Rationale and Objectives
To assess the applicability of a novel macromolecular polyethylene glycol (PEG)-core gadolinium contrast agent for monitoring early antiangiogenic effects of bevacizumab using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI).
Materials and Methods
Athymic rats ( n = 26) implanted with subcutaneous human melanoma xenografts underwent DCE-MRI at 2.0 T using two different macromolecular contrast agents. The PEG core cascade polymer PEG12,000-Gen4-(Gd-DOTA) 16 , designed for clinical development, was compared to the prototype, animal-only, macromolecular contrast medium (MMCM) albumin-(Gd-DTPA) 35 . The treatment ( n = 13) and control ( n = 13) group was imaged at baseline and 24 hours after a single dose of bevacizumab (1 mg) or saline to quantitatively assess the endothelial-surface permeability constant (K PS , μL⋅min⋅100 cm 3 ) and the fractional plasma volume (fPV,%), using a two-compartment kinetic model.
Results
Mean K PS values, assessed with PEG12,000-Gen4-(Gd-DOTA) 16 , declined significantly ( P < .05) from 29.5 ± 10 μL⋅min⋅100 cm 3 to 10.4 ± 7.8 μL⋅min⋅100 cm 3 by 24 hours after a single dose of bevacizumab. In parallel, K PS values quantified using the prototype MMCM albumin-(Gd-DTPA) 35 showed an analogous, significant decline ( P < .05) in the therapy group. No significant effects were detected on tumor vascularity or on microcirculatory parameters in the control group between the baseline and the follow-up scan at 24 hours.
Conclusion
DCE-MRI enhanced with the novel MMCM PEG12,000-Gen4-(Gd-DOTA) 16 was able to monitor the effects of bevacizumab on melanoma xenografts within 24 hours of a single application, validated by the prototype, animal-only albumin-(Gd-DTPA) 35 . PEG12,000-Gen4-(Gd-DOTA) 16 may be a promising candidate for further clinical development as a macromolecular blood pool contrast MRI agent.
Functional and molecular imaging techniques have been examined extensively to define their potential for monitoring the tumor angiogenesis. Established morphologic assessments relying on tumor size such as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 do not have adequate sensitivity for detection of tumor responses to antiangiogenic therapy in a desirable short time period . Data indicate that magnetic resonance (MR) morphology alone, including size or contrast enhancement, will not be adequate to monitor angiogenesis treatment . Dynamic, contrast-enhanced (DCE) MR imaging (MRI) enhanced with macromolecular contrast media (MMCM) has been investigated in experimental studies for monitoring tumor angiogenesis, based on the dependence of endothelial macromolecular permeability on tissue vascular endothelial growth factor (VEGF) activity. VEGF potently increases macromolecular permeability whereas inhibition of VEGF, shown with a variety of antiangiogenesis drugs and cancer models, reduces macromolecular permeability . The range of diagnostic utility for MMCM-enhanced MRI in cancer characterization has been demonstrated in recent years using animal models and the prototypic MMCM albumin-(Gd-DTPA) 35 in differentiating benign and malignant tumors, in grading the degree of tumor aggressiveness, in detecting early responses to antiangiogenesis drug therapy, and in use as a predictive biomarker of tumor response . However, albumin-(Gd-DTPA) 35 is considered to be poorly suited for use in humans because of incomplete elimination and concerns of immunogenicity . Hence, new MMCM are being sought that have blood kinetic properties similar to albumin-(Gd-DTPA) 35 and will be appropriate for application in humans. Among currently investigated macromolecular contrast agents are polymers, dendrimers, and noncovalent complexes of small molecule agents with proteins including novel biodegradable compounds such as a polydisulfide with Gd-DOTA monoamide side chains or triazine dendrimers derivatized with a DOTA or DTPA .
The current study advances the evaluation of polyethylene glycol (PEG) core Gd macromolecular contrast agents, specifically PEG12,000-Gen4-(Gd-DOTA) 16 , representing a novel class of macromolecular contrast agents. PEG-core MMCM are designed specifically for clinical safety in humans, while meeting the physicochemical and pharmacologic requirements of contrast agents intended for quantitative MRI characterization of blood vessels . This initial experimental study was conducted to investigate the applicability of PEG12,000-Gen4-(Gd-DOTA) 16 for monitoring of antiangiogenic therapy analogous to the established prototype albumin-(Gd-DTPA) 35 .
