Background

[PubMed]

The Cy5.5-labeled and gadolinium (Gd(III))-chelated chitosan nanoparticles, abbreviated as Cy5.5-CNP-Gd(III), are an optical/magnetic resonance (MR) dual imaging agent synthesized by Nam et al. for multimodality imaging of tumors (1).

The idea of using multiple modalities in a single imaging session comes from the fact that modalities with high sensitivity have relatively poor resolution, while those with high resolution have relatively poor sensitivity (2, 3). Integration of multiple modalities in imaging would take the advantages of each modality and allow better characterization of diseases and disease processes (4, 5). To date, the most successful hybrid system is derived from the fusion of positron emission tomography (PET) and computed tomography (CT) (5-8). PET is highly sensitive and allows three-dimensional images that show the concentration and location of the radiolabeled tracers of interest, while CT provides high-resolution imaging of the anatomical structures. Because of limited soft-tissue contrast and high X-ray radiation that accompanies CT imaging, considerable effort has been invested in recent years toward development of PET/magnetic resonance imaging (MRI) hybrid systems in an attempt to generate combined functional and morphological images with excellent soft tissue contrast, good spatial resolution of the anatomy, and accurate temporal and spatial image fusion (9-11). In contrast, systems integrated with optical techniques have not been investigated as extensively. Considering the advantages of multichannel imaging with single or multiple probes and the low cost of studying reporter gene expression in animal models, optical imaging integrated with other modalities may provide information at the cellular and molecular levels, which is critical in preclinical studies (1, 2, 12).

Development of hybrid imaging technology has triggered great effort in probe development to boost the benefits of hybrid instrument technology (12-15). In the case of optical/MRI probe design, the challenge is turned around to incorporate enough paramagnetic ions for detection by the relatively low sensitivity of MRI. Nam et al. have developed a dual imaging probe (Cy5.5-CNP-Gd(III)) with water-soluble glycol chitosan and the probes were preferably accumulated within the tumor xenografts in vivo (1). Chitosan has been frequently used to make nanoparticles carrying imaging reporters as well as therapeutic agents (1, 12, 15). Generally, the positively charged chitosan polymer can coat around a nanoparticle core by electrostatic adsorption, and other components are embedded in the chitosan matrix during the coating process. All components can also be entrapped simultaneously in the chitosan matrix.

Synthesis

[PubMed]

Nam et al. synthesized Cy5.5-CNP-Gd(III) by conjugating Cy5.5 to amphiphilic glycol chitosan (GC)-5β-cholanic acid (CA) conjugates (Cy5.5-GC-CA) and chelating Gd(III) with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-modified Cy5.5-GC-CA conjugates (1). Briefly, biocompatible and water-soluble GC (50 kDa) was first chemically modified with CA to form an amide linkage between the amine group of GC and the carboxyl acid of CA, resulting in the GC-CA conjugate. The molecular weight of GC-CA was 54 kDa with 11 ± 2 CA molecules per GC. For optical imaging, 0.5 ± 0.1 dyes of Cy5.5 monohydroxysuccinimide ester were then conjugated to the GC-CA (Cy5.5-GC-CA). For MRI, DOTA was first directly conjugated to the amine groups in the Cy5.5-GC-CA, and Gd(III) was then chelated. The degree of substitution of the number of DOTA molecules per nanoparticle was in the range from 13 to 45. The weight ratio of Gd(III) was maximized to ~6 ± 0.28%. The Cy5.5-CNP-Gd(III) nanoparticles were spherical in shape and ~350 nm in diameter. In phosphate-buffered saline at 37°C, Cy5.5-CNP-Gd(III) nanoparticles remained dispersed and maintained their original size for up to 40 days. Strong fluorescent signals and identical T1-weighted images were obtained under different pH conditions (pH 5.2 and 7.4). These results indicate that the chelated Gd(III) ions are highly stable in the nanoparticles.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The cellular uptake and cytotoxicity of Cy5.5-CNP-Gd(III) were evaluated in vitro with HeLa H2B-GFP cells (1). After incubation of the cells with Cy5.5-CNP-Gd(III) for 1 h, Cy5.5-CNP-Gd(III) nanoparticles were rapidly taken up by the HeLa cells and were found in the cytoplasm of cells. Cy5.5-CNP-Gd(III) exhibited almost 100% cell viability even at relatively high concentrations up to 250 μg/ml after incubation for 24 h.

Animal Studies

Human Studies

[PubMed]

No references are currently available.

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