Dendritic Iodinated Contrast Agents with PEG-Cores for CT Imaging:  Synthesis and Preliminary Characterization

Abstract

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.

Polymer platforms for drug delivery and biomedical imaging

“…Various polymeric drug delivery systems have been previously reviewed in numerous publications [1,3,[11][12][13]. Polymers have been used in the design and development of novel imaging agents for various imaging modalities, including computed tomography (CT) [14], MRI [5], single photon emission computed tomography (SPECT) [15], positron emission tomography (PET) [16], ultrasound [17] and optical imaging [18]. We summarize here our recent research progress using biomedical polymers as a platform for both drug delivery and molecular imaging, including biodegradable macromolecular MRI contrast agents; noninvasive visualization of in vivo drug delivery of polymeric conjugates with contrast enhanced MRI; and bifunctional polymeric conjugates for image-guided photodynamic therapy.…”

New-generation biomedical materials: Peptide dendrimers and their application in biomedicine

“…Brasch et al [60] synthesized a series of water-soluble peptide dendrimer-based CT contrast agents where poly- Figure 11 The structure of lactose-poly(lysine) dendron [59].…”

“…PEG-core dendrimer with multiple triiodophthalamide moieties as macromolecular contrast agents for computed tomography (CT) [60].…”

“…Fu et al [60] synthesized a class of water-soluble dendrimer-based CT contrast agents where poly(ethylene glycol) PEG(3400), PEG(6000) and PEG(12000) were used as a core. All the six iodinated PEG-core dendrimer conjugates demonstrated a high degree of size monodispersity, large apparent molecular weight, and favored physicochemical properties.…”

“…All the six iodinated PEG-core dendrimer conjugates demonstrated a high degree of size monodispersity, large apparent molecular weight, and favored physicochemical properties. The PEG12000-carbamate-Gen4-iodine conjugate ( Figure 13), 27wt% enriched 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 ( Figure 14) and Figure 14 Serial axial CT images of a normal Sprague-Dawley rat at the level of liver after intravenous injection of PEG12000-core dendrimer [60]. also showed high water-solubility, large apparent molecular size, high hydrophilicity, and stability to autoclaving conditions.…”