ABSTRACT
OBJECTIVE: To prepare VIP-125I-ASON and investigate the possibility of using it as an agent for diagnostic imaging and therapy of colon carcinoma. METHODS: The iodination of a 15-base single-stranded antisense oligonucleotide (ASON) complementary to C-myc oncogene mRNA was carried out in the presence of TICl3. The radiolabeled oligonucleotide was complexed with a VIP-polylysine conjugate under certain condition. 3-5 microCi VIP-125I-ASON was injected into the tail vein of the BALB/c nude mice bearing transplanted HT29 colon carcinoma; the nude mice were killed at specific intervals after injection, and the biodistrbution of VIP-125I-ASON in the organs were calculated. RESULTS: The biodistributed experiment showed that the 125I-ASON was excreted by kidney mostly and by liver and spleen in part. The results of studies after the injection of VIP-125I-ASON differed from those of unconjugated 125I-ASON. The conjugation of VIP to the ASON resulted in a decrease in the plasma clearance of the radiopharmaceutical, which may be due to the reduction in the renal clearance of the ASON. The highest uptake of tumor tissue (5.89% ID/g at 2 h) was significantly higher than that in nude mice given unconjugated ASON (P < 0.05). Tumor to blood ratios and tumor to muscle ratios were optimal at 4 h. CONCLUSION: VIP-125I-ASON has desirable stability and higher uptake in tumor. It may provide a new sensitive mean for diagnostic antisense imaging and radiotherapy of tumor in the future.
Subject(s)
Iodine Radioisotopes/pharmacokinetics , Oligonucleotides, Antisense/pharmacokinetics , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Vasoactive Intestinal Peptide/pharmacokinetics , Animals , Colonic Neoplasms/diagnostic imaging , Colonic Neoplasms/radiotherapy , Iodine Radioisotopes/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Nude , Oligonucleotides, Antisense/therapeutic use , Radionuclide Imaging , Radiopharmaceuticals/therapeutic use , Tissue Distribution , Vasoactive Intestinal Peptide/therapeutic useABSTRACT
This study investigated the inhibitory action of (131)I-recombinant human EGF ((131)I-rhEGF) on MCF-7 human breast cancer tumor development in nude mice. The activity and tumor uptake of (131)I-rhEGF was measured by tissue distribution assay, and its effect on tumor growth was measured by monitoring tumor size after treatment with (131)I-rhEGF. Changes in tumor cell ultrastructure were observed by transmission electron microscopy (TEM), and pathological changes in tumor tissue were observed by light microscopy. The tissue distribution assay revealed that (131)I-rhEGF was markedly absorbed by the tumor and reached its maximal uptake rate (16.73%ID. g(-1)) at 120 hours at which point the drug concentration in the tumor was 11.1-fold, 8.1-fold, and 6.6-fold higher than that in blood, liver, and kidneys, respectively. Tumor size measurements showed that tumor development was significantly inhibited by intravenously and intratumorally injected (131)I-rhEGF. Tumor inhibition rates (82.0% and 80.7%, respectively) were significantly higher than those of tumors treated with (131)I (7.49%) and (131)I-HSA (6.91%; P < 0.05). TEM and light microscopy revealed that intravenous and intratumoral injection of (131)I-rhEGF could significantly damage and ultimately kill tumor cells. Our results suggest that (131)I-rhEGF suppresses development of xenografted breast cancer cells in nude mice, providing a novel candidate for receptor-mediated targeted radiotherapy.