Targeted anti-tumor synergistic effects of Myc decoy oligodeoxynucleotides-loaded selenium nanostructure combined with chemoradiotherapy on LNCaP prostate cancer cells

In the present study,we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNCaP prostate cancer cells.Myc decoy ODNs were designed based on the promoter of Bcl-2 gene and analyzed by molecular docking and molecular dynamics assays.ODNs were loaded on the synthesized Se@BSA@Chi-MTX nanostructure.The physicochemical characteristics of nanostructures were determined by FTIR,DLS,UV-vis,TEM,EDX,in vitro release,and hemolysis tests.Subsequently,the cytotoxicity properties of them with and without X-irradiation were investigated by uptake,MTT,cell cycle,apoptosis,and scratch assays on the LNCaP cell line.The results of DLS and TEM showed negative charge(−9 mV)and nanometer size(40 nm)for Se@BSA@Chi-DEC-MTX NPs,respectively.The results of FTIR,UV-vis,and EDX showed the proper interaction of different parts and the correct synthesis of nanoparticles.The results of hemolysis showed the hemocompatibility of this nanoparticle in concentrations less than 6 mg/mL.The ODNs release from the nanostructures showed a pH-dependent manner,and the release rate was 15%higher in acidic pH.The targeted Se@BSA@Chi-labeled ODN-MTX NPs were efficiently taken up by LNCaP cells by targeting the prostate-specific membrane antigen(PSMA).The significant synergistic effects of nanostructure(containing MTX drug)treatment along with X-irradiation showed cell growth inhibition,apoptosis induction(~57%),cell cycle arrest(G2/M phase),and migration inhibition(up to 90%)compared to the control.The results suggested that the Se@BSA@Chi-DEC-MTX NPs can potentially suppress the cell growth of LNCaP cells.This nanostructure system can be a promising approach for targeted drug delivery and chemoradiotherapy in prostate cancer treatment.

INHIBITION EFFECT OF VASCULAR ENDOTHELIAL GROWTH FACTOR ANTISENSE OLIGODEOXYNUCLEOTIDES ON C6 GLIOMA

Objective: To explore the probability of vascular endothelial growth factor (VEGF) antisense oligodeoxynucleotides as a developing new therapeutic strategy for glioma. Methods: VEGF protein expression was detected by S-P immunohistochemical technique. Tumor cell apoptosis was observed by TUNEL method. Results: Compared with control, VEGF protein expression was inhibited by antisense oligodeoxynucleotides in vitro. And the inhibitory effects increased with the increasing concentration. VEGF positive rate was 82.10% in control group, while in 2.5, 5, 10 mmol/L AODN groups, they were 70.00%, 57.85%, 53.20% respectively. No inhibition effect was found in the cell lines treated with missense and sense oligodeoxynucleotides. In vivo, antisense oligodeoxy-nucleotides therapy also inhibited VEGF protein expression and induced the increase of apoptotic tumor cells. However, it has no effect on tumor cell proliferation. Conclusion: It is hopeful that VEGF antisense oligodeoxynucleotides may be a new gene therapy method to glioma through its antiangiogenesis effect by inhibition of VEGF.

Antisense Oligodeoxynucleotide Inhibits Expression of Re-com binantPorcine Follicle-Stim ulating Horm one Receptor

