Cristina Vaghi (1), Anne Rodallec (2), Guillaume Sicard (2), Florian Correard (3), Raphaelle Fanciullino (2), Joseph Ciccolini (2), Sebastien Benzekry (1), Clair Poignard (1)
(1) Inria Sud Ouest Bordeaux, Insitut de Mathématiques de Bordeaux CNRS UMR5251, France; (2)SMARTc CRCM Aix-Marseille University, France; (3) INP, CNRS, UMR 7051, Aix Marseille Université, France.
Introduction: The toxicity of chemotherapeutic agents remains one of the major challenges in breast cancer treatment. Nanoparticles conjugated with cancer cell specific antibodies provide an interesting alternative to improve drug delivery to the tumor, while sparing healthy tissues. The SMARTc lab developed antibody nano-conjugates (ANCs) consisting in docetaxel-encapsulated liposomes engrafted with trastuzumab on the surface [1]. However, intra-tumor penetration properties of these ANCs are not fully understood and could be improved. To this aim, mathematical modeling can provide quantitative tools to obtain a description of the ANCs transport inside a tumor. Few models in literature characterize the nanoparticle penetration in tumors [2][3][4]. We derive a multi-scale model to obtain a description of the fluid flow and nanoparticle transport in the tumor interstitium and vessels. Moreover, there is a lack of studies that integrate spatial data to theoretical models. Here, we aim at filling this gap.
Objectives:
- – Understand nanoparticle properties
- – Characterize the tumor microenvironment using mathematical modeling
- – Analyze the impact of the tumor microenvironment on nanoparticle penetration
Methods: Experimental data – carried on the MDA-MB-231 breast cancer cell line – included in vitro data to analyse nanoparticle specific properties (such as penetration in spheroids and cellular uptake) and ex-vivo microscopy images of tumor sections obtained from different regions of the tumor (central and peripheral) using fluorescence imaging. This data allowed to recover the tumor microstucture. Our multi-scale model consisted in two Darcy equations for the fluid flow and two convection-diffusion equations governing the ANCs penetration, including the porosity of the medium. In particular, we were able to link the microstructure of the tumor vasculature to the macroscopic description of the fluid flow and nanoparticle transport in the tumor. Eventually, our model was calibrated with the in vitro data and ex-vivo images.
Results: Simulations confirmed that the tumor microsctructure influences the macroscale flow dynamics and ANC delivery in the tumor interstitium. The model also provides quantitative predictions of the impact of the tumor microenvironment (e.g., heterogeneity, vessel leakage and interstitium permeability) on the accumulation and penetration of ANCs.
Conclusion: We have proposed a rigorous model of nanoparticle transport within tumors. The model provides a direct link between the microstructure of the tumor (the vasculature and the permeability properties of the capillaries) to the macroscale transport. The model is enriched to provide quantitative predictions of the impact of the tumor microenvironment (e.g., heterogeneity, vessel leakage and interstitial permeability) on the accumulation and penetration of ANCs. This methodology could be further applied to personalize the dose of injected nanoparticles according to a patient’s specific tumor histology.
References:
[1] A. Rodallec et al., “From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer,” Int. J. Nanomedicine, vol. Volume 13, pp. 6677–6688, Oct. 2018, doi: 10.2147/IJN.S179290.
[2] R. K. Jain and T. Stylianopoulos, “Delivering nanomedicine to solid tumors,” Nat. Rev. Clin. Oncol., vol. 7, no. 11, pp. 653–664, Nov. 2010, doi: 10.1038/nrclinonc.2010.139.
[3] R. J. Shipley and S. J. Chapman, “Multiscale Modelling of Fluid and Drug Transport in Vascular Tumours,” Bull. Math. Biol., vol. 72, no. 6, pp. 1464–1491, Aug. 2010, doi: 10.1007/s11538-010-9504-9.
[4] R. Penta, D. Ambrosi, and A. Quarteroni, “Multiscale homogenization for fluid and drug transport in vascularized malignant tissues,” Math. Models Methods Appl. Sci., vol. 25, no. 01, pp. 79–108, Jan. 2015, doi: 10.1142/S0218202515500037.
Reference: PAGE () Abstr 9462 [www.page-meeting.org/?abstract=9462]
Poster: Drug/Disease Modelling - Oncology