Small interfering RNA (siRNA) holds great potential to treat many difficult-to-treat diseases, but its delivery remains the central challenge. This study aimed at investigating the suitability of polymer-lipid hybrid nanomedicines (HNMeds) as novel siRNA delivery platforms for locoregional therapy of glioblastoma. Two HNMed formulations were developed from poly(lactic-co-glycolic acid) polymer and a cationic lipid: 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or 3 ss-[N-(N' ,N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol). After characterization of the HNMeds, a model siRNA was complexed onto their surface to form HNMed/siRNA complexes. The physicochemical properties and siRNA binding ability of complexes were assessed over a range of nitrogen-to-phosphate (N/P) ratios to optimize the formulations. At the optimal N/P ratio of 10, complexes effectively bound siRNA and improved its protection from enzymatic degradation. Using the NIH3T3 mouse fibroblast cell line, DOTAP-based HNMeds were shown to possess higher cytocompatibility in vitro over the DCChol-based ones. As proof-of-concept, uptake and bioefficacy of formulations were also assessed in vitro on U87MG human glioblastoma cell line expressing luciferase gene. Complexes were able to deliver anti-luciferase siRNA and induce a remarkable suppression of gene expression. Noteworthy, the effect of DOTAP-based formulation was not only about three-times higher than DC-Chol-based one, but also comparable to lipofectamine model transfection reagent. These findings set the basis to exploit this nanosystem for silencing relevant GB-related genes in further in vitro and in vivo studies.

Polymer-lipid hybrid nanomedicines to deliver siRNA in and against glioblastoma cells / Rinaldi, A.; Dumas, F.; Duskey, J. T.; Imbriano, C.; Belluti, S.; Roy, C.; Ottonelli, I.; Vandelli, M. A.; Ruozi, B.; Garcion, E.; Tosi, G.; Boury, F.. - In: INTERNATIONAL JOURNAL OF PHARMACEUTICS. - ISSN 0378-5173. - 654:(2024), pp. 1-16. [10.1016/j.ijpharm.2024.123994]

Polymer-lipid hybrid nanomedicines to deliver siRNA in and against glioblastoma cells

Rinaldi A.;Duskey J. T.;Imbriano C.;Belluti S.;Ottonelli I.;Vandelli M. A.;Ruozi B.;Tosi G.;Boury F.
2024

Abstract

Small interfering RNA (siRNA) holds great potential to treat many difficult-to-treat diseases, but its delivery remains the central challenge. This study aimed at investigating the suitability of polymer-lipid hybrid nanomedicines (HNMeds) as novel siRNA delivery platforms for locoregional therapy of glioblastoma. Two HNMed formulations were developed from poly(lactic-co-glycolic acid) polymer and a cationic lipid: 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or 3 ss-[N-(N' ,N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol). After characterization of the HNMeds, a model siRNA was complexed onto their surface to form HNMed/siRNA complexes. The physicochemical properties and siRNA binding ability of complexes were assessed over a range of nitrogen-to-phosphate (N/P) ratios to optimize the formulations. At the optimal N/P ratio of 10, complexes effectively bound siRNA and improved its protection from enzymatic degradation. Using the NIH3T3 mouse fibroblast cell line, DOTAP-based HNMeds were shown to possess higher cytocompatibility in vitro over the DCChol-based ones. As proof-of-concept, uptake and bioefficacy of formulations were also assessed in vitro on U87MG human glioblastoma cell line expressing luciferase gene. Complexes were able to deliver anti-luciferase siRNA and induce a remarkable suppression of gene expression. Noteworthy, the effect of DOTAP-based formulation was not only about three-times higher than DC-Chol-based one, but also comparable to lipofectamine model transfection reagent. These findings set the basis to exploit this nanosystem for silencing relevant GB-related genes in further in vitro and in vivo studies.
2024
654
1
16
Polymer-lipid hybrid nanomedicines to deliver siRNA in and against glioblastoma cells / Rinaldi, A.; Dumas, F.; Duskey, J. T.; Imbriano, C.; Belluti, S.; Roy, C.; Ottonelli, I.; Vandelli, M. A.; Ruozi, B.; Garcion, E.; Tosi, G.; Boury, F.. - In: INTERNATIONAL JOURNAL OF PHARMACEUTICS. - ISSN 0378-5173. - 654:(2024), pp. 1-16. [10.1016/j.ijpharm.2024.123994]
Rinaldi, A.; Dumas, F.; Duskey, J. T.; Imbriano, C.; Belluti, S.; Roy, C.; Ottonelli, I.; Vandelli, M. A.; Ruozi, B.; Garcion, E.; Tosi, G.; Boury, F.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1340766
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