To assess the role of follicle stimulating hormone receptor(FSHR) gene expression in regulating expression of FSHR protein in the plasma membrane, the effects of a porcine FSHR cDNA antisense oligodeoxynucleotide (ODN) on FSHR mRNA levels and 125 I FSH binding were determined in Chinese hamster ovary cells expression recombinant porcine FSHR (pFSHR CHO cells). An 18 mer phosphorothioate endcapped antisense ODN that corresponded to the region surrounding the translation initiation codon of the porcine FSHR cDNA was synthesized. An 18 mer nonsense sequence of identical nucleotide composition, which had little homology to known DNA sequences, was synthesized for use as a control. pFSHR CHO cells were cultured in 24 well plates (10 5 cells/well) in the absence or presence of 1 20 μmol/L antisense or nonsense ODN for 24 h and then assayed for porcine FSHR mRNA, using quantitative reverse transcription and competitive polymerase chain reaction, and for 125 I FSH binding activity. Treatment with 10 μmol/L antisense ODN caused a paradoxical increase in porcine FSHR mRNA from 0.89±0.06 to 1.64±0.08 ng/mg total RNA ( P <0.05). Transfection with lipofectamine and 0.33 μmol/L antisense ODN caused an increase in porcine mRNA from 0.95±0.08 to 1.53±0.07 ng/mg total RAN. This was probably due to upregulation of mRNA synthesis resulting from inhibition of porcine FSHR protein translation. The nonsense ODN had no effect on porcine FSHR mRNA. Antisense, but not nonsense, ODN (10 μmol/L) inhibited membrane binding of 125 I FSH by 13.6± 0.8 % ( P <0.05) in 24 h. Treatment of cells with antisense ODN (10 μmol/L) for 48 h resulted in a 76±1.5 % ( P <0.05) inhibition of 125 I FSH binding. In contrast, transfection with lipofectamine and 0.33 μmol/L antisense ODN at 0 h caused a 76.1±1.3 % ( P <0.05) reduction in binding within 24 h. Binding had returned to 52.3±2.3 % ( P < 0.05) of normal by 48 h. These results indicate that an antisense ODN corresponding to the region of the translation start site of the porcine FSHR cDNA is an effective specific inhibitor of porcine FSHR synthesis and that inhibition of receptor synthesis causes a decrease in functional membrane bound FSHR.

Effect of Antisense Oligodeoxynucleotide Directed to NF-κB-RelA on Bcl-x_L mRNA in Extended Drug Resistance Leukemia Cell Line HL- 60/E6

To explore the effect of NF κB on bcl x gene transcription in extended drug resistance leukemia cell line HL 60/E6, drug resistant subline HL 60/E6 was derived by intermittently exposing HL 60 cells to 6 ng/ml epirubicin. Indirect immunofluorescence was used to demonstrate the location of NF κB RelA in HL 60/E6 cells. FCM analysis and RT PCR were used to detect the efficiency of liposome mediated ODN transfection and the change of bcl x L mRNA levels after 5 μmol/L phosphorothioate (PS) derivatized antisense (AS) oligodeoxynucleotide (ODN) directed to RelA was transferred into HL 60/E6 cells. The results showed that RelA remained persistently active and located at the nuclei of HL 60/E6 cells,but in the cytoplasm of HL 60 cells, the efficiency of liposome mediated ODN transfection was significantly higher than that of null ODN ( P <0.01 in 4 h, 6 h, 12 h, 24 h). Exposure of HL 60/E6 cells to 5 μmol/L AS PS ODN directed to RelA led to a maximal 40 % decline of bcl x L mRNA levels within 8 h. The inhibition rate of bcl x L mRNA was (15±1.79) %, (28±2.34) %, (40±3.47) %, (20±1.54) % in 4 h, 6 h, 8 h, 15 h, respectively, but it was less than 15 % in control group. It was concluded that NF κB was involved in regulating bcl x transcription. It was suggested that NF κB was an important factor for drug resistance in leukemia cells.

Transfection of Antisense Oligodeoxynucleotide Inhibits Heparanase Gene Expression and Invasive Ability of Human Pancreatic Cancer Cell in vitro

Extracellular matrix （ECM） degradation is an essential step that allows tumor cells to penetrate a tissue barrier and become metastatic. Heparanase （HPSE） is an endoglycosidase that specifically degrades heparin sulfate proteoglycans （HSPG）, a chief component of ECM, HPSE is not expressed in normal epithelial cells but can be detected in a variety of human carcinomas including pancreatic cancer. In the present study, human pancreatic cancer cell line Panc-1 was transfected with HPSE antisense oligodeoxynucleotide （AS-ODN） in vitro, then the inhibitory effect of ASODN on HPSE gene expression and invasive ability of Panc-1 cells in vitro was examined. The HPSE mRNA and protein expression of Panc-1 cells transfected with AS-ODN was significantly inhibited. However, there were no marked inhibitory effects in Panc-1 cells treated with nonsense oligodeoxynucleotide （NS-ODN）. Moreover, a modified Boyden chamber assay demonstrated that transfection with HPSE AS-ODN significantly inhibited invasive potential of Panc-1 cells in vitro after AS-ODN transfection. This suggests that HPSE AS-ODN may contribute to the inhibition of HPSE mRNA and protein expression, and results in a decrease of the invasive ability of Panc-1 in vitro.

