Marta RodrÃguez1, Alejandro Serrano1,2, Ainara Salgado1,2, Sara Zalba1,2, MarÃa Jesús Garrido1,2, Iñaki Fernández de Trocóniz1,2,3
1Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, 2Navarra Institute of Health Research (IdisNa) , 3Institute of Data Science and Artificial Intelligence DATAI
Introduction: Although immunotherapy (IT) has transformed cancer treatment, tumors can evade immunosurveillance by inducing infiltration of immune cells such as regulatory T cells (Treg) into tumor microenvironment (TME), rendering IT ineffective [1]. Therefore, new strategies are being developed to target Treg activity. P60 is a Foxp3 blockade peptide capable of inhibiting Treg activity. However, its low systemic stability and non-specific Treg targeting have limited its ability for clinical translation [2,3]. To overcome these limitations, the P60 encapsulation in a lipid nanoparticle decorated with the monovalent variable fragment of an anti-CD25 mAb has the advantages of increasing the in-vivo stability of the peptide and selectively targeting Treg, the immune cell population the overexpresses CD25 [4]. Thus, a new Treg targeted formulation was successfully developed with promising antitumor activity in tumors with significant Treg tumor infiltration (ILDIR CF-P60). Objectives: •To propose a physiological framework to explore the biodistribution of this new Treg targeted nanoparticle. •To explore the longitudinal data of nanoparticles concentrations in the different organs. •Finally, to develop a PBPK model based in the previous framework to describe data simultaneously in the different organs. Methods: For encapsulating P60 lipid nanoparticles were used, composed of hydro-soy phosphatidylcholine, cholesterol and polyethylene-glycol-750. To quantitively characterize both P60 and liposomes amount, P60 was bounded to carboxyfluorescein and the nanoparticles were dyed with DiT. 26 C57B6/J mice (50% female) were inoculated with MC38 cells. Seven days after, when the tumor size was approximately 50 mm3, mice were randomly divided to receive either saline (control group) or a single 10 µg i.v. administration of ILDIR CF-P60. Levels of nanoparticle were measured in blood, heart, lung, kidney, spleen, thymus, liver and tumor at different sampling times for a period of 48 hours after administration. Each animal contributed with a single measurement for each of the biological matrices afore mentioned. Longitudinal data of P60 were analyzed simultaneously using the naïve pool approach (NPA) with Monolix2023R1 (Simulation Plus, Inc). Results: A PBPK model assuming first perfusion limited distribution was first developed. This model performance show major model misspecifications as the majority of the observations were clearly under predicted. To improve the description of the data, several mechanisms were included in the structure of the PBPK: (i) the lymphatic system, (ii) an accumulation mechanism for the tumor compartment, supported by physiological factors such as the enhanced permeability and retention (EPR) effect and (iii) size-dependent nanoparticle extravasation for the different endothelial groups based on the pore size of the vascular endothelium. This key aspect allowed us to characterize three partition coefficients, an aspect that is not included in other similar models in literature although it has been recognized as a potential factor influencing distribution. The obtained values for these parameters were 0.028, 0.17 and 3.51 for continuous, discontinuous and fenestrated endothelium, respectively. Conclusion: A pharmacokinetic model based on physiological principles for targeted nanoparticles has been developed in tumor-bearing mice, accurately describing the time course of nanoparticle concentrations in blood, various organs, and the tumor after a single intravenous administration.
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Reference: PAGE 33 (2025) Abstr 11649 [www.page-meeting.org/?abstract=11649]
Poster: Drug/Disease Modelling - Absorption & PBPK