mPEG-b-PCL-Based Nanoformulations of Aziridine-Functionalized 1,3,5-Triazine Derivative for Cancer Treatment

Abstract

Developing nanoformulations of antitumor drugs represents a critical priority in addressing key challenges of free drug administration such as low therapeutic efficacy, poor bioavailability, and severe side effects, including high systemic toxicity. In this study, mPEG-b-PCL block copolymers of different molecular weights were synthesized and applied to develop nanoformulations of the antitumor aziridine-functionalized 1,3,5-triazine derivative, dioxadet (DOD) via nanoprecipitation. The resulting DOD-loaded nanoparticles exhibited optimal characteristics for intravenous administration, and high encapsulation efficiency. The effect of mPEG-b-PCL molecular weight on drug encapsulation and release was investigated, and the results were elucidated through computational analysis of the molecular binding mechanism between DOD and PCL. Release profiles showed a sustained biphasic pattern. Determination of DOD concentration in blood of healthy rats indicated that the nanoformulation extended DOD’s circulation time. The empty nanoparticles were well-tolerated by both normal and cancer cells. The nanoformulation maintained inhibitory activity against A549 cells with an IC50, comparable to that of free DOD. The antitumor efficacy and reduced toxicity of the optimized nanoformulation were demonstrated in mice using two ascitic tumor models (Ehrlich ascites carcinoma and L1210 lymphoid leukemia) and one solid tumor model (Lewis lung epidermoid carcinoma) with the greatest therapeutic effect observed against the solid tumor.