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Photocrosslinked Bioreducible Polymeric Nanoparticles for Enhanced Systemic siRNA Delivery as Cancer Therapy.
Karlsson, Johan; Tzeng, Stephany Y; Hemmati, Shayan; Luly, Kathryn M; Choi, Olivia; Rui, Yuan; Wilson, David R; Kozielski, Kristen L; Quiñones-Hinojosa, Alfredo; Green, Jordan J.
Afiliación
  • Karlsson J; Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemistry-Ångström Laboratory, Uppsala University, Uppsala SE-75121, Sweden.
  • Tzeng SY; Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • Hemmati S; Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • Luly KM; Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • Choi O; Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • Rui Y; Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • Wilson DR; Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
  • Kozielski KL; Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Institute for Functional Interfaces, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen 76344, Germany.
  • Quiñones-Hinojosa A; Department of Neurosurgery, Mayo Clinic Florida, Jacksonville, FL 32224, USA.
  • Green JJ; Department of Biomedical Engineering and Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Departments of Materials Science and Engineering, Neurosurgery, Oncology, Ophthalmology, and Chemical and Biomolecular Engineering, Sidney Kimmel Comprehen
Adv Funct Mater ; 31(17)2021 Apr 22.
Article en En | MEDLINE | ID: mdl-34650390
ABSTRACT
Clinical translation of polymer-based nanocarriers for systemic delivery of RNA has been limited due to poor colloidal stability in the blood stream and intracellular delivery of the RNA to the cytosol. To address these limitations, this study reports a new strategy incorporating photocrosslinking of bioreducible nanoparticles for improved stability extracellularly and rapid release of RNA intracellularly. In this design, the polymeric nanocarriers contain ester bonds for hydrolytic degradation and disulfide bonds for environmentally triggered small interfering RNA (siRNA) release in the cytosol. These photocrosslinked bioreducible nanoparticles (XbNPs) have a shielded surface charge, reduced adsorption of serum proteins, and enable superior siRNA-mediated knockdown in both glioma and melanoma cells in high-serum conditions compared to non-crosslinked formulations. Mechanistically, XbNPs promote cellular uptake and the presence of secondary and tertiary amines enables efficient endosomal escape. Following systemic administration, XbNPs facilitate targeting of cancer cells and tissue-mediated siRNA delivery beyond the liver, unlike conventional nanoparticle-based delivery. These attributes of XbNPs facilitate robust siRNA-mediated knockdown in vivo in melanoma tumors colonized in the lungs following systemic administration. Thus, biodegradable polymeric nanoparticles, via photocrosslinking, demonstrate extended colloidal stability and efficient delivery of RNA therapeutics under physiological conditions, and thereby potentially advance systemic delivery technologies for nucleic acid-based therapeutics.
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Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: Adv Funct Mater Año: 2021 Tipo del documento: Article País de afiliación: Suecia

Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: Adv Funct Mater Año: 2021 Tipo del documento: Article País de afiliación: Suecia