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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).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.Mean K(PS) values, assessed with PEG12,000-Gen4-(Gd-DOTA)16, declined significantly (P. Materials and MethodsAthymic 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, μLmin100 cm 3) and the fractional plasma volume (fPV,%), using a two-compartment kinetic model. ResultsMean K PS values, assessed with PEG12,000-Gen4-(Gd-DOTA) 16, declined significantly ( P. 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.

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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.Bevacizumab is a humanized monoclonal antibody directed against VEGF-A, a potent signaling molecule produced by many types of cancer cells. VEGF promotes angiogenesis known to result in new tumor vessel formation necessary for both exponential growth and metastasis.

Development

Bevacizumab was the first governmentally approved and commercially available angiogenesis inhibitor in the United States and it remains in approved clinical use for treatment of colon, lung, kidney, and brain cancers. The Food and Drug Administration decision to revoke bevacizumab approval in breast cancer patients in November 2011 was mainly based on the circumstance that patients risk potentially life-threatening side effects without definite proof that bevacizumab will provide a benefit, such as delay tumor growth, that would justify those risks. This underscores the need in health care to identify clinically feasible, quantitative, cost-effective, and reliable methods to characterize tumor on an individual patient basis.

An imaging-based technique capable of monitoring angiogenesis inhibition on an individual patient basis could find widespread application in the management of patients with breast cancer or other neoplastic diseases. The technique ideally should indicate efficacy of therapy both quickly and, in the case of drugs, after only a single test administration.We therefore hypothesized that DCE-MRI enhanced with the novel PEG-core MMCM is able to assess the early antiangiogenic effects of bevacizumab on experimental melanoma xenografts 24 hours after a single dose, compared to an established, animal-only prototype MMCM, albumin-(Gd-DTPA)35. The purpose of our study was to investigate if significant changes in tumor endothelial permeability or tumor vascularity induced by bevacizumab can be assessed with PEG12,000-Gen4-(Gd-DOTA) 16 and compare the results to albumin-(Gd-DTPA) 35 for validation purposes. Animal ModelExperiments were conducted in accordance with guidelines for the care and use of laboratory animals as described by the National Institutes of Health and were approved by the institutional animal care committee.

A total of 26 athymic rats (Hsd: RH-Foxn1 rnu, Harlan, Indianapolis, Indiana) were implanted with subcutaneous melanoma xenografts (MDA-MB-435) over the right abdominal flank, randomized to the therapy ( n = 13) or the control group ( n = 13), and imaged by DCE-MRI at 2.0 T. In the treatment and control group, seven subjects were investigated by PEG12,000-Gen4-(Gd-DOTA) 16-enhanced MRI; in six subjects, MRI was enhanced with albumin-(Gd-DTPA) 35.

All rats were imaged twice, at baseline and 24 hours after a single intraperitoneal dose of bevacizumab (1 mg) or a volume-equivalent injection of saline. DCE-MRI enhancement data were analyzed using a two-compartment kinetic model, described in detail elsewhere , to generate quantitative estimates of the endothelial-surface permeability constant (K PS) ( μLmin100 cm 3) as a parameter of vascular permeability, and the fractional plasma volume (fPV,%) as a parameter of tumor vascularity.

Contrast MediaSeven bevacizumab-treated and seven control subjects received the PEG-cascade polymer PEG12,000-Gen4-(Gd-DOTA) 16 with an effective molecular weight of 194 kDa and a T1-relaxivity (mM −1s−1) of 9.9 (at 10 MHz and 37°C) (–,) by standardized fast manual bolus injection via a tail vein catheter at a dose of 0.04 mmol Gd/kg body weight. The remaining 12 subjects were imaged using the prototype MMCM albumin-(Gd-DTPA) 35, synthesized in our laboratory following the methods of Ogan et al. This prototype MMCM has an effective molecular weight of a 180 kDa, a T1-relaxivity of 11 mM −1s −1/Gd ion and 385 mM −1s −1/Gd albumin core, was administered at a dose of 0.03 mmol Gd/kg body weight. Blood half-lives for PEG12,000-Gen4-(Gd-DOTA) 16 and for albumin-(Gd-DTPA) 35 were was 49 ± 6 minutes and 54 ± 11 minutes, respectively. 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). PEG Core MMCM SynthesisPEG diols (the form of PEG with two hydroxyl terminal groups) having near-uniform size (polydispersity index 99.9%) and formulated as a 20 mM Gd solution and sterile-filtered twice. Dynamic MRIFor both contrast media, MRI was performed using an Omega CSI-II system operating at 2.0 Tesla (Bruker Instruments, Fremont, California). The system is equipped with Acustar S-150 self-shielded gradient coils. Rats were placed within a custom-built, birdcage radiofrequency coil (length 7.6 cm, inner diameter 4.5 cm) in the supine position.

A series of nine precontrast T1-weighted inversion recovery centric-ordered fast gradient-recalled echo images (repetition time/echo time = 6.0/1.5 milliseconds, NA = 1, flip angle α = 10°, matrix 64 × 64 field of view 50 × 50 mm, slice thickness = 3 mm), with TI varying between 100 and 2500 milliseconds, were obtained to calculate baseline relaxation rates (R1) for tumor in each animal by curve fitting. Because the inversion recovery snapshot fast low-angle shot method is inadequate for measuring the R1 of flowing blood, the baseline R1 in the inferior vena cava was taken to be 0.752 seconds −1, which is the mean blood R1 in rats at 37° C and 2 Tesla measured in more than 200 previous specimens.