Inhibitory Effect of Tissue Transglutaminase (tTG) Antisense Oligodeoxynucleotides on tTG Expression in Cultured Bovine Trabecular Meshwork Cells

To study the effect of tTG fully phosphorothioated antisense oligodeoxynucleotides （tTG-ASDON） on tTG expression in cultured bovine trabecular meshwork cells （BTMCs） in vitro and explore a new treatment alternative for primary open angle glaucoma （POAG）, the ASDON1 and ASDON2 complementary to the protein codogram region of tTG were designed, synthesized and phosphorothioated according to the secondary structure of tTG. The ASDON1 and ASDON2 were embedded in Lipofectamine and transfected into BTMCs. The untreated group served as negative controls. The expression of tTG in the mRNA and protein level were measured by semi-quantitative RT-PCR and immunohistochemical technique-Supervision method respectively. Our results showed that both the mRNA and the protein of tTG with tTG-ASDON1 and tTCr-ASDON2 were significantly decreased as compared with that of the controls （P〈0.05）. On the other hand, no significant difference was found between the ASDON1 group and the ASDON2 group. It is concluded that the expression of tTG mRNA and protein in cultured BTMC are down-regulated by tTG- ASDON. As a result, tTG-ASDON may be used for the treatment of POAG through the inhibitory effect on the expression of tTG.

Effect of C-myc Antisense Oligodeoxynucleotides on Hypoxia-induced Proliferation of Pulmonary Vascular Pericytes

To study the effect of c myc antisense oligodeoxynucleotides (ODNs) on proliferation of pulmonary vascular pericytes (PC) induced by hypoxia, cell culture, dot hybridization using probe of digoxigenin 11 dUTP labeled cDNA, 3H thymidine incorporation, immunocytochemical technique and image analysis methods were used to observe the effect of c myc antisense ODNs on expression of c myc gene and proliferating cell nuclear antigen (PCNA), and 3H thymidine incorporation of PC induced by hypoxia. The results showed that hypoxia could significantly enhance the expression of c myc and PCNA ( P <0.01), and elevate 3H thymidine incorporation of PC ( P <0.01), but antisense ODNs could significantly inhibit the expression of c myc and PCNA ( P <0.05), and 3H thymidine incorporation of PC ( P <0.01). It was suggested that hypoxia could promote the proliferation of PC by up regulating the expression of c myc gene, but c myc antisense ODNs could inhibit hypoxia induced proliferation of PC by downregulating the expression of c myc gene.

Inhibitory effect of EGFR antisense oligodeoxynucleotide on human hepatoma cell line

Hepatocellular carcinoma (HCC) is one of the most common cancer-related causes of death worldwide. The epidermal growth factor receptor (EGFR) is highly expressed in many human tumors and provides a new target for anticancer drug development. The aim of the present study was to explore the effect of EGFR antisense oligodeoxynucleotide on human HCC. METHODS:SMMC-7721 cells in culture were treated with 10 μmol/L antisense-odn for 24, 48, 72 hours respectively and MTT assay was adopted to determine the proliferation of tumor cells in vitro. About 2 ×106 SMMC-7721 cells with or without pretreatment(30 μmol/L oligodeoxynucleotide) were inoculated into subcutaneous flap of 21 nude mice, of which 7 were treated with EGFR antisense-odn, 7 with scrambled oligodeoxynucleotide (scrambled-odn), and 7 not treated in vivo. RESULTS:In vitro, after 24, 48, 72 hours the inhibitory rate of proliferation of SMMC-7721 cells treated with EGFR antisense-odn was 8%, 32%, and 34% respectively. In vivo after 8 weeks, no palpable tumor was found in 1/7 mice receiving cells pretreated with antisense-odn, whereas 7/7 untreated mice and 6/7 mice treated with scrambled-odn developed palpable tumors. Tumor growth in antisense-odn treated mice was significantly inhibited in comparison with that of those untreated (P【0.01) or treated with scram-bled-odn (P【0.05). CONCLUSIONS:Antisense oligodeoxynucleotide acts as a specific growth inhibitor on SMMC-7721 in a sequence specific and time-dependent manner. EGFR antisense-odn can significantly inhibit the proliferation of human hepatoma cell in vitro as well as in vivo, indicating that EGFR may play an important role in the development of hepatoma and will be a new target for its treatment.

