Abstract 3295: The Nanoprimer: A nanoparticle designed to the efficacy of nucleic acid-based therapeutics in oncology

Abstract

Abstract Nucleic acid drugs have shown promise in oncology, however their use is limited by hepatic clearance. Due to the mononuclear phagocytic system (MPS), a large part of the intravenously-administered dose does not reach the therapeutic target. Our approach aims to address this issue using biocompatible nanoparticles—the Nanoprimer—that is administered prior to the therapeutic. Due to its physico-chemical properties, the Nanoprimer is transiently internalized by Kupffer cells (KC), and endothelial cells of the MPS, enabling temporary reduction of hepatic clearance. These data further explore the Nanoprimer’s mechanism of action and demonstrate that scavenger receptor-A (SR) is the main receptor involved in Nanoprimer binding and uptake by KC. Efficacy studies in mouse model show that the Nanoprimer dramatically increases the anti-tumor efficacy of nucleic acid-based treatment without introducing additional toxicities. An in vitro toxicity evaluation was performed investigating the Nanoprimer’s hemolytic properties and its potential ability to activate the complement system, platelet aggregation and pro-inflammatory cytokines*. SR-mediated binding and uptake of Nanoprimer by KC were assessed using a competitive binding assay with SR inhibitor polyinosinic acid. The impact of the Nanoprimer on anti-tumor efficacy was evaluated on orthotopic triple negative breast cancer (TNBC) model in combination with siRNA-loaded lipid nanoparticles (LNPs) targeting a novel cancer-specific gene transcript of a master regulator of invadopodia formation and Wnt, Hedgehog and Notch oncogenic pathways. Results showed that the Nanoprimer is safe at the effective dose. The Nanoprimer does not activate the complement components, induce hemolysis, platelet aggregation, or cytokine storm syndrome elements. The competitive inhibition of SR-A decreases Nanoprimer binding and KC-uptake by 70%, indicating SR-A selective uptake of the Nanoprimer by macrophages. The efficacy study shows that combining the Nanoprimer with siRNA LNP therapy significantly increased treatment efficiency, with a mean tumor growth inhibition ratio of 36.3% for LNPs alone versus 84.6% for the combination. Moreover, the combination therapy more efficiently prevents the development of pulmonary metastatic tumors, with a metastasis-inhibition rate of 98%. These data demonstrate the safety of the Nanoprimer, along with its ability to maximize the inhibition of primary tumor growth and pulmonary metastasis by systemic siRNA LNP therapy in a TNBC mouse model. They also highlight the capacity of Nanoprimer technology to unlock the potential of nucleic acid-based treatments. The ubiquitous nature of its mode of action allows its application to a broad spectrum of anti-cancer therapeutics. *we acknowledge NCL, Frederick National Laboratory for Cancer Research sponsored by the NCI for the help with conducting these experiments Citation Format: Julie Devallière, Laurence Poul, Maxime Bergère, Audrey Darmon, Océane Jibault, Francis Mpambani, Kelvin Tsai, Matthieu Germain. The Nanoprimer: A nanoparticle designed to the efficacy of nucleic acid-based therapeutics in oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3295.