Magnetic resonance molecular imaging of extradomain B fibronectin enables detection of pancreatic ductal adenocarcinoma metastasis

Qiao, Peter; Gargesha, Mahdusudhana; Liu, Yiqiao; Laney, Victoria; Hall, Ryan; Vaidya, Amita; Gilmore, Hannah; Gawelek, Kara L.; Scott, Bryan; Roy, Debashish; Wilson, David L.; Lü, Zheng Rong

doi:10.1016/j.mri.2021.11.008

Cited by 14 publications

(12 citation statements)

References 40 publications

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“…As a result, MT218 produces robust T 1 contrast enhancement at substantially lower doses than the clinical GBCA throughout the EDB-FN-rich aggressive solid tumors for at least 30 minutes postinjection, which indicated a potential lower dose for clinical diagnostic MRI. The results are consistent with the previously reported results from different types of solid tumors 17,29–31,41 …”

Section: Discussionsupporting

confidence: 93%

“…The results are consistent with the previously reported results from different types of solid tumors. 17,[29][30][31]41 MT218 shows chelating stability at physiological pH and only minor dissociation was observed exclusively at acidic pH and the presence of chelating agents, results similar to those of gadoteridol. 6,43 The peptide in the contrast agent is susceptible to enzymatic degradation in the blood plasma.…”

Section: Discussionsupporting

confidence: 53%

“…In recent studies, it has been shown that MT218 is effective in producing robust contrast enhancement in both orthotopic and metastatic pancreatic cancer in mouse models at a dose of 0.1 mmol/kg. 30 , 41 Here, we assessed the dosing effect of MT218 for MRMI of pancreatic cancer in immune competent mice bearing subcutaneous KPC murine tumors of different sizes or stages. Once primary tumors reached about 100 mm 3 (~1 week), MRMI was performed before and after IV injection of MT218 at a dose of 0.1 or 0.04 mmol/kg.…”

Section: Resultsmentioning

confidence: 99%

“…The results are consistent with the previously reported results from different types of solid tumors. 17 , 29 – 31 , 41 …”

Section: Discussionmentioning

confidence: 99%

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Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218

Gao

Jiang

et al. 2022

Invest Radiol

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Objectives Preclinical assessments were performed according to the US Food and Drug Administration guidelines to determine the physicochemical properties, pharmacokinetics, clearance, safety, and tumor-specific magnetic resonance (MR) imaging of MT218, a peptidic gadolinium-based MR imaging agent targeting to extradomain B fibronectin for MR molecular imaging of aggressive tumors. Materials and Methods Relaxivity, chelation stability, binding affinity, safety-related target profiling, and effects on CYP450 enzymes and transporters were evaluated in vitro. Magnetic resonance imaging was performed with rats bearing prostate cancer xenografts, immunocompetent mice bearing murine pancreatic cancer allografts, and mice bearing lung cancer xenografts at different doses of MT218. Pharmacological effects on cardiovascular, respiratory, and central nervous systems were determined in rats and conscious beagle dogs. Pharmacokinetics were tested in rats and dogs. Biodistribution and excretion were studied in rats. Single and repeated dosing toxicity was evaluated in rats and dogs. In vitro and in vivo genotoxicity, in vitro hemolysis, and anaphylactic reactivity were also performed. Results At 1.4 T, the r 1 and r 2 relaxivities of MT218 were 5.43 and 7.40 mM −1 s −1 in pure water, 6.58 and 8.87 mM −1 s −1 in phosphate-buffered saline, and 6.54 and 8.70 mM −1 s −1 in aqueous solution of human serum albumin, respectively. The binding affinity of MT218 to extradomain B fragment is 3.45 μM. MT218 exhibited no dissociation of the Gd(III) chelates under physiological conditions. The peptide degradation half-life ( t 1/2 ) of MT218 was 1.63, 5.85, and 2.63 hours in rat, dog, and human plasma, respectively. It had little effect on CYP450 enzymes and transporters. MT218 produced up to 7-fold increase of contrast-to-noise ratios in the extradomain B fibronectin–rich tumors with a dose of 0.04 mmol/kg for at least 30 minutes. MT218 had little pharmacological effect on central nervous, cardiovascular, or respiratory systems. MT218 had a mean plasma elimination half-life ( t 1/2 ) of 0.31 and 0.89 hours in rats and dogs at 0.1 mmol/kg, respectively. No detectable Gd deposition was observed in the brain at 6 hours postinjection of MT218 at 0.1 mmol/kg in rats. MT218 was not mutagenic and had no mortality or morbidity in the rats or dogs up to 1.39 and 0.70 mmol/kg/d, respectively. The no observed adverse effect level of MT218 in Sprague-Dawley rats was 1.39 mmol/kg for single dosing and 0.46 mmol/kg/d for repeated dosing. The no observed adverse effect level in dogs was 0.07 mmol/kg/d. MT218 exhibited no genotoxicity, hemolysis, and anaphylacti...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 53%

