TY - JOUR
T1 - A new nanomedicine based on didanosine glycerolipidic prodrug enhances the long term accumulation of drug in a HIV sanctuary
AU - Skanji, Rym
AU - Andrieux, Karine
AU - Lalanne, Muriel
AU - Caron, Joachim
AU - Bourgaux, Claudie
AU - Degrouard, Jéril
AU - Brisset, Franois
AU - Gueutin, Claire
AU - Chacun, Hélne
AU - Dereuddre-Bosquet, Nathalie
AU - Paci, Angelo
AU - Vassal, Gilles
AU - Bauduin, Laurent
AU - Garcia-Argote, Sébastien
AU - Rousseau, Bernard
AU - Clayette, Pascal
AU - Desmaële, Didier
AU - Couvreur, Patrick
N1 - Funding Information:
The financial support of “ Agence Nationale de la Recherche ” (ANR, grant NT05-1_43236 SYLIANNU) and the PRES Universud Paris (Institut du médicament, appel d’offre 2008) are acknowledged. Authors thank MENRT for providing financial support to M. Lalanne, for technical support M. Besnard (CNRS, UMR 8612), V. Domergue (Animalerie centrale, Faculté de Pharmacie, Chatenay-Malabry), Emeline CHU-VAN et Céline DECLEIN (Bertin Pharma, CEA) and Nicolas Tsapis (CNRS, UMR 8612) for manuscript corrections.
PY - 2011/7/29
Y1 - 2011/7/29
N2 - New nanomedicines could improve drug accumulation in HIV sanctuaries and ameliorate their antiretroviral efficiency. In this view, we propose herein a combined strategy based on a biomimetic prodrug of ddI and its formulation in well-characterized lipid nanoobjects. The glycerolipidic prodrug of ddI (ProddINP) has been synthesized and its bulk structure was characterized. An appropriate formulation of this prodrug has been designed using a rational approach combining different physicochemical techniques. The high incorporation ratio of the prodrug into dipalmitoylphosphatidylcholine (DPPC) bilayers was determined by DSC. Then two liposome preparation methods were compared, with respect to size, incorporation yield and molecular/supramolecular organization of vesicles. The best liposomal formulation of ProddINP has been checked to keep intact the anti-HIV activity of ddI. This formulation was finally compared to ddI after oral route in rat. The animal experiments evidenced the increase of ddI blood half life (3-fold) and its enhanced accumulation as prodrug form at 24 h in numerous organs and especially intestine after administration of ProddINP in comparison with free drug. Finally, the tested liposomal formulation of ProddINP seems to be a promising approach to eradicate HIV infection from intestinal sanctuaries where the virus can concentrate.
AB - New nanomedicines could improve drug accumulation in HIV sanctuaries and ameliorate their antiretroviral efficiency. In this view, we propose herein a combined strategy based on a biomimetic prodrug of ddI and its formulation in well-characterized lipid nanoobjects. The glycerolipidic prodrug of ddI (ProddINP) has been synthesized and its bulk structure was characterized. An appropriate formulation of this prodrug has been designed using a rational approach combining different physicochemical techniques. The high incorporation ratio of the prodrug into dipalmitoylphosphatidylcholine (DPPC) bilayers was determined by DSC. Then two liposome preparation methods were compared, with respect to size, incorporation yield and molecular/supramolecular organization of vesicles. The best liposomal formulation of ProddINP has been checked to keep intact the anti-HIV activity of ddI. This formulation was finally compared to ddI after oral route in rat. The animal experiments evidenced the increase of ddI blood half life (3-fold) and its enhanced accumulation as prodrug form at 24 h in numerous organs and especially intestine after administration of ProddINP in comparison with free drug. Finally, the tested liposomal formulation of ProddINP seems to be a promising approach to eradicate HIV infection from intestinal sanctuaries where the virus can concentrate.
KW - Antiviral activity
KW - Didanosine
KW - In vivo experiments
KW - Liposomes
KW - Prodrug
UR - http://www.scopus.com/inward/record.url?scp=79959754349&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2011.05.005
DO - 10.1016/j.ijpharm.2011.05.005
M3 - Article
C2 - 21596125
AN - SCOPUS:79959754349
SN - 0378-5173
VL - 414
SP - 285
EP - 297
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
IS - 1-2
ER -