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Materials and Methods
Animal Model
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Contrast Media
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![Figure 1, Schematic chemical structure of the polyethylene glycol (PEG) core dendrimeric contrast agent PEG12,000-Gen4-(Gd-DOTA) 16 . This new class of macromolecular contrast medium consists of a linear PEG core and two peripheral lysine-dendrimer amplifiers, which are conjugated, with multiple highly stable Gd-DOTA chelates serving as signal enhancing groups in magnetic resonance imaging. PEG12,000-Gen4-(Gd-DOTA) 16 , being extremely hydrophilic and bulky, creates a water shield around the polymer, making the effective size (molecular weight [MW] = 194 kDa) much greater than indicated by the actual MW (27 kDa).](https://storage.googleapis.com/dl.dentistrykey.com/clinical/EvaluationofaNovelMacromolecularCascadePolymerContrastMediumforDynamicContrastEnhancedMRIMonitoringofAntiangiogenicBevacizumabTherapyinaHumanMelanomaModel/0_1s20S1076633213003401.jpg)
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PEG Core MMCM Synthesis
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Dynamic MRI
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Data Analysis
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Results
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Table 1
Individual Values of K PS and fPV Quantified by DCE-MRI Enhanced With the Polymer MMCM PEG12,000-Gen4-(Gd-DOTA) 16 and the MMCM Prototype Albumin-(Gd-DTPA) 35 at Baseline and 24 Hours After a Single Intraperitoneal Injection of the Monoclonal Anti-VEGF Antibody Bevacizumab
PEG12,000-Gen4-(Gd-DOTA) 16 Therapy Control Baseline Follow-up Baseline Follow-up Tumor K PS (μL⋅min⋅100 cm 3 ) fPV (%) K PS (μL⋅min⋅100 cm 3 ) fPV (%) K PS (μL⋅min⋅100 cm 3 ) fPV (%) K PS (μL⋅min⋅100 cm 3 ) fPV (%) 1 30 1.8 8 2.7 29 4.5 32 3.5 2 44 4.3 0 2.8 118 6.4 19 3.3 3 36 3.0 14 5.9 35 5.4 15 4.1 4 17 2.2 17 3.6 21 2.5 33 5.8 5 38 2.2 0 2.7 31 3.9 45 2.9 6 22 2.2 15 5.0 31 5.1 47 4.4 7 19 6.1 18 2.4 26 3.4 53 5.7 Mean ± SD 29.5 ± 10.4 3.1 ± 1.6 10.4 ± 7.8 ∗ 3.6 ± 1.4 41 ± 34 4.5 ± 1.3 35 ± 14 4.2 ± 1.1
Albumin-(Gd-DTPA) Therapy Control Baseline Follow-up Baseline Follow-up Tumor K PS (μL⋅min⋅100 cm 3 ) fPV (%) K PS (μL⋅min⋅100 cm 3 ) fPV (%) K PS (μL⋅min⋅100 cm 3 ) fPV (%) K PS (μL⋅min⋅100 cm 3 ) fPV (%) 1 11 3.3 0 2.8 16 2.6 7 2.7 2 45 5.2 0 2.6 34 4.1 10 2.4 3 16 2.8 0 3.3 27 3.3 15 4.3 4 45 6.2 0 6.5 37 3.7 12 1.8 5 35 4.6 0 8.4 38 3.5 19 3.0 6 38 5.6 0 3.7 13 1.9 11 1.1 Mean ± SD 32 ± 15 4.6 ± 1.3 0 ∗ 4.5 ± 2.3 28 ± 11 3.2 ± 0.8 12 ± 4 2.5 ± 1
DCE, dynamic contrast-enhanced; fPV, tumor vascularity; K PS , tumor endothelial permeability; MMCM, macromolecular contrast medium; MRI, magnetic resonance imaging; PEG, poly ethylene; SD, standard deviation; VEGF, vascular endothelial growth factor.
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Table 2
Theoretical and Measured Effective MW, T1 Relaxivities, and Blood Half-Lives for PEG12,000-Gen4-(Gd-DOTA) and Albumin-(Gd-DTPA) 35
Contrast Agent Theoretical MW (kDa) Effective MW (kDa) T1 Relaxivity per Gd Ion (mM −1 •s −1 ) Blood Half-Life Mean ± SD (Minutes) PEG12,000-Gen4-(Gd-DOTA) 16 27 194 9.9 49 ± 6 Albumin-(Gd-DTPA) 35 92 180 10.4 54 ± 11
MW, molecular weight; PEG, polyethylene glycol; SD, standard deviation.
Effective molecular weights were determined by comparison to protein standards on size exclusion chromatography. T1 relaxivities were measured at 10 MHz and 37°C.
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DCE-MRI Enhanced With PEG12,000-Gen4-(Gd-DOTA) 16
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DCE-MRI Enhanced With Albumin-(Gd-DTPA) 35
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Discussion
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Acknowledgment
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