Qiaomei Jin

Discovery of radioiodinated monomeric anthraquinones as a novel class of necrosis avid agents for early imaging of necrotic myocardium

Assessment of myocardial viability is deemed necessary to aid in clinical decision making whether to recommend revascularization therapy for patients with myocardial infarction (MI). Dianthraquinones such as hypericin (Hyp) selectively accumulate in necrotic myocardium, but were unsuitable for early imaging after administration to assess myocardial viability. Since dianthraquinones can be composed by coupling two molecules of monomeric anthraquinone and the active center can be found by splitting chemical structure, we propose that monomeric anthraquinones may be effective functional groups for necrosis targetability. In this study, eight radioiodinated monomeric anthraquinones were evaluated as novel necrosis avid agents (NAAs) for imaging of necrotic myocardium. All 131I-anthraquinones showed high affinity to necrotic tissues and 131I-rhein emerged as the most promising compound. Infarcts were visualized on SPECT/CT images at 6 h after injection of 131I-rhein, which was earlier than that with 131I-Hyp. Moreover, 131I-rhein showed satisfactory heart-to-blood, heart-to-liver and heart-to-lung ratios for obtaining images of good diagnostic quality. 131I-rhein was a more promising “hot spot imaging” tracer for earlier visualization of necrotic myocardium than 131I-Hyp, which supported further development of radiopharmaceuticals based on rhein for SPECT/CT (123I and 99mTc) or PET/CT imaging (18F and 124I) of myocardial necrosis.

Synthesis and preclinical evaluation of radioiodinated hypericin dicarboxylic acid as a necrosis avid agent in rat models of induced hepatic, muscular and myocardial necroses

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 phagocyte system (MPS). Herein, HDA was synthesized and characterized, and self-aggregation constant Kα was analyzed by spectrophotometry. Plasma half-life was determined in healthy rats by γ-counting. (131)I-HDA and (131)I-Hyp were prepared with iodogen as oxidant. In vitro necrosis avidity of (131)I-HDA and (131)I-Hyp was evaluated in necrotic cells induced by hyperthermia. Biodistribution was determined in rat models of induced necrosis using γ-counting, autoradiography, and histopathology. Earlier imaging of necrotic myocardium to assess myocardial viability was performed in rat models of reperfused myocardium infarction using single photon emission computed tomography/computed tomography (SPECT/CT). As a result, the self-aggregation constant Kα of HDA was lower than that of Hyp (105602 vs 194644, p < 0.01). (131)I-HDA displayed a shorter blood half-life compared with (131)I-Hyp (9.21 vs 31.20 h, p < 0.01). The necrotic-viable ratio in cells was higher with (131)I-HDA relative to that with (131)I-Hyp (5.48 vs 4.63, p < 0.05). (131)I-HDA showed a higher necrotic-viable myocardium ratio (7.32 vs 3.20, p < 0.01), necrotic myocardium-blood ratio (3.34 vs 1.74, p < 0.05), and necrotic myocardium-lung ratio (3.09 vs 0.61, p < 0.01) compared with (131)I-Hyp. (131)I-HDA achieved imaging of necrotic myocardium at 6 h postinjection (p.i.) with SPECT/CT, earlier than what (131)I-Hyp did. Therefore, (131)I-HDA may serve as a promising necrosis-avid diagnostic agent for earlier imaging of necrotic myocardium compared with (131)I-Hyp. This may support further development of radiopharmaceuticals ((123)I and (99m)Tc) based on HDA for SPECT/CT of necrotic myocardium.

