Knowledge-Based Design of 5‑Fluororacil Prodrug
Liposomal Formulation: Molecular Packing and Interaction Revealed
by Interfacial Isotherms and X‑ray Scattering Techniques
posted on 2021-11-05, 19:34authored byTiep Pham, Paola Leon Plata, Pin Zhang, Anand Vellara, Wei Bu, Binhua Lin, Gang Cheng, Ying Liu
Prodrugs and nanoformulations are
two effective strategies for
sustained drug release and targeting drug delivery. In this study,
we combined the two strategies to judiciously design the liposome
formulation incorporating an amphiphilic prodrug of 5-fouroracil (5-FU),
named 5-FCPal, for sustained drug release and enhanced bioavailability.
5-FCPal is an analogue of capecitabine (N4-pentyloxycarbonyl-5′-deoxy-5-fluorocytidine,
Xeloda) by substituting the pentyl group at the N4 position
with the palmityl. The amphiphilic molecule of 5-FCPal can self-assemble
with the phospholipids to form stable vesicle structures with high
drug loading. Although lipid vesicles have been widely studied and
commercially used for clinical applications, because of the enormous
options of the lipids and the equitable balance of hydrophobicity
and bioavailability, it is essential to fundamentally understand the
molecular interactions when designing and optimizing the liposomal
prodrug formulations. We report the study of using X-ray liquid surface
scattering techniques integrated with a Langmuir trough to explicitly
reveal the interfacial behavior of the monolayer membrane of 5-FCPal
with various saturated and unsaturated lipids with positively charged,
neutral, and negatively charged head groups. More specifically, interfacial
packing of the molecules was quantified using interfacial isotherms,
X-ray reflectivity (XR), and grazing-incidence diffraction (GIXD).
The results indicate that the interactions between the prodrug and
the cationic lipids are most favorable. The highest drug loading is
quantified by increasing the molar ratio of the prodrug until stable
monolayer structures were disrupted by the multiple-layer domain of
prodrug aggregates. Stable liposomes of 100 nm with 50% drug loading
of 5-FCPal were generated based on the findings from the X-ray studies.