Biodistribution and anticancer activity of a new vinca alkaloid encapsulated into long-circulating liposomes

Abstract

S12363 is a potent therapeutic agent with a strong in vitro activity against a variety of tumor types but also a high in vivo toxicity. Loading of this drug into long-circulating liposomes is expected to enhance its therapeutic index. Pharmacokinetics of liposomal S12363 showed that circulating S12363 was entrapped into liposomes until 24 hours after intravenous injection in mice. The liposomal formulation significantly increased the plasma concentration, half-life, and AUC and decreased the plasma clearance rates and volume of distribution of S12363. Liposome extravasation was evaluated with two tumor models by both microscopic analysis and liposome radiolabeling. Liposome accumulation was much more important in the case of B16 melanoma, compared to H460 tumor, with both inoculated subcutaneously and with comparable size. H460 tumor was also inoculated into the lung. The tumor localization did not influence liposome accumulation into the tissue. The liposomal formulation injected into mice bearing B16 melanoma allowed a 10-fold accumulation of S12363 into the tumor interstitium, as compared to the solution. Bioluminescence data, supported by the survival curves of the animals, showed that S12363-liposomes were able to significantly restrict B16 melanoma progression and increase mice survival.

Keywords::

• Cancer chemotherapy
• long circulatory
• nanotechnology

Acknowledgments

The authors gratefully acknowledge Antoine Lhumeau (Technologie SERVIER, Orléans, France), Dr. Stéphanie Rétif, Marilyne Le Mee, and Stéphanie Lerondel (UPS CNRS 0044, Orléans, France) for technical aid on animal experiments, Dr. Thomas Arnauld (Technologie SERVIER, Orléans, France) and Dr. Serge Bernard (INRA, Nouzilly, Tours, France) for helpful assistance on S12363 radiolabeling, and Loïc Meunier and Dr. Vincent Croixmarie (Technologie SERVIER, Orléans, France) for chemometric analysis.

Declaration of interest: The authors report no financial conflicts of interest. The authors alone are responsible for the content and writing of this paper.