s-1 for the micelles vs. 9.11 mM-1s-1 for the monomer chelate (20 MHz; 25°C)).Fundação para a Ciência e a Tecnologia (FCT) - POCTI/QUI/47005/2002). EU Cost Action D18 "Lanthanide chemistry for diagnosis and therapy". Swiss National Science Foundation. Swiss Federal Office for Education and Science

Radiolabeled dendrimer coated nanoparticles for radionuclide imaging and therapy: a systematic review

Background: Dendrimers are nanoscale-size polymers with a globular structure. They are composed of an internal core and branching dendrons with surface active groups which can be functionalized for medical applications. Different complexes have been developed for imaging and therapeutic purposes. This systematic review aims to summarize the development of newer dendrimers for oncological applications in nuclear medicine. Methods: An online literature search was conducted on Pubmed, Scopus, Medline, Cochrane Library, and Web Of Science databases selecting published studies from January 1999 to December 2022. The accepted studies considered the synthesis of dendrimer complexes for oncological nuclear medicine imaging and therapy. Results: 111 articles were identified; 69 articles were excluded because they did not satisfy the selection criteria. Thus, nine duplicate records were removed. The remaining 33 articles were included and selected for quality assessment. Conclusion: Nanomedicine has led researchers to create novel nanocarriers with high affinity for the target. Dendrimers represent feasible imaging probes and therapeutic agents since, through the functionalization of external chemical groups and thanks to the possibility to carry pharmaceuticals, it can be possible to exploit different therapeutic strategies and develop a useful weapon for oncological treatments

Synthesis and Characterisation of Multifunctional Bioresponsive Magnetic Resonance Imaging Probes

The development of bioresponsive magnetic resonance imaging (MRI) contrast agents (CAs) specific to monitoring Ca2+ fluctuations are of increasing interest for fMRI studies of neural activity. Such probes can provide key information regarding their microenvironment through changes in MR signal which in turn can lead to vital information concerning the functioning of tissue being extracted. Thus far, a number of CAs sensitive to Ca2+ have been developed ranging from ‘small’ molecular systems to larger nano-sized derivatives. Here, an extension to this ever growing field with the development of a range monomeric, multimeric and nano-sized Ca2+-responsive smart contrast agents (SCAs) is described. A range of bioresponsive dendrimeric CAs with different structures and charge distributions are described in the pursuit of probes for T1-weighted imaging and r2/r1 ratiometric imaging probes. The use of nano-sized platforms enabled higher Gd3+ loading and slower diffusion rates, which are favoured characteristics for in vivo applications. The impact of structural and charge changes resulted in significant consequences for the performance of the probes as Ca2+-responsive MRI CAs. The most active probe displayed common changes in r1 while also exhibiting a remarkable increase in the r2/r1 ratio, greater than that previously achieved. Further investigation revealed that only through a synergistic combination of an increase in q with a change in size and rigidity of the conjugate could such relaxometric changes be realised. This ultimately provided significant insights into the behaviour of such dendrimeric systems and provided a model in which future preparations should be based in the development of T1-weighted and r2/r1 ratiometric probes to visualise Ca2+ fluctuations dynamically. Deeper structural studies were performed on two monomeric systems in which the linker length between the MR reporting moiety and the bioresponsive unit were extended. Various studies revealed significant differences in relaxometric behaviour between the probes. Characterisation with a range of techniques revealed structural changes in the complex coordination environment between the ‘off’ and ‘on’ states which is expected for such systems. Furthermore, the diffusive behaviour of each complex described systems which do not significantly change upon Ca2+ coordination. The results of this study revealed how subtle structural changes can significantly impact the performance of a SCA, thus helping to identify the requirements for future probes. The final parts of this work focused on employing solid phase synthetic techniques as an alternative to standard solution phase chemistry in the preparation of more ‘complex’ SCA derivatives. In one approach, a functionalised bismacrocyclic derivative was assembled on solid phase through the use of multiple building blocks in a straightforward manner. The potency of this probe was confirmed by relaxometric titrations. In a second study, a targeted multimeric probe consisting of three SCA monomers and the RGD peptide sequence was developed. This multimer showed significant increases in relaxivity upon Ca2+ addition. The use of solid phase protocols in both of these cases allowed for more complex SCAs to be developed, which would otherwise be extremely difficult following solution phase protocols. Furthermore, the use of peptide scaffolds allows for simple customisation in which multimeric or multifunctional probes can be developed, providing an additional synthetic tool for chemists attempting to develop bioresponsive MRI CAs

