Encapsulation of c-myc antisense oligodeoxynucleotides in lipid particles improves antitumoral efficacy in vivo in a human melanoma line

Phosphorothioate c-myc antisense oligodeoxynucleotides [S]ODNs (free INX-62 95) were encapsulated in a new liposome formulation and the antitumor activ ity was compared to the unencapsulated antisense in a human melanoma xenogr aft. The systemic administration of INX-6295 encapsulated in stabilized ant isense lipid particles (SALP INX-6295) improved plasma AUC (area under the plasma concentration -time curve) and initial half-life of free INX-6295, r esulting in a significant enhancement in tumor accumulation and improvement in tumor distribution of antisense oligodeoxynucleotides. Animals treated with SALP INX-6295 exhibited a prolonged reduction of c-myc expression, red uced tumor growth and increased mice survival. When administered in combina tion with cisplatin (DDP), SALP INX-6295 produced a complete tumor regressi on in approximately 30% of treated mice, which persisted for at least 60 da ys following the first cycle of treatment. Finally, the median survival of mice treated with DDP/SALP INX-6295 increased by 105% compared to 84% for a nimals treated with the combination DDP/free INX-6295. These data indicate that the biological activity and the therapeutic efficacy of c-myc antisens e therapy may be improved when these agents are administered in lipid-based delivery systems.