Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria

Redox cycling of iron powers various enzyme functions crucial for life, making the study of iron acquisition, storage, and disposition in the whole organism a worthy topic of inquiry. However, despite its important role in biology and disease, imaging iron in animals with oxidation-state specificity remains an outstanding problem in biology and medicine. Here we report a first-generation reactivity-based probe of labile ferrous iron suitable for positron emission tomography studies in live animals. The responses of this reagent to systemic changes in labile iron disposition were revealed using iron supplementation and sequestration treatments in mice, while the potential of this approach for in vivo imaging of cancer was demonstrated using genetically and pathologically diverse mouse models, including spontaneous tumors arising in a genetically engineered model of prostate cancer driven by loss of PTEN.

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“…Uptake in the brain was very low, consistent with previous observations that other TRX conjugates do not cross the blood–brain barrier. 31…”

Section: Resultsmentioning

confidence: 99%

Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography

et al. 2019

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“…Our design of ICL-1 involved caging D-luciferin with a 1,2,4-trioxolane scaffold (51) used previously for in vivo delivery of therapeutic payloads in an Fe 2+ -dependent manner (50,54). The excellent pharmacokinetic properties of these therapeutic conjugates suggested that ICL-1 would have suitable in vivo properties for the desired imaging applications.…”

Section: Resultsmentioning

confidence: 99%

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

Aron

Heffern

Lonergan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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120

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Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release D-aminoluciferin for selective reactivity-based detection of Fe 2+ with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe 2+ levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.labile iron | molecular imaging | luciferin | metal homeostasis | infectious disease I ron is an essential mineral for nearly every form of life, owing in large part to its ability to cycle between different oxidation states for processes such as nucleotide synthesis, oxygen transport, and respiration (1, 2). At the same time, the potent redox activity of iron is potentially toxic, particularly in unregulated labile forms that can trigger aberrant production of reactive oxygen species via Fenton chemistry (3). Indeed, iron deficiency remains one of the most common nutritional deficiencies in the world (4), and aberrant iron levels have been linked to various ailments, including cancer (5-7), cardiovascular (8), and neurodegenerative (9) disorders, as well as aging (10). The situation is especially complex in infectious diseases, where the requirement for iron by both host organism and invading pathogen leads to an intricate chemical tug-of-war for this metal nutrient during various stages of the immune response (11,12).The foregoing examples provide motivation for developing technologies to monitor biological iron status, with particular interest in methods to achieve in vivo iron imaging in live animal models that go beyond current state-of-the-art assays that are limited primarily to cell culture specimens. In this regard, detection of iron with both metal and oxidation state specificity is of central importance, because while iron is stored primarily in the ferric oxidation state, a ferrous iron pool loosely bound to cellular ligands, defined as the labile iron pool (LIP), exists at the center of highly regulated networks that control iron acquisition, trafficking, and excretion. Indeed, as a weak binder on the Irving-Williams stability series (13), Fe 2+ provides a challenge for d...

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“…In previous studies, we demonstrated the utility of the TRX scaffold by efficiently and selectively delivering antimalarial payloads to ferrous iron/heme rich compartments of the malaria parasite, both in vitro 30,31 and in vivo. 32,33 …”

Section: Introductionmentioning

confidence: 99%

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

et al. 2016

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Here we describe a new approach for tumor targeting in which augmented concentrations of Fe(II) in cancer cells and/or the tumor microenvironment triggers drug release from an Fe(II)-reactive prodrug conjugate. The 1,2,4-trioxolane scaffold developed to enable this approach can in principle be applied to a broad range of cancer therapeutics and is illustrated here with Fe(II)-targeted forms of a microtubule toxin and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic reactivity/toxicity of the duocarmycin analog is masked in the conjugated form and this greatly reduced toxicity in mice. This in turn permitted elevated dosing levels, leading to higher systemic exposure and a significantly improved response in tumor xenograft models. Overall our results suggest that Fe(II)-dependent drug delivery via trioxolane conjugates could have significant utility in expanding the therapeutic index of a range of clinical and preclinical stage cancer chemotherapeutics.

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Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria

Cited by 14 publications

References 18 publications

Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography

Measuring Dynamic Changes in the Labile Iron Pool in Vivo with a Reactivity-Based Probe for Positron Emission Tomography

In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection

A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

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