Showing papers by "Xiaoyuan Chen published in 2005"

microPET Imaging of Glioma Integrin αvβ3 Expression Using 64Cu-Labeled Tetrameric RGD Peptide

Abstract: Integrin αvβ3 plays a critical role in tumor-induced angiogenesis and metastasis and has become a promising diagnostic indicator and therapeutic target for various solid tumors. Radiolabeled RGD peptides that are integrin specific can be used for noninvasive imaging of integrin expression level as well as for integrin-targeted radionuclide therapy. Methods: In this study we developed a tetrameric RGD peptide tracer 64Cu-DOTA-E{E[c(RGDfK)]2}2 (DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid) for PET imaging of integrin αvβ3 expression in female athymic nude mice bearing the subcutaneous UG87MG glioma xenografts. Results: The RGD tetramer showed significantly higher integrin binding affinity than the corresponding monomeric and dimeric RGD analogs, most likely due to a polyvalency effect. The radiolabeled peptide showed rapid blood clearance (0.61 ± 0.01 %ID/g at 30 min and 0.21 ± 0.01 %ID/g at 4 h after injection, respectively [%ID/g is percentage injected dose per gram]) and predominantly renal excretion. Tumor uptake was rapid and high, and the tumor washout was slow (9.93 ± 1.05 %ID/g at 30 min after injection and 4.56 ± 0.51 %ID/g at 24 h after injection). The metabolic stability of 64Cu-DOTA-E{E[c(RGDfK)]2}2 was determined in mouse blood, urine, and liver and kidney homogenates at different times after tracer injection. The average fractions of intact tracer in these organs at 1 h were approximately 70%, 58%, 51%, and 26%, respectively. Noninvasive microPET studies showed significant tumor uptake and good contrast in the subcutaneous tumor-bearing mice, which agreed well with the biodistribution results. Integrin αvβ3 specificity was demonstrated by successful blocking of tumor uptake of 64Cu-DOTA-E{E[c(RGDfK)]2}2 in the presence of excess c(RGDyK) at 1 h after injection. The highest absorbed radiation doses determined for the human reference adult were received by the urinary bladder wall (0.262 mGy/MBq), kidneys (0.0296 mGy/MBq), and liver (0.0242 mGy/MBq). The average effective dose resulting from a single 64Cu-DOTA-E{E[c(RGDfK)]2}2 injection was estimated to be 0.0164 mSv/MBq. Conclusion: The high integrin and avidity and favorable biokinetics make 64Cu-DOTA-E{E[c(RGDfK)]2}2 a promising agent for peptide receptor radionuclide imaging and therapy of integrin-positive tumors.

Synthesis and biological evaluation of dimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drug delivery.

Abstract: Targeting drugs to receptors involved in tumor angiogenesis is a novel and promising approach to improve cancer treatment. In this study, we evaluated the antitumor activity of paclitaxel (PTX) conjugated with a bicyclic peptide E[c(RGDyK)](2) (RGD) in a metastatic breast cancer cell line (MDA-MB-435). The cyclic RGD peptide selectively binds to alpha(v) integrin receptors that are highly expressed in metastatic cancer cells. PTX, an antimicrotubule agent, is a potent antitumor agent commonly used in the treatment of advanced metastatic breast cancer. The in vitro results showed that RGD peptide inhibited cell cycle proliferation by arresting cells in G(0)/G(1)-phase. The PTX-RGD conjugate inhibited cell proliferation with activity comparable to that observed for paclitaxel, both of which were mediated by an arrest of G(2)/M-phase of the cell cycle followed by apoptosis. Although the PTX-RGD conjugate showed slightly decreased integrin binding affinity than the unconjugated peptide, it indicated integrin specific accumulation in vivo. (125)I-Labeled PTX-RGD showed highest tumor uptake at 2 h postinjection (2.72 +/-0.16%ID/g) and best tumor/background contrast after 4 h postinjection. Our results demonstrate the potential of tumor-targeted delivery of paclitaxel based on the specific recognition of cell adhesion molecule alpha(v)beta(3) integrin to reduce toxicity and enhance selective killing of cancer cells.

Multimodality tumor imaging targeting integrin αvβ3

Abstract: The cell adhesion molecule integrin αvβ3 is an important player in the process of tumor angiogenesis and metastasis. Antibodies, peptides, peptidomimetics, and small molecule antagonists against in...

Comparison of [14C]FMAU, [3H]FEAU, [14C]FIAU, and [3H]PCV for monitoring reporter gene expression of wild type and mutant herpes simplex virus type 1 thymidine kinase in cell culture.

