Synthesis and Preclinical Evaluation of Radioiodinated Hypericin Dicarboxylic Acid as a Necrosis Avid Agent in Rat Models of Induced Hepatic, Muscular, and Myocardial Necroses
Abstract:ABSTRACT:Myocardial infarction (MI) leads to substantial morbidity and mortality around the world.Accurate assessment of myocardial viability is essential to assist therapies and improve patient outcomes. 131 I-hypericin dicarboxylic acid ( 131 I-HDA) was synthesized and evaluated as a potential diagnostic agent for earlier assessment of myocardium viability compared to its preceding counterpart 131 I-hypericin ( 131 I-Hyp) with strong hydrophobic property, long plasma half-life and high uptake in mononuclear … Show more
“…. Considering that HDA and Hyp have the same target of necrotic tissues 67 , we conclude that the necrosis avidity mechanism of HDA may also be due to the intercalation with exposed DNA. Figure 2 (A) Coronal and transversal SPECT/CT images obtained at 4 h post injection of 131 I-Shyp or 131 I-Hyp in rats with reperfused myocardium infarction (MI) or sham operation.…”
Section: Molecular Imaging and Therapeutic Strategies Targeting Necromentioning
confidence: 82%
“…of 131 I-Shyp by SPECT/CT imaging in rat models with MI ( Fig. 2 ), both earlier than that of iodine-131 labeled Hyp ( 131 I-Hyp) 67. , 68.…”
Section: Molecular Imaging and Therapeutic Strategies Targeting Necromentioning
confidence: 85%
“…Moreover, we synthesized and separated two median dianthranone compounds by further reducing the size of π -conjugated core and studied the effects of molecular skeleton structure on necrosis targeting of radioiodinated dianthrones 178 . The results demonstrated that the destruction of rigid skeleton structure dramatically reduced the necrosis targeting ability of iodine-131 labeled dianthrones and the skeleton structure of Hyp was a lead structure for further optimization of dianthrones 178 , which led to the further studies of 131 I-HDA and 131 I-Shyp as described above 67. , 68.…”
Section: Molecular Imaging and Therapeutic Strategies Targeting Necromentioning
confidence: 85%
“…This suggested that introduction of hydrophilic groups into a probe entity was a feasible strategy to improve its pharmacokinetic and biodistribution characteristics. The in vitro DNA binding studies and in vivo blocking experiments suggested that the necrosis avidity mechanism of Shyp and Hyp might be attributable to the intercalation with exposed DNA 67. , 68.…”
Section: Molecular Imaging and Therapeutic Strategies Targeting Necromentioning
Cell death plays important roles in living organisms and is a hallmark of numerous disorders such as cardiovascular diseases, sepsis and acute pancreatitis. Moreover, cell death also plays a pivotal role in the treatment of certain diseases, for example, cancer. Noninvasive visualization of cell death contributes to gained insight into diseases, development of individualized treatment plans, evaluation of treatment responses, and prediction of patient prognosis. On the other hand, cell death can also be targeted for the treatment of diseases. Although there are many ways for a cell to die, only apoptosis and necrosis have been extensively studied in terms of cell death related theranostics. This review mainly focuses on molecular imaging and therapeutic strategies directed against necrosis. Necrosis shares common morphological characteristics including the rupture of cell membrane integrity and release of cellular contents, which provide potential biomarkers for visualization of necrosis and necrosis targeted therapy. In the present review, we summarize the updated joint efforts to develop molecular imaging probes and therapeutic strategies targeting the biomarkers exposed by necrotic cells. Moreover, we also discuss the challenges in developing necrosis imaging probes and propose several biomarkers of necrosis that deserve to be explored in future imaging and therapy research.
