Abstract 2871: The Nanoprimer: a nanoparticle designed to transiently occupy the mononuclear phagocytic system in order to increase nanomedicine-based treatments efficacy
Authors: Devalliere Julie , Poul Laurence , Darmon Audrey , Jibault Oceane , Bergere Maxime , Mpambani Francis , Saunders Nell , Paolini Marion , Langer Robert , Germain Matthieu 
Published: September 2020

Abstract
Introduction: Most nanomedicines are currently limited in their efficacy due to a sub-optimal biodistribution/accumulation in the target tissues. 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 in liver). We designed a new approach based on the use of an engineered, biocompatible nanoparticle–the Nanoprimer–that is administered before the nanomedicine in order to transiently and specifically occupy the liver clearance pathways responsible for sub-optimal therapeutic bioavailability. The Nanoprimer's effect is only based on its specific physico-chemical properties, there is no active principal ingredient encapsulated in it. Here we demonstrate the ability of the Nanoprimer to redefine the bioavailability and efficacy of nanomedicines loaded with small molecules or nucleic acid. We evaluated the biodistribution and the safety of the Nanoprimer alone and of an irinotecan loaded liposome combined with the Nanoprimer.
Methods: Quantitative evaluation of the Nanoprimer's biodistribution was performed by mass spectrometry. Safety profile of the Nanoprimer was evaluated in vitro (cell viability, cytokines/interleukins expression profile, complement activation, phagoburst and phagotest on different cell lines) and in vivo, in mice, by a follow up of body weight and clinical signs, histological observations of liver, spleen and lungs and blood parameters titration, after the injection of a maximized dose of Nanoprimer. The impact of the Nanoprimer on the bioavailability and biodistribution of nanomedicines loaded with irinotecan or nucleic acids (mRNA / SiRNA) was evaluated by HPLC and fluorescence quantification, respectively. Finally, the impact of the Nanoprimer on treatment was evaluated using nanomedicines encapsulating human erythropoietin (hEPO) mRNA, Factor VII (FVII) siRNA or irinotecan.
Results: The Nanoprimer presents a rapid accumulation within liver and spleen. The Nanoprimer was well tolerated with no sign of toxicity observed using therapeutic dosage. The administration of the Nanoprimer increases systemic bioavailability of different type of nanomedicines and enhances their accumulation in target tissues. This improved bioavailability is correlated with an increased secretion of hEPO by 30%, for mRNA-loaded nanomedicines, an increased silencing of FVII by 50%, for siRNA-loaded nanomedicines, and an increased anti-tumor efficacy by 50%, for irinotecan-loaded nanomedicines.
Here, we showed the safe profile of the Nanoprimer and its ability to increase the treatment outcomes for different nature of nanomedicines. The separation of the functions ensuring the efficacy of a treatment into two distinct objects opens perspectives for designing future nanomedicines and a shift in the therapeutic paradigm.
Citation Format: Julie Devalliere, Laurence Poul, Audrey Darmon, Oceane Jibault, Maxime Bergere, Francis Mpambani, Nell Saunders, Marion Paolini, Robert Langer, Matthieu Germain. The Nanoprimer: a nanoparticle designed to transiently occupy the mononuclear phagocytic system in order to increase nanomedicine-based treatments efficacy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2871.