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Tumor Detection at 3 Tesla with an Activatable Cell Penetrating Peptide Dendrimer (ACPPD-Gd), a T1 Magnetic Resonance (MR) Molecular Imaging Agent.

Malone CD, Olson ES, Mattrey RF, Jiang T, Tsien RY, Nguyen QT - PLoS ONE (2015)

Bottom Line: The ability to detect small malignant lesions with magnetic resonance imaging (MRI) is limited by inadequate accumulations of Gd with standard chelate agents.Receiver operator characteristic (ROC) curves and area-under-curve (AUC) values were constructed and analyzed.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, University of California, San Diego, San Diego, CA, United States of America.

ABSTRACT

Purpose: 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.

Materials and 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).

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Tumor size and enhancement of all tumors.a, The normalized signal of all 107 tumors is shown as a function of tumor size that ranged from 0.03 to 107.4 mm3. Note that tumor enhancement was consistently greater for ACPPD-Gd animals at all tumor sizes. b, Bar graph of normalized mean enhancement ± SD of tumors >1mm3 shows that ACPPD-Gd caused the greatest enhancement. *** indicates p<0.001. c, Representative axial fat-saturated T1w MR images of a tumor bearing mouse given ACPPD-Gd and imaged on days 4, 9, and 14 after inoculation showing a thin strip of enhancement on day 4 (arrow) at the site where the tumor became apparent on days 9 and 14 (arrow). This was not observed in the gadobutrol group (not shown). Scale bars = 5mm for each image.
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pone.0137104.g002: Tumor size and enhancement of all tumors.a, The normalized signal of all 107 tumors is shown as a function of tumor size that ranged from 0.03 to 107.4 mm3. Note that tumor enhancement was consistently greater for ACPPD-Gd animals at all tumor sizes. b, Bar graph of normalized mean enhancement ± SD of tumors >1mm3 shows that ACPPD-Gd caused the greatest enhancement. *** indicates p<0.001. c, Representative axial fat-saturated T1w MR images of a tumor bearing mouse given ACPPD-Gd and imaged on days 4, 9, and 14 after inoculation showing a thin strip of enhancement on day 4 (arrow) at the site where the tumor became apparent on days 9 and 14 (arrow). This was not observed in the gadobutrol group (not shown). Scale bars = 5mm for each image.

Mentions: Degree of tumor Intensity relative to muscle for all 107 tumors is shown in Fig 2a; mean relative intensity and standard deviation of those tumors ≥1mm3 are shown in Fig 2b. Note that while pre-contrast tumors (n = 19) were essentially iso-intense to muscle (1.06±0.10), they enhanced by 24.8%±12.8, p<0.001, 2–3 minutes after gadobutrol injection. Tumors ≥1mm3 (n = 29) imaged 1 day after ACPPD-Gd, enhanced by 49.0%±20.0 relative to the non-contrast group, p<0.001, and 26.0% greater than the gadobutrol group, p<0.001 (Fig 2b). ACPPD-Gd administration outlined a very small strip of enhancement at the earliest time point in breasts destined to develop tumors (Fig 2c). This strip of enhancement was not seen at control saline injection sites. Representative images of pre and post-gadobutrol and those imaged 24 hours after ACPPD-Gd are shown in Fig 3a. Note that ACPPD-Gd produced diffuse homogenous tumor enhancement, while gadobutrol enhancement was more apparent at the tumor periphery. Tumor enhancement with gadobutrol was independent of tumor size (Fig 3b). Tumors as small as 1-5mm3 showed significantly greater enhancement following ACPPD-Gd as compared to gadobutrol (45±19% vs. 19±18%, p = 0.03).


Tumor Detection at 3 Tesla with an Activatable Cell Penetrating Peptide Dendrimer (ACPPD-Gd), a T1 Magnetic Resonance (MR) Molecular Imaging Agent.

Malone CD, Olson ES, Mattrey RF, Jiang T, Tsien RY, Nguyen QT - PLoS ONE (2015)

Tumor size and enhancement of all tumors.a, The normalized signal of all 107 tumors is shown as a function of tumor size that ranged from 0.03 to 107.4 mm3. Note that tumor enhancement was consistently greater for ACPPD-Gd animals at all tumor sizes. b, Bar graph of normalized mean enhancement ± SD of tumors >1mm3 shows that ACPPD-Gd caused the greatest enhancement. *** indicates p<0.001. c, Representative axial fat-saturated T1w MR images of a tumor bearing mouse given ACPPD-Gd and imaged on days 4, 9, and 14 after inoculation showing a thin strip of enhancement on day 4 (arrow) at the site where the tumor became apparent on days 9 and 14 (arrow). This was not observed in the gadobutrol group (not shown). Scale bars = 5mm for each image.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4559389&req=5

pone.0137104.g002: Tumor size and enhancement of all tumors.a, The normalized signal of all 107 tumors is shown as a function of tumor size that ranged from 0.03 to 107.4 mm3. Note that tumor enhancement was consistently greater for ACPPD-Gd animals at all tumor sizes. b, Bar graph of normalized mean enhancement ± SD of tumors >1mm3 shows that ACPPD-Gd caused the greatest enhancement. *** indicates p<0.001. c, Representative axial fat-saturated T1w MR images of a tumor bearing mouse given ACPPD-Gd and imaged on days 4, 9, and 14 after inoculation showing a thin strip of enhancement on day 4 (arrow) at the site where the tumor became apparent on days 9 and 14 (arrow). This was not observed in the gadobutrol group (not shown). Scale bars = 5mm for each image.
Mentions: Degree of tumor Intensity relative to muscle for all 107 tumors is shown in Fig 2a; mean relative intensity and standard deviation of those tumors ≥1mm3 are shown in Fig 2b. Note that while pre-contrast tumors (n = 19) were essentially iso-intense to muscle (1.06±0.10), they enhanced by 24.8%±12.8, p<0.001, 2–3 minutes after gadobutrol injection. Tumors ≥1mm3 (n = 29) imaged 1 day after ACPPD-Gd, enhanced by 49.0%±20.0 relative to the non-contrast group, p<0.001, and 26.0% greater than the gadobutrol group, p<0.001 (Fig 2b). ACPPD-Gd administration outlined a very small strip of enhancement at the earliest time point in breasts destined to develop tumors (Fig 2c). This strip of enhancement was not seen at control saline injection sites. Representative images of pre and post-gadobutrol and those imaged 24 hours after ACPPD-Gd are shown in Fig 3a. Note that ACPPD-Gd produced diffuse homogenous tumor enhancement, while gadobutrol enhancement was more apparent at the tumor periphery. Tumor enhancement with gadobutrol was independent of tumor size (Fig 3b). Tumors as small as 1-5mm3 showed significantly greater enhancement following ACPPD-Gd as compared to gadobutrol (45±19% vs. 19±18%, p = 0.03).

Bottom Line: The ability to detect small malignant lesions with magnetic resonance imaging (MRI) is limited by inadequate accumulations of Gd with standard chelate agents.Receiver operator characteristic (ROC) curves and area-under-curve (AUC) values were constructed and analyzed.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiology, University of California, San Diego, San Diego, CA, United States of America.

ABSTRACT

Purpose: 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.

Materials and 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).

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus