Redesign and Develop Effective Liposomal Formulation for Prodrug Delivery Through Synchrotron X-ray Studies of Molecular Interactions*

Liposomal formulations may provide advantages for drug delivery to overcome high dose and toxicity issues of anticancer chemotherapy prodrugs such as capecitabine. However, because of the enormous combination and the unique molecular structure of the prodrug, it is difficult to prepare liposomal-capcitabine fomulations with high drug loading and long-term stability based on empirical trials.

In this study, we synthesized a capecitabine analogue by conjugating a carbon chain of cetyl chloroformate with 5- fluorouracil (5FU) (5FU-PAL). We optimized the liposomal formulation of 5FU-PAL for prolonged blood circulation and sustained release based on the understanding of molecular packing and interactions of 5FU-PAL and phospholipids at the gas-water interface by employing synchrotron X-ray reflectivity (XR) and grazing incidence X-ray diffraction (GIXD) integrated with a Langmuir trough. It was found that 5FU-PAL interacts strongly with positively charged lipid in the head group region. The studied could precisely quantify the maximum drug loading in the liposomal formulations. It is also found that 5FU-PAL at the air-water interface folded into highly-ordered multiple layer structures.