ABSTRACT
Cobra venom cytotoxin (CVC) loaded in poly (lactide-co-glycolide) (PLGA) microspheres was mixed with ricin and encapsulated in a thermosensitive PLGA-PEG-PLGA hydrogel for this study. This sequential sustained-release preparation (SSRP) containing ricin and CVC could avoid burst release effect of CVC from microspheres. In addition, in SSRP, the two biotoxins have different drug release rates and antitumor mechanisms, which can be complementary to each other. Ricin has a faster release rate than CVC. It can combine with the tumor cell membrane and enter the cell, inhibiting protein synthesis within 2 weeks. Whereas CVC releases slowly in 5 weeks directly dissolving the tumor cell membrane and killing the cells which are less-sensitive to ricin. The in vivo experiments showed that intratumoral injection of SSRP could inhibit hepatocellular carcinoma growth significantly, and the tumor growth inhibition rate reached 73.5%. It appears that a new medicine preparation for cancer local treatment should be further studied for clinical applications.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Elapid Venoms/administration & dosage , Elapid Venoms/pharmacology , Ricin/administration & dosage , Ricin/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/chemistry , Cell Line, Tumor , Cell Survival/drug effects , Delayed-Action Preparations , Drug Carriers , Elapid Venoms/chemistry , Excipients , Humans , Hydrogels , Lactic Acid , Mice , Mice, Inbred BALB C , Mice, Nude , Microscopy, Electron, Scanning , Microspheres , Neoplasm Transplantation , Particle Size , Polyglycolic Acid , Polylactic Acid-Polyglycolic Acid Copolymer , Ricin/chemistry , Temperature , Xenograft Model Antitumor AssaysABSTRACT
To investigate the antiangiogenic effect of sustained-release poly (lactic-co-glycolic acid) microspheres containing docetaxel (PMCD) in human hepatoma xenograft. PMCD were prepared by solvent evaporation method with an encapsulation efficiency of 98.7% and a release period of about 3 weeks in vitro. PMCD were intratumorally injected once for mice bearing a human hepatocellular carcinoma. On day 21 post-treatment, the inhibition rate of tumor growth was 72.7% in the high-dose group, indicating a significant antitumor activity. Meanwhile, excellent antiangiogenic effect was observed based on the contrast-enhanced ultrasonography as well as microvessel density determination. Additionally, the real-time fluorescence quantitative PCR revealed that the expressions of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and angiopoietin-2 (Ang2) genes were down-regulated significantly. Interstitial chemotherapy using PMCD was highly effective and safe for the treatment of the human hepatoma xenograft and that decreasing angiogenesis could be one of the most important mechanisms involved in the antitumor activity.