Combretastatin-A4 phosphate improves the distribution and antitumor efficacy of albumin-bound paclitaxel in W256 breast carcinoma model

Nanomedicine holds great promise for fighting against malignant tumors. However, tumor elevated interstitial fluid pressure (IFP) seriously hinders convective transvascular and interstitial transport of nanomedicines and thus damages its antitumor efficacy. In this study, combretastatin-A4 phosphate (CA4P) was utilized to reduce tumor IFP, and thereby to improve the intratumoral distribution and antitumor efficacy of nanoparticle albumin-bound paclitaxel (nab-paclitaxel). IFP was measured using the wick-in-needle method in tumors growing subcutaneously pretreatment and posttreatment with a single intravenous injection of CA4P. The tracing method of iodine 131 isotope was used for biodistribution analysis of nab-paclitaxel. Liquid chromatography coupled with tandem mass spectrometry was used to detect the intratumoral concentration of paclitaxel. Magnetic resonance imaging was applied to monitor tumor volume and ratios of necrosis. The tumor IFP continued to decline gradually over time following CA4P treatment, reaching approximately 31% of the pretreatment value by 1 h posttreatment. Biodistribution data indicated that both 131I-nab-paclitaxel and paclitaxel exhibited higher tumor uptake in CA4P + 131I-nab-paclitaxel group compared with I131-nab-paclitaxel group. Nab-paclitaxel combined with CA4Pshowed significant tumor growth inhibition and higher tumor necrosis ratio relative to PBS, CA4P and nab-paclitaxel group, respectively. In conclusion, CA4P improved the intratumoral distribution and antitumor efficacy of nab-paclitaxel in W256 tumor-bearing rats.

First Evaluation of Radioiodinated Flavonoids as Necrosis-Avid Agents and Application in Early Assessment of Tumor Necrosis

A rapid and accurate identification of necrotic tissues is of great importance to define disease severity, predict prognosis, and monitor responses to therapies. To seek necrosis-avid agents with clinically translational potential, we first evaluated the necrosis avidity of flavonoids in rodent models of muscular, myocardial, and tumoral necrosis. In this study, the necrosis avidity of eight radioiodinated 5,7-dihydroxyflavones was tested by ex vivo gamma counting, histochemical staining, and autoradiography in mouse models of ethanol-induced muscular necrosis. The necrosis avidity of a lead tracer, 131I-5, was further assessed in rat models of myocardial infarction and reperfusion. Therapy response was evaluated by 131I-5 single photon emission computed tomography/computed tomography imaging 24 h after combretastatin A-4 disodium phosphate (CA4P) therapy on rats bearing W256 breast carcinomas. The necrosis avidity mechanism for the tracers was studied by in vitro DNA binding experiments of 12 5,7-dihydroxyflavones and in vivo blocking experiments of 131I-5. In the results, all 131I-5,7-dihydroxyflavones showed intense uptake to necrotic muscles, and 131I-5 emerged as the most potential tracer among them. 131I-5 obtained a necrotic-viable myocardium ratio of 5.0 ± 0.9 in post-mortem biodistribution on reperfused myocardial infarction models and achieved necrosis imaging on CA4P-treated W256 tumors 4 h after tracer injection. DNA binding studies suggested that necrosis avidity was related to DNA binding to a certain extent. The uptake of 131I-5 in necrotic muscle was markedly blocked by excessive ethidium bromide and cold 5 with a 51.95% and 64.29% decline at 1 h after coinjection, respectively. In conclusion, flavonoids are necrosis-avid agents. Furthermore, 131I-5 can serve as a promising necrosis-avid diagnostic tracer for the rapid imaging of necrotic tissues, supporting the further molecular design of radiotracer based on 5.

Preclinical Evaluation of Radioiodinated Hoechst 33258 for Early Prediction of Tumor Response to Treatment of Vascular-Disrupting Agents

