Dendritic Iodinated Contrast Agents with PEG-Cores for CT Imaging: Synthesis and Preliminary Characterization
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- 作者：Yanjun Fu ; Danute E. Nitecki ; David Maltby ; Gerhard H. Simon ; Kirill Berejnoi ; Hans-Juergen Raatschen ; Benjamin M. Yeh ; David M. Shames ; and Robert C. Brasch
- 刊名：Bioconjugate Chemistry
- 出版年：2006
- 出版时间：July 2006
- 年：2006
- 卷：17
- 期：4
- 页码：1043 - 1056
- 全文大小：510K
- 年卷期：v.17,no.4(July 2006)
- ISSN：1520-4812
文摘
The purpose of this study was to design, synthesize, and initially characterize a representative set of novel constructsfor large-molecular radiographic/computed tomography (CT) contrast agents, intended for a primarily intravasculardistribution. A new assembly of well-known and biocompatible components consists of paired, symmetrical dendriticpolylysines initiated from both ends of a poly(ethylene glycol) (PEG) core, yielding an array of multiple freeamino groups to which were conjugated highly soluble and stable triiodophthalamide ("triiodo") moieties. Anarray 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 aminogroups for conjugation with reactive triiodo moieties. A clinically used, nonionic, small molecular CT contrastagent, iobitridol, was derivatized via a hydroxyl protection/deprotection strategy, introducing a new carboxylgroup available for conjugation to the lysine amino groups of dendrimers. Final products were purified by sizeexclusion chromatography and characterized by NMR, UV, HPLC, and elemental analysis. Preliminary evaluationswere conducted for physicochemical characterization and in vivo CT contrast enhancement in a rat model. Allsix iodinated PEG-core dendrimer conjugates were synthesized in good yields, with a high degree of sizemonodispersity, 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 persistentintravascular enhancement with a monoexponential blood half-life of approximately 35 min assayed by dynamicCT imaging and also showed high water solubility (>550 mg/mL at 25 
C), large apparent molecular size(comparable to a 143-kDa protein), high hydrophilicity (butanol-water partition coefficient 0.015), and stabilityto autoclaving conditions. This study showed the synthetic feasibility, desired basic characteristics, and potentialutility for CT contrast enhancement achieved with a new type of iodinated, large-molecular PEG-core dendriticconstruct. Further development of this class of macromolecular contrast agents will be required to define theoptimal formulation, pharmacology, safety profile, and the full range of diagnostic applications including tumormicrovascular quantitative characterization by CT imaging.
C), large apparent molecular size(comparable to a 143-kDa protein), high hydrophilicity (butanol-water partition coefficient 0.015), and stabilityto autoclaving conditions. This study showed the synthetic feasibility, desired basic characteristics, and potentialutility for CT contrast enhancement achieved with a new type of iodinated, large-molecular PEG-core dendriticconstruct. Further development of this class of macromolecular contrast agents will be required to define theoptimal formulation, pharmacology, safety profile, and the full range of diagnostic applications including tumormicrovascular quantitative characterization by CT imaging.