Design, Synthesis and Characterization of Targeted and Calcium Responsive Nano-size Contrast Agents for Magnetic Resonance Neuroimaging

Magnetic resonance imaging (MRI) is a powerful imaging technique for biomedicine and neuroscience. The contrast agents (CAs) have been developed to help increasing signal intensity for high resolution MR images. Here we report the synthesis of novel multimodal and multivalent CA targeted to the protein (Neutr/strept) avidin and calcium responsive multivalent CAs for MR neuroimaging

Cation, anion and ion-pair complexes with a G-3 poly(ethylene imine) dendrimer in aqueous solution

The G-3 poly(ethylene imine) ligand L2 shows a multifaceted coordination ability, being able to bind metal cations, anions and ion-pairs. The equilibrium constants for the formation of metal (Cu2+, Zn2+), anion (SO42−) and ion-pair (Cu2+/SO42−) complexes were determined in 0.1 M Me4NCl aqueous solution at 298.1 ± 0.1 K by means of potentiometric titrations. Thanks to its dendrimeric nature, L2 can form highly nucleated metal complexes, such as Cu5L210+ and Zn4L28+, in successive and well-defined complexation steps. Protonated forms of L2 give rise to relatively weak anion complexes with SO42−, but the addition of Cu2+ significantly enhances the binding ability of the ligand toward this anion below pH 9. In more alkaline solutions, an opposite trend is observed. The coordination properties of L2 are discussed with the support of modelling calculations. According to results, L2 is a promising molecule for the preparation of solid supported materials for the recovery of cations and anions from aqueous media and/or for applications in heterogeneous catalysis

Synthesis and Evaluation of 177Lu-DOTA-DN(PTX)-BN for Selective and Concomitant Radio and Drug—Therapeutic E ect on Breast Cancer Cells

The peptide-receptor radionuclide therapy (PRRT) is a successful approach for selectively delivering radiation within tumor sites through specific recognition of radiolabeled peptides by overexpressed receptors on cancer cell surfaces. The e cacy of PRRT could be improved by using polymeric radio- and drug- therapy nanoparticles for a concomitant therapeutic e ect on malignant cells. This research aimed to prepare and evaluate, a novel drug and radiation delivery nanosystem based on the 177Lu-labeled polyamidoamine (PAMAM) dendrimer (DN) loaded with paclitaxel (PTX) and functionalized on the surface with the Lys1Lys3(DOTA)-bombesin (BN) peptide for specific targeting to gastrin-releasing peptide receptors (GRPr) overexpressed on breast cancer cells. DN was first conjugated covalently to BN and DOTA (chemical moiety for lutetium-177 complexing) and subsequently loaded with PTX. The characterization by microscopic and spectroscopic techniques, in-vitro drug delivery tests as well as in in-vitro and in-vivo cellular uptake of 177Lu-DOTA-DN(PTX)-BN by T47D breast cancer cells (GRPr-positive), indicated the formation of an improved delivery nanosystem with target-specific recognition by GRPr. Results of the 177Lu-DOTA-DN(PTX)-BN e ect on T47D cell viability (1.3%, compared with 10.9% of 177Lu-DOTA-DN-BN and 14.0% of DOTA-DN-(PTX)-BN) demonstrated the concomitant radiotherapeutic and chemotherapeutic properties of the polymeric nanosystem as a potential agent for the treatment of GRPr-positive tumors.This study was supported by the grant CONACyT-CB-A1S38087 and the International Atomic Energy Agency (CRP-F2264). It was performed as part of the activities of the “Laboratorio Nacional de Investigación y Desarrollo de Radiofármacos, CONACyT”

Metal complexes based on monomeric and dendrimeric pyrrole-imine ligands as catalytic precursors

Magister Scientiae - MScOver the recent past, organometallic chemistry has grown and the impact of catalytic applications in various chemical technologies has rapidly evolved from the realm of academic laboratories into full-scale industrial processes. Pyrrole-imine ligands were prepared by condensation of pyrrole-2-carboxylaldehyde with propyl amine, 2,6-diisopropylanaline, poly(propylene) imine dendrimer and 3-aminopropyl-triethoxysilane to give the desired ligands in good yields. These ligands were charaterized via combination of techniques to establish the molecular structure. Microanalysis was performed to confirm the purity of the product.South Afric