A Janus Chelator Enables Biochemically Responsive MRI Contrast with Exceptional Dynamic Range

Gale, Eric M.; Jones, Chloe; Ramsay, Ian; Farrar, Christian T.; Caravan, Peter

doi:10.1021/jacs.6b10898

Cited by 63 publications

(60 citation statements)

References 40 publications

(76 reference statements)

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“…Since the calibration curves only contained diluted Mn 2+ ions and the calculated Mn concentration from MRI and ICP-OES were similar at pH 6.5 and 5 (S3 Table), it is likely that Mn 3+ ions minimally contributed to the MRI signal and Mn 2+ ions were the dominant species responsible for the MRI signal increase. According to Gale et al [43], chelated Mn 2+ has a 6.6 fold higher r 1 relaxivity compared to chelated Mn 3+ at 1.4 T, which supports that our main MRI signal likely originates from Mn 2+ .…”

Section: Plos Onesupporting

confidence: 88%

Tuning the size and composition of manganese oxide nanoparticles through varying temperature ramp and aging time

et al. 2020

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Manganese oxide (MnO) nanoparticles (NPs) can serve as robust pH-sensitive contrast agents for magnetic resonance imaging (MRI) due to Mn 2+ release at low pH, which generates a~30 fold change in T 1 relaxivity. Strategies to control NP size, composition, and Mn 2+ dissolution rates are essential to improve diagnostic performance of pH-responsive MnO NPs. We are the first to demonstrate that MnO NP size and composition can be tuned by the temperature ramping rate and aging time used during thermal decomposition of manganese (II) acetylacetonate. Two different temperature ramping rates (10˚C/min and 20˚C/min) were applied to reach 300˚C and NPs were aged at that temperature for 5, 15, or 30 min. A faster ramping rate and shorter aging time produced the smallest NPs of~23 nm. Shorter aging times created a mixture of MnO and Mn 3 O 4 NPs, whereas longer aging times formed MnO. Our results indicate that a 20˚C/min ramp rate with an aging time of 30 min was the ideal temperature condition to form the smallest pure MnO NPs of~32 nm. However, Mn 2+ dissolution rates at low pH were unaffected by synthesis conditions. Although Mn 2+ production was high at pH 5 mimicking endosomes inside cells, minimal Mn 2+ was released at pH 6.5 and 7.4, which mimic the tumor extracellular space and blood, respectively. To further elucidate the effects of NP composition and size on Mn 2+ release and MRI contrast, the ideal MnO NP formulation (~32 nm) was compared with smaller MnO and Mn 3 O 4 NPs. Small MnO NPs produced the highest amount of Mn 2+ at acidic pH with maximum T 1 MRI signal; Mn 3 O 4 NPs generated the lowest MRI signal. MnO NPs encapsulated within poly (lactide-co-glycolide) (PLGA) retained significantly higher Mn 2+ release and MRI signal compared to PLGA Mn 3 O 4 NPs. Therefore, MnO instead of Mn 3 O 4 should be targeted intracellularly to maximize MRI contrast.

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Section: Plos Onesupporting

confidence: 88%

Tuning the size and composition of manganese oxide nanoparticles through varying temperature ramp and aging time

et al. 2020

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“…To compensate, the semi-quantitative parameter IAUGC 30 was alternatively applied as a sensitive detector for changes of tumor blood flow [25,26]. In the study using hepatobiliary CA [27], contrast enhancement of HCC tumors appeared fainter than that of earlier studies [33][34][35]51,52], which might result from the following reasons: 1) field-strength dependence of contrast enhancement [79] could lead to a marked decrease of R1 relaxivity of Mn-DPDP at a 3.0T magnet, compared with the previous CA studies conducted at a 1.0T or 1.5T magnet [33][34][35]51,52]; and 2) since Mn-DPDP (Teslascan ® ) was purchased and stocked in 2012 before being withdrawn from the market, oxidation of Mn2+ into Mn3+ under years of storage may weaken its relaxation property [80], hence reduced enhancement degree of HCCs on T1WI.…”