Effect of MUC2 Antisense Oligodeoxynucleotide on Cell Proliferation,Adhesion,and Proteolytic Enzyme in Human Gastric Carcinoma in vitro

Objective：To investigate the effect of MUC2 antisense oligodeoxynucleotide （ASODN） on cell proliferation, adhesion and proteolytic enzyme inhuman gastric carcinoma cell line （SGC7901）. Methods： Phosphorothioate MUC2 ASODN was synthesized and packaged by lipofectin, and then transfected to SGC7901 cells. The expression of MUC2 mRNA and protein after transfection was detected by reverse transcription-polymerase chain reaction （RT-PCR） and immunohistochemical method respectively, and the effect of MUC2 ASODN on cell proliferation, adhesion and proteolytic enzyme was determined by flow cytometry（FCM）, MTT method, Rose Bengal and immunohistochemical method. Results： Compared with the blank control group, ASODN efficiently downregulated the expression of MUC2 mRNA and protein in SGC7901 cells 48h after transfection（P〈0.01）. Various concentrations of ASODN could significantly inhibit the growth of SGC7901, and the inhibition peaked at the 48th hour after transfection（P〈0.05）. The apoptosis rate of the experimental group was about 4.38%, and the percentage of S-phase cells rose while G0/G1-phase cells fell because most of them were blocked at S-phase. In addition, cells treated with MUC2 ASODN showed lower adhesion ability with matrix and endothelial cells than control cells in vitro（P〈0.01）. By immunohistochemical method, the upregulation of E-cadherin proteins and the downregulation of MMP2 and cathepsinD proteins were also observed（P〈0.05）. Conclusion： MUC2 ASODN could efficiently inhibit SGC7901 cell proliferation, reduce cell adhesion ability and downregulate the expression levels of proteolytic enzyme in vitro.

A new approach to transfect NF-κB decoy oligodeoxynucleotides into the periodontal tissue using the ultrasound-microbubble method

The objective of this study is to investigate the effect of the ultrasound-microbubble technique in nuclear factor kappa B(NF-κB) decoy oligodeoxynucleotide(ODN) transfection in the gingival tissue in mice. The 6-FAM-labeled scrambled decoy ODN with microbubbles was applied to the periodontal tissue in 8-week-old male C57BL/6J mice by ultrasound radiation at low(LUM-Sc) and high(HUM-Sc) intensities to optimize the transfection condition of the ultrasound-microbubble method.Histological inspections were performed two hours after transfection to compare the expression with that in the sham-operated group without ultrasound radiation(A-Sc). Then, an NF-κB decoy was transfected into the periodontal tissue using the highintensity ultrasound-microbubble(HUM-NF) technique to examine the anti-inflammatory effects of the decoy ODN. Western blot analysis was performed to investigate the expression of interleukin(IL)-1β, IL-6 and intercellular adhesion molecule-1(ICAM-1)in the gingival tissues in the HUM-Sc, the HUM-NF and control groups. The fluorescence microscopy results showed that the fluorescent intensity in the periodontal tissues in the LUM-Sc and HUM-Sc groups was significantly higher than that in the A-Sc and the control groups. The fluorescent intensity in the HUM-Sc group, especially in the gingival connective tissue,was the highest of all groups. Western blot analysis indicated that the protein expression levels of IL-1β, IL-6 and ICAM-1 in the HUM-NF group were significantly lower than those in the HUM-Sc and the control groups. These findings suggest that the high-intensity ultrasound-microbubble technique is an effective tool for decoy transfection into the periodontal tissue.

Effects of Antisense Oligodeoxynucleotide to Follicle-stimulating Hormone Receptor on the Cell Proliferation and Apoptosis in Cells Derived from Human Ovarian Mucinous Cystadenocarcinoma in Vitro

