title: Degradable cationic shell cross-linked knedel-like nanoparticles: synthesis, degradation, nucleic acid binding, and in vitro evaluation.
abstract: In this work, degradable cationic shell cross-linked knedel-like (deg-cSCK) nanoparticles were developed as an alternative platform to replace similar nondegradable cSCK nanoparticles that have been utilized for nucleic acids delivery. An amphiphilic diblock copolymer poly(acrylamidoethylamine)(90)-block-poly(DL-lactide)(40) (PAEA(90)-b-PDLLA(40)) was synthesized, self-assembled in aqueous solution, and shell cross-linked using a hydrolyzable cross-linker to afford deg-cSCKs with an average core diameter of 45 ± 7 nm. These nanoparticles were fluorescently labeled for in vitro tracking. The enzymatic- and hydrolytic-degradability, siRNA binding affinity, cell uptake and cytotoxicity of the deg-cSCKs were evaluated. Esterase-catalyzed hydrolysis of the nanoparticles resulted in the degradation of ca. 24% of the PDLLA core into lactic acid within 5 d, as opposed to only ca. 9% degradation from aqueous solutions of the deg-cSCK nanoparticles in the absence of enzyme. Cellular uptake of deg-cSCKs was efficient, while exhibiting low cytotoxicity with LD50 values of ca. 90 and 30 μg/mL in RAW 264.7 mouse macrophages and MLE 12 cell lines, respectively, ca. 5- to 6-fold lower than the cytotoxicity observed for nondegradable cSCK analogs. Additionally, deg-cSCKs were able to complex siRNA at an N/P ratio as low as 2, and were efficiently able to facilitate cellular uptake of the complexed nucleic acids.
authors.affiliation: Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842, USA.
authors.forename: Sandani
authors.initials: S
authors.lastname: Samarajeewa
authors.forename: Aida
authors.initials: A
authors.lastname: Ibricevic
authors.forename: Sean P
authors.initials: SP
authors.lastname: Gunsten
authors.forename: Ritu
authors.initials: R
authors.lastname: Shrestha
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Elsabahy
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
authors.forename: Karen L
authors.initials: KL
authors.lastname: Wooley
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002470:Cell Survival; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008264:Macrophages; D051379:Mice; D053758:Nanoparticles; D009696:Nucleic Acids / Q000378:metabolism*; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D014162:Transfection
chemical_list: D009696:Nucleic Acids; D011108:Polymers; D034741:RNA, Small Interfering