Hyaluronate siRNA nanoparticles with positive charge display rapid attachment to tumor endothelium and penetration into tumors

Luo, Jie; Schmaus, Johannes; Cui, Mochen; Hörterer, Elisa; Wilk, Ulrich; Höhn, Miriam; Daether, Maike; Berger, Simone; Benli-Hoppe, Teoman; Peng, Lun und Wagner, Ernst (2021): Hyaluronate siRNA nanoparticles with positive charge display rapid attachment to tumor endothelium and penetration into tumors. In: Journal of Controlled Release, Bd. 329: S. 919-933

Abstract

A cationizable sequence-defined lipo-oligoaminoamide (lipo-OAA) conferring stable assembly of siRNA into similar to 200 nm sized complexes contains an N-terminal azidolysine for covalent coating of formed nanoparticles with dibenzocyclooctyne-amine (DBCO)-modified hyaluronic acid (HA). Depending on the applied equivalents of DBCO-HA, stable nanoparticles with either cationic or anionic surface charge can be formed. The unmodified and two types of covalent HA-modified siRNA nanoparticles differ in their biological characteristics. Both types of HA coated siRNA complexes show an enhanced cellular uptake over uncoated complexes and facilitate efficient gene silencing, but differ in intracellular uptake pathways and distribution. Upon intravenous administration in mice, beyond our expectation and in contrast to the in vitro findings, only the cationic HA nanoparticles but neither the non-coated cationic nor the anionic HA complexes were able to target subcutaneous Huh 7 tumors and exert potent (78%) gene silencing. The favorable and very fast accumulation of cationic HA nanoparticles was confirmed in another subcutaneous tumor model. As evidenced by 3D nanoparticle distribution within Huh 7 tumors evaluated at early time points of 5 min and 45 min, only the cationic HA-based nanoparticles rapidly attach to the tumor endothelium and subsequently penetrate into tumor, in contrast to the analogous anionic HA coated or the cationic non-coated formulation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0168-3659
• Sprache: Englisch