Section: Resultsmentioning

confidence: 99%

“…The results are consistent with the previously reported results from different types of solid tumors. 17 , 29 – 31 , 41 …”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218

Gao

Jiang

et al. 2022

Invest Radiol

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“…Life 2022, 12, 327 2 of 16 Recently, advances have been made to detect metastatic pancreatic ductal adenocarcinoma (PDAC) using molecular magnetic resonance imaging (MMRI) [14]. Additionally, advances have been made in liquid biopsy [15] and in finding specific biomolecular or subcellular targets [16][17][18][19], new therapeutic agents [20], and nanomedicine applications [21][22][23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

A Review on the Efficacy and Safety of Nab-Paclitaxel with Gemcitabine in Combination with Other Therapeutic Agents as New Treatment Strategies in Pancreatic Cancer

González

López

Lomelí

et al. 2022

Life

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Pancreatic cancer has one of the highest mortality rates among cancers, and a combination of nab-paclitaxel with gemcitabine remains the cornerstone of first-line therapy. However, major advances are required to achieve improvements in patient outcomes. For this reason, several research groups have proposed supplementing treatment with other therapeutic agents. Ongoing studies are being conducted to find the optimal treatment in a first-line setting. In this work, we used a search strategy to compare studies on the efficacy and safety of nab-paclitaxel with gemcitabine in combination with other therapeutic agents based on the criteria of the Preferred Reporting Items for Systematic Reviews. We found seven studies in different clinical phases that met the inclusion criteria. The seven therapeutic agents were ibrutinib, necuparanib, tarextumab, apatorsen, cisplatin, enzalutamide, and momelotinib. Although these therapeutic agents have different mechanisms of action, and molecular biology studies are still needed, the present review was aimed to answer the following question: which formulations of the nab-paclitaxel/gemcitabine regimen in combination with other therapeutic agents are safest for patients with previously untreated metastatic pancreas ductal adenocarcinoma? The triple regimen is emerging as the first-line option for patients with pancreatic cancer, albeit with some limitations. Thus, further studies of this regimen are recommended.

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Extracellular Matrix Targeted MRI Probes

et al. 2022

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Dysregulated remodeling of the extracellular matrix (ECM) can lead to excessive accumulation of ECM proteins (primarily collagen, elastin/ tropoelastin, fibronectin and fibrin) resulting in tissue fibrosis. In many pathologies, changes in the molecular pattern of ECM components have been related to the progression and severity of fibrosis. Thus, magnetic resonance imaging (MRI) probes sensing specific ECM components hold promise for accurate staging of fibrotic diseases. This paper focuses on gadolinium-based contrast agents (GBCA) targeted to ECM components, including structural proteins and enzymes. According to available examples, they can be grouped into: 1) GBCA conjugated to targeting vectors that recognize and noncovalently bind to specific sites on the molecular target; 2) GBCA carrying a reactive chemical function able to bind covalently to the complementary chemical function of the molecular target; and 3) enzyme-responsive probes, whose relaxivity and pharmacokinetics change after enzymatic processing. Pros and cons of each approach are discussed.

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Magnetic resonance molecular imaging of extradomain B fibronectin enables detection of pancreatic ductal adenocarcinoma metastasis

Cited by 14 publications

References 40 publications

Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218

Evaluation of Physicochemical Properties, Pharmacokinetics, Biodistribution, Toxicity, and Contrast-Enhanced Cancer MRI of a Cancer-Targeting Contrast Agent, MT218

A Review on the Efficacy and Safety of Nab-Paclitaxel with Gemcitabine in Combination with Other Therapeutic Agents as New Treatment Strategies in Pancreatic Cancer

Extracellular Matrix Targeted MRI Probes

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