Abstract: To assess the optimal reporter probe/reporter gene combination for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression, we compared the cellular uptake of 1-(2′-fluoro-2′-deoxy-d-arabinofuranosyl)-5-methyluracil (FMAU), 2′-fluoro-2′-deoxyarabinofuranosyl-5-ethyluracil (FEAU), 2′-fluoro-2′-deoxy-β-d-arabinofuranosyl-5-iodouracil (FIAU) and penciclovir (PCV) in both HSV1-tk and HSV1-sr39tk expressing cells. For stably transfected cell studies, C6 rat glioma cells, C6 HSV1-tk transfectant, C6 mutant HSV1-sr39tk transfectant, rat Morris hepatoma cells (MH3924A), and MH3924A HSV1-tk transfectant cells were used. For adenoviral infection studies, C6 rat glioma cells were exposed to serial titers of AdCMV–HSV1-tk, AdCMV–HSV1-sr39tk, or AdCMV–fluc for 24 hours. These cells were incubated with [14C]FMAU, [3H]FEAU, [14C]FIAU, and [3H]PCV, and cellular uptake of radioactivity was measured. [3H]FEAU exhibited the highest or second highest accumulation and the most selectivity regardless of the mode of gene transfer for both HSV1-tk and mutant HSV1-sr39tk reporter genes. This combination of high accumulation and high selectivity for both HSV1-tk and HSV1-sr39tk makes suitably radiolabeled FEAU a promising candidate as a radiotracer for imaging HSV1-tk/HSV1-sr39tk gene expression in living subjects.

Traditional Chinese medicine information database

Abstract: 1. Niemi M, Cascorbi I, Timm R, Kroemer H, Neuvonen P, Kivisto K. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther 2002;71:32632. 2. Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol 1998;45:525-38. 3. Langtry HD, Balfour JA. Glimepiride. A review of its use in the management of type 2 diabetes mellitus. Drugs 1998;55:563-84. 4. Wen SY, Wang H, Sun OJ, Wang SQ. Rapid detection of the known SNPs of CYP2C9 using oligonucleotide microarray. World J Gastroenterol 2003;9:1342-6. 5. Lehr KH, Damn P. Simultaneous determination of sulphonylurea glimepiride and its metabolites in human serum and urine by high-performance liquid chromatography after pre-column derivatization. J Chromatogr 1990;526:497-505.

Synthesis of (4-[18F]fluorophenyl)triphenylphosphonium as a potential imaging agent for mitochondrial dysfunction

Abstract: Tetraphenylphosphonium (TPP) cation is able to function as a molecular probe for monitoring mitochondrial disease. The F-18 labeled TPP, (4-[18F]fluorophenyl) triphenylphosphonium (18FTPP), was therefore developed as a PET radioligand for in vivo molecular imaging of mitochondrial dysfunction. 18FTPP was synthesized via direct nucleophilic substitution of no-carrier-added [18F]fluoride with the precursor 4-nitrophenyltriphenylphosphonium. After purification by HPLC, the average radiochemical yield was determined to be 10–15% and the specific activity was >500 Ci/mmol at the end of synthesis. The total synthesis time was within 60 min, and the radiochemical purity of the 18FTPP was above 95%. Copyright © 2005 John Wiley & Sons, Ltd.

Prediction of functional class of the SARS coronavirus proteins by a statistical learning method.

Abstract: The complete genome of severe acute respiratory syndrome coronavirus (SARS-CoV) reveals the existence of putative proteins unique to SARS-CoV. Identification of their function facilitates a mechanistic understanding of SARS infection and drug development for its treatment. The sequence of the majority of these putative proteins has no significant similarity to those of known proteins, which complicates the task of using sequence analysis tools to probe their function. Support vector machines (SVM), useful for predicting the functional class of distantly related proteins, is employed to ascribe a possible functional class to SARS-CoV proteins. Testing results indicate that SVM is able to predict the functional class of 73% of the known SARS-CoV proteins with available sequences and 67% of 18 other novel viral proteins. A combination of the sequence comparison method BLAST and SVMProt can further improve the prediction accuracy of SMVProt such that the functional class of two additional SARS-CoV proteins is correctly predicted. Our study suggests that the SARS-CoV genome possibly contains a putative voltage-gated ion channel, structural proteins, a carbon-oxygen lyase, oxidoreductases acting on the CH-OH group of donors, and an ATP-binding cassette transporter. A web version of our software, SVMProt, is accessible at http://jing.cz3.nus.edu.sg/cgi-bin/svmprot.cgi .