Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach

Research output: Contribution to journalJournal articlepeer-review

Standard

Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach. / Thanki, Kaushik; Zeng, Xianghui; Justesen, Sarah; Tejlmann, Sarah; Falkenberg, Emily; Van Driessche, Elize; Nielsen, Hanne Mørck; Franzyk, Henrik; Foged, Camilla.

In: European Journal of Pharmaceutics and Biopharmaceutics, Vol. 120, 11.2017, p. 22-33.

Research output: Contribution to journalJournal articlepeer-review

Harvard

Thanki, K, Zeng, X, Justesen, S, Tejlmann, S, Falkenberg, E, Van Driessche, E, Nielsen, HM, Franzyk, H & Foged, C 2017, 'Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach', European Journal of Pharmaceutics and Biopharmaceutics, vol. 120, pp. 22-33. https://doi.org/10.1016/j.ejpb.2017.07.014

APA

Thanki, K., Zeng, X., Justesen, S., Tejlmann, S., Falkenberg, E., Van Driessche, E., Nielsen, H. M., Franzyk, H., & Foged, C. (2017). Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach. European Journal of Pharmaceutics and Biopharmaceutics, 120, 22-33. https://doi.org/10.1016/j.ejpb.2017.07.014

Vancouver

Thanki K, Zeng X, Justesen S, Tejlmann S, Falkenberg E, Van Driessche E et al. Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach. European Journal of Pharmaceutics and Biopharmaceutics. 2017 Nov;120:22-33. https://doi.org/10.1016/j.ejpb.2017.07.014

Author

Thanki, Kaushik ; Zeng, Xianghui ; Justesen, Sarah ; Tejlmann, Sarah ; Falkenberg, Emily ; Van Driessche, Elize ; Nielsen, Hanne Mørck ; Franzyk, Henrik ; Foged, Camilla. / Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach. In: European Journal of Pharmaceutics and Biopharmaceutics. 2017 ; Vol. 120. pp. 22-33.

Bibtex

@article{0db0fe2dc57746ffb9fd971f25717b53,
title = "Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach",
abstract = "Safety and efficacy of therapeutics based on RNA interference, e.g., small interfering RNA (siRNA), are dependent on the optimal engineering of the delivery technology, which is used for intracellular delivery of siRNA to the cytosol of target cells. We investigated the hypothesis that commonly used and poorly tolerated cationic lipids might be replaced with more efficacious and safe lipidoids as the lipid component of siRNA-loaded lipid-polymer hybrid nanoparticles (LPNs) for achieving more efficient gene silencing at lower and safer doses. However, formulation design of such a complex formulation is highly challenging due to a strong interplay between several contributing factors. Hence, critical formulation variables, i.e. the lipidoid content and siRNA:lipidoid ratio, were initially identified, followed by a systematic quality-by-design approach to define the optimal operating space (OOS), eventually resulting in the identification of a robust, highly efficacious and safe formulation. A 17-run design of experiment with an I-optimal approach was performed to systematically assess the effect of selected variables on critical quality attributes (CQAs), i.e. physicochemical properties (hydrodynamic size, zeta potential, siRNA encapsulation/loading) and the biological performance (in vitro gene silencing and cell viability). Model fitting of the obtained data to construct predictive models revealed non-linear relationships for all CQAs, which can be readily overlooked in one-factor-at-a-time optimization approaches. The response surface methodology further enabled the identification of an OOS that met the desired quality target product profile. The optimized lipidoid-modified LPNs revealed more than 50-fold higher in vitro gene silencing at well-tolerated doses and approx. a two-fold increase in siRNA loading as compared to reference LPNs modified with the commonly used cationic lipid dioleyltrimethylammonium propane (DOTAP). Thus, lipidoid-modified LPNs show highly promising prospects for efficient and safe intracellular delivery of siRNA.",
author = "Kaushik Thanki and Xianghui Zeng and Sarah Justesen and Sarah Tejlmann and Emily Falkenberg and {Van Driessche}, Elize and Nielsen, {Hanne M{\o}rck} and Henrik Franzyk and Camilla Foged",
year = "2017",
month = nov,
doi = "10.1016/j.ejpb.2017.07.014",
language = "English",
volume = "120",
pages = "22--33",
journal = "European Journal of Pharmaceutics and Biopharmaceutics",
issn = "0939-6411",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach

