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

Mössbauer Spectroscopic Study and Magnetic Investigation of Iron(III) Complexes on a Dendrimeric Basis

The functionalization of the molecular surface of various dendrimer generations with a phosphorous core and external amine groups is obtained by converting those amine groups into the corresponding imines of salicylaldehyde creating multiple coordination sites for the iron atoms. Treatment with iron(III) chloride yields multinuclear iron(III) complexes on a dendrimeric basis. The obtained multinuclear molecular systems exhibit extremely high total spin values. The influence of the generation growth on this type of coordination compounds is investigated by Mossbauer spectroscopy and SQUIDmagnetometry

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

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

Energy harvesting: a review of the interplay between structure and mechanism

The science of energy harvesting has recently undergone radical change, with the advent of new materials exploiting mechanisms fundamentally different from those of traditional solar cells. Utilizing principles that are in many cases acquired from breakthroughs in molecular photobiology, the introduction of a range of new synthetic polymers, multichromophore arrays and nanoparticle-based materials heralds a marked resurgence of interest, a shift of focus and heightened expectations in the science of light-harvesting. The interplay between structure and mechanism significantly impinges upon issues extending from fundamental theory to the principles of energy-harvesting materials design. Understanding and exploiting the principles allows materials to be engineered that can harness absorbed energy with heightened efficiency. Two of the key areas of application are dendrimers and rare-earth doped solids

Methods for treating subjects suffering from acute myeloid leukemia with FLT3 ligand-targeted miR-150 nanoparticles

A nanoparticle delivery system designed for sustained delivery of microRNA-150 (miR-150) to FLT3-overexpressing acute myeloid leukemia (AML) cells, the delivery system comprising poly(amidoamine) (PAMAM) dendrimers complexed with miR-150, wherein at least one dendrimer is surface-functionalized with a ligand specific for FLT3 receptor, and methods for treating AML characterized by FLT3-overexpression are provided

Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers.

Peptide dendrimers are a novel class of macromolecules of emerging interest with the potential of delayed renal clearance due to their molecular size and enhanced activity due to the multivalency effect. In this work, an active analogue of the disulfide-rich χ-conotoxin χ-MrIA (χ-MrIA), a norepinephrine reuptake (norepinephrine transporter) inhibitor, was grafted onto a polylysine dendron. Dendron decoration was achieved by employing copper-catalyzed alkyne-azide cycloaddition with azido-PEG chain-modified χ-MrIA analogues, leading to homogenous 4-mer and 8-mer χ-MrIA dendrimers with molecular weights ranging from 8 to 22 kDa. These dendrimers were investigated for their impact on peptide secondary structure, in vitro functional activity, and potential anti-allodynia in vivo. NMR studies showed that the χ-MrIA tertiary structure was maintained in the χ-MrIA dendrimers. In a functional norepinephrine transporter reuptake assay, χ-MrIA dendrimers showed slightly increased potency relative to the azido-PEGylated χ-MrIA analogues with similar potency to the parent peptide. In contrast to χ-MrIA, no anti-allodynic action was observed when the χ-MrIA dendrimers were administered intrathecally in a rat model of neuropathic pain, suggesting that the larger dendrimer structures are unable to diffuse through the spinal column tissue and reach the norepinephrine transporter.NHMRC Grants: 1045964 & 107211

Controlled Growth of Dendrimer-Coated Gold Nanoparticles: A Solvent-Free Process in Mild Conditions

Monodisperse dendrimer-coated gold nanoparticles with a spherical shape have been obtained by direct reduction of HAuCl4 with sodium borohydride in the presence of dodecanethiol as a stabilizer and subsequent functionalization by ligand exchange reaction with polybenzylic thiolated dendrons. The substitution pattern of the dendrimeric units plays a fundamental role in the rate of the functionalization exchange process and consequently conditions the size and the polydispersity of the NPs obtained. An ulterior growth process occurs by thermal stimuli (150 °C) in a solvent-free environment. This method, carried out in mild conditions, allows the formation of highly monodisperse gold NPs with different sizes for different time reactions, and we discuss the mechanisms involved in this process. Finally, we demonstrate the chemical composition and stability of our compounds by structural, thermal, and chemical characterization of the samples before and after thermal treatment

Gold nanoparticles modification with liquid crystalline polybenzylic dendrons via 1,3-Dipolar cycloaddition

A series of six polybenzylic dendrons with an alkynyl focal point were synthesized for their incorporation to gold nanoparticles. Five of these compounds showed columnar mesomorphism in a wide range of temperatures. These dendrons were reacted with gold nanoparticles stabilized with a combination of a dodecanethiol and 11-azidoundecane-1-thiol. The azido group of the last compound allowed the functionalization of the nanoparticles with the six polybenzylic dendrons by 1,3-dipolar cycloaddition between their alkynyl groups and the terminal azido groups of the thiols. A high efficiency of the cycloaddition process (47–69%) was confirmed by several experimental techniques and no decomposition or aggregation phenomena were detected in the dendron-coated nanoparticles. The involved mechanism and the resulting percentage composition of the final materials are discussed. The results of the ulterior growth of the nanoparticles by thermal treatment are influenced by the size and the shape of the dendron and the temperature of the process. The structures of the final nanoparticles were investigated by TEM, DSC, TGA, NMR and UV-Vis spectroscopy. These nanoparticles do not show liquid crystal properties. However, a melting process between a crystalline and a fluid phase is observed. In the solid phase, the nanomaterials prepared show a short-range interaction between nanoparticles with a 2D local hexagonal order. A near-field effect was observed in the UV-vis spectra by coupling of different surface plasmon resonance bands (SPR) probably due to the short-range interactions. The main novelty of this work lies in the scarcity of previous studies of gold nanoparticles coated with dendrons forming themselves columnar mesophases. Most of the studies reported in the literature deal with gold nanoparticles coated with calamitic mesogens. Additionally, the effect of the thermal treatment, which in a previous paper was shown to increase the mean size of the nanoparticles without increasing their size polydispersity, has been studied in these materials