Development of polymeric nanoparticles loaded with STAT3 inhibitory stattic for targeted cancer therapy

Abstract

Introduction: STAT3, an oncogenic signaling factor, is found constitutively active in many types of human malignancies including 82% of prostate cancers, 70% of breast cancer, more than 82% of the carcinomas of the head and neck. Constitutively active STAT3 plays a key role in cancer progression through modulation of the genes involved in cell proliferation, apoptosis, metastasis, angiogenesis, and tumor-induced immunosuppression. Stattic is a small molecule shown to selectively inhibit STAT3 function through blocking its phosphorylation and dimerization. It is a promising drug for cancer targeted therapy. However the poor water solubility and low bioavailability of stattic has limited its clinical application. Aim: The aim of this project was to develop poly (ethylene glycole)-block-poly(caprolactone) (PEG-b-PCL)-based polymeric micelles loaded with stattic and characterize the developed formulations for drug encapsulation and release. Methods: Stattic loaded micellar formulations were prepared by co-solvent evaporation method. Mean diameter and polydispersity index of micelles were defined by light scattering. Encapsulated drug levels were measured using high performance liquid chromatography. Results: Stattic was loaded in the polymeric micelles with encapsulation efficiency ranging from 40 to 73 %. Drug loaded micelles were between 90 and 130 nm in size. Encapsulation of stattic in PEG-b-PBCL micellar formulation resulted in more than 6-folds increase in the apparent water solubility of stattic (0.36 vs 0.06 mg/mL). However none of the developed micellar formulations could efficiently sustain the release of drug such that 70-80% of loaded drug was released within the first hour during release study. Conclusion: These findings have shown that PEG-b-PBCL copolymers