AU - Thanki, Kaushik

AU - Zeng, Xianghui

AU - Justesen, Sarah

AU - Tejlmann, Sarah

AU - Falkenberg, Emily

AU - Van Driessche, Elize

AU - Nielsen, Hanne Mørck

AU - Franzyk, Henrik

AU - Foged, Camilla

PY - 2017/11

Y1 - 2017/11

N2 - Safety and efficacy of therapeutics based on RNA interference, e.g., small interfering RNA (siRNA), are dependent on the optimal engineering of the delivery technology, which is used for intracellular delivery of siRNA to the cytosol of target cells. We investigated the hypothesis that commonly used and poorly tolerated cationic lipids might be replaced with more efficacious and safe lipidoids as the lipid component of siRNA-loaded lipid-polymer hybrid nanoparticles (LPNs) for achieving more efficient gene silencing at lower and safer doses. However, formulation design of such a complex formulation is highly challenging due to a strong interplay between several contributing factors. Hence, critical formulation variables, i.e. the lipidoid content and siRNA:lipidoid ratio, were initially identified, followed by a systematic quality-by-design approach to define the optimal operating space (OOS), eventually resulting in the identification of a robust, highly efficacious and safe formulation. A 17-run design of experiment with an I-optimal approach was performed to systematically assess the effect of selected variables on critical quality attributes (CQAs), i.e. physicochemical properties (hydrodynamic size, zeta potential, siRNA encapsulation/loading) and the biological performance (in vitro gene silencing and cell viability). Model fitting of the obtained data to construct predictive models revealed non-linear relationships for all CQAs, which can be readily overlooked in one-factor-at-a-time optimization approaches. The response surface methodology further enabled the identification of an OOS that met the desired quality target product profile. The optimized lipidoid-modified LPNs revealed more than 50-fold higher in vitro gene silencing at well-tolerated doses and approx. a two-fold increase in siRNA loading as compared to reference LPNs modified with the commonly used cationic lipid dioleyltrimethylammonium propane (DOTAP). Thus, lipidoid-modified LPNs show highly promising prospects for efficient and safe intracellular delivery of siRNA.

AB - Safety and efficacy of therapeutics based on RNA interference, e.g., small interfering RNA (siRNA), are dependent on the optimal engineering of the delivery technology, which is used for intracellular delivery of siRNA to the cytosol of target cells. We investigated the hypothesis that commonly used and poorly tolerated cationic lipids might be replaced with more efficacious and safe lipidoids as the lipid component of siRNA-loaded lipid-polymer hybrid nanoparticles (LPNs) for achieving more efficient gene silencing at lower and safer doses. However, formulation design of such a complex formulation is highly challenging due to a strong interplay between several contributing factors. Hence, critical formulation variables, i.e. the lipidoid content and siRNA:lipidoid ratio, were initially identified, followed by a systematic quality-by-design approach to define the optimal operating space (OOS), eventually resulting in the identification of a robust, highly efficacious and safe formulation. A 17-run design of experiment with an I-optimal approach was performed to systematically assess the effect of selected variables on critical quality attributes (CQAs), i.e. physicochemical properties (hydrodynamic size, zeta potential, siRNA encapsulation/loading) and the biological performance (in vitro gene silencing and cell viability). Model fitting of the obtained data to construct predictive models revealed non-linear relationships for all CQAs, which can be readily overlooked in one-factor-at-a-time optimization approaches. The response surface methodology further enabled the identification of an OOS that met the desired quality target product profile. The optimized lipidoid-modified LPNs revealed more than 50-fold higher in vitro gene silencing at well-tolerated doses and approx. a two-fold increase in siRNA loading as compared to reference LPNs modified with the commonly used cationic lipid dioleyltrimethylammonium propane (DOTAP). Thus, lipidoid-modified LPNs show highly promising prospects for efficient and safe intracellular delivery of siRNA.

U2 - 10.1016/j.ejpb.2017.07.014

DO - 10.1016/j.ejpb.2017.07.014

M3 - Journal article

C2 - 28756280

VL - 120

SP - 22

EP - 33

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

ER -

ID: 181207877