Dynamic MRI was performed using a T1-weighted three-dimensional spoiled gradient refocused sequence acquiring two precontrast and 28 postcontrast images with high spatial resolution and repetition time = 50 ms, echo time = 3 ms, NA = 1, flip angle ( α) = 90°, matrix = 128 × 128 × 16, field of view = 50 × 50 × 48 mm, slice thickness = 3 mm, acquisition time 1 minute, 42 seconds, per image. Data AnalysisA Sun Sparc 10 workstation (Sun Microsystems, Mountain View, California) with MR Vision Software (MR Vision Co., Winchester, Massachusetts) was used to process and analyze the acquired image data. Regions of interest signal intensity measurements were acquired over the blood in the inferior vena cava and the tumor periphery at each time point. The tumor periphery was defined as the outer 2-mm rim of the whole tumor, shown in previous studies to be a sensitive tumor zone in which to evaluate the effects of angiogenesis inhibitors on vital tumor tissue.

Post-contrast R1 values were calculated based on the measured signal intensities and the calculated values of precontrast R1 based on the inversion recovery data. Differences between the precontrast and post-contrast R1 values (ΔR1) in blood as well as in tumor tissue were assumed to be directly proportional to the concentration of gadolinium in the tissue. Estimates of the K PS ( μLmin100 cm 3) and the fPV (%) were calculated based on kinetic analysis of the ΔR1 data. Briefly, a monoexponential function was used to fit the blood ΔR1 data, serving as a forcing function for the two-compartment, unidirectional kinetic model used to fit the tumor ΔR1 data. Both blood and tissue models were fit to the data concurrently using the SAAM II software (SAAM Institute, Seattle, Washington), which employs a weighted, nonlinear least-squares estimation algorithm. Measurement errors in the ΔR1 data were assumed to be independent and Gaussian, with zero mean and fractional standard deviation (SD) known within a scale factor determined from the data.

Weights were optimally chosen (ie, equal to the inverse of the variance of the measurement error). The precision of the parameter value estimates was determined from the covariance matrix at the least-squares fit. For statistical analysis, comparison of MMCM-based estimates for K PS and fPV was performed using one-way analysis of variance. Statistical significance was defined as P. ResultsContrast agents were well tolerated in all animals without adverse effects noted during the course of the experiment.

Mean tumor volume at baseline in the therapy group was 826 ± 35 mm 3, in the control group 797 ± 26 mm 3, measured in three dimensions by caliper, with no significant effects on tumor size within the short 24-hour course of the experiment. Individual values for MRI-estimated parameters of tumor microcirculation are presented in. Theoretical and measured effective molecular weights (MW), T1 relaxivities, and blood half-lives for PEG12,000-Gen4-(Gd-DOTA) and albumin-(Gd-DTPA) 35 are presented in. Line graphs depict the development of individual values for polyethylene glycol 12,000-Gen4-(Gd-DOTA) 16 for tumor endothelial permeability and tumor vascularity from baseline to follow-up (24 hours) in the therapy and the control groups. Note the decline of endothelial-surface permeability constant (K PS) after a single intraperitoneal dose of 1 mg bevacizumab in the therapy group as well as the omnidirectional development of K PS in the control group.

No significant effects on tumor vascularity were noted in the therapy or in the control groups. DCE-MRI Enhanced With PEG12,000-Gen4-(Gd-DOTA) 16In the bevacizumab-treated therapy group imaged with PEG12,000-Gen4-(Gd-DOTA) 16, the K PS declined significantly ( P.05, saline group: 4.5 ± 13% vs. 4.2 ± 1.1%, P.05).

A representative set of PEG-enhanced DCE-MRI images is shown in. Representative set of T1-weighted spoiled gradient dynamic magnetic resonance images enhanced with the candidate polymer macromolecular contrast medium polyethylene glycol 12,000-Gen4-(Gd-DOTA) 16 precontrast and 2, 5, 10, 15, 20, 25, 30, 40, 50, and 60 minutes after injection. Note the enhancement of the human cancer xenograft over the left lateral flank ( arrowhead), most prominent in the tumor periphery, as well as the strong and time persistent enhancement of the inferior vena cava ( arrow) as it passes through the rat liver. DCE-MRI Enhanced With Albumin-(Gd-DTPA) 35DCE-MRI in bevacizumab-treated tumors enhanced with albumin-(Gd-DTPA) 35 revealed a significant reduction( P.05). A representative set of DCE-MRI images enhanced with albumin-(Gd-DTPA) 35 is shown in. Representative set of T1-weighted spoiled gradient dynamic magnetic resonance images enhanced with the prototype macromolecular contrast medium albumin-(Gd-DTPA) 35 precontrast and 2, 5, 10, 15, 20, 25, 30, 40, 50, and 60 minutes after injection. Note the enhancement of the human cancer xenograft over the left lateral flank ( arrowhead), most prominent in the tumor periphery, as well as the strong and time persistent enhancement of the inferior vena cava ( arrow) as it passes through the rat liver.

DiscussionWith increasing clinical application of novel molecular cancer therapies, such as inhibitors of angiogenesis, functional and molecular imaging modalities are increasingly complementing established morphological imaging. These techniques, such as RECIST 1.1, have been shown to be not sufficiently sensitive for timely monitoring of therapy.

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However, the use of DCE-MRI does allow for the noninvasive investigation of functional parameters of tissue microcirculation that may be applicable as imaging biomarkers of therapy response to anti-angiogenic therapies. Additionally, novel developments in molecular imaging including nanosized contrast agents and theranostic agents increasingly allow for the characterization of the tumor microenvironment on a cellular level with options for dedicated drug delivery (–).

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