Further quantitative understanding of the biological effects and mechanisms involved in cellular and intracellular delivery of nucleic acid materials is required to produce clinical applications of gene therapy. Several modeling approaches have been used in this field; however, a comprehensive approach that integrates all the key pharmacological issues into a holistic framework that is applicable for in vivo conditions is still lacking. This contribution presents a pharmacokinetic/pharmacodynamic model-based control study of non-viral siRNA delivery describing the dynamics of the delivery process and takes into account the main multi-objective optimization issues such as efficacy and toxicity, as well as the effect of uncertainty in cell doubling time. The methodology developed in this work is used to predict the optimal dosage injection rate and optimal intracellular exposure of siRNAs in order to improve the pharmacological effects before cell division occurs. The present analysis successfully provides quantitative predictions of non-viral siRNA activity paving the path for further experimental work to probe more efficient delivery systems.
Keywords: cell division; efficacy; optimal control; pharmacokinetic/pharmacodynamic modeling; siRNA delivery; toxicity.
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