Multifunctional gadolinium-based dendritic macromolecules as liver targeting imaging probes

National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
Biomaterials (Impact Factor: 8.56). 04/2011; 32(10):2575-85. DOI: 10.1016/j.biomaterials.2010.12.049
Source: PubMed


The quest for highly efficient and safe contrast agents has become the key factor for successful application of magnetic resonance imaging (MRI). The gadolinium (Gd) based dendritic macromolecules, with precise and tunable nanoscopic sizes, are excellent candidates as multivalent MRI probes. In this paper, a novel series of Gd-based multifunctional peptide dendritic probes (generation 2, 3, and 4) possessing highly controlled structures and single molecular weight were designed and prepared as liver MRI probes. These macromolecular Gd-ligand agents exhibited up to 3-fold increase in T(1) relaxivity comparing to Gd-DTPA complexes. No obvious in vitro cytotoxicity was observed from the measured concentrations. These dendritic probes were further functionalized with multiple galactosyl moieties and led to much higher cell uptake in vitro as demonstrated in T(1)-weighted scans. During in vivo animal studies, the probes provided better signal intensity (SI) enhancement in mouse liver, especially at 60 min post-injection, with the most efficient enhancement from the galactosyl moiety decorated third generation dendrimer. The imaging results were verified with analysis of Gd content in liver tissues. The design strategy of multifunctional Gd-ligand peptide dendritic macromolecules in this study may be used for developing other sensitive MRI probes with targeting capability.

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    • "Spherical polyaminoamide dendrimers (PAMAMs) have been studied as potential drug carriers and gene delivery systems for a long time (Svenson and Tomalia, 2005; Borowska et al., 2010; Dong et al., 2010; Ma et al., 2007; Man et al., 2006; Chandrasekar et al., 2007; Beezer et al., 2003; Cheng et al., 2007, 2008; Shi et al., 2005; Klajnert et al., 2004; Zhou et al., 2007). Conjugates of PAMAMs with bifunctional chelators enabling stable binding of paramagnetic metals can be applied as nanosized MRI contrast agents (Kobayashi et al., 2001; Nwe et al., 2009, 2010, 2011; Luo et al., 2011; Han et al., 2011; Rudovský et al., 2006; Jászberényi et al., 2007; Villaraza et al., 2010). Modified dendrimers can also be applied to cancer RIT to improve their safety and efficacy. "
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    ABSTRACT: (177)Lu radiolabeling of the first (G1-) or fourth (G4-) generation polyaminoamide (PAMAM) dendrimer conjugates with DOTA-like bifunctional chelator with one methylenepyridine-N-oxide pendant arm (DO3A-py(NO-C)) stability of the radiolabeled species and their pharmacokinetic characteristics were evaluated in preclinical experiments. The results showed that the G1- and G4-dendrimer conjugates, modified in average with 7.5 or 57 DO3A-py(NO-C) chelating units, respectively, can also be labeled with (177)Lu with a high specific activity and radiochemical purity even at 37°C. The radiolabeled species were stable for at least 24h. Distribution profile of G1-dendrimer conjugate in organs and tissues of rats was more favorable than that of G4 one. On the other hand, the later dendrimer conjugate bears a substantially higher number of metal chelators per molecule enabling binding of a considerably larger number of radiometals. Our results indicate that an employment of dendrimer-chelate conjugates with bound radiometals might represent a prospective way for radiolabeling of biologically active target-specific macromolecules to obtain markedly high specific activity.
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    • "Therein, 1 H NMR, ESI-TOF MS, MALDI-TOF MS and ICP-AES were employed to determine the degree of dendrimer surface decoration. Mass spectrometry confirmed that each of synthesized dendrimers 7 and 11 have the expected molecular weight [38]. For dendrimer 4 (G3- 6NHBoc-18NHCbz, M ¼ 5852.1), the MALDI-TOF MS showed peak (m/z ¼ 5875.9 [M þ Na] þ ) corresponding only fully substituted materials (Fig. 2a). "
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    ABSTRACT: Gadolinium (Gd(3+)) based dendrimers with precise and tunable nanoscopic sizes are excellent candidates as magnetic resonance imaging (MRI) contrast agents. Control of agents' sensitivity, biosafety and functionality is key to the successful applications. We report the synthesis of Gd(III)-based peptide dendrimers possessing highly controlled and precise structures, and their potential applications as MRI contrast agents. These agents have no obvious cytotoxicity as verified by in vitro studies. One of the dendrimer formulations with mPEG modification showed a 9-fold increase in T(1) relaxivity to 39.2 Gd(III) mM(-1) s(-1) comparing to Gd-DTPA. In vivo studies have shown that the mPEGylated Gd(III)-based dendrimer provided much higher signal intensity enhancement (SI) in mouse kidney, especially at 60 min post-injection, with 54.8% relatively enhanced SI. The accumulations of mPEGylated dendrimer in mouse liver and kidney were confirmed through measurement of gadolinium by inductively coupled plasma atomic emission spectroscopy (ICP-AES). Meanwhile, mPEGylated dendrimer showed much higher Gd(III) concentration in blood with 38 μg Gd(III)/g blood at 1 h post-injection comparing to other dendrimer formulations. These findings provide an attractive alternative strategy to the design of multifunctional gadolinium-based dendrimers with controlled structures, and open up possibilities of using the Gd(III)-based peptide dendrimers as MRI probes.
    Full-text · Article · Nov 2011 · Biomaterials
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    • "Polyamidoamine dendrimers (PAMAMs) have been studied as potential drug carriers, gene delivery carriers and moieties for modification of drug solubility and/or absorption for a many years [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]. Conjugation of these dendritic polymers with metal chelators and subsequent complexation with metal ions have led to a range of magnetic resonance imaging contrast agents (MRI CA) [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]. "
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    ABSTRACT: Polyamidoamine dendrimers (PAMAMs) of generations 1 (G1) and 4 (G4) were conjugated with a bifunctional pyridine-N-oxide DOTA analog, 10-[(4-carboxy-1-oxidopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H(4)do3a-py(NO-C)), through the pyridine-4-carboxylic acid group, and the conjugates were radiolabeled with indium-111. Reaction conditions for the radiolabelling were optimized. Both radiolabeled conjugates, G1-[(111)In(do3a-py(NO-C))] and G4-[(111)In(do3a-py(NO-C))], were kinetically stable for at least 48h after preparation; in the presence of competitive ligands, the radiochemical purity of the conjugates slightly decreased (4-7%) over the same time period. The preclinical pharmacokinetics of both agents were evaluated. Biodistribution and elimination in rats were more favorable for the G1-[(111)In(do3a-py(NO-C))] conjugate than G4-[(111)In(do3a-py(NO-C))] conjugate. However, the G1-[(111)In(do3a-py(NO-C))] conjugate was rapidly eliminated from the body, mainly through urine, while, significant and long-term radioactivity uptake in the liver and kidney was observed for the G4-[(111)In(do3a-py(NO-C))] conjugate.
    Full-text · Article · Nov 2011 · Journal of pharmaceutical and biomedical analysis
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