Mathematical Modeling: A Tool for Optimization of Lipid Nanoparticle-Mediated Delivery of siRNA

Mihaila, Radu; Ruhela, Dipali; Keough, Edward; Cherkaev, Elena; Chang, Silvia D.; Galinski, Beverly; Bartz, René; Brown, D. H.; Howell, Bonnie J.; Cunningham, James J.

doi:10.1016/j.omtn.2017.04.003

Cited by 17 publications

(16 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, Arcturus Therapeutics, 173 Dicerna Pharmaceuticals, 174 Silence Therapeutics, 175,176 Sirna Therapeutics (acquired by Alnylam from Merck & Co., Inc. in 2014) 177,178 and Suzhou Ribo Life Science 142 also made great efforts to develop lipid-based siRNA delivery systems, some of which have been advanced to the clinical stage.…”

Section: Sirna Modificationmentioning

confidence: 99%

Therapeutic siRNA: state of the art

Zhong

Weng

et al. 2020

Sig Transduct Target Ther

946

705

View full text Add to dashboard Cite

RNA interference (RNAi) is an ancient biological mechanism used to defend against external invasion. It theoretically can silence any disease-related genes in a sequence-specific manner, making small interfering RNA (siRNA) a promising therapeutic modality. After a two-decade journey from its discovery, two approvals of siRNA therapeutics, ONPATTRO ® (patisiran) and GIVLAARI™ (givosiran), have been achieved by Alnylam Pharmaceuticals. Reviewing the long-term pharmaceutical history of human beings, siRNA therapy currently has set up an extraordinary milestone, as it has already changed and will continue to change the treatment and management of human diseases. It can be administered quarterly, even twice-yearly, to achieve therapeutic effects, which is not the case for small molecules and antibodies. The drug development process was extremely hard, aiming to surmount complex obstacles, such as how to efficiently and safely deliver siRNAs to desired tissues and cells and how to enhance the performance of siRNAs with respect to their activity, stability, specificity and potential off-target effects. In this review, the evolution of siRNA chemical modifications and their biomedical performance are comprehensively reviewed. All clinically explored and commercialized siRNA delivery platforms, including the GalNAc (N-acetylgalactosamine)-siRNA conjugate, and their fundamental design principles are thoroughly discussed. The latest progress in siRNA therapeutic development is also summarized. This review provides a comprehensive view and roadmap for general readers working in the field.

show abstract

Section: Sirna Modificationmentioning

confidence: 99%

Therapeutic siRNA: state of the art

Zhong

Weng

et al. 2020

Sig Transduct Target Ther

946

705

View full text Add to dashboard Cite

show abstract

“…In addition, liposome/DNA lipoplex must bind to the cell surface, enter cells by adsorption-mediated endocytosis, and accumulate in endosomes [ 11 , 12 ]. Finally, lipoplexes escape from the endosomes and release the nucleic acid for successful gene expression [ 13 – 15 ].…”

Section: Introductionmentioning

confidence: 99%

Interaction kinetics of peptide lipids-mediated gene delivery

Zhao

et al. 2020

J Nanobiotechnol

View full text Add to dashboard Cite

Background During the course of gene transfection, the interaction kinetics between liposomes and DNA is speculated to play very important role for blood stability, cellular uptake, DNA release and finally transfection efficiency. Results As cationic peptide liposomes exhibited great gene transfer activities both in vitro and in vivo, two peptide lipids, containing a tri-ornithine head (LOrn3) and a mono-ornithine head (LOrn1), were chosen to further clarify the process of liposome-mediated gene delivery in this study. The results show that the electrostatically-driven binding between DNA and liposomes reached nearly 100% at equilibrium, and high affinity of LOrn3 to DNA led to fast binding rate between them. The binding process between LOrn3 and DNA conformed to the kinetics equation: y = 1.663631 × exp (− 0.003427x) + 6.278163. Compared to liposome LOrn1, the liposome LOrn3/DNA lipoplex exhibited a faster and more uniform uptake in HeLa cells, as LOrn3 with a tri-ornithine peptide headgroup had a stronger interaction with the negatively charged cell membrane than LOrn1. The efficient endosomal escape of DNA from LOrn3 lipoplex was facilitated by the acidity in late endosomes, resulting in broken carbamate bonds, as well as the “proton sponge effect” of the lipid. Conclusions The interaction kinetics is a key factor for DNA transfection efficiency. This work provided insights into peptide lipid-mediated DNA delivery that could guide the development of the next generation of delivery systems for gene therapeutics.

show abstract

“…Finally, lipoplexes escape from the endosomes and release the nucleic acid for successful gene expression [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Interaction Kinetics of Peptide Lipids-Mediated Gene Delivery

Zhao

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: During the course of gene transfection, the interaction kinetics between liposomes and DNA is speculated to play very important role for blood stability, cellular uptake, DNA release and finally transfection efficiency. Results: As cationic peptide liposomes exhibited great gene transfer activities both in vitro and in vivo, two peptide lipids, containing a tri-ornithine head (LOrn3) and a mono-ornithine head (LOrn1), were chosen to further clarify the process of liposome-mediated gene delivery in this study. The results show that the electrostatically-driven binding between DNA and liposomes reached nearly 100% at equilibrium, and high affinity of LOrn3 to DNA led to fast binding rate between them. The binding process between LOrn3 and DNA conformed to the kinetics equation: y = 1.663631 × exp(-0.003427x) + 6.278163. Compared to liposome LOrn1, the liposome LOrn3/DNA lipoplex exhibited a faster and more uniform uptake in HeLa cells, as LOrn3 with a tri-ornithine peptide headgroup had a stronger interaction with the negatively charged cell membrane than LOrn1. The efficient endosomal escape of DNA from LOrn3 lipoplex was facilitated by the acidity in late endosomes, resulting in broken carbamate bonds, as well as the“proton sponge effect”of the lipid. Conclusions: The interaction kinetics is a key factor for DNA transfection efficiency. This work provided insights into peptide lipid-mediated DNA delivery that could guide the development of the next generation of delivery systems for gene therapeutics.

show abstract

Mathematical Modeling: A Tool for Optimization of Lipid Nanoparticle-Mediated Delivery of siRNA

Cited by 17 publications

References 39 publications

Therapeutic siRNA: state of the art

Therapeutic siRNA: state of the art

Interaction kinetics of peptide lipids-mediated gene delivery

Interaction Kinetics of Peptide Lipids-Mediated Gene Delivery

Contact Info

Product

Resources

About