A doxorubicin loaded chitosan–poloxamer <i>in situ</i> 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 <i>in situ</i> implants have attracted a lot of attention. In the present study, we aimed to design and optimize a doxorubicin-loaded chitosan-poloxamer <i>in situ</i> implant for breast cancer treatment. Utilizing Box-Behnken Design and a Quality-by-Design (QbD) methodology, the <i>in situ</i> implant was prepared with chitosan (X1), poloxamer 407 concentration (X2), and stirring time (X3) as the independent variables. It was characterized for its <i>in vitro</i> gelation time, pH, rheology, and morphology, and evaluated based on drug release profile, <i>in vitro</i> cytotoxicity activities, <i>in vitro</i> anti-inflammatory potential, <i>in vitro</i> cellular uptake, and <i>in vivo</i> 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 <i>in situ</i> implant increases the intracellular accumulation of DOX in the MCF-7 cells. The <i>in vivo</i> pharmacokinetic investigations depicted an increase in <i>t</i> _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 <i>in situ</i> implant may offer a viable option for breast cancer treatment.