This study aimed to explore the use of 131I-Hoechst 33258 (131I-H33258) for early prediction of tumor response to vascular-disrupting agents (VDAs) with combretastatin-A4 phosphate (CA4P) as a representative. Necrosis avidity of 131I-H33258 was evaluated in mouse models with muscle necrosis and blocking was used to confirm the tracer specificity. Therapy response was evaluated by 131I-H33258 SPECT/CT imaging 24 h after CA4P therapy in W256 tumor-bearing rats. Radiotracer uptake in tumors was validated ex vivo using γ-counting, autoradiography, and histopathological staining. Results showed that 131I-H33258 had predominant necrosis avidity and could specifically bind to necrotic tissue. SPECT/CT imaging demonstrated that an obvious “hot spot” could be observed in the CA4P-treated tumor. Ex vivo γ-counting revealed 131I-H33258 uptake in tumors was increased 2.8-fold in rats treated with CA4P relative to rats treated with vehicle. Autoradiography and corresponding H&E staining suggested that 131I-H33258 was mainly localized in necrotic tumor area and the higher overall uptake in the treated tumors was attributed to the increased necrosis. These results suggest that 131I-H33258 can be used to image induction of cell necrosis 24 h after CA4P therapy, which support further molecular design of probes based on scaffold H33258 for monitoring of tumor response to VDAs treatment.

Excretion and toxicity evaluation of 131I-Sennoside A as a necrosis-avid agent

Abstract 1. Sennoside A (SA) is a newly identified necrosis-avid agent that shows capability for imaging diagnosis and tumor necrosis targeted radiotherapy. As a water-soluble compound, 131I-Sennoside A (131I-SA) might be excreted predominately through the kidneys with the possibility of nephrotoxicity. 2. To further verify excretion pathway and examine nephrotoxicity of 131I-SA, excretion and nephrotoxicity were appraised. The pharmacokinetics, hepatotoxicity and hematotoxicity of 131I-SA were also evaluated to accelerate its possible clinical translation. All these studies were conducted in mice with ethanol-induced muscular necrosis following a single intravenous administration of 131I-SA at 18.5 MBq/kg or 370 MBq/kg. 3. Excretion data revealed that 131I-SA was predominately (73.5% of the injected dose (% ID)) excreted via the kidneys with 69.5% ID detected in urine within 72 h post injection. Biodistribution study indicated that 131I-SA exhibited initial high distribution in the kidneys but subsequently a fast renal clearance, which was further confirmed by the results of autoradiography and single-photon emission computed tomography-computed tomography (SPECT-CT) imaging. The maximum necrotic to normal muscle ratio reached to 7.9-fold at 48 h post injection, which further verified the necrosis avidity of 131I-SA. Pharmacokinetic parameters showed that 131I-SA had fast blood clearance with an elimination half-life of 6.7 h. Various functional indexes were no significant difference (p > 0.05) between before administration and 1 d, 8 d, 16 d after administration. Histopathology showed no signs of tissue damage. 4. These data suggest 131I-SA is a safe and promising necrosis-avid agent applicable in imaging diagnosis and tumor necrosis targeted radiotherapy.

131 I-Evans blue: evaluation of necrosis targeting property and preliminary assessment of the mechanism in animal models

Necrosis is a form of cell death, which is related to various serious diseases such as cardiovascular disease, cancer, and neurodegeneration. Necrosis-avid agents (NAAs) selectively accumulated in the necrotic tissues can be used for imaging and/or therapy of related diseases. The aim of this study was to preliminarily investigate necrosis avidity of 131I-evans blue (131I-EB) and its mechanism. The biodistribution of 131I-EB at 24 h after intravenous administration showed that the radioactivity ratio of necrotic to viable tissue was 3.41 in the liver and 11.82 in the muscle as determined by γ counting in model rats. Autoradiography and histological staining displayed preferential uptake of 131I-EB in necrotic tissues. In vitro nuclear extracts from necrotic cells exhibited 82.3% of the uptake in nuclei at 15 min, as well as 79.2% of the uptake at 2 h after 131I-EB incubation. The DNA binding study demonstrated that evans blue (EB) has strong binding affinity with calf-thymus DNA (CT-DNA) (Ksv=5.08×105 L/(mol/L)). Furthermore, the accumulation of 131I-EB in necrotic muscle was efficiently blocked by an excess amount of unlabeled EB. In conclusion, 131I-EB can not only detect necrosis by binding the DNA released from necrotic cells, but also image necrotic tissues generated from the disease clinically.