N. Rodichenko (1,2), T. Slastnikova (1, 3), M. Durymanov(1, 3), E. Beletkaia (1,3), Y. Khramtsov (1), A. Rosenkranz (1,3), V. Fomichev(2), A. Sobolev (1,3)
(1) Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, RAS, Moscow, Russia; (2) Department of Nonlinear dynamical systems and control processes, Faculty of Computational mathematics and cybernetics, Moscow State University, Moscow, Russia; (3)Department of Biophysics, Biological Faculty, Moscow State University, Moscow, Russia
Objectives: The modular nanotransporters (MNT), a recombinant multidomain protein, used for delivery of various cytotoxic agents (radioisotopes, photosensitizers) to solid tumours and metastases [1-3] is currently in pre-clinical evaluation. This study is aimed at assessing delivery kinetics and tumour-specificity of the MNT, and developing a physiologically-based pharmacokinetic model for estimating overall tumour drug exposure, cytotoxicity, and efficiency for various cytotoxic agents and doses. A framework and efficiency criteria are also developed for future population pharmacokinetic analysis.
Methods: Intracellular kinetic multi-compartmental model was constructed and evaluated in MATLAB. Overall tissue distribution model was constructed and evaluated using custom C++ code and NVidia CUDA GPU parallel computing framework. Parameter estimation for intracellular kinetic model was done in MATLAB using Global Optimization Toolbox. Parameter estimation for tissue distribution model was done using custom global optimization routines. Both extracellular and intracellular processes were incorporated into single model and evaluated using CUDA framework.
Results: A method for multimodal estimation of therapeutic efficiency and specificity of tumour-targeting MNT is proposed. Using this method, a model for estimation of therapeutic efficiency and specificity of radioisotope-carrying MNT against dose and radioisotope type was developed. After estimating the model parameters with experimental data, a panel of specificity and efficiency dependence on dose and isotope type was derived. To efficiently carry out computations, a high-performance parallel-computing software for evaluation of tissue distribution of MRT was developed.
Conclusions: Physiologically-based modelling of MNT tissue distribution and intracellular trafficking kinetics allowed preliminary estimation of therapeutic efficiency and tissue-specificity of various MNT-drug conjugates based on limited experimental data. Due to physiologically-based nature of this approach, it allows translation to various organisms, including human, for model-based assessment and evaluation of clinical trials.
References:
[1] Gilyazova DG, Rosenkranz AA, Gulak PV, Lunin VG, Sergienko OV, Khramtsov YV, Timofeyev KN, Grin MA, Mironov AF, Rubin AB, Georgiev GP, Sobolev AS. Targeting cancer cells by novel engineered modular transporters. Cancer Res. 2006, 66:10534-10540.
[2] Sobolev AS. Modular transporters. In: Encyclopedia of Cancer 2nd edition in 4 volumes. Schwab M, ed. Berlin-Heidelberg-New York-Tokyo, Springer-Verlag, 2008, pp. 1932-1933.
[3] Slastnikova TA, Rosenkranz AA, Gulak PV, Schiffelers RM, Lupanova TN, Khramtsov YV, Zalutsky MR, Sobolev AS. Modular nanotransporters: a multi-purpose in vivo working platform for targeted drug delivery. Int J Nanomed, 2012, 7:467-482.
Reference: PAGE 21 (2012) Abstr 2589 [www.page-meeting.org/?abstract=2589]
Poster: New Modelling Approaches