Your browser doesn't support javascript.
loading
Zwitterionic Nanocarrier Surface Chemistry Improves siRNA Tumor Delivery and Silencing Activity Relative to Polyethylene Glycol.
Jackson, Meredith A; Werfel, Thomas A; Curvino, Elizabeth J; Yu, Fang; Kavanaugh, Taylor E; Sarett, Samantha M; Dockery, Mary D; Kilchrist, Kameron V; Jackson, Ayisha N; Giorgio, Todd D; Duvall, Craig L.
Afiliação
  • Jackson MA; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Werfel TA; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Curvino EJ; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Yu F; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Kavanaugh TE; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Sarett SM; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Dockery MD; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Kilchrist KV; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Jackson AN; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Giorgio TD; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
  • Duvall CL; Department of Biomedical Engineering, Vanderbilt University , Nashville, Tennessee 37240, United States.
ACS Nano ; 11(6): 5680-5696, 2017 06 27.
Article em En | MEDLINE | ID: mdl-28548843
ABSTRACT
Although siRNA-based nanomedicines hold promise for cancer treatment, conventional siRNA-polymer complex (polyplex) nanocarrier systems have poor pharmacokinetics following intravenous delivery, hindering tumor accumulation. Here, we determined the impact of surface chemistry on the in vivo pharmacokinetics and tumor delivery of siRNA polyplexes. A library of diblock polymers was synthesized, all containing the same pH-responsive, endosomolytic polyplex core-forming block but different corona blocks 5 kDa (benchmark) and 20 kDa linear polyethylene glycol (PEG), 10 kDa and 20 kDa brush-like poly(oligo ethylene glycol), and 10 kDa and 20 kDa zwitterionic phosphorylcholine-based polymers (PMPC). In vitro, it was found that 20 kDa PEG and 20 kDa PMPC had the highest stability in the presence of salt or heparin and were the most effective at blocking protein adsorption. Following intravenous delivery, 20 kDa PEG and PMPC coronas both extended circulation half-lives 5-fold compared to 5 kDa PEG. However, in mouse orthotopic xenograft tumors, zwitterionic PMPC-based polyplexes showed highest in vivo luciferase silencing (>75% knockdown for 10 days with single IV 1 mg/kg dose) and 3-fold higher average tumor cell uptake than 5 kDa PEG polyplexes (20 kDa PEG polyplexes were only 2-fold higher than 5 kDa PEG). These results show that high molecular weight zwitterionic polyplex coronas significantly enhance siRNA polyplex pharmacokinetics without sacrificing polyplex uptake and bioactivity within tumors when compared to traditional PEG architectures.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosforilcolina / Polietilenoglicóis / Portadores de Fármacos / RNA Interferente Pequeno / Nanoestruturas / Terapêutica com RNAi / Neoplasias Limite: Animals / Female / Humans / Male Idioma: En Revista: ACS Nano Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosforilcolina / Polietilenoglicóis / Portadores de Fármacos / RNA Interferente Pequeno / Nanoestruturas / Terapêutica com RNAi / Neoplasias Limite: Animals / Female / Humans / Male Idioma: En Revista: ACS Nano Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos