Tumor Detection at 3 Tesla with an Activatable Cell Penetrating Peptide Dendrimer (ACPPD-Gd), a T1 Magnetic Resonance (MR) Molecular Imaging Agent.
OBJECTIVE
The ability to detect small malignant lesions with magnetic resonance imaging (MRI) is limited by inadequate accumulations of Gd with standard chelate agents. To date, no T1-targeted agents have proven superiority to Gd chelates in their ability to detect small tumors at clinically relevant field strengths. Activatable cell-penetrating peptides and their Gd-loaded dendrimeric form (ACPPD-Gd) have been shown to selectively accumulate in tumors. In this study we compared the performance of ACPPD-Gd vs. untargeted Gd chelates to detect small tumors in rodent models using a clinical 3T-MR system.


METHODS
This study was approved by the Institutional-Animal Care-and-Use Committee. 2 of 4 inguinal breast fat pads of 16 albino-C57BL/6 mice were inoculated with tumor Py8119 cells and the other 2 with saline at random. MRI at 3T was performed at 4, 9, and 14 days after inoculation on 8 mice 24-hours after injection of 0.036mmol Gd/kg (ACPPD-Gd), and before and 2-3 minutes after 0.1 mmol/kg gadobutrol on the other 8 mice. T1-weighted (T1w) tumor signal normalized to muscle, was compared among the non-contrast, gadobutrol, and ACPPD-Gd groups using ANOVA. Experienced and trainee readers blinded to experimental conditions assessed for the presence of tumor in each of the 4 breast regions. Receiver operator characteristic (ROC) curves and area-under-curve (AUC) values were constructed and analyzed.


RESULTS
Tumors ≥1mm3 were iso-intense to muscle without contrast on T1w sequences. They enhanced diffusely and homogeneously by 57±20% (p<0.001) 24 hours after ACPPD-Gd and by 25±13% (p<0.001) immediately after gadobutrol. The nearly 2-fold difference was similar for small tumors (1-5mm3) (45±19% vs. 19±18%, p = 0.03). ACPPD-Gd tended to improve tumor detection by an experienced reader (AUC 0.98 vs 0.91) and significantly more for a trainee (0.93 vs. 0.82, p = 0.02) compared to gadobutrol. This improvement was more pronounced when obvious tumors (>5mm3) were removed from the ROC analysis for both the experienced observer (0.96 vs. 0.86) and more so for the trainee (0.86 vs. 0.69, p = 0.04).


CONCLUSIONS
ACPPD-Gd enhances MMP-expressing tumors of any size at 3T 24 hours after administration, improving their detection by blinded observers when compared to non-contrast and contrast groups given commercial Gd-chelates and imaged during the equilibrium phase.
Department of Radiology, University of California, San Diego, San Diego, CA, United States of America.
Christopher D
CD
Malone
Department of Radiology, University of California, San Diego, San Diego, CA, United States of America.
Emilia S
ES
Olson
Department of Radiology, University of California, San Diego, San Diego, CA, United States of America.
Robert F
RF
Mattrey
Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, United States of America.
Tao
T
Jiang
Howard Hughes Medical Institute, University of California, San Diego, San Diego, CA, United States of America; Department of Pharmacology. University of California, San Diego, San Diego, CA, United States of America; Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, CA, United States of America.
Roger Y
RY
Tsien
Department of Otolaryngology-Head and Neck Surgery University of California, San Diego, San Diego, CA, United States of America.
Quyen T
QT
Nguyen
D064591:Allografts; D000818:Animals; D019540:Area Under Curve; D003287:Contrast Media / Q000493:pharmacokinetics; D050091:Dendrimers; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D012372:ROC Curve; D016037:Single-Blind Method; D014018:Tissue Distribution
D003287:Contrast Media; D050091:Dendrimers; D009363:Neoplasm Proteins; C104700:PAMAM Starburst; D020782:Matrix Metalloproteinases