The human ovarian mucinous cystadenocarcinoma （hOMC） cells were co-cultured with antisense oligodeoxynucleotide （antisense ODN）, nonsense ODN, and follicle-stimulating hormone （FSH） at different concentrations for the purpose of observing the effects of antisense ODN to FSH receptor （FSHR） on the proliferation and apoptosis of cultured hOMC cells in vitro. The inhibitory rates of growth were measured by using MTT method on the 2nd, 4th, 6th, 8th and 10th days after the interference of antisense ODN, nonsense ODN, and FSH, respectively. The apoptotic rates and the cell cycles were determined by means of flow cytometry, the apoptosis indexes were detected by using TUNEL, and the expression of caspase-3 was measured by using SP immunohistochemistry. Compared with that in the control group, the proliferative activity of hOMC cells was increased obviously in FSH groups （P〈0.05 or P〈0.01）, decreased distinctly in antisense ODN groups （P〈0.05 or P〈0.01）, and unchanged in nonsense ODN groups, respectively. Meanwhile, antisense ODN could significantly antagonize the FSH-promoted cell proliferative activity （P〈0.01）. Compared with those in the control group, the apoptotic rates and the expression of caspase-3 were dramatically increased in the mid- and high-dose antisense ODN groups （P〈0.05 or P〈0.01）, while the number of cells in G1/G0 phase was significantly decreased and that in S phase distinctly increased （P〈0.01）, There was no change in nonsense ODN groups （P〉0.05）, It was suggested that FSH may improve the development of hOMC cells, However, antisense ODN could inhibit proliferative activity and the FSH-promoted proliferative activity in hOMC cells, at the same time, antisense ODN could inhibit hOMC cell growth by inducing apoptosis.

Growth of Pb S nanoclusters on specific sites of programmed oligodeoxynucleotides

We develope a method to synthesize Pb S nanoclusters（NCs） using guanine-containing oligodeoxynucleotides（ODNs）as templates. The NCs on the ODNs are ultra small（ranging from ～ 0.5 nm to 2.1 nm） and luminescent in the visible region. They are characterized by photoluminescence（PL） spectra, transmission electron microscopy（TEM）, and X-ray powder diffraction（XRD）. The ODN–NC complexes can be used as customer-designed fluorophores which do not have the problem of multiple conjugations. The same method enables us to fabricate Pb S quantum dot molecules and connect them into nanowires, expanding their potential applications in molecule electronics and quantum computing.

Destabilization of Basic Fibroblast Growth Factor by Oligodeoxynucleotides

The effects of oligodeoxynucleotide （ODN） on the conformation of basic fibroblast growth factor （bFGF） were studied by spectral method. The results showed that ODN destabilized the protein.

Inhibitory effects of antisense oligodeoxynucleotide on replication and expression of HDV genome in vitro and in vivo

Objective:To studytheinhibitoryeffectsof antisenseoligodeoxynucleotide(ASODN)anditsthiophosphate(S-ASODN)on thereplicationandexpressionof hepatitisD virus(HDV)in H1δ9cellsandin tupaiabody.Methods:After15mer-ASODNandS-ASODNweresynthesized,differentconcentrationsof ASODNandS-ASODNwereaddedto theculturemediumof H1δ9celllineandthenHDAgin thesupernatantof theculturewas examinedwithELISAand HDV-RNAinthecellsdeterminedwithdotblothybridization.SixteentupaiaeweresuccessfullyinfectedwithHDVand thenequallyrandomizedinto2groups.In thetreatedgroup,theanimalsreceivedintravenousinjectionsof S-ASODN3mg everyotherdayfor7timesandthecontrolgroupwereinjected withsamevolumeof normalsaline.On the5th,10th,15thand20thdayaftertheadministration,samplesof bloodandlivertissueswereexaminedwithimmunohistochemical methodforHDAganddotblothybridizationandin situ hybridizationforHDV-RNA.Results:Twenty-fourhoursafter theadditionof a finalconcentrationof6μmol/Lof S-ASODN,thereplicationof HDV-RNAandthereleaseof HDAgin theH1δ9cellsweresuppressedby84.5%and76.14%respectively.Theinhibitionwas dose-dependentwhenthefinal concentrationsof2,4and6μmol/Lof S-ASODNweregiven.WhenASODNandS-ASODNwereadministeredinthe samedosage,theinhibitionshowedno significantlydifferencebetweenthe2agents.On thelastdayof theadministration of S-ASODN,7outof the8tupaiaeof thetreatedgroupshowednegativeHDAgandHDV-RNAinthelivertissuewhile only1outof the8tupaiaeof thecontrolgroupwasnegative.Tendaysafterthecessationof drugadministration,3tupaiae of thetreatedgroupand7of controlwerepositiveof HDAgandHDV-RNA.Conclusion:OurfindingsshowthatS-ASODNefficientlyinhibitesthereplicationandexpressionof HDVgeneinH1δ9cellsandin thebodyof tupaia,which providesanexperimentalbasisfortheanti-HDVapplicationof antisenseoligonucleotides.

