Dual carrier-cargo hydrophobization and charge ratio optimization improve the systemic circulation and safety of zwitterionic nano-polyplexes.

Autor: Jackson MA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Bedingfield SK; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Yu F; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Stokan ME; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Miles RE; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Curvino EJ; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Hoogenboezem EN; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Bonami RH; Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA., Patel SS; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Kendall PL; Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, Vanderbilt University Medical Center, Nashville, TN, USA., Giorgio TD; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA., Duvall CL; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. Electronic address: craig.duvall@vanderbilt.edu.
Jazyk: angličtina
Zdroj: Biomaterials [Biomaterials] 2019 Feb; Vol. 192, pp. 245-259. Date of Electronic Publication: 2018 Nov 10.
DOI: 10.1016/j.biomaterials.2018.11.010
Abstrakt: While polymeric nano-formulations for RNAi therapeutics hold great promise for molecularly-targeted, personalized medicine, they possess significant systemic delivery challenges including rapid clearance from circulation and the potential for carrier-associated toxicity due to cationic polymer or lipid components. Herein, we evaluated the in vivo pharmacokinetic and safety impact of often-overlooked formulation parameters, including the ratio of carrier polymer to cargo siRNA and hydrophobic siRNA modification in combination with hydrophobic polymer components (dual hydrophobization). For these studies, we used nano-polyplexes (NPs) with well-shielded, zwitterionic coronas, resulting in various NP formulations of equivalent hydrodynamic size and neutral surface charge regardless of charge ratio. Doubling nano-polyplex charge ratio from 10 to 20 increased circulation half-life five-fold and pharmacokinetic area under the curve four-fold, but was also associated with increased liver enzymes, a marker of hepatic damage. Dual hydrophobization achieved by formulating NPs with palmitic acid-modified siRNA (siPA-NPs) both reduced the amount of carrier polymer required to achieve optimal pharmacokinetic profiles and abrogated liver toxicities. We also show that optimized zwitterionic siPA-NPs are well-tolerated upon long-term, repeated administration in mice and exhibit greater than two-fold increased uptake in orthotopic MDA-MB-231 xenografts compared to commercial transfection reagent, in vivo-jetPEI ® . These data suggest that charge ratio optimization has important in vivo implications and that dual hydrophobization strategies can be used to maximize both NP circulation time and safety.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: