Cascade Polymeric MRI Contrast Media Derived from Poly(ethylene glycol) Cores: Initial Syntheses and Characterizations

详细信息    查看全文

• 作者：Yanjun Fu ; Hans-Juergen Raatschen ; Danute E. Nitecki ; Michael F. Wendland ; Viktor Novikov ; Laure S. Fournier ; Clemens Cyran ; Victor Rogut ; David M. Shames ; Robert C. Brasch
• 刊名：Biomacromolecules
• 出版年：2007
• 出版时间：May 2007
• 年：2007
• 卷：8
• 期：5
• 页码：1519 - 1529
• 全文大小：385K
• 年卷期：v.8,no.5(May 2007)
• ISSN：1526-4602

文摘

Diagnostic contrast media for magnetic resonance imaging (MRI) are often applied to enhance the signal ofblood allowing for quantitative definition of vascular functional characteristics including tissue blood volume,flow, and leakiness. Well-tolerated and safe macromolecular formulations are currently being sought that remainin the blood for a relatively long period and that leak selectively from diseased vessels, particularly cancer vessels.We synthesized a new class of macromolecular, water-soluble MRI contrast media by introducing two divergingpolylysine cascade amplifiers at each end of a poly(ethylene glycol) (PEG) backbone, followed by substitution ofterminal lysine amino groups with Gd-DTPA chelates. Four candidate PEG cascade conjugates are reportedhere, PEG3400-Gen4-(Gd-DTPA)₈, PEG6000-Gen4-(Gd-DTPA)₈, PEG12000-Gen4-(Gd-DTPA)₈, and PEG3400-Gen5-(Gd-DTPA)₁₃ with descriptions of their basic physical, biological, and kinetic properties, including realand effective molecular sizes, proton T1 relaxivities in water and plasma, partition coefficients, osmolalities,chelate stability, stability in plasma, stability to autoclaving, certain in vivo pharmacokinetics (blood half-life,blood clearance, volume of distribution), and whole body elimination profiles in normal rodents. These candidatePEG-core cascade MRI contrast media showed a range of effective molecular sizes similar to proteins weighing74-132 kDa, although their actual molecular weights were much smaller, 12-20 kDa. All compounds exhibiteda narrow range of size dispersity and relatively high T1 relaxivities (approximately 3 times the value forunconjugated Gd-DTPA at 2 T and 37 f">C). Representative compounds also showed a high degree of hydrophilicity,stability in solution buffer and plasma, and lack of binding to proteins. The two candidate compounds with thelargest effective molecular sizes, PEG12000-Gen4-(Gd-DTPA)₈ and PEG3400-Gen5-(Gd-DTPA)₁₃, had longerblood half-lives, 36 and 73 min, respectively (monoexponential kinetics for both), and showed strong, prolongedMRI enhancement of vessels. Results also indicate that in vivo pharmacokinetics and bodily elimination profilescan be adjusted by the selection of molecular size for the PEG core and the selection of the amplification degreeof the cascade polylysine clusters. The initially evaluated compounds from this new class of contrast media showacceptable, desirable characteristics in many, but not all, respects. Further efforts are directed toward candidatemacromolecules having higher thermodynamic stability, higher degree of substitution by gadolinium chelates,and more rapid bodily elimination.