Introduction: The benefit of a nanomedicine is due to its bioavailability, its intrinsic efficacy balanced with its toxicity profile. The nanomedicine should exhibit sufficient blood bioavailability for efficient 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 hepatic Kupffer cells). Enhanced bioavailability can be achieved by modifying physico-chemical properties of the nanomedicine but such modification affects also its efficacy and toxicity profiles. Ultimately, nanomedicines design results usually in a compromise between bioavailability, efficacy or toxicity. Here we propose a new approach to change the way nanomedicine are biodistributed, by priming the body to receive the treatment. This approach relies on the 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 the nanomedicine. As such, the nanoprimer allows to redefine the bioavailability of the nanomedicine.
Methods: For proof of concept we designed a liposomal nanoprimer with specific physico-chemical properties. Its biodistribution was evaluated by labelling with gold nanoparticles. 24h after intravenous (IV) administration on mice, gold quantification was performed on sampled organs by ICPMS. Toxicity evaluation was performed by 3 IV injections of nanoprimer spaced of 24h on mice followed by a one week follow up of body weight and clinical signs. Histological liver and spleen observations and transaminases titration were performed 1 and 7 days after last injection. Evaluation of the impact of nanoprimer on nanomedicines bioavailability was performed by in vivo follow up of a fluorescent nanomedicine IV injected 10min after nanoprimer IV injection. Tumor growth delay experiment was performed by IV administration of nanoprimer 10min before irinotecan loaded liposomes on mice xenografted with HT29 (colorectal adenocarcinoma) tumor model once the tumor reached 150mm3. Treatment was repeated one week later.
Results: The liposomal nanoprimer presents a preferential hepatic accumulation. No signs of systemic or hepatic toxicity were observed with maximized dose of this nanoprimer. Nanomedicine bioavailability studies showed a transient increase of nanomedicine blood bioavailability correlated with a lower hepatic accumulation when combined to nanoprimer. Finally efficacy study showed that nanoprimer markedly enhanced anti-tumor efficacy of irinotecan loaded liposomes in the HT-29 model when compared to the nanomedicine alone.
Body priming may benefit to a wide variety of existing products modulating their bioavailability and may open perspective to design new nanomedicines by decreasing the notion of compromise between bioavailability, efficacy and toxicity.
Citation Format: Matthieu Germain, Laurence Poul, Marie-Edith Meyre, Marion Paolini, Francis Mpambani, Maxime Bergere, Agnes Pottier, Laurent Levy. Redefine nanomedicine products bioavailability to improve anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-072.