title: Lyotropic liquid crystalline self-assembly material behavior and nanoparticulate dispersions of a phytanyl pro-drug analogue of capecitabine-a chemotherapy agent.
abstract: An amphiphile prodrug, 5'-deoxy-5-fluoro-N⁴-(phytanyloxycarbonyl) cytidine (5-FCPhy) has been prepared and investigated for its self-assembly material properties, in vitro cytotoxicity, and in vivo efficacy as a chemotherapy agent. The phase transitions and stability of the neat amphiphile were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). X-ray diffraction (XRD) was used to confirm the structure of the neat amphiphile, which was an amorphous glassy material. The lyotropic liquid crystalline self-assembly behavior of the amphiphile prodrug in water was examined by cross polarizing optical microscopy (POM) and small-angle X-ray scattering (SAXS). Under excess water conditions at room temperature, the amphiphile prodrug self-assembles into lyotropic liquid crystalline mesophases of inverse bicontinuous cubic symmetry. Upon aging, the inverse cubic phase slowly transformed to an inverse hexagonal phase. This amphiphile was successfully dispersed into nanoparticles of cubic and hexagonal symmetry. The in vitro cytotoxicity of dispersed nanoparticles was evaluated in seven different normal and cancer cell types and exhibited IC₅₀ values between 70 and 90 μM for all cell types. Evaluation of 5-FCPhy in vivo against a mouse 4T1 breast tumor model displayed a trend of increasing efficacy with increasing dose. Furthermore, after 21 days, tumor volumes in the 0.5 mmol 5-FCPhy treatment group were significantly smaller than all other treatment groups including mice receiving a short chain water-soluble analogue, Capecitabine (a commercially available oral chemotherapy agent), delivered at the same dosage.
authors: CSIRO Materials Science and Engineering , PO Box 184, North Ryde, NSW 1670, Australia.
authors: Xiaojuan
authors: X
authors: Gong
authors: Minoo J
authors: MJ
authors: Moghaddam
authors: Sharon M
authors: SM
authors: Sagnella
authors: Charlotte E
authors: CE
authors: Conn
authors: Stephen J
authors: SJ
authors: Danon
authors: Lynne J
authors: LJ
authors: Waddington
authors: Calum J
authors: CJ
authors: Drummond
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy; D000069287:Capecitabine; D002470:Cell Survival; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004355:Drug Stability; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D050866:Liquid Crystals / Q000737:chemistry*; D051379:Mice; D044367:Phase Transition; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil