The Preparation Of Conjugates Of Ricin Toxin A-Chain Modified By Polyethylene Glycol And The Studies On Their Biological Properties

OBJECTIVE: To modify RTA with two different molecular weight mPEGs, and study the difference in toxicity in vivo and pharmacokinetics of them.METHODS: mPEGs with two different molecular weight (5KD and 10KD, respectively) were conjugated with RTA through disulfide bond. And the toxicity in vivo and in vitro of them were compared by the determination of their LD50 and MTT method respectively. The model of rats bearing tumors was built. And they were divided in three groups, injected 125I-RTA, 125I-RTA-mPEG-MAL and 125I-RTA-mPEG-OPSS through tail venous and sacrificed at different time intervals. Then their biodistributions were assessed and compared.RESULTS: The toxicity of RTA decreased remarkably when it had been modified with mPEG. And the reduction of toxicity of mPEG modified RTA was related with the molecular weight of the PEGs which were conjugated with them. The biologic half-lives of RTA-mPEG conjugates were prolonged significantly compared with RTA. The ratios of radioactivity of T/TN for 125I-labeled PEG-RTAs appeared a clear step-up tendency as a function of time. And the take-ups of liver and spleen for 125I-RTA were greater than those for PEG-RTAs after 1h administration.CONCLUSION: The toxicity of mPEG modified RTA decreased significantly in vivo compared with free RTA probably as PEG can cover the activity area of RTA. And the biologic half-life of RTA can be prolonged through PEGylation. And RTA modified by PEG can avoid the take-ups of liver and spleen,at the same time accumulate in tumor tissues.