“…. Considering that HDA and Hyp have the same target of necrotic tissues 67 , we conclude that the necrosis avidity mechanism of HDA may also be due to the intercalation with exposed DNA. Figure 2 (A) Coronal and transversal SPECT/CT images obtained at 4 h post injection of 131 I-Shyp or 131 I-Hyp in rats with reperfused myocardium infarction (MI) or sham operation.…”
Section: Molecular Imaging and Therapeutic Strategies Targeting Necromentioning
confidence: 82%
“…of 131 I-Shyp by SPECT/CT imaging in rat models with MI ( Fig. 2 ), both earlier than that of iodine-131 labeled Hyp ( 131 I-Hyp) 67. , 68.…”
Section: Molecular Imaging and Therapeutic Strategies Targeting Necromentioning
confidence: 85%
“…Moreover, we synthesized and separated two median dianthranone compounds by further reducing the size of π -conjugated core and studied the effects of molecular skeleton structure on necrosis targeting of radioiodinated dianthrones 178 . The results demonstrated that the destruction of rigid skeleton structure dramatically reduced the necrosis targeting ability of iodine-131 labeled dianthrones and the skeleton structure of Hyp was a lead structure for further optimization of dianthrones 178 , which led to the further studies of 131 I-HDA and 131 I-Shyp as described above 67. , 68.…”
Section: Molecular Imaging and Therapeutic Strategies Targeting Necromentioning
confidence: 85%
“…This suggested that introduction of hydrophilic groups into a probe entity was a feasible strategy to improve its pharmacokinetic and biodistribution characteristics. The in vitro DNA binding studies and in vivo blocking experiments suggested that the necrosis avidity mechanism of Shyp and Hyp might be attributable to the intercalation with exposed DNA 67. , 68.…”
Section: Molecular Imaging and Therapeutic Strategies Targeting Necromentioning
Cell death plays important roles in living organisms and is a hallmark of numerous disorders such as cardiovascular diseases, sepsis and acute pancreatitis. Moreover, cell death also plays a pivotal role in the treatment of certain diseases, for example, cancer. Noninvasive visualization of cell death contributes to gained insight into diseases, development of individualized treatment plans, evaluation of treatment responses, and prediction of patient prognosis. On the other hand, cell death can also be targeted for the treatment of diseases. Although there are many ways for a cell to die, only apoptosis and necrosis have been extensively studied in terms of cell death related theranostics. This review mainly focuses on molecular imaging and therapeutic strategies directed against necrosis. Necrosis shares common morphological characteristics including the rupture of cell membrane integrity and release of cellular contents, which provide potential biomarkers for visualization of necrosis and necrosis targeted therapy. In the present review, we summarize the updated joint efforts to develop molecular imaging probes and therapeutic strategies targeting the biomarkers exposed by necrotic cells. Moreover, we also discuss the challenges in developing necrosis imaging probes and propose several biomarkers of necrosis that deserve to be explored in future imaging and therapy research.
Successful treatment of cancer patients requires balancing of the dose, timing, and type of therapeutic regimen. Detection of increased cell death may serve as a predictor of the eventual therapeutic success. Imaging of cell death may thus lead to early identification of treatment responders and nonresponders, and to “patient‐tailored therapy.” Cell death in organs and tissues of the human body can be visualized, using positron emission tomography or single‐photon emission computed tomography, although unsolved problems remain concerning target selection, tracer pharmacokinetics, target‐to‐nontarget ratio, and spatial and temporal resolution of the scans. Phosphatidylserine exposure by dying cells has been the most extensively studied imaging target. However, visualization of this process with radiolabeled Annexin A5 has not become routine in the clinical setting. Classification of death modes is no longer based only on cell morphology but also on biochemistry, and apoptosis is no longer found to be the preponderant mechanism of cell death after antitumor therapy, as was earlier believed. These conceptual changes have affected radiochemical efforts. Novel probes targeting changes in membrane permeability, cytoplasmic pH, mitochondrial membrane potential, or caspase activation have recently been explored. In this review, we discuss molecular changes in tumors which can be targeted to visualize cell death and we propose promising biomarkers for future exploration.
Stimulating photosensitizers (PS) by Cerenkov radiation (CR) can overcome the light penetration limitation in traditional photodynamic therapy. However, separate injection of radiopharmaceuticals and PS cannot guarantee their efficient interaction in tumor areas, while co‐delivery of radionuclides and PS face the problem of nonnegligible phototoxicity in normal tissues. Here, we describe a 131I‐labeled smart photosensitizer, composed of pyropheophorbide‐a (photosensitizer), a diisopropylamino group (pH‐sensitive group), an 131I‐labeled tyrosine group (CR donor), and polyethylene glycol, which can self‐assemble into nanoparticles (131I‐sPS NPs). The 131I‐sPS NPs showed low phototoxicity in normal tissues due to aggregation‐caused quenching effect, but could self‐produce reactive oxygen species in tumor sites upon disassembly. Upon intravenous injection, 131I‐sPS NPs showed great tumor inhibition capability in subcutaneous 4T1‐tumor‐bearing Balb/c mice and orthotopic VX2 liver tumor bearing rabbits. We believed 131I‐sPS NPs could expand the application of CR and provide an effective strategy for deep tumor theranostics.
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