Dendritic iodinated contrast agents with PEG-cores for CT imaging: synthesis and preliminary characterization.

The purpose of this study was to design, synthesize, and initially characterize a representative set of novel constructs for large-molecular radiographic/computed tomography (CT) contrast agents, intended for a primarily intravascular distribution. A new assembly of well-known and biocompatible components consists of paired, symmetrical dendritic polylysines initiated from both ends of a poly(ethylene glycol) (PEG) core, yielding an array of multiple free amino groups to which were conjugated highly soluble and stable triiodophthalamide ("triiodo") moieties. An array of six dendritic contrast agents was synthesized originally, using three different PEG cores (3, 6, 12 kDa) with t-Boc lysine-generated dendrimer "amplifiers" (from three to five generations) containing 16 to 64 amino groups for conjugation with reactive triiodo moieties. A clinically used, nonionic, small molecular CT contrast agent, iobitridol, was derivatized via a hydroxyl protection/deprotection strategy, introducing a new carboxyl group available for conjugation to the lysine amino groups of dendrimers. Final products were purified by size exclusion chromatography and characterized by NMR, UV, HPLC, and elemental analysis. Preliminary evaluations were conducted for physicochemical characterization and in vivo CT contrast enhancement in a rat model. All six iodinated PEG-core dendrimer conjugates were synthesized in good yields, with a high degree of size monodispersity, large apparent molecular weight, favored physicochemical properties. A representative compound, PEG12000-carbamate-Gen4-IOB conjugate, 27% (w%) rich in iodine, demonstrated a desirable strong and persistent intravascular enhancement with a monoexponential blood half-life of approximately 35 min assayed by dynamic CT imaging and also showed high water solubility (>550 mg/mL at 25 degrees C), large apparent molecular size (comparable to a 143-kDa protein), high hydrophilicity (butanol-water partition coefficient 0.015), and stability to autoclaving conditions. This study showed the synthetic feasibility, desired basic characteristics, and potential utility for CT contrast enhancement achieved with a new type of iodinated, large-molecular PEG-core dendritic construct. Further development of this class of macromolecular contrast agents will be required to define the optimal formulation, pharmacology, safety profile, and the full range of diagnostic applications including tumor microvascular quantitative characterization by CT imaging.

In-vivo NIR autofluorescence imaging of rat mammary tumors.

We investigate in vivo detection of mammary tumors in a rat model using autofluorescence imaging in the red and far-red spectral regions. The objective was to explore this method for non-invasive detection of malignant tumors and correlation between autofluorescence properties of tumors and their pathologic status. Eighteen tumor-bearing rats, bearing eight benign and seventeen malignant tumors were imaged. Autofluorescence images were acquired using spectral windows centered at 700-nm, 750-nm and 800-nm under laser excitation at 632.8-nm and 670- nm. Intensity in the autofluorescence images of malignant tumors under 670-nm excitation was higher than that of the adjacent normal tissue. whereas intensity of benign tumors was lower compared to normal tissue.

Initial computed tomography imaging experience using a new macromolecular iodinated contrast medium in experimental breast cancer.

OBJECTIVE: The objective of this study was to evaluate computed tomography (CT) enhancement characteristics for a new iodinated macromolecular contrast medium (MMCM), PEG12000-Gen4-triiodo, for angiographic effect and for assessment of abnormal vascular permeability in cancer. MATERIALS AND METHODS: Time persistence of angiographic effect was evaluated on rat CT images acquired over 30 minutes using the iodinated polyethyleneglycol- (PEG) based macromolecule. Dynamic CT imaging after PEG12000-Gen4-triiodo-enhancement in tumor-bearing rats was used to quantitatively estimate plasma volume and microvascular transendothelial permeability for both tumor and normal soft tissue. Using identical doses of iodine, 300 mg iodine/kg, blood curves for this MMCM and iohexol were compared. RESULTS: Serial whole-body CT angiograms using PEG12000-Gen4-triiodo showed diagnostic vascular detail through 20 minutes, and the blood enhancement curve was higher and more persistent than with small-molecular iohexol. Permeability estimates were significantly (P<0.02; paired t test) higher in tumors (48.2+/-18.1 microL/min-1 100 mL) than in muscle (2.5+/-5.7 microL/min-1 100 mL). CONCLUSIONS: Use of PEG-based MMCM for experimental CT allowed for a persistent angiographic enhancement and for quantitative estimation of tumor microvascular characteristics.