Targeted dendrimer-based contrast agents for articular cartilage assessment by MR imaging.
OBJECTIVE
Magnetic resonance (MR) imaging with contrast media has shown promise for articular cartilage assessment. Dendrimer-linked nitroxides, a new family of MR contrast agents targeted to glycosaminoglycan, may improve cartilage evaluation. This study is designed to determine the ability of dendrimer-linked nitroxides to enhance articular cartilage and measure the intra-articular life-time of these agents.


METHODS
Cartilage T(1) was evaluated using immature bovine patella in solutions of five different dendrimer-linked nitroxides, saline or Gd-DTPA at 1.5T. The "relaxivity per dose" (change in cartilage 1/T(1) produced by a given concentration of agent) was calculated. The half-life of joint fluid enhancement was measured at 2T after solutions of three dendrimer-linked nitroxides, Gd-DTPA, and saline were injected into rabbit stifle joints. Twenty-four hours after injection, the joints were examined grossly and by histology for toxicity.


RESULTS
All but the largest dendrimer-linked nitroxide were able to intensely enhance articular cartilage on MR. Relaxivity per dose measurements were between 3.5 and 68 times greater than Gd-DTPA. The largest nitroxide appeared to be excluded from articular cartilage. Intra-articular half-lives of the dendrimer-linked nitroxides were sufficiently long (160-208 min) for in vivo MR imaging to be performed. Histological assessments of joints showed minimal synovial inflammatory and necrosis scores 1 day post-injection that were similar for all agents, including Gd-DTPA.


CONCLUSIONS
Dendrimer-linked nitroxides strongly enhance cartilage and are promising as articular cartilage-specific MR contrast agents. The intra-articular life-time is sufficient for imaging studies and, in initial evaluation, the agents exhibit minimal toxicity in rabbit joints.
Winalski
C S
CS
Imaging Institute, Cleveland Clinic, Cleveland, OH 44195, USA. winalsc@ccf.org
Shortkroff
S
S
Schneider
E
E
Yoshioka
H
H
Mulkern
R V
RV
Rosen
G M
GM
D000818:Animals; D002358:Cartilage, Articular / Q000033:anatomy & histology* / Q000378:metabolism; D002417:Cattle; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D050091:Dendrimers / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D006207:Half-Life; D008279:Magnetic Resonance Imaging / Q000379:methods; D008970:Molecular Weight; D009589:Nitrogen Oxides / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity; D010329:Patella / Q000033:anatomy & histology / Q000378:metabolism; D013329:Structure-Activity Relationship; D046509:Tissue Culture Techniques
D003287:Contrast Media; D050091:Dendrimers; D009589:Nitrogen Oxides; D019786:Gadolinium DTPA