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Lyophilization and nebulization of pulmonary surfactant-coated nanogels for siRNA inhalation therapy

Pieterjan Merckx (UGent) , Joris Lammens (UGent) , Gust Nuytten (UGent) , Bram Bogaert (UGent) , Roberta Guagliardo, Tania Maes (UGent) , Chris Vervaet (UGent) , Thomas De Beer (UGent) , Stefaan De Smedt (UGent) and Koen Raemdonck (UGent)
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Abstract
RNA interference (RNAi) enables highly specific silencing of potential target genes for treatment of pulmonary pathologies. The intracellular RNAi pathway can be activated by cytosolic delivery of small interfering RNA (siRNA), inducing sequence-specific gene knockdown on the post-transcriptional level. Although siRNA drugs hold many advantages over currently applied therapies, their clinical translation is hampered by inefficient delivery across cellular membranes. We previously developed hybrid nanoparticles consisting of an siRNA-loaded nanosized hydrogel core (nanogel) coated with Curosurf (R), a clinically used pulmonary surfactant (PS). The latter enhances both particle stability as well as intracellular siRNA delivery, which was shown to be governed by the PS-associated surfactant protein B (SP-B). Despite having a proven in vitro and in vivo siRNA delivery potential when prepared ex novo, clinical translation of this liquid nanoparticle suspension requires the identification of a long-term preservation strategy that maintains nanoparticle stability and potency. In addition, to achieve optimal pulmonary deposition of the nanocomposite, its compatibility with state-of-the-art pulmonary administration techniques should be evaluated. Here, we demonstrate that PS-coated nanogels can be lyophilized, reconstituted and subsequently nebulized via a vibrating mesh nebulizer. The particles retain their physicochemical integrity and their ability to deliver siRNA in a human lung epithelial cell line. The latter result suggests that the functional integrity of SP-B in the PS coat towards siRNA delivery might be preserved as well. Of note, successful lyophilization was achieved without the need for stabilizing lyoor cryoprotectants. Our results demonstrate that PS-coated siRNA-loaded nanogels can be lyophilized, which offers the prospect of long-term storage. In addition, the formulation was demonstrated to be suitable for local administration with a state-ofthe-art nebulizer for human use upon reconstitution. Hence, the data presented in this study represent an important step towards clinical application of such nanocomposites for treatment of pulmonary disease.
Keywords
POLYMER HYBRID NANOPARTICLES, DRUG-DELIVERY, SP-B, FREEZE, STABILITY, PROTEIN, FORMULATION, PLATFORM, DEXTRAN, IMPACT, Nanomedicines, siRNA, Pulmonary surfactant, Pulmonary delivery, Inhalation therapy, Nebulization, Lyophilisation

