Prolonged local delivery of doxorubicin to cancer cells using lipid liquid crystalline system

Abstract

Exploring efficient strategies to eradicate the tumor tissue and enhance patient outcomes still remained a serious challenge. Systemic toxicity of the current chemotherapeutics and their low concentration in the tumor site limited reaching a practical approach in their administration and combinational therapy. Besides, complicated delivery platforms could not receive the marketing approval due to difficulties in scale up procedures. To this aim, we developed a simple injectable local delivery platform which provided a sufficient dose of the chemotherapeutic in the cancerous tissue with sustained release properties. Herein, various injectable in situ forming LLC formulations loaded with doxorubicin (DOX) were developed. Although there were many previous studies on lipid liquid crystal (LLC) based formulations, their performance as an injectable intratumoral depot system for local chemotherapy has not been extensively investigated yet. In the current study we developed 18 formulations of DOX loaded LLCs using Box-Behnken method via different ratios of phosphatidyl choline: sorbitan monooleate (PC: SMO), N-Methyl-2-pyrrolidone (NMP), and tween 80. The physicochemical properties of the formulations were investigated and their in vivo tumor inhibition efficiencies in C26 tumor bearing mouse model was further studied. The results indicated that DOX loaded PC: SMO/NMP/Tween 80 (50:50/50/2 w/w%) and DOX loaded PC: SMO/NMP (50:50/50 w/w%) formulations were syringeable with pseudoplastic behavior. Also, they could release the cargo in a sustained manner for 60 days. Compared to intravascular administration of DOX, intratumoral injection of the developed formulations led to a significant decrease in tumor volume and enhancement of the survival rate in murine tumor model. Additionally, animal imaging studies proved their prolonged accumulation in the tumor site. Histopathological studies showed that treatment with the DOX-loaded LLC formulations did not cause any systemic toxicity to vital organs. Taken together, we believe that the developed simple and efficient local delivery platform can be further used in combinational therapies and treatment of various solid tumors.