The Comparative Study of Antitumor Activity and Safety of the Novel Protein-targeted Actinomycin Drugs Delivery in Experimental Tumor Models of Mice.

Abstract

Introduction. The possible acute toxicity and antitumor activity of the novel protein-targeted delivery drug — “Afotid” — was investigated. The active cytostatic agent is dactinomycin incorporated into biodegradable polylactide (PLGA) nanoparticles with AFP as a protein carrier. Objective. To study and compare drug toxicity and anti-neoplastic activity in solid and liquid tumor models in mice. Materials and Methods. Ehrlich ascites carcinoma (EAC) model was developed in 90 outbred female mice, and Lymphocytic leukemia P388 solid tumor model – in 140 female DBA/2 mice. The toxicometry with survival rate of mice was estimated by escalation the dosing according to J.Т. Litchfield and F. Wilcoxon method. The antitumor activity was estimated by the indexes of tumor growth inhibition (TGI) and average lifespan (ALS). Results. The targeted drug delivery is significantly less toxic than the prototype. The phenomenon of substantial decrease of toxic effects in mice with tumor model equalized to healthy animals was detected. LD50 increased up to 1.580 mg/kg for dactinomycin vs 0.601 mg/kg for prototype in healthy mice. This is critically upscale potentialities for clinical use of protein-targeted drug delivery of “Aftotid” in therapy with higher single and course doses which results in the significant increase of antitumor activity and decrease of toxic side effects. 7-Aminoactinomycin D (7-AAD) conjugated with AFP in nanoparticles shows substantially higher cumulation (4.6 fold P<0.0001) in tumor cells after intraperitoneal injection to EAC mice compared to prototype compound. The antitumor effect of protein-targeted delivery drug in comparison with prototype is significantly higher. The effect based on TGI criteria for “Afotid” is 1.48 fold higher in dactinomycin-vulnerable lymphocytic leukemia P388 model and 2.32 fold higher for dactinomycin-resistant lymphocytic leukemia P388 model. According to ALS criteria, the increasing rates are 2.71 fold and 3.525 fold higher respectively. Conclusion. The novel protein-targeted delivery compound has significantly higher antitumor activity and lower toxicity as compared with the prototype.