c－Ha－ras and c－myc antisense oligodeoxynucleotides inhibit the proliferation and DNA synthesis in human gastric carcinoma cel

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Antiviral effects of two antisense phosphorothioate oligodeoxynucleotides against Japanese encephalitis virus strain SA--14 in cultured BHK21 cells

To investigate the potential utility of nuclease--resistant oligodeoxynucleotides (S-ODN) as anew class of antiviral agents. Methods: Two antisense phosphorothioate analogues (20--iner) complementary to thesequences of the first AUG codon and 5’ terminus of NSS of JEV SA--14 genome have been synthesized and their effects on CPE, viral antigen expression and virus plaque formation were tested in vitro. Results: The resultsshowed that 1. 0 pmol/L of S-ODN greatly deferred the onset of CPE in cultured BHKZI cells for at least 48 h.Addition of 5. 0 pmol/L or more S--ODN to culture medium fluid, 2 h prior to 100TCID,,virus inoculum, notablysuppressed viral antigen expression in the cells by making it lower than the limit of EIA detection in 48 h. The inhibition lasted more than 96 h. Viral plaque assay results demonstrated that S-ODN were most effect’ive within 18h with plaque inhibition rate over 90% by 5. 0 pmol/L S--ODNI. The inhibitory activity soon faded in 24 h. In addition, high concentrations (up to 80. 0 pmol/L) of S--ODN did not show any obvious cytotoxicity in 6 d by usingtrypan blue dye exclusion method. Conclusion: The specific synthetic S--ODN transitorily inhibited JEV replicationin BHK--ZI cells with characteristics of specificity and S--ODN dose--dependence.

Inhibition of α_1(Ⅰ) collagen gene in vitro transcription by antisense oligodeoxynucleotides

Objective and Methods: Excessive accumulation of collagen typeⅠ and type Ⅲ causes the formation of keloids and hypertrophic scars. To understand the mechanism by which antisense oligodeoxynucleotide (Oligo) acts on in vitro transcrption α1 (I) collagen gene, isotopes (α-32pGTP) was incorporated into 2 SP6 in vitro transcription systems. Results and Conclu- sion: Oligo 2 (at the transcription start region) could effectively inhibit in vitro transcription of pGEM3-Col13 and the control (random oligodeoxynucleotides) showed no inhibition. However, oligo 1 (at the transcription start region) obviously inhibited the in vitro transcription of pGEM3-Col14, while Oligo 2, which targeted at the down stream region (about 200 bp) of the promoter showed no significant inhibition effect.

Local Delivery of C-myc Antisense Oligodeoxynucleotide by Gelatin Coated Platinium-Iridium Stent to Prevent Restenosis in a Normal Rabbit Carotid Artery

Objectives To investigate the feasibility and effect of local deliveryof c-myc antisense oligodeoxynucleotide (ASODN) by gelatin coated Platinium-Iridium stent to prevent restenosis in a normal rabbit carotid artery. Methods Gelatin coated Platinium-Iridium stent were implanted in the right carotid arteries of 32 rabbits under vision. Animals were randomized to the control group and the treated group receiving c-myc ASODN (n=16 respectively).7, 14, 30,90 days following the stenting procedure, morphometry for caculation of neointimal area and mean neointimal thickness were performed.The expression of c-myc protein was detected by immunohistochemical methods. Results 32 stents were successfully implanted into the right carotid arteries in 32 animals.Morphometric analysis showed that neointimal area and mean neointimal thickness siginificantly increased continuously up to 12 weeks after stent implantation,and at each time point , neointimal area and mean neointimal thickness were siginificantly smaller in the treated group than control group. (P<0.001,respectively).c-myc protein expression was weak positive or negative in treated group and positive in control group. Conclusions Gelatin coated Platinium-Iridium stent mediated local delivery of c- myc ASODN is feasibility , and it can inhibit neointimal hyperplasia to prevent restenosis in a normal rabbit carotid artery.