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MLA
Merckx, Pieterjan, et al. “Lyophilization and Nebulization of Pulmonary Surfactant-Coated Nanogels for SiRNA Inhalation Therapy.” EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 157, 2020, pp. 191–99, doi:10.1016/j.ejpb.2020.09.011.
APA
Merckx, P., Lammens, J., Nuytten, G., Bogaert, B., Guagliardo, R., Maes, T., … Raemdonck, K. (2020). Lyophilization and nebulization of pulmonary surfactant-coated nanogels for siRNA inhalation therapy. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 157, 191–199. https://doi.org/10.1016/j.ejpb.2020.09.011
Chicago author-date
Merckx, Pieterjan, Joris Lammens, Gust Nuytten, Bram Bogaert, Roberta Guagliardo, Tania Maes, Chris Vervaet, Thomas De Beer, Stefaan De Smedt, and Koen Raemdonck. 2020. “Lyophilization and Nebulization of Pulmonary Surfactant-Coated Nanogels for SiRNA Inhalation Therapy.” EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS 157: 191–99. https://doi.org/10.1016/j.ejpb.2020.09.011.
Chicago author-date (all authors)
Merckx, Pieterjan, Joris Lammens, Gust Nuytten, Bram Bogaert, Roberta Guagliardo, Tania Maes, Chris Vervaet, Thomas De Beer, Stefaan De Smedt, and Koen Raemdonck. 2020. “Lyophilization and Nebulization of Pulmonary Surfactant-Coated Nanogels for SiRNA Inhalation Therapy.” EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS 157: 191–199. doi:10.1016/j.ejpb.2020.09.011.
Vancouver
1.
Merckx P, Lammens J, Nuytten G, Bogaert B, Guagliardo R, Maes T, et al. Lyophilization and nebulization of pulmonary surfactant-coated nanogels for siRNA inhalation therapy. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS. 2020;157:191–9.
IEEE
[1]
P. Merckx et al., “Lyophilization and nebulization of pulmonary surfactant-coated nanogels for siRNA inhalation therapy,” EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 157, pp. 191–199, 2020.
@article{8690526,
  abstract     = {{RNA interference (RNAi) enables highly specific silencing of potential target genes for treatment of pulmonary pathologies. The intracellular RNAi pathway can be activated by cytosolic delivery of small interfering RNA (siRNA), inducing sequence-specific gene knockdown on the post-transcriptional level. Although siRNA drugs hold many advantages over currently applied therapies, their clinical translation is hampered by inefficient delivery across cellular membranes. We previously developed hybrid nanoparticles consisting of an siRNA-loaded nanosized hydrogel core (nanogel) coated with Curosurf (R), a clinically used pulmonary surfactant (PS). The latter enhances both particle stability as well as intracellular siRNA delivery, which was shown to be governed by the PS-associated surfactant protein B (SP-B). Despite having a proven in vitro and in vivo siRNA delivery potential when prepared ex novo, clinical translation of this liquid nanoparticle suspension requires the identification of a long-term preservation strategy that maintains nanoparticle stability and potency. In addition, to achieve optimal pulmonary deposition of the nanocomposite, its compatibility with state-of-the-art pulmonary administration techniques should be evaluated. Here, we demonstrate that PS-coated nanogels can be lyophilized, reconstituted and subsequently nebulized via a vibrating mesh nebulizer. The particles retain their physicochemical integrity and their ability to deliver siRNA in a human lung epithelial cell line. The latter result suggests that the functional integrity of SP-B in the PS coat towards siRNA delivery might be preserved as well. Of note, successful lyophilization was achieved without the need for stabilizing lyoor cryoprotectants. Our results demonstrate that PS-coated siRNA-loaded nanogels can be lyophilized, which offers the prospect of long-term storage. In addition, the formulation was demonstrated to be suitable for local administration with a state-ofthe-art nebulizer for human use upon reconstitution. Hence, the data presented in this study represent an important step towards clinical application of such nanocomposites for treatment of pulmonary disease.}},
  author       = {{Merckx, Pieterjan and Lammens, Joris and Nuytten, Gust and Bogaert, Bram and Guagliardo, Roberta and Maes, Tania and Vervaet, Chris and De Beer, Thomas and De Smedt, Stefaan and Raemdonck, Koen}},
  issn         = {{0939-6411}},
  journal      = {{EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS}},
  keywords     = {{POLYMER HYBRID NANOPARTICLES,DRUG-DELIVERY,SP-B,FREEZE,STABILITY,PROTEIN,FORMULATION,PLATFORM,DEXTRAN,IMPACT,Nanomedicines,siRNA,Pulmonary surfactant,Pulmonary delivery,Inhalation therapy,Nebulization,Lyophilisation}},
  language     = {{eng}},
  pages        = {{191--199}},
  title        = {{Lyophilization and nebulization of pulmonary surfactant-coated nanogels for siRNA inhalation therapy}},
  url          = {{http://dx.doi.org/10.1016/j.ejpb.2020.09.011}},
  volume       = {{157}},
  year         = {{2020}},
}

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