Introduction: To efficiently deliver treatment, nanomedicines must exhibit sufficient blood bioavailability for further accumulation at the target site. So far, a large part of the administered dose remains useless due to the high rate of clearance by the mononuclear phagocytic system (mainly by Kupffer cells). Here we propose a new approach to redefine nanomedicines bioavailability by priming the body before receiving the treatment as a sequential administration of a nanoprimer before the nanomedicine. The nanoprimer is a nanoparticle designed to transiently occupy the main pathway responsible for the limited bioavailability of nanomedicines. As such, the nanoprimer allows to redefine the bioavailability of different nanomedicines and improve treatment’s outcomes for a large panel of therapeutic agents (e. g. small molecules or nucleic acids).
Methods: Optimization of nanomedicines bioavailability was performed using a liposomal nanoprimer with specific physico-chemical properties. First we evaluated the nanoprimer’s biodistribution by in vivo imaging system, and its accumulation within the different hepatic cell populations by flow cytometry. Then we evaluated the impact of this nanoprimer on the bioavailability of different nanomedicines: for this, blood bioavailability and biodistribution of irinotecan loaded liposomes or mRNA loaded nanoparticles (lipidic and polymeric) were evaluated by HPLC and fluorescence respectively. We compared distribution of each nanomedicine administered intravenously alone or 10min after a single intravenous (IV) injection of nanoprimer on HT29 (colorectal adenocarcinoma) xenografted mice. Finally, the impact of nanoprimer on efficacy was evaluated by a tumor growth delay experiment for irinotecan loaded liposomes by IV administration of nanoprimer 10min before irinotecan loaded liposomes in HT29 xenografted mice. Treatment cycle was repeated one week later. For nucleic acid loaded nanoparticles, the impact of the nanoprimer was evaluated by measuring transfection efficiency on HT29 xenografted mice 24h after IV administration of the nanoprimer 10min before nanomedicine.
Results: liposomal nanoprimers present a rapid accumulation in the liver with a preferential localization in Kupffer cells and liver sinusoidal endothelial cells. This accumulation leads to transient cells saturation and decreased hepatic trapping of the nanomedicines. Increased bioavailability resulted in a higher accumulation of irinotecan loaded liposomes within the HT29 tumor and in an increased efficacy. Such a bioavailability increase is also related with the transfection profile obtained for the nucleic acid loaded nanoparticles.
Here we showed that a same nanoprimer could be used to prime the body to receive different types of nanomedicines and improve treatment’s outcomes. Such approach may decrease compromises between bioavailability, efficacy and toxicity.
Citation Format: matthieu germain, Laurence Poul, Julie Devalliere, Marion Paolini, Audrey Darmon, Maxime Bergere, Oceane Jibault, Francis Mpambani. Mononuclear phagocytic system occupancy to increase nanomedicines based treatment efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3613.