Section: Study Limitations and Practical Challengesmentioning

confidence: 81%

Predicting Clinical Efficacy of Vascular Disrupting Agents in Rodent Models of Primary and Secondary Liver Cancers: An Overview with Imaging-Histopathology Correlation

et al. 2020

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Vascular disrupting agents (VDAs) have entered clinical trials for over 15 years. As the leading VDA, combretastatin A4 phosphate (CA4P) has been evaluated in combination with chemotherapy and molecular targeting agents among patients with ovarian cancer, lung cancer and thyroid cancer, but still remains rarely explored in human liver cancers. To overcome tumor residues and regrowth after CA4P monotherapy, a novel dual targeting pan-anticancer theragnostic strategy, i.e., OncoCiDia, has been developed and shown promise previously in secondary liver tumor models. Animal model of primary liver cancer is time consuming to induce, but of value for more closely mimicking human liver cancers in terms of tumor angiogenesis, histopathological heterogeneity, cellular differentiation, tumor components, cancer progression and therapeutic response. Being increasingly adopted in VDA researches, multiparametric magnetic resonance imaging (MRI) provides imaging biomarkers to reflect in vivo tumor responses to drugs. In this article as a chapter of a doctoral thesis, we overview the construction and clinical relevance of primary and secondary liver cancer models in rodents. Target selection for CA4P therapy assisted by enhanced MRI using hepatobiliary contrast agents (CAs), and therapeutic efficacy evaluated by using MRI with a non-specific contrast agent, dynamic contrast enhanced (DCE) imaging, diffusion weighted imaging (DWI) are also described. We then summarize diverse responses among primary hepatocellular carcinomas (HCCs), secondary liver and pancreatic tumors to CA4P, which appeared to be related to tumor size, vascularity, and cellular differentiation. In general, imaging-histopathology correlation studies allow to conclude that CA4P tends to be more effective in secondary liver tumors and in more differentiated HCCs, but less effective in less differentiated HCCs and implanted pancreatic tumor. Notably, cirrhotic liver may be responsive to CA4P as well. All these could be instructive for future clinical trials of VDAs.

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“…In general, these CAs produce as ignificant signal already before the activation, and upon activation this signal is enhanced up to tenfold. As ar epresentative example, Gale et al [82] described a Janus ligand that, mediated by biologically relevant redox reactions, isomerizes between binding modes that favor either Mn 2 + or Mn 3 + .I nt his example, the longitudinal relaxivityo f the chelates varied from 0.5 mm À1 s À1 for Mn 3 + to 3.3mm À1 s À1 after activation to Mn 2 + (see Ta ble 1). Figure 5.…”

Section: Mri Performancementioning

confidence: 99%

Recent Progress on Manganese‐Based Nanostructures as Responsive MRI Contrast Agents

García‐Hevia

Bañobre‐López

Gallo

2018

Chemistry A European J

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Manganese-based nanostructured contrast agents (CAs) entered the field of medical diagnosis through magnetic resonance imaging (MRI) some years ago. Although some of these Mn-based CAs behave as classic T contrast enhancers in the same way as clinical Gd-based molecules do, a new type of Mn nanomaterials have been developed to improve MRI sensitivity and potentially gather new functional information from tissues by using traditional T contrast enhanced MRI. These nanomaterials have been designed to respond to biological environments, mainly to pH and redox potential variations. In many cases, the differences in signal generation in these responsive Mn-based nanostructures come from intrinsic changes in the magnetic properties of Mn cations depending on their oxidation state. In other cases, no changes in the nature of Mn take place, but rather the nanomaterial as a whole responds to the change in the environment through different mechanisms, including changes in integrity and hydration state. This review focusses on the chemistry and MR performance of these responsive Mn-based nanomaterials.

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A Janus Chelator Enables Biochemically Responsive MRI Contrast with Exceptional Dynamic Range

Cited by 63 publications

References 40 publications

Tuning the size and composition of manganese oxide nanoparticles through varying temperature ramp and aging time

Tuning the size and composition of manganese oxide nanoparticles through varying temperature ramp and aging time

Predicting Clinical Efficacy of Vascular Disrupting Agents in Rodent Models of Primary and Secondary Liver Cancers: An Overview with Imaging-Histopathology Correlation

Recent Progress on Manganese‐Based Nanostructures as Responsive MRI Contrast Agents

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