Nadia Ayat1, Sarah Roelle1, Songqi Gao1, Yajuan Li1, and Zheng-Rong Lu1
1Case Western Reserve University, Cleveland, OH, United States
Synopsis
This research highlights the potential of a
targeted contrast agent specific to the extra-domain B (EDB-FN) to be utilized
in the diagnosis of prostate cancer at reduced dosages. EDB-FN specific MR contrast agent MT218
produced robust tumor enhancement at dosages as low as 0.02 mmol Gd/kg.
Introduction
Gadolinium (III) based contrast agents (GBCAs)
are commonly used for contrast enhanced MRI of cancerous lesions1. However, clinically used GBCAs are tumor-specific
and unable to accurately detect and characterize aggressive tumors. In addition,
repeated use of these agents at a relatively high dose may lead to adverse side
effects including nephrogenic systemic fibrosis in patients with compromised
renal function, and nonspecific brain accumulation. We have previously developed
and characterized a targeted MRI contrast agent, named ZD2-N3-Gd(HP-DO3A)
(MT218), that is specific to tumor extracellular matrix protein extradomain-B
fibronectin (EDB-FN)2. MT218 produces superior enhancement in aggressive
prostate cancer using 0.1 mmol Gd/kg, the clinical dosage for most GBCAs, and has
shown the ability to differentiate aggressive prostate tumors from non-invasive
tumors in mouse tumor models. We hypothesized that MT218 could be effective for
magnetic resonance molecular imaging (MRMI) of aggressive tumors at substantially
reduced doses due to its tumor specificity. This would significantly reduce the
dose-dependent side effects related to GBCAs. In this study, we have evaluated
the dosing effects of MT218 for tumor contrast enhancement in a rat tumor
xenograft model with the dose as low as 0.02 mmol Gd/kg, only 1/5 of the clinical
dose. To further evaluate the safety profile of MT218, we analyzed the
biodistribution of MT218 for up to two weeks after intravenous administration.Methods
The contrast agent MT218 was provided by
Molecular Theranostics LLC (Cleveland, OH). MRMI was conducted in male rats
bearing PC3 human prostate tumor xenografts using a 3T MRS 3000 scanner (MR
Solutions) with a rat short quad coil. Axial T1-weighted images were
acquired pre and post-injection of MT218 at doses of 0.04 and 0.02 mmol Gd/kg using
a fast spin echo (FSE) sequence with respiratory gating (TR = 305
ms, TE = 11 ms, FOV = 80 x 80 mm, slice thickness = 1 mm, Nav
= 2, matrix = 128 x 128). The imaging protocol was repeated with the clinical
agent ProHance at 0.1 mmol Gd/kg. Biodistribution studies were conducted to
analyze the metabolic clearance and two-week tissue retention of MT218. Sprague
dawley rats (5m + 5f, 7-8 weeks old) were randomly divided and injected with
either MT218 or ProHance at a dose of 0.1 mmol Gd/kg via tail vein. The rats
were placed in metabolic cages for 3 days, were feces and urine samples were
collected at 8, 24, 48 and 72 hours post-injection. The rats were sacrificed at
14 days post-injection. Tissue samples, including brain, femur, heart, lung,
liver, muscle, spleen and kidneys, were collected and weighed. The tissue
samples were subsequently processed as previously reported, and Gd3+ concentration
was measured by ICP-OES3.Results
Contrast-enhanced MRMI of PC3 tumor xenografts
using MT218 produced strong signal enhancement at both subclinical doses of MT218.
Figure 1A shows representative axial images at 10, 20 and 30 min post
injection. Strong contrast enhancement was observed in the tumors with MT218 at
both doses as early as 10 min post injection, persisting for at least 30 min. Much
lower contrast enhancement was observed with the clinical agent ProHance.
Quantitative analysis reveals that MT218 generates approximately 13-fold
enhancement in rat tumors at 0.04 mmol Gd/kg (Figure 1B). MT218 at 0.02 mmol
Gd/kg showed a dose-dependent decrease in contrast enhancement, but still exhibited
up to 8-fold CNR increase. In contrast, clinical Gd(HP-DO3A) at 0.1 mmol/kg
produced only a 3-fold CNR enhancement in the tumors. MT218 has no significant
Gd(III) detected in tissues in rats 2 weeks post administration at a dose of
0.1 mmol/kg, same as the clinical agent ProHance.Discussion
Specific binding of MT218 to abundant EDB-FN in the extracellular
matrix of aggressive PC3 human prostate tumor xenografts resulted in robust
tumor enhancement in the aggressive prostate carcinomas for effective MRMI at
reduced doses. MT218 at dosages as low as 0.02 mmol Gd/kg was able to produce more
tumor enhancement than the clinical agent ProHance at a full dose. The results
have validated our hypothesis and demonstrated the effectiveness of the MT218
for MRMI of aggressive tumors at subclinical doses. While administration of
MT218 at the clinical dose reveals no significant long-term Gd accumulation, robust
contrast enhancement of MT218 at a significant reduced dose will greatly
minimize the potential toxic side effects of GBCAs. In conclusion, MT218 has
the great promise for effective MRMI of aggressive prostate tumors at a
substantially reduced doses with minimal dose-dependent side effects.Acknowledgements
This research was supported by the NIH grants R01CA211762 and R44CA199826.References
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