["Squalenoylation": a new approach to the design of anticancer and antiviral nanomedicines].
Some nucleoside analogs display significant activity against malignancies (gemcitabine, cytarabine) or viruses (ddl, ddC, AZT) by interfering with DNA synthesis. However, their use is limited by their relatively poor intracellular diffusion, rapid metabolism and induction of resistance. We have discovered that linking nucleoside analogs to squalene produces amphiphilic molecules that self-organize in water as nanoassemblies of 100-300 nm, irrespective of the nucleoside analog used. Gemcitabine nanoassemblies exhibited far greater activity than free gemcitabine against both subcutaneously grafted solid tumors (L1210 and P388) and aggressive metastatic leukemia (leukemia L1210 wt, P388 and RNK-16 LGL). Likewise, squalenated ddI and ddC nanoassemblies were more efficient than free ddI and ddC against HIV-infected lymphocytes. It is of prime importance to unravel the supramolecular organization of these nanoassemblies. For example, it has been shown that squalenated gemcitabine nanoassemblies form inverted hexagonal phases.
Couvreur
Patrick
P
Université Paris Sud, 5, rue Jean-Baptiste Clément, 92296 Chatenay-Malabry.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage*; D036103:Nanotechnology; D013185:Squalene / Q000494:pharmacology*
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D013185:Squalene