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Science to Practice |
1 Department of Radiology, Klinikum Karlsruhe, Academic Teaching Hospital of the University of Freiburg, Moltkestrasse 90, D-76133 Karlsruhe, Germany peter.reimer@klinik.uni-karlsruhe.de
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Clinically approved contrast agents for magnetic resonance (MR) imaging belong to the class of either extracellular gadolinium chelates or liver-targeted contrast agents. Blood pool contrast agents are on the clinical horizon, while tumor-targeted contrast agents represent the least-developed agents. To achieve tumor specificity, different magnetic signal markers have been linked to carriers with a high affinity for a specific target (1,2).
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The Science
In recent years, investigators have pursued various strategies to assess solid tumors by using contrast agents, mainly with nuclear medicine techniques or MR imaging (1). Other investigators have reported the application of a liposome-type vector (2). Liposomes represent lipid vesicles and typically exhibit a short blood half-life. In order to extend the blood half-life, different coatings, such as polyethylene glycol (PEG), may be used to produce "stealth" liposomes (4). The reduced clearance with increased vesicle recirculation of stealth liposomes may be an explanation for the documented passive-targeting effect of different phospholipid vesicles to tumor tissues, while active targeting has been less studied (5).
In their study, Luciani et al present their work on the development of an MR imaging contrast agent actively targeted to glucose receptors on tumor cells (3). The authors prepared four formulations of niosomes (nonionic vesicles) loaded with a gadolinium chelate: two of the four were glycosylated with N-palmitoyl glucosamine (NPG), and one of the two was also coated with PEG4400. The rationale for using glucose-type conjugates was to actively target for overexpressed glucose receptors.
In a carefully conducted experiment, the fraction of gadolinium chelate taken up by human prostate adenocarcinoma PC3 tumor cells was quantified by means of pulsed electron paramagnetic resonance (EPR). Gadolinium was detected with EPR only in cell pellets incubated with the two glycosylated niosomes. Subsequently, the authors used MR imaging to study the in vivo distribution of the four niosome formulations in mice. No significant difference (P > .05) in relative intensity values between the niosome formulations was observed in liver or muscle tissue. In brain tissue, both of the glycosylated niosomes showed a regular increase in relative signal intensity. Finally, experiments were performed in nude mice with subcutaneously implanted tumors. Marked predominant tumor enhancement was demonstrated 24 hours after injection of the glycosylated PEG4400 niosomes, whereas no significant difference (P > .05) in tissue enhancement was observed following injection of the other formulations. Twenty-four hours after injection of glycosylated PEG4400 niosomes, relative intensity values within tumors were significantly higher than those observed after the injection of any of the other formulations (P < .01).
The Practice
Clinical use.—The experimental concept of use of a liposome-based contrast agent with specificity for glucose receptors, achieved by combining the glucose conjugate NPG and the protective coating agent PEG4400, elegantly mimics the concept established with fluorodeoxyglucose positron emission tomography (PET) imaging of glucose receptors (6). Luciani et al (3) hypothesize that the combination allows a simultaneous passive-targeting process mediated by PEG4400 radicals and an active-targeting process related to the interaction of glucosamine residues with overexpressed glucose transporters.
Future opportunities and challenges.—The higher spatial resolution of MR imaging compared with that of PET imaging and the presence of various approved contrast agents, such as the one used in the study by Luciani et al, as a magnetic marker represent favorable circumstances for the development of receptor-specific MR contrast agents for oncologic imaging. The combination of PEG- and glucosamine-coated niosomes may also be useful as a drug carrier.
Summary
Luciani and colleagues have shown that the combination of both PEG4400 radicals and a glucose conjugate on the surface of niosomes led to a significant improvement in tumor targeting of an entrapped paramagnetic agent, as assessed by using MR imaging in a human carcinoma xenograft model. To date, no MR contrast agent using the overexpressed glucose receptors in tumor cells has been synthesized. The study concept of Luciani et al combines the unsurpassed spatial and contrast resolution of MR imaging with the cellular and molecular information obtained by using fluorodeoxyglucose PET.
FOOTNOTES
See also the article by Luciani et al in this issue.
REFERENCES
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