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Center for nano- and biophotonics (NB-Photonics)
Abstract
The applicability of small interfering RNA (siRNA) in future therapies depends on the availability of safe and efficient carrier systems. Ideally, siRNA delivery requires a system that is stable in the circulation but upon specific uptake into target cells can rapidly release its cargo into the cytoplasm. Previously, we evaluated a novel generation of carrier systems (decationized polyplexes) for DNA delivery, and it was shown that folate targeted decationized polyplexes had an excellent safety profile and showed intracellular triggered release upon cell specific uptake. Targeted decationized polyplexes consist of a core of disulfide cross-linked poly(hydroxypropyl methacrylamide) (pHPMA) stably entrapping nucleic acids and a shell of poly(ethylene glycol) (PEG) decorated with folate molecules. In the present study, the applicability of folate targeted decationized polyplexes for siRNA delivery was investigated. This required optimization of the carrier system particularly regarding the cross-linking density of the core of the polyplexes. Stable and nanosized siRNA decationized polyplexes were successfully prepared by optimizing the cross-link density of their core. Upon incubation in human plasma, a significant portion of siRNA remained entrapped in the decationized polyplexes as determined by fluorescence correlation spectroscopy (FCS). When tested in a folate receptor overexpressing cell line stably expressing luciferase, Skov3-luc, sequence specific gene silencing was observed. As expected, neither interference on the intrinsic luciferase expression nor on the cell metabolic activity (determined by XTT) was induced by the free-polymer or the siRNA polyplexes. In conclusion, targeted decationized polyplexes are safe and stable carriers that interact with the targeted cells and rapidly disassemble upon cell entry making them promising siRNA delivery systems.
Keywords
polymer, siRNA delivery, targeting, nanoparticle, biocompatibility, IN-VITRO CYTOTOXICITY, GENE DELIVERY, DRUG-DELIVERY, POLYMERIC MICELLES, RNA INTERFERENCE, CATIONIC LIPIDS, PLASMID DNA, NANOPARTICLES, THERAPEUTICS, CIRCULATION

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Citation

Please use this url to cite or link to this publication:

Chicago
Novo, Luis, Kaori M Takeda, Tamara Petteta, George Dakwar, Joep B van den Dikkenberg, Katrien Remaut, Kevin Braeckmans, Cornelus F van Nostrum, Enrico Mastrobattista, and Wim E Hennink. 2015. “Targeted Decationized Polyplexes for siRNA Delivery.” Molecular Pharmaceutics 12 (1): 150–161.
APA
Novo, Luis, Takeda, K. M., Petteta, T., Dakwar, G., van den Dikkenberg, J. B., Remaut, K., Braeckmans, K., et al. (2015). Targeted decationized polyplexes for siRNA delivery. MOLECULAR PHARMACEUTICS, 12(1), 150–161.
Vancouver
1.
Novo L, Takeda KM, Petteta T, Dakwar G, van den Dikkenberg JB, Remaut K, et al. Targeted decationized polyplexes for siRNA delivery. MOLECULAR PHARMACEUTICS. 2015;12(1):150–61.
MLA
Novo, Luis, Kaori M Takeda, Tamara Petteta, et al. “Targeted Decationized Polyplexes for siRNA Delivery.” MOLECULAR PHARMACEUTICS 12.1 (2015): 150–161. Print.
@article{5786834,
  abstract     = {The applicability of small interfering RNA (siRNA) in future therapies depends on the availability of safe and efficient carrier systems. Ideally, siRNA delivery requires a system that is stable in the circulation but upon specific uptake into target cells can rapidly release its cargo into the cytoplasm. Previously, we evaluated a novel generation of carrier systems (decationized polyplexes) for DNA delivery, and it was shown that folate targeted decationized polyplexes had an excellent safety profile and showed intracellular triggered release upon cell specific uptake. Targeted decationized polyplexes consist of a core of disulfide cross-linked poly(hydroxypropyl methacrylamide) (pHPMA) stably entrapping nucleic acids and a shell of poly(ethylene glycol) (PEG) decorated with folate molecules. In the present study, the applicability of folate targeted decationized polyplexes for siRNA delivery was investigated. This required optimization of the carrier system particularly regarding the cross-linking density of the core of the polyplexes. Stable and nanosized siRNA decationized polyplexes were successfully prepared by optimizing the cross-link density of their core. Upon incubation in human plasma, a significant portion of siRNA remained entrapped in the decationized polyplexes as determined by fluorescence correlation spectroscopy (FCS). When tested in a folate receptor overexpressing cell line stably expressing luciferase, Skov3-luc, sequence specific gene silencing was observed. As expected, neither interference on the intrinsic luciferase expression nor on the cell metabolic activity (determined by XTT) was induced by the free-polymer or the siRNA polyplexes. In conclusion, targeted decationized polyplexes are safe and stable carriers that interact with the targeted cells and rapidly disassemble upon cell entry making them promising siRNA delivery systems.},
  author       = {Novo, Luis and Takeda, Kaori M and Petteta, Tamara and Dakwar, George and van den Dikkenberg, Joep B and Remaut, Katrien and Braeckmans, Kevin and van Nostrum, Cornelus F and Mastrobattista, Enrico and Hennink, Wim E},
  issn         = {1543-8384},
  journal      = {MOLECULAR PHARMACEUTICS},
  keyword      = {polymer,siRNA delivery,targeting,nanoparticle,biocompatibility,IN-VITRO CYTOTOXICITY,GENE DELIVERY,DRUG-DELIVERY,POLYMERIC MICELLES,RNA INTERFERENCE,CATIONIC LIPIDS,PLASMID DNA,NANOPARTICLES,THERAPEUTICS,CIRCULATION},
  language     = {eng},
  number       = {1},
  pages        = {150--161},
  title        = {Targeted decationized polyplexes for siRNA delivery},
  url          = {http://dx.doi.org/10.1021/mp500499x},
  volume       = {12},
  year         = {2015},
}

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