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

ABSTRACT 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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    • "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.
    Biomaterials 11/2011; 32(31):7951-60. DOI:10.1016/j.biomaterials.2011.07.006 · 8.56 Impact Factor
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    • "To overcome these drawbacks, contrast agents prepared by nanotechnology have been studied for decades and showed great potential in tumor diagnosis. These nanoparticles (NPs) include lipid-based NPs [7], polymeric NPs [8], micells [9], dendrimers [10] and silica NPs [11]. Advantages of these novel contrast agents such as passive targeting properties, the prolonged imaging time, the enhancement of the contrast and low toxicity were observed [8]. "
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    ABSTRACT: Molecular imaging is essential to increase the sensitivity and selectivity of cancer diagnosis especially in the early stage of tumor. Here, we designed a novel multifunctional polymeric nanoparticle contrast agent (Anti-VEGF PLA-PEG-PLL-Gd NP) simultaneously modified with Gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and anti-vascular endothelial growth factor (VEGF) antibody to deliver Gd-DTPA to the tumor area and achieve the early diagnosis of hepatocellular carcinoma (HCC). The Anti-VEGF PLA-PEG-PLL-Gd NPs exhibited high T(1) relaxivity and no obvious cytotoxicity under the experimental concentrations in human hepatocellular carcinoma (HepG2) cells. The results of in vitro cell uptake experiments demonstrated that the uptake process of NPs was both concentration and time depended. Compared with non-targeted NPs, the Anti-VEGF antibody modified NPs showed much higher cell uptake in the HepG2 cells. During in vivo studies, the targeted NPs showed significantly signal intensity enhancement at the tumor site (mouse hepatocarcinoma tumor, H22) compared with non-targeted NPs and Gd-DTPA injection in tumor-bearing mice and the imaging time was significantly prolonged from less than an hour (Gd-DTPA injection group) to 12 h. These results demonstrated that this novel MRI contrast agent Anti-VEGF PLA-PEG-PLL-Gd NPs showed great potential in the early diagnosis of liver tumors.
    Biomaterials 08/2011; 32(22):5167-76. DOI:10.1016/j.biomaterials.2011.03.077 · 8.56 Impact Factor
  • Journal of the American College of Cardiology 04/2011; 57(14). DOI:10.1016/S0735-1097(11)61169-8 · 16.50 Impact Factor
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