Non-linear pharmacodynamics in a non-viral gene delivery system: Positive non-linear relationship between dose and transfection efficiency

Moriguchi, Rumiko; Kogure, Kentaro; Iwasa, Akitada; Akita, Hidetaka; Harashima, Hideyoshi

doi:10.1016/j.jconrel.2005.10.021

Cited by 39 publications

(44 citation statements)

References 11 publications

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“…Hama et al [36] quantified by RT-PCR 4.1 × 10 4 and 7.3 pDNA copies/nucleus after lipoplex and viral transfection, respectively, with an unsynchronized A549 cell line but the viral vector was ∼8000 times more efficient in terms of expression efficiency. A non-linear correlation between the amount of nuclear pDNA and transgene expression has also been noted previously with lipoplexes but the fundamental reason is not well known [36,37].…”

Section: Effects Of Polyplex Type On Gene Deliverymentioning

confidence: 63%

Polyplex‐mediated gene transfer and cell cycle: effect of carrier on cellular uptake and intracellular kinetics, and significance of glycosaminoglycans

Männistö

Reinisalo

Ruponen

et al. 2007

The Journal of Gene Medicine

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Section: Effects Of Polyplex Type On Gene Deliverymentioning

confidence: 63%

Polyplex‐mediated gene transfer and cell cycle: effect of carrier on cellular uptake and intracellular kinetics, and significance of glycosaminoglycans

Männistö

Reinisalo

Ruponen

et al. 2007

The Journal of Gene Medicine

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“…Moriguchi et al (55) studied this phenomenon and found also a remarkable positive non-linear relationship between dose and transfection activities in nonviral gene delivery systems in vitro. This non-linearity was attributed to PD processes (nuclear stability, transcriptional efficiency, etc.…”

Section: Pharmacodynamicsmentioning

confidence: 92%

Gene Therapy: A Pharmacokinetic/Pharmacodynamic Modelling Overview

Parra-Guillén

González‐Aseguinolaza²,

Berraondo³

et al. 2010

Pharm Res

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Since gene therapy started over 20 years ago, more than one-thousand clinical trials have been carried out. Nonviral vectors present interesting properties for their clinical application, but their efficiency in vivo is relatively low, and further improvements in these vectors are needed. Elucidating how nonviral vectors behave at the intracellular level is enlightening for vector improvement and optimization. Model-based approach is a powerful tool to understand and describe the different processes that gene transfer systems should overcome inside the body. Model-based approach allows for proposing and predicting the effect of parameter changes on the overall gene therapy response, as well as the known application of the pharmacokinetic/pharmacodynamic modelling in conventional therapies. The objective of this paper is to critically review the works in which the time-course of naked or formulated DNA have been quantitatively studied or modelled.

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“…On the other hand, the prominence of PD has been exhibited in gene delivery systems [7]. In a previous study, we reported on a remarkable non-linearity between the number of pDNA molecules delivered to the nucleus and their gene expression activity in the case of LipofectAMINE and the PLUS reagent [8,9] and R8-MEND [10]. In addition, Wei J et al demonstrated that a saturated PD effect existed in the case of an siRNA delivery system [11].…”

Section: Introductionmentioning

confidence: 93%

“…We initially focused on the PD, which can be analyzed based on the relationship between the number of cytosolic siRNA molecules and its gene silencing activity, because previous reports suggested that PD contributed to the non-linear relationship in both pDNA and siRNA delivery systems [8][9][10][11]. In this study, the number of siRNA molecules in the cells was used to estimate PD of siRNA.…”

Section: Analysis Of a Pd Between In Vitro And In Vivomentioning

confidence: 99%

Non-linear pharmacokinetics of octaarginine-modified lipid nanoparticles: Barriers from in vitro to in vivo

Hayashi

Noguchi

Harashima

2012

Journal of Controlled Release

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A rational development of an efficient siRNA delivery system is important for streamlining the RNAi-based drug development process. However, a huge gap frequently exists between in vitro and in vivo activity, which is the rate limiting step for developing versatile nanoparticles. We report herein on a remarkable non-linearity in the pharmacokinetics (PK), but not the pharmacodynamics (PD) using octaarginine (R8) modified lipid nanoparticles in mice. A quantitative study of siRNA molecules between cultured cells and mouse liver revealed a high correlation between intracellular siRNA molecules and their RNAi activities, indicating that there was no significant difference in the efficiency in PD. In contrast, a remarkable difference was observed in the non-linearity in PK. Quantitative analysis of the time profile for siRNA showed that the percentage of siRNA accumulation in mice was severely decreased with decreasing input dose compared to in vitro data. These unexpected data reveal an important clue to bridging the gap between in vitro and in vivo activity.

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Non-linear pharmacodynamics in a non-viral gene delivery system: Positive non-linear relationship between dose and transfection efficiency

Cited by 39 publications

References 11 publications

Polyplex‐mediated gene transfer and cell cycle: effect of carrier on cellular uptake and intracellular kinetics, and significance of glycosaminoglycans

Polyplex‐mediated gene transfer and cell cycle: effect of carrier on cellular uptake and intracellular kinetics, and significance of glycosaminoglycans

Gene Therapy: A Pharmacokinetic/Pharmacodynamic Modelling Overview

Non-linear pharmacokinetics of octaarginine-modified lipid nanoparticles: Barriers from in vitro to in vivo

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