(229aq) Incorporating Time Constraints in Model Based Control of siRNA Delivery

Small-interfering RNA (siRNA) is a therapeutic RNA interference (RNAi) agent with strong potential for the treatment of a wide range of diseases that are associated with undesirable gene expression [1]. Safe and effective targeted delivery of siRNA therapeutics to cells in the human body remains a main barrier to realize its clinical potential. Several modelling approaches have been used in the field of gene therapy; however, a comprehensive approach that integrates all the key pharmacological issues into a framework that is applicable for in vivo conditions is still lacking. This contribution presents a model-based control study of non-viral siRNA delivery that describes the dynamics of the delivery process and takes into account the main pharmacological issues such as efficacy and toxicity, as well as the influence of cell division on intracellular transport.

In this work, pharmacokinetic (PK) and pharmacodynamic (PD) modelling approach was developed based upon the experimental analysis of siRNA delivery that had been measured in the intracellular compartments, which is reported in the literature [2]. The PK model was used to describe intracellular transport processes responsible for siRNA delivery during in vitro cell transfection, and modified to incorporate the infusion rate of siRNA therapeutics for in vivo conditions. The PD model was constructed to describe the correlation between siRNA concentration and its pharmacological effects. The developed modeling and control framework provides integration of the pharmacokinetic and pharmacodynamic models, which is then used for computation of optimal siRNA delivery profile. The optimization formulation is set up to control the siRNA delivery system in the presence of different practical constraints while simultaneously considering the key pharmacological issues such as cytotoxicity. The impact of cell division was evaluated by incorporating time constraints into the optimal control framework in order to achieve the desired therapeutic effect before the cell division takes place. The siRNA delivery optimal control problem was formulated and solved while considering different cell doubling times to account for uncertainty in the pace of cell cycling. The obtained results suggest the optimal dosage injection rate and optimal cellular exposure of siRNA in order to exert maximum therapeutic effect during the therapy while simultaneously preserving cell viability. The solution of the constrained optimization problem indicates how these profiles are affected by the trade-offs between efficacy and toxicity.

[1] WANG, J., LU, Z., WIENTJES, M. G. & AU, J. L. S. 2010. Delivery of siRNA Therapeutics: Barriers and Carriers. AAPS Journal, 12, 492-503.

[2] ZHOU, C. G., ZHANG, Y., YU, B., PHELPS, M. A., LEE, L. J. & LEE, R. J. 2013. Comparative cellular pharmacokinetics and pharmacodynamics of siRNA delivery by SPANosomes and by cationic liposomes. Nanomedicine-Nanotechnology Biology and Medicine, 9, 504-513.