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Title: Nanostructured self-assembly materials from neat and aqueous solutions of C18 lipid pro-drug analogues of Capecitabine—a chemotherapy agent. Focus on nanoparticulate cubosomes™ of the oleyl analogue

A series of prodrug analogues based on the established chemotherapy agent, 5-fluorouracil, have been prepared and characterized. C18 alkyl and alkenyl chains with increasing degree of unsaturation were attached to the N4 position of the 5-fluorocytosine (5-FC) base via a carbamate bond. Physicochemical characterization of the prodrug analogues was carried out using a combination of differential scanning calorimetry, cross-polarized optical microscopy, X-ray diffraction and small-angle X-ray scattering. The presence of a monounsaturated oleyl chain was found to promote lyotropic liquid crystalline phase formation in excess water with a fluid lamellar phase observed at room temperature and one or more bicontinuous cubic phases at 37 °C. The bulk phase was successfully dispersed into liposomes or cubosomes at room and physiological temperature respectively. In vitro toxicity of the nanoparticulate 5-FCOle dispersions was evaluated against several normal and cancer cell types over a 48 h period and exhibited an IC50 of -100 μM against all cell types. The in vivo efficacy of 5-FCOle cubosomes was assessed against the highly aggressive mouse 4T1 breast cancer model and compared to Capecitabine (a water-soluble commercially available 5-FU prodrug) delivered at the same dosages. After 21 days of treatment, the 0.5 mmol 5-FCOle treatment group exhibited amore » significantly smaller average tumour volume than all other treatment groups including Capecitabine at similar dosage. These results exemplify the potential of self-assembled amphiphile prodrugs for delivery of bioactives in vivo.« less
Authors:
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Publication Date:
OSTI Identifier:
1028505
Resource Type:
Journal Article
Resource Relation:
Journal Name: Soft Matter; Journal Volume: 7; Journal Issue: (12) ; 05, 2011
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AQUEOUS SOLUTIONS; CALORIMETRY; CARBAMATES; CHEMOTHERAPY; FLUOROURACILS; IN VITRO; IN VIVO; LIPIDS; LIPOSOMES; MAMMARY GLANDS; NEOPLASMS; OPTICAL MICROSCOPY; SCATTERING; TOXICITY; WATER; X-RAY DIFFRACTION