Anti-HIV efficacy and biodistribution of nucleoside reverse transcriptase inhibitors delivered as squalenoylated prodrug nanoassemblies.

Due to their hydrophilic nature, most nucleoside reverse transcriptase inhibitors (NRTIs) display a variable bioavailability after oral administration and a poor control over their biodistribution, thus hampering their access to HIV sanctuaries. The limited cellular uptake and activation in the triphosphate form of NRTIs further restrict their efficacy and favour the emergence of viral resistance. We have shown that the conjugation of squalene (sq) to the nucleoside analogues dideoxycytidine (ddC) and didanosine (ddI) leads to amphiphilic prodrugs (ddC-sq and ddI-sq) that spontaneously self-organize in water as stable nanoassemblies of 100-300 nm. These nanoassemblies can also be formulated with polyethylene glycol coupled to either cholesterol (Chol-PEG) or squalene (sq-PEG). When incubated with peripheral blood mononuclear cells (PBMCs) in vitro infected with HIV, the NRTI-sq prodrugs enhanced the antiviral efficacy of the parent NRTIs, with a 2- to 3-fold decrease of the 50% effective doses and a nearly 2-fold increase of the selectivity index. This was also the case with HIV-1 strains resistant to ddC and/or ddI. The enhanced antiviral activity of ddI-sq was correlated with an up to 5-fold increase in the intracellular concentration of the corresponding pharmacologically active metabolite ddA-TP. The ddI-sq prodrug was further investigated in vivo by the oral route, the preferred route of administration of NRTIs. Pharmacokinetics studies performed on rats showed that the prodrug maintained low amounts of free ddI in the plasma. Administration of (3)H-ddI-sq led to radioactivity levels higher in the plasma and relevant organs in HIV infection as compared to administration of free (3)H-ddI. Taken together, these results show the potential of the squalenoylated prodrugs of NRTIs to enhance their absorption and improve their biodistribution, but also to enhance their intracellular delivery and antiviral efficacy towards HIV-infected cells.

Intestinal permeation enhancement of docetaxel encapsulated into methyl-ß-cyclodextrin/poly(isobutylcyanoacrylate) nanoparticles coated with thiolated chitosan.

In this study we investigated the potential of mucoadhesive nanoparticles to enhance the intestinal permeability of docetaxel (Dtx). These nanoparticles were composed of methyl-ß-cyclodextrin (Me-ß-CD) combined with poly(isobutylcyanoacrylate) and coated with thiolated chitosan. In order to encapsulate the highest amount of Dtx into nanoparticles, the anionic emulsion polymerization of isobutylcyanoacrylate was carried out in a solution of Me-ß-CD/Dtx inclusion complex. The resulting nanoparticles were spherical with diameters ranging from 200 to 400 nm, and positively charged. Depending on the formulation, the encapsulation efficiency of Dtx was 70-80%. In vitro experiments in simulated intestinal medium containing 1% w/v of pancreatin showed that Dtx was gradually released to reach 60% after 24h and 100% after 48 h. The capacity of these nanoparticles to enhance the flux of Dtx across the intestinal membrane was then investigated using the Ussing chamber technique. The intestinal permeation of Dtx loaded into nanoparticles was found to be higher than the ethanol control solution of Dtx. Interestingly, when mucoadhesive interactions between nanoparticles and the mucosa were avoided, the intestinal permeation of Dtx significantly decreased, confirming that the mucoadhesion of the nanoparticles was a mandatory condition to enhance the intestinal permeation of Dtx.

A new nanomedicine based on didanosine glycerolipidic prodrug enhances the long term accumulation of drug in a HIV sanctuary.

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 24h 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.