A doxorubicin loaded chitosan–poloxamer in situ implant for the treatment of breast cancer

Abstract

Breast cancer is a serious concern for many women worldwide. Drug-loaded implants have shown several benefits over systemic administrations. To provide anti-cancer drugs with controlled release and reduced systemic toxicity, biodegradable in situ implants have attracted a lot of attention. In the present study, we aimed to design and optimize a doxorubicin-loaded chitosan–poloxamer in situ implant for breast cancer treatment. Utilizing Box–Behnken Design and a Quality-by-Design (QbD) methodology, the in situ implant was prepared with chitosan (X1), poloxamer 407 concentration (X2), and stirring time (X3) as the independent variables. It was characterized for its in vitro gelation time, pH, rheology, and morphology, and evaluated based on drug release profile, in vitro cytotoxicity activities, in vitro anti-inflammatory potential, in vitro cellular uptake, and in vivo anti-inflammatory and pharmacokinetics to ensure their therapeutic outcomes. The results revealed that the prepared formulation showed a gelation time of 26 ± 0.2 s with a viscosity of 8312.6 ± 114.2 cPs at 37 °C. The developed formulation showed better cytotoxic activity in MCF-7 cell lines compared to the free drug solution. It demonstrated reduced levels of pro-inflammatory cytokines in RAW 264.7 macrophages. Further, the prepared in situ implant increases the intracellular accumulation of DOX in the MCF-7 cells. The in vivo pharmacokinetic investigations depicted an increase in t_1/2 and a decrease in AUC of the developed formulation resulting in prolonged drug release and there could be a lower drug concentration in the bloodstream than for the free drug. Therefore, the developed in situ implant may offer a viable option for breast cancer treatment.