Doaa Ahmed Mohamed (1), Henry Pertinez (1), Ibane Abasolo (3,4), Maiara Montanha (1), Monserrat Llaguno (3), Rajith Rajoli (1), Paul Southern (2), Quentin A. Pankhurst (2), Zamira V. DÃaz-Riascos (3,4), Neill Liptrott (1)
(1) University of Liverpool, UK, (2) Resonant Circuits Limited, UK, (3) Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), Spain, (4) Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Spain.
Introduction: Iron oxide nanoparticles (NPs), particularly magnetic iron oxide (MIO) nanoparticles, may provide a potential therapeutic intervention in therapy, due to their ability to induce hyperthermia at sites in which they accumulate, such as solid mass tumours. Following accumulation within cancer cells, hyperthermic treatment using MIO, leads to their shrinkage and death. It is, therefore, essential to define both local (tumoral) and systemic MIO distribution following intratumoral injection to clarify their efficacy and safety profile.
Objectives: The study aimed to simulate systemic distribution of MIO NPs ≥ 100 nm after intratumoral/interstitial injection using a novel mechanistic and physiologically based pharmacokinetic (m-PBPK) model.
Methods: A m-PBPK tumour connected to a whole-body murine model was designed in Simbiology v. 9.6.0 (MATLAB R2019a). The model used to simulate mice aged 7-19 weeks (weighing 18-28 g). A pancreatic solid tumour mass was integrated as 3-D sphere composed of three tumoral sub-compartmental regions: proliferative, quiescent and necrotic. The tumour model (volume = 235 mm3) was connected to the rest of the body via blood and lymphatic circulation. The m-PBPK model used first order kinetics to describe the MIO NPs distribution process. MIO NPs movement was mainly driven by organs blood flows, transcytosis, and uptake by macrophages. Transcytosis mechanisms were implemented according to MIO NPs size and organ capillary pore size. The model was validated against preclinical pancreatic tumour bearing mice data with MIO NPs (1 mgFe/100 mm3Tumour) intratumoral administration. The model was determined to be valid if the absolute average-fold error (AAFE) was within 2-fold of the mean reported values.
Results: Mean retention amounts of injected dose (%ID) of MIO after 28 days in tumour, liver, spleen and kidneys were computed to be 15.44 ± 2.5, 19.89 ± 0.5, 1.58 ± 0.02 and 2.45 ± 0.04 compared to the observed %ID values of 12.93 ± 7.07, 20.42 ± 11.60, 3.22 ± 0.68 and 0.59 ± 0.09, respectively. AAFE estimation was 1.194, 1.027, 2.077 and 4.153, respectively. The simulations showed high accumulation of MIO in the organ vascular space compared to the interstitial space.
Conclusions: The m-PBPK model successfully provided valuable estimates of MIO accumulation in the tumour and liver, with underestimation of accumulation in the spleen and overestimation of accumulation in the kidneys. A potential explanation of overprediction in the kidneys is the high regional blood flow. Therefore, a correction factor with 25% has been tested to control MIO NPs amount distributed with blood, this leaded to %ID reduction to 0.62 ± 0.017. This indicates that an unknown factor may affect kidneys distribution rather than blood flow solely. Further optimisation of the m-PBPK approach with integration of experimental in vitro data, such as macrophage uptake and release, would be beneficial to improve these quantitative pharmacokinetic predictions.
Reference: PAGE 30 (2022) Abstr 9953 [www.page-meeting.org/?abstract=9953]
Poster: Drug/Disease Modelling - Oncology