Ph-Responsive Alendronic Acid-Coated Liposomes for Improved Treatment Osteosarcoma

Abstract

Objective Current research work aimed to develop pH-responsive osteosarcoma-targeted liposomes composed of non-oncology drugs previously identified for repositioning purposes. Material and Methods Using thin film hydration method, the Ketoconazole (KCZ)-, Simvastatin (SVN)-, and Niclosamide (NSD)-loaded non-targeted liposomes (KLs, SLs, and NLs respectively) were developed individually. The Aledronic acid-Choleteryl hemiscuccinate conjugate (AA-CHSC) was synthesized and confirmed using FTIR and 1H-NMR analysis. The AA-CHSC coated liposomes (pH sensitive and targeted liposome: PT-KLs, PT-SLs, and PT-NLs) were developed individually for the treatment of osteosarcoma with improved efficacy and reduced drug’s primary effects. The developed non-targeted and targeted liposomes were characterized for drug contentt,vesicle size, surface morphology using transmission electron microscope (TEM), in vitro pH-sensitive drug release behaviour using dialysis bag technique, and in vitro cytotoxicity characteristics against osteosarcoma cells. Results All non-targeted liposomes showed %drug content and mean vesicle size in the range of 41-75% and 161-182 nm, respectively. The AA-CHSC insertion into the liposomal membrane (targeted liposomes) has substantially improved the drug solubility in the membrane as a result of its amphiphilic nature. Furthermore, the targeted liposomes showed moderately increased mean vesicle size (203-210 nm) validating the surface modification. The TEM image revealed the formation of spherical, nearly spherical, and non-aggregated liposomes. The AA-CHSC insertion also caused liposomes sensitive to tumor pH (5.8); as a result, substantially higher drug release (58-80%) was observed as compared to non-targeted liposomes (34-52%). The cytotoxicity study results revealed substantially higher osteosarcoma cell (Saos-2) growth inhibition characteristics of targeted liposomes. Conclusions In conclusion, the developed targeted liposomes have potential application in the treatment of osteosarcoma. In addition, detailed anticancer activities should be revealed for the combination of targeted liposomes as the combination caused almost similar cytotoxicity as that of individual targeted liposomes.